[Federal Register Volume 79, Number 27 (Monday, February 10, 2014)]
[Rules and Regulations]
[Pages 7933-8075]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-02148]



[[Page 7933]]

Vol. 79

Monday,

No. 27

February 10, 2014

Part IV





Department of Health and Human Services





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Food and Drug Administration





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21 CFR Parts 106 and 107





Current Good Manufacturing Practices, Quality Control Procedures, 
Quality Factors, Notification Requirements, and Records and Reports, 
for Infant Formula; Final Rule

Federal Register / Vol. 79 , No. 27 / Monday, February 10, 2014 / 
Rules and Regulations

[[Page 7934]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 106 and 107

[Docket No. FDA-1995-N-0036 (formerly 95N-0309)]
RIN 0910-AF27


Current Good Manufacturing Practices, Quality Control Procedures, 
Quality Factors, Notification Requirements, and Records and Reports, 
for Infant Formula

AGENCY: Food and Drug Administration, HHS.

ACTION: Interim final rule; request for comments.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
revising our infant formula regulations to establish requirements for 
current good manufacturing practices (CGMP), including audits; to 
establish requirements for quality factors; and to amend FDA's quality 
control procedures, notification, and record and reporting requirements 
for infant formula. FDA is taking this action to improve the protection 
of infants who consume infant formula products.

DATES: Effective date: This interim final rule is effective July 10, 
2014.
    Comment date: Interested persons may submit either electronic or 
written comments on this interim final rule by March 27, 2014.
    Paperwork Reduction Act date: Submit comments on information 
collection issues under the Paperwork Reduction Act of 1995 by March 
12, 2014, (see the ``Paperwork Reduction Act of 1995'' section of this 
document). The incorporation by reference of certain publications 
listed in the rule is approved by the Director of the Federal Register 
as of July 10, 2014.

ADDRESSES: Submit either electronic or written comments on the interim 
final rule to the addresses in this ADDRESSES section. To ensure that 
comments on information collection are received, the Office of 
Information and Regulatory Affairs, Office of Management and Budget 
(OMB) recommends that written comments be faxed to the Office of 
Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, FAX: 
202-395-5806. All comments received must include the Agency name, 
Docket No. FDA-1995-N-0036, and RIN number 0910-AF27 for this 
rulemaking. You may submit comments, identified by Docket No. FDA-1995-
N-0036 (formerly 95N-0309) and/or RIN number RIN 0910-AF27, by any of 
the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Written Submissions
    Submit written submissions in the following ways:
     Mail/Hand delivery/Courier (for paper or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and Docket No. FDA-1995-N-0036 (formerly 95N-0309) and RIN 0910-AF27 
for this rulemaking. All comments received may be posted without change 
to http://www.regulations.gov, including any personal information 
provided. For additional information on submitting comments, see the 
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this 
document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number(s), found in brackets in the heading of this document, 
into the ``Search'' box and follow the prompts and/or go to the 
Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, 
MD 20852.

FOR FURTHER INFORMATION CONTACT: Benson M. Silverman, Office of 
Nutrition, Labeling, and Dietary Supplements (HFS-850), Center for Food 
Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint 
Branch Parkway, College Park, MD 20740, 240-402-1450.

SUPPLEMENTARY INFORMATION: 

Executive Summary

Purpose of the Interim Final Rule

    FDA is issuing this interim final rule to fulfill the statutory 
mandate set forth in section 412 of the Federal Food, Drug, and 
Cosmetic Act (the FD&C Act) (21 U.S.C. 350a) for the Secretary of 
Health and Human Services (the Secretary), and by delegation FDA, to 
establish requirements for quality factors for infant formulas and good 
manufacturing practices, including quality control procedures. The 
requirements in this interim final rule will prevent the manufacture of 
adulterated infant formula and ensure that the nutrients in the infant 
formula are present in a form that is bioavailable and safe. Congress 
passed the Infant Formula Act of 1980 (the Infant Formula Act) (Pub. L. 
96-359), which amended the FD&C Act to include section 412. In 1986, 
Congress, as part of the Anti-Drug Abuse Act of 1986 (Pub. L. 99-570) 
(the 1986 amendments), amended section 412 of the FD&C Act to address 
concerns related to the sufficiency of quality control testing, current 
good manufacturing practice (CGMP), recordkeeping, and recall 
requirements for infant formula. The requirements in this interim final 
rule improve protection of infants consuming infant formula products by 
establishing greater regulatory control over the formulation and 
production of infant formula.
    We previously implemented certain of the provisions in the Infant 
Formula Act and 1986 amendments. This interim final rule implements the 
remaining provisions of the 1986 amendments, including provisions for 
CGMPs and quality factor requirements.

Summary of Legal Authority

    Section 412 of the FD&C Act provides FDA with the authority to 
establish requirements for quality factors, CGMPs, quality control 
procedures, registration, submission, notification, and records and 
reports. Specifically, FDA's authority to establish requirements for 
quality factors is derived from section 412(b)(1) of the FD&C Act. The 
authority to establish requirements for CGMPs and quality control 
procedures derives from section 412(b)(2) and (b)(3) of the FD&C Act. 
FDA also has authority to establish requirements for registration, 
submission, and notification under section 412(c) and (d) of the FD&C 
Act, respectively. Finally, a number of specific authorities in section 
412 of the FD&C Act provide FDA with authority to establish 
requirements for records and reports, e.g., section 412(b)(4)(A) 
related to record retention for good manufacturing practices and 
quality control procedures, audits and complaints. Moreover, section 
701(a) of the FD&C Act (21 U.S.C. 371(a)), when coupled with other 
provisions of section 412 of the FD&C Act, provides FDA with the 
authority to issue records requirements that are necessary for the 
efficient enforcement of section 412.
    Sections 701(a) and 402 of the FD&C Act (21 U.S.C. 371(a) and 342) 
provide additional authority to establish requirements to prevent 
adulteration.

Summary of the Major Provisions of the Interim Final Rule

Current Good Manufacturing Practice

    This interim final rule issues comprehensive CGMP requirements for

[[Page 7935]]

the manufacture of infant formula by establishing a framework in which 
specific process and control decisions are assigned to the formula 
manufacturer; i.e., it specifies the result to be achieved and does not 
prescriptively mandate how the manufacturer must achieve the result.
    Under Sec.  106.6, the interim final rule requires manufacturers to 
implement a system of production and in-process controls that covers 
all stages of processing. The system must be set out in a written plan 
or set of procedures that includes establishment of specifications and 
corrective action plans, documented reviews and material disposition 
decisions for articles not meeting a specification, and the quarantine 
of any article that fails to meet a specification pending completion of 
a documented review and material disposition decision.
    The interim final rule also includes specific controls to prevent 
adulteration by workers (Sec.  106.10), facilities (Sec.  106.20), 
equipment or utensils (Sec.  106.30), automatic (mechanical or 
electronic) equipment (Sec.  106.35), and ingredients, containers, and 
closures (Sec.  106.40). Under Sec.  106.50, manufacturers are required 
to prepare and follow a written master manufacturing order that 
establishes controls and procedures for the production of an infant 
formula. In addition, controls are specified to prevent adulteration 
during packaging and labeling (Sec.  106.60) and on the release of 
finished infant formula (Sec.  106.70). The interim final rule also 
requires that infant formula be coded with a sequential number that 
permits identification of the product including the location where it 
was packed and tracing of all stages of manufacture (Sec.  106.80).
    Controls are also required to prevent adulteration of infant 
formula from microorganisms (Sec.  106.55). Because powdered infant 
formulas are not sterile products, the interim final rule requires 
testing of representative samples of powdered infant formula at the 
final product stage, before distribution, and establishes values for 
two microorganisms, Cronobacter spp. and Salmonella spp.

Quality Control Procedures

    The interim final rule revises FDA's existing infant formula 
quality control procedures regulations to implement the 1986 
amendments. Under Sec.  106.91, the revised regulations require in-
process and final product testing of infant formula to ensure that all 
required and added nutrients are present at appropriate levels. The 
revised regulations also require comprehensive stability testing for 
new infant formula and routine stability for subsequently produced 
infant formula.

Audits

    The interim final rule includes requirements for audits under 
Sec. Sec.  106.90, 106.92, and 106.94. Regularly scheduled audits of 
CGMP and quality control procedures must be conducted according to a 
written audit plan at a frequency required to ensure compliance with 
the provisions of the interim final rule.

Quality Factors

    The interim final rule identifies two infant formula quality 
factors, normal physical growth and sufficient biological quality of 
the formula's protein component, and establishes requirements for the 
two quality factors in Sec.  106.96. Under the interim final rule, 
quality factors are defined as those factors necessary to demonstrate 
the bioavailability and safety of a formula, including the 
bioavailability of individual nutrients, to ensure healthy growth 
(Sec.  106.3).
    To establish that an infant formula supports normal physical 
growth, the interim final rule requires under Sec.  106.96(b) that a 
manufacturer conduct a growth monitoring study (GMS) of the formula 
(unless the formula qualifies for an exemption). To establish 
biological protein quality, the interim final rule requires under Sec.  
106.96(f) that a manufacturer conduct a Protein Efficiency Ratio (PER) 
rat bioassay.
    The interim final rule's quality factor requirements apply to all 
infant formulas. Because, prior to this interim final rule, there were 
no established quality factors and no quality factor requirements, a 
formula manufacturer was not required to demonstrate to FDA that the 
formula supports normal physical growth or that its protein was of 
sufficient biological quality. Therefore, we provide a more flexible 
means for a manufacturer of a formula that is ``not new'' (i.e., a 
currently marketed or previously marketed formula) to demonstrate 
satisfaction of the two quality factors (Sec.  106.96(i)). The more 
flexible standards will allow manufacturers, as appropriate, to rely on 
existing scientific data and information and to voluntarily submit 
quality factor data and information on a specific infant formula 
formulation to FDA for evaluation.

Records and Reports

    The majority of the interim final rule's records and reports 
provisions are designed to support or otherwise help to actualize other 
interim final rule requirements. Manufacturers of infant formula are 
required to establish and maintain various records that help 
demonstrate compliance with the quality factor, CGMP, quality control 
procedure, registration, submission, and notification requirements. For 
example, the interim final rule includes a requirement (Sec.  
106.100(e)(5)(ii)) that a manufacturer establish and maintain records 
of the microbiological testing of infant formula required under Sec.  
106.55.

Registration, Submission, and Notification Requirements

    The registration requirements under Sec.  106.110 of the interim 
final rule require infant formula manufacturers to provide FDA with up-
to-date information about firms producing infant formula for U.S. 
distribution. Furthermore, the notification requirements under 
Sec. Sec.  106.120 and 106.121 require an infant formula manufacturer 
to submit scientific data and information to FDA to demonstrate that a 
new infant formula contains all required nutrients, is produced 
consistent with the interim final rule's CGMP and quality control 
requirements, and meets established quality factors. The submission 
provisions also permit a manufacturer of infant formula for export only 
to make an alternative submission that provides assurances that the 
relevant export provisions of the FD&C Act are satisfied and that the 
manufacturer has established adequate controls to ensure that these 
formulas are actually exported.

Costs and Benefits

    The estimated cost of the interim final rule is $7.29 million in 
the first year and $4.06 million in subsequent years. The estimated 
benefit to public health from this interim final rule is $10.00 million 
annually, resulting in total net benefits of $2.71 million in the first 
year and $5.94 million in subsequent years.

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                                            Benefit and Cost Overview
                                                  [In millions]
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                                                                     Benefits          Costs       Net Benefits
----------------------------------------------------------------------------------------------------------------
Total First Year................................................          $10.00           $7.29           $2.71
Annual Total After the First Year...............................          $10.00           $4.06           $5.94
----------------------------------------------------------------------------------------------------------------

Table of Contents

I. Background
II. Highlights of the Interim Final Rule and Summary of Significant 
Changes Made to the Proposed Rule
III. Legal Authority
IV. General Comments and Subpart A--General Provisions
    A. General Comments
    B. Status and Applicability of the Regulations (Proposed Sec.  
106.1)
    C. Definitions (Proposed Sec.  106.3)
V. Subpart B--Current Good Manufacturing Practice
    A. General Comments
    B. Current Good Manufacturing Practices (Proposed Sec.  106.5)
    C. Production and In-Process Control System (Proposed Sec.  
106.6)
    D. Controls to Prevent Adulteration by Workers (Proposed Sec.  
106.10)
    E. Controls to Prevent Adulteration Caused by Facilities 
(Proposed Sec.  106.20)
    F. Controls to Prevent Adulteration Caused by Equipment or 
Utensils (Proposed Sec.  106.30)
    G. Controls to Prevent Adulteration Due to Automatic (Mechanical 
or Electronic) Equipment (Proposed Sec.  106.35)
    H. Controls to Prevent Adulteration Caused by Ingredients, 
Containers, and Closures (Proposed Sec.  106.40)
    I. Controls to Prevent Adulteration During Manufacturing 
(Proposed Sec.  106.50)
    J. Controls to Prevent Adulteration From Microorganisms 
(Proposed Sec.  106.55)
    K. Controls to Prevent Adulteration During Packaging and 
Labeling (Proposed Sec.  106.60)
    L. Controls on the Release of Finished Infant Formula (Proposed 
Sec.  106.70)
    M. Traceability (Proposed Sec.  106.80)
    N. Audits of Current Good Manufacturing Practice (Proposed Sec.  
106.90)
VI. Subpart C--Quality Control Procedures
    A. General Quality Control (Proposed Sec.  106.91)
    B. Audits of Quality Control Procedures (Proposed Sec.  106.92)
VII. Subpart D--Conduct of Audits
VIII. Subpart E--Quality Factors
    A. Quality Factors: Legal Authority
    B. Quality Factors for Infant Formulas
    C. Quality Factor: Normal Physical Growth
    D. Exemptions From Quality Factor Requirements for Normal 
Physical Growth
    E. Quality Factor: Protein Quality
    F. Exemption From the Quality Factor of Protein Quality 
Sufficiency
    G. Miscellaneous Comments on the Quality Factor for Sufficient 
Biological Quality of Protein
    H. Application of Quality Factors to Currently Marketed and 
Previously Marketed Formulas
    I. Records Demonstrating Compliance with the Quality Factor 
Requirements for Infant Formulas That Are Not Eligible Infant 
Formulas
    J. Establishment of Other Quality Factors
    K. Miscellaneous Comments on Quality Factors
IX. Subpart F--Records and Reports
    A. General Comments on Records (Proposed Sec.  106.100)
    B. Production Aggregate Production and Control Records (Proposed 
Sec.  106.100(e))
    C. Records of CGMP (Proposed Sec.  106.100(f))
    D. Records on Infant Formula for Export Only (Proposed Sec.  
106.100(g))
    E. Means of Recordkeeping (Sec.  106.100(m))
    F. Records of Quality Factors (Sec.  106.100(p) and (q))
    G. Adulteration as a Consequence of the Failure to Keep Records 
(Sec.  106.100(r))
X. Subpart G--Registration, Submission, and Notification 
Requirements
    A. General Comments
    B. New Infant Formula Registration (Proposed Sec.  106.110)
    C. New Infant Formula Notifications (Proposed Sec.  106.120)
    D. Quality Factor Submissions for Infant Formula (Proposed Sec.  
106.121)
    E. Verification Submissions (Proposed Sec.  106.130)
    F. Submission Concerning a Change in Infant Formula That May 
Adulterate the Product (Proposed Sec.  106.140)
    G. Notification of an Adulterated or Misbranded Infant Formula 
(Proposed Sec.  106.150)
    H. Incorporation by Reference
XI. Conforming Amendments to Part 107
XII. Environmental Impact
XIII. Federalism
XIV. Regulatory Impact Analysis for Interim Final Rule
XV. Paperwork Reduction Act of 1995
XVI. Comments
XVII. References

I. Background

    The Infant Formula Act amended the FD&C Act to include section 412. 
This law was intended to improve protection of infants consuming infant 
formula products by establishing greater regulatory control over the 
formulation and production of infant formula. In 1982, FDA adopted 
infant formula recall procedures in subpart D of part 107 (21 CFR part 
107, subpart D) of its regulations (47 FR 18832, April 30, 1982), and 
infant formula quality control procedures in subpart B of part 106 (21 
CFR part 106, subpart B) (47 FR 17016, April 20, 1982). In 1985, FDA 
further implemented the Infant Formula Act by establishing subparts B, 
C, and D in part 107 regarding the labeling of infant formula, exempt 
infant formulas, and nutrient requirements for infant formula, 
respectively (50 FR 1833, January 14, 1985; 50 FR 48183, November 22, 
1985; and 50 FR 45106, October 30, 1985).
    In 1986, Congress, as part of the Anti-Drug Abuse Act of 1986 (Pub. 
L. 99-570) (the 1986 amendments), amended section 412 of the FD&C Act 
to address concerns that had been expressed by Congress and consumers 
about the Infant Formula Act and its implementation related to the 
sufficiency of quality control testing, CGMP, recordkeeping, and recall 
requirements. The 1986 amendments: (1) Provide that an infant formula 
is deemed to be adulterated if it fails to provide certain required 
nutrients, fails to meet quality factor requirements established by the 
Secretary (and, by delegation, FDA), or if it is not processed in 
compliance with the CGMP and quality control procedures established by 
the Secretary; (2) require the Secretary to issue regulations 
establishing requirements for quality factors and CGMP, including 
quality control procedures; (3) require infant formula manufacturers to 
audit their operations regularly to ensure that those operations comply 
with CGMP and quality control procedure regulations; (4) require a 
manufacturer to make a submission to FDA when there is a major change 
in an infant formula or a change that may affect whether the formula is 
adulterated; (5) specify the required nutrient quality control testing 
for each batch of infant formula; (6) modify the infant formula recall 
requirements; and (7) authorize the Secretary to establish requirements 
for records retention, including records necessary to demonstrate 
compliance with CGMP and quality control procedures. In 1989, the 
Agency implemented the provisions on recalls (sections 412(f) and (g) 
of the FD&C Act) by establishing subpart E in part 107 (54 FR 4006, 
January 27, 1989). In 1991, the Agency implemented the provisions on 
records and record retention requirements by revising Sec.  106.100 (56 
FR 66566, December 24, 1991).

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    On July 9, 1996, FDA published a notice of proposed rulemaking (the 
1996 proposal) to implement the remaining provisions of the 1986 
amendments (61 FR 36154). Specifically, FDA proposed to amend the 
infant formula regulations in parts 106 and 107 to: (1) Establish good 
manufacturing practices, including microbiological testing, to minimize 
production of adulterated infant formula; (2) revise the quality 
control procedures in part 106 to ensure that an infant formula 
contains the level of nutrients necessary to support infant growth and 
development, both when the formula enters commerce and throughout its 
shelf life; (3) specify the audit procedures necessary to ensure that 
operations comply with CGMP and quality control procedure regulations; 
(4) establish requirements for quality factors to ensure that the 
required nutrients will be in a bioavailable form; (5) establish batch 
and good manufacturing recordkeeping requirements; (6) specify the 
submission requirements for registration and notification to the Agency 
before the introduction of an infant formula into interstate commerce; 
and (7) update part 107 to reflect the 1986 amendments and the November 
1992 reorganization of the Center for Food Safety and Applied Nutrition 
(CFSAN).
    FDA initially opened the comment period for the 1996 proposal for 
90 days and subsequently extended it upon request for another 60 days 
(61 FR 49714, September 23, 1996).
    Following publication of the proposed rule in September 1996, FDA 
convened three meetings of FDA's Food Advisory Committee (FAC) or 
subcommittees of the FAC to address issues related to the regulation of 
infant formula. On April 4 and 5, 2002, the FAC met to discuss general 
scientific principles related to quality factors for infant formula. 
The FAC also discussed the scientific issues related to the 
generalization of findings from a clinical study using preterm infant 
formula consumed by preterm infants to a different formula in a 
different population (a term infant formula intended for use by term 
infants). At a meeting on November 18 and 19, 2002, the Infant Formula 
Subcommittee (IFS) of the FAC discussed the scientific issues and 
principles involved in assessing and evaluating whether a ``new'' 
infant formula supports normal physical growth in infants when consumed 
as a sole source of nutrition. Finally, the Contaminants and Natural 
Toxicants Subcommittee (CNTS) of the FAC met on March 18 and 19, 2003, 
and discussed the scientific issues and principles involved in 
assessing and evaluating Enterobacter sakazakii contamination in 
powdered infant formula, risk reduction strategies based on available 
data, and research questions and priorities. (The organism E. sakazakii 
was reclassified in 2008 to a new genus, Cronobacter spp.) (Ref. 1).
    In the Federal Register of April 28, 2003 (68 FR 22341) (the 2003 
reopening), FDA reopened the comment period for the proposed rule to 
update comments generally and to receive new information based on the 
three FAC meetings held in 2002 and 2003. FDA specifically requested 
comment on the following issues related to these meetings: (1) Whether 
there is a need for a microbiological requirement for E. sakazakii, and 
if so, what requirement the Agency should consider to ensure safety and 
whether a stricter standard was needed for powdered infant formula to 
be consumed by premature and newborn infants; (2) what changes, if any, 
in the proposed microbiological requirements would be needed to ensure 
the safety of powdered infant formula to which microorganisms are 
intentionally added; (3) which provisions in the proposed rule would 
require changes to manufacturers' current activities, and a request for 
information on the types of control systems used to separate materials 
and types of air filtration systems and associated costs of making 
changes in each case; (4) current quality control activities by 
manufacturers related to validation of automated systems and FDA's 
proposed validation requirements; (5) current frequency and conditions 
of calibration of instruments and controls by manufacturers and the 
adequacy of such procedures; (6) quality factor issues, including 
sufficiency of protein quality and normal physical growth as quality 
factors, and when clinical growth studies are required for a new or 
reformulated infant formula; which growth reference should be the 
standard of comparison for infant growth; and duration of study and 
enrollment age; and (7) removal of the reference to Institutional 
Review Board (IRB) review and informed consent from the proposed rule 
as the requirements are now codified in 21 CFR parts 50 and 56, and 
removal of the other clinical study protocol provisions from the 
proposed rule for consideration in a future guidance document.
    Interested persons were originally given until June 27, 2003, to 
comment on these issues and the 1996 proposal. However, in response to 
a request, the comment period was extended to August 26, 2003 (68 FR 
38247, June 27, 2003).
    Based on three reports published after the 2003 reopening, FDA 
again reopened the comment period on August 1, 2006 (71 FR 43392) (the 
2006 reopening), for 45 days to accept comment on a limited set of 
issues related to these reports. Two reports address microbiological 
standards for E. sakazakii and other microbes; the third report 
addresses, in part, clinical studies as a means to assess the growth 
and development of infants. The reports addressing microbiological 
standards are products of a series of expert consultations related to 
the efforts of the Codex Committee on Food Hygiene (CCFH) of the Codex 
Alimentarius Commission to update the 1979 Recommended International 
Code of Hygienic Practice for Foods for Infants and Children (the 1979 
Code). These reports (``Enterobacter sakazakii and Salmonella in 
Powdered Infant Formula: Meeting Report'' (the 2004 FAO/WHO Report) 
(Ref. 2) and ``E. sakazakii and Salmonella spp. in Powdered Infant 
Formula'' (the 2006 FAO/WHO Report) (Ref. 3)) were issued by the Food 
and Agriculture Organization of the United Nations, World Health 
Organization (WHO), in 2004 and 2006 and provide scientific advice 
concerning E. sakazakii, Salmonella spp, and other microorganisms in 
powdered infant formula. The third report is from the Committee on the 
Evaluation of the Addition of Ingredients New to Infant Formula, which 
the Institute of Medicine (IOM) of the National Academy of Sciences 
(NAS) convened at the request of FDA and Health Canada, FDA's Canadian 
counterpart. The purpose of the report was, in part, to evaluate the 
performance of a new infant formula. The committee made several 
recommendations regarding growth studies, including the recommendation 
that ``Growth studies should include precise and reliable measurements 
of weight and length velocity and head circumference. Duration of 
measurements should cover at least the period when infant formula 
remains the sole source of nutrients in the infant diet.'' (Ref. 4, p. 
108).
    In reopening the comment period in August 2006, FDA requested 
comment on the following issues:
     Whether FDA should require a microbiological standard for 
E. sakazakii for powdered infant formula of negative in 30 x 10 gram 
(g) samples;
     Whether FDA should require microbiological standards for 
aerobic plate count, coliforms, fecal coliforms, Listeria 
monocytogenes, Bacillus cereus, and Staphylococcus aureus;

[[Page 7938]]

     Whether FDA should require measurements of healthy growth 
beyond the two proposed quality factors of normal physical growth (as 
measured by body weight, recumbent length, head circumference, and 
average daily weight increment) and protein quality;
     Whether FDA should require a measure for body composition 
as an indicator of normal physical growth, and if so, what measure; and
     Whether FDA should require that the duration for a 
clinical study, if required, be no less than 15 weeks, and commence 
when infants are no older than 2 weeks of age.

II. Highlights of the Interim Final Rule and Summary of Significant 
Changes Made to the Proposed Rule

    The highlights of this interim final rule are as follows:
     FDA is establishing CGMP requirements for the production 
of nonexempt infant formula. FDA is also clarifying the current 
requirements related to the validation of manufacturing systems and the 
establishment of specifications in the manufacture of infant formula.
     FDA is establishing requirements for microbiological 
quality to prevent adulteration of powdered infant formula.
     FDA is establishing requirements for quality factors to 
provide assurance that, as a sole source of nutrition, an infant 
formula supports infants' healthy growth. These provisions include a 
requirement to conduct an adequate and well-controlled growth 
monitoring study to measure physical growth and exemptions from the 
requirement to conduct such a study.
     FDA is establishing requirements for recordkeeping and 
reports that, where possible, reduce redundancy.

III. Legal Authority

    FDA's authority to issue regulations that establish requirements 
for quality factors, current good manufacturing practices, quality 
control procedures, registration, submission, notification, and records 
and reports is derived from section 412 of the FD&C Act. FDA also 
relies on other sections of the FD&C Act, including sections 701(a) and 
402 (21 U.S.C. 371(a) and 342). The regulations in this interim final 
rule are consistent with FDA's explicit statutory mission, which is, in 
part, to protect the public health by ensuring that foods (including 
infant formula) are safe, wholesome, sanitary, and properly labeled 
(section 903(b)(2)(A) of the FD&C Act (21 U.S.C. 393(b)(2)(A))). The 
regulations are also consistent with the overall purpose of section 412 
of the FD&C Act (see Pub. L. 96-359, 94 Stat. 1190, 1190 (1980) 
(stating the purpose of the Infant Formula Act is to provide for the 
``safety and nutrition'' of infant formula)).
    FDA's authority to establish requirements for quality factors is 
explicit in section 412(b)(1) of the FD&C Act, which states that the 
``Secretary shall by regulation establish requirements for quality 
factors.'' Infant formulas that are not in compliance with the quality 
factor requirements are adulterated under section 412(a)(2) of the FD&C 
Act. In section IV of this interim final rule FDA defines ``quality 
factors,'' and in section VIII FDA establishes specific quality factor 
requirements.
    Similarly, FDA's authority to establish current good manufacturing 
practices and quality control procedure requirements is explicit in 
section 412(b)(2) of the FD&C Act. Section 412(b)(2) of the FD&C Act 
specifies certain overarching requirements that must be included as 
part of CGMP and quality control procedure requirements. Specifically, 
the section states that the ``Secretary shall by regulation establish 
good manufacturing practices for infant formulas, including quality 
control procedures that the Secretary determines are necessary to 
assure that an infant formula . . . is manufactured in a manner 
designed to prevent adulteration of the infant formula.'' Infant 
formulas that are not in compliance with the CGMP and quality control 
procedure requirements are adulterated under section 412(a)(3) of the 
FD&C Act. In addition, the failure to comply with certain CGMP 
requirements will result in the infant formula being adulterated under 
sections 402(a)(1), (a)(2), (a)(3), or (a)(4) of the FD&C Act. Although 
Congress has identified specific provisions that must be included as 
CGMP and quality control procedure requirements (see section 412(b)(2) 
and (b)(3) of the FD&C Act), it did not prescribe all such 
requirements. Rather, Congress left a gap for FDA to prescribe, by 
regulation, such other practices and procedures necessary to ensure the 
nutrient content of infant formula and prevent adulteration under 
section 412(b)(2) of the FD&C Act.
    In addition, FDA has explicit authority under sections 412(c), (d), 
and (e) of the FD&C Act to establish registration, submission, and 
notification requirements, respectively. Section 412(c)(1)(A) of the 
FD&C Act states that no person may introduce a new infant formula into 
interstate commerce, unless the person has ``registered with the 
Secretary the name of such person, the place of business of such 
person, and all establishments at which such person intends to 
manufacturer such infant formula.'' The registration requirements in 
the interim final rule set forth the information that must be included 
in a new infant formula registration sent to FDA.
    Further, the interim final rule sets forth the information that 
must be included in a new infant formula submission to FDA. Section 
412(d) of the FD&C Act requires that a manufacturer make an infant 
formula submission and describes the type of information that must be 
included in such submission. For example, section 412(d)(1)(A) of the 
FD&C Act requires that the submission include the quantitative 
formulation of the formula. Additionally, section 412(d)(1)(C) of the 
FD&C Act requires, in part, assurances that the infant formula will not 
be marketed unless it meets the requirements of section 412(b)(1) of 
the FD&C Act (quality factor requirements). Section 412(d)(1)(D) of the 
FD&C Act requires assurances that the formula will not be marketed 
unless the processing of the formula complies with section 412(b)(2) of 
the FD&C Act (the CGMP and quality control procedure requirements). The 
interim final rule prescribes requirements for the assurances required 
by these sections of the FD&C Act.
    The notification requirements in the interim final rule describe 
when a notification must be provided to FDA, as required by section 
412(e) of the FD&C Act. Section 412(e) of the FD&C Act sets forth the 
circumstances in which a manufacturer must notify FDA that an infant 
formula processed by the manufacturer has left an establishment under 
the manufacturer's control and may be adulterated or misbranded.
    FDA also has authority to establish requirements for records under 
section 412(b)(4)(A) of the FD&C Act. This interim final rule includes 
record requirements for CGMP and quality control procedures and for the 
conduct of audits. For example, under section 412(b)(4)(A)(i) of the 
FD&C Act, FDA has authority to establish recordkeeping requirements 
necessary to demonstrate compliance with CGMP and quality control 
procedure requirements, including records containing the results of all 
testing designed to prevent the adulteration of infant formula. Thus, 
FDA is establishing requirements in this interim final rule for 
manufacturers to make and retain records that include complete 
information relating to the production and control of each production 
aggregate (for discussion of this term see section IV.C.1 of this 
document) of infant formula to ensure

[[Page 7939]]

compliance with the CGMP and quality control procedure requirements 
related to the production aggregate. Specifically, Sec.  106.100(e) 
requires manufacturers to make and retain records that include complete 
information relating to the production and control of the production 
aggregate. Information about the processing of the production aggregate 
is important to the manufacturer, which must ensure that it is 
producing the formula it intends to produce under the master 
manufacturing order. In addition, if a problem arises from a particular 
production aggregate of formula, such records will assist the 
manufacturer and FDA in identifying the source of the problem and what 
action may be necessary to correct it. For example, Sec.  106.100(e)(3) 
requires documentation of the monitoring at any point, step, or stage 
in the production process where control is deemed necessary to prevent 
adulteration.
    Moreover, FDA has authority to establish record requirements under 
other provisions of section 412 of the FD&C Act, as well as section 
701(a) of the FD&C Act. For example, as is discussed in greater detail 
in section VIII, it is necessary for manufacturers to create records 
pertaining to a growth monitoring study in order to determine whether 
their infant formula meets the quality factor requirement of normal 
physical growth established under section 412(b)(1) of the FD&C Act. It 
is also necessary for the enforcement of section 412(a)(2) of the FD&C 
Act, with respect to meeting quality factor requirements, for FDA to 
require records pertaining to a growth monitoring study, when such a 
study is required. Without such records, FDA cannot determine whether 
the quality factor requirements have been met. Additionally, FDA has 
authority under section 701(a) of the FD&C Act, when coupled with the 
specific authorities granted to FDA under section 412 of the FD&C Act, 
to establish record requirements that are necessary for the efficient 
enforcement of the FD&C Act.

IV. General Comments and Subpart A--General Provisions

    During the three periods provided for comments, FDA received a 
number of comments in response to the proposed rule. Some of the 
comments supported the proposal generally or supported aspects of the 
proposal. Other comments objected to specific provisions and requested 
revisions. A few comments addressed issues outside the scope of the 
proposal and will not be discussed in this document. To make it easier 
to identify comments and FDA's responses to the comments, the word 
``Comment'' will appear in parentheses before the description of the 
comment, and the word, ``Response'' will appear in parentheses before 
FDA's response. FDA has also numbered each comment to make it easier to 
identify a particular comment. The number assigned to each comment is 
for organizational purposes only and does not signify the comment's 
value, importance, or the order in which it was submitted. Comments 
generally are not distinguished by year of receipt.

A. General Comments

    The general comments discussed in this section are those that 
addressed the rule in its entirety.
    (Comment 1) One comment stated that many provisions of the infant 
formula proposal are ``overly redundant'' with other FDA laws and 
regulations, such as the food CGMP and food additive regulations. These 
redundancies include personnel requirements and the permitted use of 
food ingredients and food contact materials. The comment claims that 
these redundancies do not provide the public with greater protection, 
but serve only to create unnecessary confusion in those plants 
manufacturing both infant formulas and similar products not intended 
for use by infants. The comment noted that FDA's stated intent in 
promulgating the food CGMP regulations was to have those regulations 
function as ``umbrella'' regulations, to which FDA would add additional 
regulations targeted at specific industries.
    (Response) As stated in the proposed rule, the CGMP requirements 
for infant formula are based, in part, on FDA's existing regulations 
concerning CGMP for foods (61 FR 36154 at 36157). Infant formulas are 
food, and thus, the Agency would expect that certain CGMP requirements 
for infant formula would parallel the CGMP provisions in part 110 (21 
CFR part 110).
    FDA disagrees, however, that many provisions of the infant formula 
rule are overly redundant with other FDA laws and regulations. The food 
CGMP regulations (part 110) predate the 1986 amendments. Thus, Congress 
was aware of these regulations at the time of the 1986 amendments when 
it established an explicit mandate for infant formula CGMP. By 
mandating that FDA establish good manufacturing practices, including 
quality control procedures, Congress recognized that requirements in 
addition to the food CGMP were necessary for infant formula. The CGMP 
regulations established by this interim final rule implement Congress' 
express mandate. As noted, section 412(b)(2)(A) of the FD&C Act 
specifically mandates that FDA establish CGMP for infant formula: ``The 
Secretary shall, by regulation, establish good manufacturing practices 
for infant formulas, including quality control procedures that the 
Secretary determines are necessary to assure that an infant formula 
provides nutrients in accordance with [section 412] and is manufactured 
in a manner designed to prevent adulteration of the infant formula.'' 
In addition, section 412(a)(3) of the FD&C Act provides that an infant 
formula is deemed to be adulterated if ``the processing of such infant 
formula is not in compliance with the good manufacturing practices and 
the quality control procedures prescribed by the Secretary'' under 
section 412(b)(2). This provision of section 412 of the FD&C Act 
underscores the Congressional determination that product-specific CGMP 
requirements are necessary for infant formula.
    Moreover, the purpose of section 412 of the FD&C Act is to ensure 
product safety for the vulnerable population that consumes infant 
formula. To this end, FDA may include CGMP requirements in this interim 
final rule that are the same or similar to those found in 21 CFR part 
110 for foods in general. FDA has included in this interim final rule 
the part 110 requirements that are common to most or all infant formula 
manufacturing. The Agency recognizes that there may be aspects of 
infant formula manufacturing operations for which certain provisions in 
part 110 apply, but that FDA did not determine to be common to most 
infant formula manufacturing operations. Infant formula manufacturers 
are responsible for understanding and following all of the regulations 
that govern their products even if the regulations are not in parts 106 
and 107.\1\ Thus, a manufacturer is subject to the regulations in part 
110 in addition to the regulations in part 106. To the extent that the 
regulations conflict, the infant formula manufacturer must comply with 
part 106.
---------------------------------------------------------------------------

    \1\ FDA notes that the FDA Food Safety Modernization Act (FSMA) 
creates new requirements with respect to food safety and requires 
FDA to issue certain regulations. For example, section 103 of FSMA 
requires FDA to issue regulations establishing science-based minimum 
standards for certain food facilities to conduct a hazard analysis, 
document hazards, implement preventive controls, and document 
implementation of such preventive controls (Pub. L. 111-353, 124 
Stat. 3885 (2011)). The purpose of this interim final rule is not to 
implement the requirements of FSMA. Any additional requirements in 
the rulemakings implementing FSMA that may apply to infant formula 
will be addressed in those rulemakings.

---------------------------------------------------------------------------

[[Page 7940]]

    In addition, FDA may include CGMP requirements in this interim 
final rule concerning the use of lawful ingredients and food packaging 
materials. Section 106.40(a) states that only substances that are safe 
and suitable under the applicable food safety provisions of the FD&C 
Act may be used in infant formulas. Section 106.40(b) requires that 
packaging material that comes in contact with infant formula be 
composed of substances that are safe and lawful for such use. FDA 
disagrees such requirements are ``overly redundant.'' The statute 
contains express authority to establish by regulation CGMP requirements 
for infant formula to prevent adulteration, in general (see section 
412(b)(2)(A) of the FD&C Act) and to prevent adulteration of each 
production aggregate of infant formula, specifically (see section 
412(b)(2)(B)(iii) of the FD&C Act). The use of ingredients in the 
formula, and of substances in food packaging materials that would come 
into contact with the formula, that are safe and lawful is important to 
ensuring that each production aggregate of infant formula is not 
adulterated. Sections 106.40(a) and (b) help to ensure that appropriate 
manufacturing processes are in place such that only safe and lawful 
food ingredients and food packaging materials are used to manufacture 
infant formula, a food intended for consumption by a vulnerable 
population. These requirements are necessary to ensure the safety of 
all of the formula's ingredients and food packaging materials used in 
the manufacture of an infant formula to prevent adulteration of the 
infant formula. A failure to do so would result in the infant formula 
being deemed adulterated under section 412 of the FD&C Act.
    For the reasons set forth previously in this document, the Agency 
is making no changes to the language set forth in the proposed rule in 
response to this comment.
    (Comment 2) One comment stated that since the proposed rule was 
published, FDA's Center for Drug Evaluation and Research (CDER) 
announced a new initiative on August 21, 2002, ``Pharmaceutical CGMP 
for the 21st Century: A Risk Based Approach'' (Ref. 5) that involves 
significant examination and reevaluation of FDA's drug CGMP. The 
comment suggested that the infant formula CGMP may benefit from using 
this risk-based drug CGMP initiative as a model and that the infant 
formula industry partner with CFSAN in the same way that CDER and other 
FDA Centers are partnering with the industries they regulate.
    (Response) In developing this interim final rule, FDA did consider 
the drug CGMPs and those for other FDA-regulated products. FDA has on 
many occasions held discussions with, solicited comments from, and 
partnered with the infant formula industry to work toward a risk-based 
philosophy that provides for process control that is scientifically 
validated, rather than on a system that is overly reliant on testing. 
In addition to the three FAC meetings described previously in this 
document, the Agency and the infant formula industry have worked 
collaboratively to provide input for the WHO expert consultation on 
testing for microorganisms of public health significance in powdered 
infant formula, and to provide input on the revision of the Codex 
hygienic practices for production of powdered infant formula. In 
addition, the Agency has provided opportunities for the public, 
including the infant formula industry, to communicate with FDA by 
reopening the comment period on the proposed rule on two occasions, and 
again by accepting comments upon publication of this interim final 
rule. Thus, this rulemaking has been a collaborative process that has 
resulted in a sound, risk-based approach to process control for infant 
formula manufacture.
    An example of the Agency's risk-based approach is the resolution in 
the interim final rule of the requirements for microbiological testing. 
As discussed in more detail in section V, in the 1996 proposed rule, 
FDA proposed broad microbiological testing requirements for powdered 
formula. Upon further evaluation, the Agency determined that most of 
the pathogens originally proposed for testing have not been associated 
with infant formula. Instead, relying on the WHO risk assessment model 
set out in the 2006 FAO/WHO Report (Ref. 3), FDA determined that 
Cronobacter spp. (formerly classified as E sakazakii) and Salmonella 
spp. are the only two pathogens of concern for powdered infant formula. 
Thus, the interim final rule replaces the broad microbiological testing 
mandate in the proposal with more narrow, risk-based requirements.
    (Comment 3) One comment asked FDA to acknowledge in the preamble to 
the final rule that under the FD&C Act and Sec.  107.50(c) of the 
regulations, exempt infant formulas are not subject to the CGMP, 
quality control, and quality factor requirements of part 106. The 
comment identified some logistical issues associated with the 
application of quality factor requirements to exempt infant formulas. 
The comment also requested that FDA state in the preamble that during 
inspections of special infant formula manufacturing plants (referring 
to plants that manufacture exempt infant formula), the Agency will 
accept quality control activities other than those articulated in part 
106 provided that the manufacturer documents those activities, 
demonstrates that the product meets the nutrient requirements of the 
FD&C Act, and manufactures the product in a manner designed to prevent 
adulteration. The comment stated that FDA should encourage 
manufacturers of exempt infant formula to comply voluntarily with part 
106, where practical, because exempt formulas should be manufactured to 
a high standard of quality.
    (Response) The regulations in Sec.  107.50 pertaining to exempt 
infant formula were finalized in 1985 (50 FR 48183) prior to the 1986 
amendments. As FDA explained in the 1996 proposal, the Agency intends 
to address, in a separate rulemaking, the exempt infant formula 
regulations and the effect of the 1986 amendments on exempt infant 
formulas (61 FR 36154 at 36201-36202). In the interim, FDA encourages 
exempt infant formula manufacturers to use the requirements in this 
interim final rule as guidance because infant formulas for use by 
infants with inborn errors of metabolism, low birth weight, or other 
unusual medical or dietary problems should conform to the same 
standards set forth in the requirements of this interim final rule 
applicable to formulas for healthy term infants, unless there is a 
medical, nutritional, scientific, or technological rationale for a 
deviation from such requirements. Elsewhere in this issue of the 
Federal Register, FDA is issuing a notice of availability for a draft 
guidance document that addresses the application of new part 106 to 
exempt infant formulas. Manufacturers are encouraged to consult with 
CFSAN prior to the submission of an exempt infant formula submission to 
the extent a manufacturer believes there is such a rationale for a 
deviation from the provisions of this interim final rule.
    (Comment 4) One comment stated that its review of the authorities 
cited in support of the 1996 proposed requirements calls into question 
the existence of concrete bases for a number of the proposed 
``requirements'' and thus, appears to reflect ``administrative'' 
expertise and thinking as opposed to practical hands-on experience that 
the industry possesses. Another comment emphasized that the real GMP 
expertise rests with the infant formula industry, and further argues 
that reliance by FDA on Agency administrative expertise in response to 
comments, if unsupported

[[Page 7941]]

by additional data, outside expert recommendations, or detailed 
explanation, may be neither good nor reasonable administrative 
practice.
    (Response) FDA disagrees that real GMP ``expertise'' rests only 
with industry and disagrees with the comment's suggestion that the 
Agency does not have the expertise it needs to establish requirements. 
Such assertions are unfounded because FDA does have staff with ``real 
GMP expertise'' and, in addition, has consulted with experts outside 
the Agency through the FAC process. Moreover, FDA field and compliance 
personnel regularly interact with industry staff during inspections and 
other compliance activities. FDA has also achieved greater insight into 
the industry's concerns by virtue of the extensive comments submitted 
by the industry during this lengthy rule-making process. Further, the 
comment identifies no specific proposed requirement for which it 
questions the underlying support. Accordingly, FDA is making no changes 
in response to this comment.
    (Comment 5) One comment stated that many of the provisions in the 
proposed regulation are inflexible and overly prescriptive. The comment 
requested that FDA establish the results to be achieved in the infant 
formula manufacturing process, but not prescribe or limit the ways in 
which the required results can be achieved.
    (Response) FDA agrees in part with this comment. To the extent 
feasible, FDA is establishing requirements for the manufacturing 
process in a way that describes the result to be achieved and does not 
specifically mandate how to achieve that result. For example, as noted 
in this document, Sec.  106.50(d)(3) mandates that the manufacturer 
establish controls for the removal of air from the finished product, 
because such controls are necessary to ensure that nutrient 
deterioration does not occur. The method used and extent of air removal 
are left to the discretion of the manufacturer. In other cases, the 
statutory language mandates how to achieve a result, e.g., the vitamins 
that must be tested at the final product stage for each batch 
(production aggregate) of infant formula to ensure compliance with 
required nutrient levels (section 412(b)(3) of the FD&C Act). Specific 
statutory mandates are reflected in the interim final rule.
    (Comment 6) One comment submitted in 2003 states that instead of 
responding to comments submitted in response to the 1996 proposed rule, 
the 2003 comment period reopening merely requests comment again without 
giving any indication of FDA's current views on the rule's major 
issues. The comment further stated that the 2003 reopening raises new 
issues not covered in the proposed rule and fails to provide guidance 
on how FDA proposes to address these issues. The comment argued that 
the 2003 reopening is at odds with FDA's obligation under the 
Administrative Procedure Act (APA) to make its views known to the 
public in a concrete and focused form in order to make criticism or 
formulation of alternatives possible, and that this format forces 
industry to comment on a rule that the public does not see until it is 
in final form. Accordingly, this comment requests that FDA permit an 
additional round of notice and comment, especially to the extent that 
FDA intends to draft regulations addressing new substantive issues not 
in the proposed rule.
    (Response) FDA disagrees with the comment's criticism of the 2003 
reopening and suggestion that an additional round of notice and comment 
on the proposed rule is needed. The 2003 reopening provided a 60-day 
comment period that ended on June 27, 2003. FDA extended the reopened 
comment period for an additional 60 days to allow interested persons 
additional time to comment, as requested in a comment. With this 
extension, the public was provided with a total of 120 days to submit 
comments during the 2003 reopening.
    As noted previously in this document, in 2003, FDA reopened the 
comment period to receive comments on all issues presented by the 1996 
proposed rule. Thus, at the time of the 2003 reopening, the 1996 
proposal identified FDA's views on the issues in the rulemaking. This 
interim final rule only addresses issues that are within the scope of 
the original proposal. In light of three meetings that occurred between 
the issuance of the 1996 proposal and the 2003 reopening, FDA also 
specifically requested in the 2003 reopening comments on a discrete set 
of issues that were within the scope of the original proposal. These 
issues were explained clearly, and opportunity to provide comments on 
these discrete issues, as well as the rule generally, was provided. In 
2006, FDA again reopened the comment period on a specific 
microbiological standard it was considering for E. sakazakii (now 
classified as Cronobacter spp.), in addition to other specific issues.
    Under the APA, in order to provide adequate notice, a proposed 
rulemaking, unless a specific exception applies, must include ``either 
the terms or substance of the proposed rule or a description of the 
subjects and issues involved'' (5 U.S.C. 553(b)(3).) In other words, 
the notice must be sufficient to fairly apprise interested parties of 
issues involved, but it does not need to specify every precise proposal 
which the Agency may ultimately adopt as a rule. Action for Children's 
Television v. FCC, 564 F.2d 458, 470 (D.C. Cir. 1977). The notice given 
by FDA in the original 1996 proposal, the 2003 reopening, and later in 
the 2006 reopening, was sufficient to fairly apprise all interested 
parties of the issues involved in the rulemaking. Thus, sufficient 
notice has been given and additional opportunity for comment is not 
required. Notwithstanding the adequacy of the prior comment periods, we 
are accepting comments on this interim final rule. For more details on 
the comment period, see part XVI of this document.
    (Comment 7) One 2006 comment objected to the Agency's limiting the 
additional 2006 comment period to certain issues and expressed concern 
that the effect of this limitation would be to prevent the submission 
of information that could have a negative impact on the resolution of 
important issues. The comment stated that the limited 2006 reopening 
may result in the promulgation of a GMP regulation that does not 
reflect current good manufacturing practices and requested that the 
entire proposed regulation be reopened and that the public be given the 
opportunity to respond to FDA's reactions to the voluminous comments 
submitted since 1996.
    (Response) FDA disagrees with this comment. First, the 1996 
proposal provided sufficient notice of all issues in this interim final 
rule. Further, the 2003 reopening provided the public with a lengthy 
opportunity to comment on all issues raised by the 1996 proposal, and 
this 2006 comment does not specifically address why an opportunity in 
addition to that provided in 2003 is needed to comment on all issues. 
Finally, the 2006 reopening provided sufficient notice of the matters 
at issue in the reopening. In particular, FDA described the significant 
expert consultations held since the 2003 reopening and provided the 
Agency's tentative conclusions, including the basis for such 
conclusions, relying on the information added to the administrative 
record and comments received on such information from the 2003 
reopening. Therefore, ample notice and opportunity for comment has been 
provided on all aspects of this interim final rule. As noted previously 
in this document, however, notwithstanding the adequacy of the prior 
comment periods, we are accepting comments on

[[Page 7942]]

this interim final rule (see part XVI of this document).

B. Status and Applicability of the Regulations (Proposed Sec.  106.1)

    Proposed Sec.  106.1 described the authority for each subpart of 
the proposal and the consequences under the FD&C Act of a failure to 
comply with any of the proposed regulations. FDA is including Sec.  
106.1 because it is important for those in the infant formula industry 
to be aware of the legal consequences of failing to comply with these 
regulations, which are being issued to implement specific sections of 
the FD&C Act.
    FDA did receive comments supporting Sec.  106.1 as proposed but did 
not receive any adverse comments. On its own initiative, however, FDA 
is revising Sec.  106.1 to clarify all of the requirements in subparts 
F and G of this interim final rule, and also to clarify the legal 
consequences of failing to comply with certain requirements in subparts 
F and G of the interim final rule.
    Proposed Sec.  106.1(a) stated that subparts B, C, and D prescribe 
the steps that shall be taken under section 412(b)(2) and (b)(3) of the 
FD&C Act (i.e., CGMP and quality control procedures requirements, 
including audit requirements) in processing infant formula, and that 
the failure to comply with any regulation under these subparts would 
adulterate the formula under section 412(a)(3) of the FD&C Act. While 
it is true that subparts B, C, and D describe CGMP and quality control 
procedures requirements issued under section 412(b)(2) and (b)(3) of 
the FD&C Act, these are not the only subparts of the interim final rule 
that contain CGMP and quality control procedures requirements. Subpart 
F of this interim final rule prescribes records requirements, some of 
which are part of the requirements for CGMP and quality control 
procedures issued under the authority of section 412(b)(2) of the FD&C 
Act. Additionally, some of the CGMP and quality control procedures 
requirements are codified in subpart G of this interim final rule. 
Subpart G describes, in part, the content of submissions. Some of the 
records that make up the content of these submissions are records made 
as part of requirements for CGMP and quality control procedures issued 
under the authority of section 412(b)(2).
    Because subparts F and G also contain requirements that are 
properly classified as CGMP and quality control procedures requirements 
issued under the authority of section 412(b)(2) of the FD&C Act, FDA is 
revising proposed Sec.  106.1(c) and (d) to include these requirements 
and the authority under which they are issued. FDA is also revising 
proposed Sec.  106.1(c) and (d) to explain that the failure to follow 
these requirements issued under section 412(b)(2) of the FD&C Act will 
result in an infant formula that is deemed to be adulterated under 
section 412(a)(3) of the FD&C Act.
    Furthermore, FDA is revising proposed Sec.  106.1(c) and (d) to 
describe requirements in subparts F and G that are issued under the 
authority of section 412(b)(1) of the FD&C Act, which requires FDA to 
establish requirements for quality factors. Proposed Sec.  106.1(b) 
stated that subpart E prescribed the quality factor requirements issued 
under section 412(b)(1) of the Act. As with CGMP and quality control 
procedures requirements, however, quality factor requirements are also 
contained in subparts F and G. Some of the records requirements that 
are codified in subpart F are records required under the authority to 
issue quality factor requirements in section 412(b)(1) of the FD&C Act. 
Likewise, some of the records that make up the content of the 
submissions required under subpart G of this interim final rule are 
required under the authority to issue quality factor requirements under 
section 412(b)(1) of the FD&C Act. Therefore, because subparts F and G 
contain records requirements that are part of the quality factor 
requirements, FDA is also revising proposed Sec.  106.1(c) and (d) to 
explain that the failure to follow any quality factor requirements 
issued under section 412(b)(1) of the FD&C Act will result in an infant 
formula that is deemed adulterated under section 412(a)(2) of the FD&C 
Act.

C. Definitions (Proposed Sec.  106.3)

    Section 106.3 of the 1996 proposed rule provided definitions for 
the following terms: Batch; final-product-stage; indicator nutrient; 
infant; infant formula; in-process batch; lot; lot number, control 
number or batch number; major change; manufacturer; microorganism; new 
infant formula; nutrient; nutrient premix; quality factors; 
representative sample; shall; and should. In the 1996 proposed rule, 
each definition in proposed Sec.  106.3 was designated as a 
subparagraph of the section using letters (for example, the definition 
of ``batch'' was proposed Sec.  106.3(a)). Individual designation of 
definitions in a regulation is no longer standard in Federal 
regulations. Accordingly, these individual designations have been 
removed in the interim final rule and are not used in the discussion in 
this document. Consistent with the 1996 proposed rule, the definitions 
continue to be listed in alphabetical order.
    No comments suggest modification of the definition of proposed 
Sec.  106.3(q) for ``shall'' and thus, it is included, as proposed, in 
Sec.  106.3 of the interim final rule. Because all of the provisions in 
this interim final rule are mandatory, there is no need for the 
definition ``should'' (proposed Sec.  106.3(r)) and accordingly, this 
definition is deleted in this interim final rule.
    The comments FDA received on the definitions of final-product-
stage; indicator nutrient; infant; infant formula; nutrient premix; and 
representative sample supported the proposed definitions. Thus, these 
definitions are included, as proposed, in the interim final rule.
    FDA received comments that suggested revisions to the definitions 
of the following terms in the proposed rule: Batch; lot; major change; 
manufacturer; microorganism; new infant formula; nutrient; and quality 
factors. Based on changes to the proposed definitions of ``lot'' and 
``batch,'' FDA has made conforming changes to the proposed definitions 
of ``in-process batch'' and ``lot number, control number, or batch 
number.'' FDA also received comments that recommended that FDA include 
additional definitions of the following terms: Minor change; 
responsible party; specifications; target values; and critical. FDA 
responds to these comments in this interim final rule.
    In addition, FDA is adding a definition for ``eligible infant 
formula'' on its own initiative. As discussed in section VIII, FDA is 
adding provisions to the quality factor requirements in Sec.  106.96 
that relate to a formula that could have been or was lawfully 
distributed in the United States on the 89th day after the publication 
of this interim final rule. FDA is describing these formulas as 
``eligible infant formulas,'' and for clarity, FDA is adding a 
definition in Sec.  106.3 to describe these formulas.
1. Batch (Proposed Sec.  106.3(a) and Lot (Proposed Sec.  106.3(g))
    As described in more detail in this document, FDA believes that 
during the course of this rulemaking, two related terms, ``batch'' and 
``lot,'' have been used in different ways, potentially causing 
confusion. These terms describe two volumes of formula that have 
significance in the production of infant formula. At the same time, FDA 
has come to understand that the food industry and the drug industry 
generally do not use these terms in the same way. This is particularly 
relevant because the

[[Page 7943]]

definitions originally proposed were based on FDA's drug manufacturing 
CGMP regulations in part 210 (21 CFR part 210) and because some formula 
manufacturers are part of a larger drug manufacturing firm and others 
are part of a larger food manufacturing firm. Accordingly, in order to 
achieve necessary clarity, the interim final rule establishes and 
defines two new terms, ``production unit'' and ``production 
aggregate,'' which are substituted for the terms ``batch'' and ``lot'' 
used in the earlier stages of this rulemaking.
    The discussion that follows recounts the background and history of 
the use of the terms ``batch'' and ``lot'' in this rulemaking.
    In current industry practice, two volumes of formula have 
significance during the infant formula manufacturing phase: the 
quantity of formula that can be mixed in the production equipment at 
one time (the relatively smaller volume) and the amount of formula 
manufactured during a single production run (the relatively larger 
volume.) With a continuous production process (which is used by all 
formula manufacturers), the larger volume is necessarily somewhat co-
mingled because there is no cleaning between production of each smaller 
volume, and in fact, may be purposefully co-mingled through the 
combination of several smaller volumes to create a single larger 
volume. Generally speaking, the larger volume is the production volume 
of particular interest to the formula manufacturer. At certain times, 
the quantity produced during a single production run may be a much 
smaller amount. In most cases, the production of two different larger 
volumes of formula (two different production runs) will be separated by 
an intervening cleaning of the production equipment. Manufacturers 
currently sample from the final volume produced from a single 
production run, which may include co-mingled volumes, for testing both 
for nutrients and for microbial contamination.
    Although section 412 uses the term ``batch,'' the term is not 
defined. Specifically, section 412(b)(2)(B)(i) of the FD&C Act (21 
U.S.C. 350a(b)(2)(B)(i)) requires testing of ``each batch of infant 
formula'' for nutrients prior to distribution of the ``batch;'' section 
412(b)(3)(A) of the FD&C Act (21 U.S.C. 350a(b)(3)(A)) requires that 
``at the final product stage, each batch of infant formula'' shall be 
tested for certain vitamins; and section 412(b)(3)(C) of the FD&C Act 
(21 U.S.C. 350a(b)(3)(C)) requires that ``during the manufacturing 
process or at the final product stage and before distribution,'' 
(emphasis added) the formula shall be tested for all nutrients; and 
section 412(b)(3)(D) (21 U.S.C. 350a(b)(3)(D)) requires that if a 
nutrient is added to the list in section 412(i) of the FD&C Act (21 
U.S.C. (350a(i)), the Secretary shall require that the manufacturer 
test ``each batch.'' Section 412(b)(2)(E) of the FD&C Act (21 U.S.C. 
350a(b)(2)(E)) defines ``final product stage'' as ``the point in the 
manufacturing process, before distribution of an infant formula, at 
which an infant formula is homogenous and not subject to further 
degradation.'' The fact that section 412 of the FD&C Act either 
requires or permits testing of each ``batch'' of a formula at the 
``final product stage'' illustrates that Congress used the term 
``batch'' to mean the relatively larger, often co-mingled portion of 
formula in which individually mixed portions of formula are combined.
    Unlike ``batch,'' the term ``lot'' is not used in section 412 of 
the FD&C Act. The 1996 proposed rule included definitions for ``batch'' 
and ``lot'' (proposed Sec.  106.3(a) and (g), respectively.) These 
definitions were derived from FDA's drug CGMP regulations in part 210. 
The proposed rule defined ``batch'' to mean ``a specific quantity of an 
infant formula or other material that is intended to have uniform 
character and quality, within specified limits, and is produced 
according to a single manufacturing order during the same cycle of 
manufacture.'' The proposed rule defined ``lot'' to mean ``a batch, or 
a specifically identified portion of a batch, having uniform character 
and quality within specified limits; or, in the case of an infant 
formula produced by continuous process, it is a specific identified 
amount produced in a unit of time or quantity in a manner that assures 
its having uniform character and quality within specified limits.''
    The proposed rule stated that it was important to maintain 
consistency throughout FDA's regulations. Therefore, where possible and 
appropriate, the proposed definitions relied on FDA's regulations in 
part 210, the CGMP for drugs. Specifically, the definitions in the 
proposed rule for ``batch,'' ``lot,'' ``lot number, control number, or 
batch number,'' and ``representative sample'' were based on the 
definitions in part 210.
    The proposed definitions of ``batch'' and ``lot'' contemplated that 
infant formula would be produced in bulk, that ``batch'' was considered 
the relatively larger volume, that ``lot'' was the relatively smaller 
volume, and that more than one ``lot'' could comprise a ``batch.'' The 
1996 proposed rule (Sec.  106.55) used the term ``batch'' when 
describing the requirements for evaluating the microbiological quality 
of powdered formula at the final product stage.
    In 2006, following the emergence of Enterobacter sakazakii as a 
contaminant in powdered infant formula, FDA reopened the comment period 
on the 1996 proposal to receive comments on the microbiological testing 
scheme. (The organism E. sakazakii was reclassified in 2008 to new 
genus, Cronobacter spp. (Ref. 1).) In that reopening, FDA proposed a 
new microbiological testing scheme for powdered infant formula. The 
revised testing requirement proposed in the 2006 reopening was confined 
to testing for E. sakazakii and Salmonella ssp. This change was based 
on the findings of the 2006 FAO/WHO Report (Ref. 3) which provided, for 
the first time, a risk assessment model to describe the factors leading 
to E. sakazakii infection in infants and identified potential risk 
mitigation strategies. The 2006 FAO/WHO Report also described a 
microbiological standard sampling plan for E. sakazakii, of negative 
for E. sakazakii in 30 x 10 gram samples from each lot of powdered 
infant formula. The microbiological standard for Salmonella spp. of 
negative in 60 x 25 gram samples is well established and was not 
changed. Details concerning the microbiological testing required for 
powdered infant formula by this interim final rule are discussed in 
section V of this document.
    In proposing to adopt this microbiological standard, FDA also 
proposed that the definition of ``lot'' be modified to be consistent 
with the statistical basis for the proposed microbiological testing 
requirements and the agreed upon international terminology. 
Specifically, FDA stated that the Agency was considering modifying the 
definition of ``lot'' to mean ``a quantity of product, having uniform 
character or quality, within specified limits, or, in the case of an 
infant formula produced by continuous process, it is a specific 
identified amount produced in a unit of time or quantity in a manner 
that assures its having uniform character and quality within specified 
limits'' (71 FR 43392 at 43395).
    Unfortunately, the terms ``batch'' and ``lot'' were used without 
adequate distinction in the 2006 FAO/WHO Report and in the 2006 
reopening. As noted, the 2006 reopening proposed a revised definition 
of ``lot'' (71 FR 43392 at 44395; August 1, 2006.) Under this 
definition, ``lot'' would have been the relatively larger quantity of 
formula, a definition inconsistent with both the

[[Page 7944]]

1996 proposal and FDA's drug CGMP definition. Also, at the time of the 
2006 reopening, the Agency did not propose a comparable modification of 
the definition of ``batch.'' As a result of this oversight, the most 
recently proposed definitions for ``lot'' and ``batch'' both refer to 
the relatively larger quantity of infant formula. Elsewhere in the 2006 
reopening notice, the Agency referred to ``batch testing'' of 
microorganisms (71 FR 43392 at 43396), a reference intended to identify 
the relatively larger quantity of formula.
    The confusion surrounding ``lot'' and ``batch'' is further 
illustrated by the comments FDA received on the definitions of 
``batch'' and ``lot'' in response to the 1996 proposal. Specifically, 
comments reflected that these terms are used inconsistently and that 
the terms are not used in the same way in formula manufacturing and in 
drug manufacturing. As a result of the foregoing, FDA believes that 
there is significant confusion about the meaning of ``batch'' and 
``lot,'' about the relationship between ``batch'' and ``lot,'' and, 
most significantly, about the quantity of formula under discussion for 
the microbial testing requirements of the interim final rule.
    FDA has considered the need to resolve this confusion as well as 
the importance of clarifying the volume of formula associated with the 
master manufacturing order and the requirements for nutrient and 
microbiological testing and has concluded that the terms ``batch'' and 
``lot'' should be replaced in the interim final rule with two new 
terms, ``production aggregate'' and ``production unit.'' The interim 
final rule defines ``production aggregate'' and ``production unit'' in 
a manner that clarifies the volume of formula and stage of production 
contemplated by each term as well as the relationship between the two 
volumes of formula. In addition, the definitions of the two terms 
reflect changes made in response to comments on ``batch'' and ``lot.'' 
By incorporating ``production unit'' and ``production aggregate'' into 
the interim final rule, however, FDA does not intend to introduce new 
concepts or to make significant changes. Rather, the Agency is using 
new descriptors to clarify the quantity of formula associated with the 
master manufacturing order and with the requirements for 
microbiological and nutrient testing.
    ``Production unit'' represents the individually mixed portion of 
formula and is defined in Sec.  106.3 as ``a specific quantity of an 
infant formula produced during a single cycle of manufacture that has 
uniform composition, character, and quality, within specified limits.'' 
``Production aggregate'' is frequently a co-mingled portion of formula 
composed of one or more production units; it is defined in Sec.  106.3 
as ``a quantity of product, or, in the case of an infant formula 
produced by continuous process, a specific identified amount produced 
in a unit of time, that is intended to have uniform composition, 
character, and quality, within specified limits, and is produced 
according to a master manufacturing order.'' Thus, under this interim 
final rule, as a result of the revision of these definitions and the 
addition of these new terms:
     ``Production aggregate'' represents the relatively larger 
volume of formula and thus, effectively replaces ``batch'' (the 1996 
proposal) and ``lot'' (the 2006 reopening).
     ``Production unit'' represents the relatively smaller 
volume of formula and effectively replaces ``lot'' (the 1996 proposal). 
(The 2006 reopening did not specifically propose a term or definition 
for the relatively smaller volume.)
     A ``production aggregate'' may consist of one or more 
``production units.'' This is consistent with the definition of lot 
proposed in 1996. (``Lot means a batch or a specifically identified 
portion of a batch. . . .'')
     As with ``batch'' (the 1996 proposal) and ``lot'' (the 
2006 reopening), the term ``production aggregate,'' the term 
representing the relatively larger volume of formula, incorporates the 
concept of being produced according to a master manufacturing order.
     The term ``production aggregate'' (Sec.  106.3), which 
refers to the relatively larger volume of formula, is defined both for 
purposes of conventional manufacturing and continuous process 
manufacturing. The comparable term from the 1996 proposal did not 
address the application of the concept to continuous processing.
     As discussed in section V, the requirements for controls 
to prevent adulteration from microorganisms (Sec.  106.55) stipulate 
that testing be conducted on each ``production aggregate'' of formula. 
Imposing the testing requirement on the relatively larger volume of 
formula is consistent with the FAO/WHO report and is also necessitated 
by the formula industry's use of continuous processing, a production 
method that generally does not always result in identifiable smaller 
volumes. Testing the relatively larger volume is consistent with the 
proposed rule (which would have required each ``batch'' to be tested), 
the 2006 reopening (which would have required each ``lot'' to be 
tested), and the language in section 412 (which uses the term ``batch'' 
to mean the relatively larger, often co-mingled portion of formula in 
which individually mixed portions of formula are combined.)
    In the remainder of this preamble, FDA uses the terms ``production 
unit'' and ``production aggregate,'' as appropriate, to minimize 
confusion and misunderstanding.
    (Comment 8) One comment requested that the term ``composition'' be 
added to the definition of ``batch'' in proposed Sec.  106.3, so that 
the definition would read ``uniform composition, character, and 
quality.'' The comment stated that the word ``composition'' adds to the 
accepted concept of the characteristics of a batch.
    (Response) FDA agrees with this comment, and has added the word 
``composition'' to the definition of ``production aggregate'' in Sec.  
106.3. The ordinary meaning of the word ``composition'' is ``a product 
of mixing or combining various elements or ingredients.'' (Ref. 6, 
p.236) A formula with uniform composition will have the various formula 
components evenly distributed throughout the quantity of formula 
manufactured; uniform composition directly contributes to the uniform 
character and quality of a formula, the two other elements in the 
definition of ``production aggregate.''
    (Comment 9) One comment requested that the Agency strike the term 
``single'' from, and substitute the word ``master'' in, the proposed 
definition of ``batch.'' In the proposed definition, ``single'' 
modified ``manufacturing order.'' The comment suggested that modifying 
``manufacturing order'' with the word ``master'' would ensure that in-
process adjustments, undertaken so that the batch meets nutritional 
requirements, would not contravene the definition.
    (Response) FDA does not disagree with this comment and thus, has 
replaced the term ``single'' with ``master'' to describe a 
manufacturing order. ``Master manufacturing order'' is a term commonly 
used in the infant formula industry and is used to describe the 
``recipe'' the manufacturer uses to prepare the production aggregate. 
The Agency understands the comment's underlying concern to be that the 
proposed definition, which referred to a ``single manufacturing 
order,'' could be interpreted to mean that a manufacturer is precluded 
from making in-process adjustments in what this interim final rule 
refers to as the ``production aggregate'' as defined in Sec.  106.3. 
FDA recognizes that a formula manufacturer may be required to make in-
process adjustments to ensure that established specifications for the 
in-process or final product are met. Given the potential

[[Page 7945]]

confusion, FDA is making the change requested in this comment.
    (Comment 10) One comment stated that the meaning of the phrase ``or 
other material'' in the proposed definition of batch was unclear and 
recommended that it be removed.
    (Response) FDA agrees that the phrase ``or other material'' is not 
clear. Also, this phrase is not necessary and thus, it is being deleted 
from the definition of ``production aggregate'' in Sec.  106.3.
    (Comment 11) A comment requested that FDA delete the phrase 
``within specified limits'' from the definition of ``batch'' asserting 
that the phrase creates a substantive requirement that could cause 
confusion. The comment also claimed that manufacturers determine some 
of the specifications related to the disposition of a batch on a case-
by-case basis. The comment further stated that manufacturers have not 
identified every outer limit for every process and product parameter 
that would result in rejection and determination of these limits would 
require an overwhelming amount of technical and administrative 
resources.
    (Response) FDA disagrees that the phrase ``within specified 
limits'' creates a substantive requirement for the identification of 
every outer limit for every process and product parameter that would 
result in product rejection. The purpose of the ``within specified 
limits'' language in this definition is to ensure that the manufactured 
infant formula is what the manufacturer intends, and reflects both 
customary practice in the formula industry as well as the requirements 
in Sec.  106.6(c)(1) to establish specifications. The manufacturer 
establishes specifications for each production aggregate of formula, 
which ensures that the manufactured formula meets the nutrient 
requirements and applicable microbial contamination standards. Thus, 
the term ``within specified limits'' ensures that a production 
aggregate has the uniform composition, character, and quality intended.
    As noted, the comment also requested deletion of ``within specified 
limits'' because, the comment asserted, specifications are established 
on a case-by-case basis. FDA disagrees with this justification because 
manufacturers should not be determining specifications on a case-by-
case basis during production of a formula, as the comment seems to 
suggest. It is crucial that a manufacturer establish appropriate 
specifications at any point, step, or stage where control is necessary 
to prevent adulteration prior to manufacturing formula so that the 
manufacturer can ensure that its process is under control and is able 
to produce what is intended. Failure to meet predetermined 
specifications, or failure to perform necessary in-process adjustments 
to ensure such specifications are met, suggests that the manufacturing 
process is not adequately controlled to prevent adulteration.
    For all of the foregoing reasons, the Agency declines to delete the 
phrase ``within specified limits'' and is retaining such phrase in the 
definition of ``production aggregate'' in Sec.  106.3.
    (Comment 12) FDA received comments on the definition of ``lot'' (as 
proposed in 1996) that were similar to comments on the definition of 
``batch.'' In particular, these comments suggested removing the phrase 
``within specified limits'' from the definition of ``lot,'' and also 
recommended that the definition of ``lot'' include the term 
``composition.'' The comments also requested that the definition of 
``lot'' be clarified in terms of production of infant formula by 
continuous process.
    (Response) As explained previously in this document, the concepts 
of ``production aggregate'' and ``production unit'' are closely related 
and thus, the definitions of these terms should be consistent with one 
another. Accordingly, FDA agrees that the term ``composition'' should 
be added to the definition of ``production unit.'' In addition, in 
continuous processing manufacture, each production unit needs to have 
uniform composition, which will help to ensure that the composition of 
the production aggregate will be uniform and within the specified 
limits. Accordingly, for the reasons stated in the responses to comment 
11, FDA has also added the term ``composition'' to the definition of 
``production unit'' in Sec.  106.3.
    Similarly, for the reasons stated in the response to comment 11, 
FDA is also retaining the phrase ``within specified limits'' in the 
definition of ``production unit'' in Sec.  106.3.
    Finally, the definition of ``production aggregate'' refers to the 
production of infant formula by continuous process. FDA recognizes that 
a single production unit may also be a production aggregate where, for 
example, only smaller volumes of infant formula are produced.
    (Comment 13) One comment stated that the phrase ``or other 
material'' is more appropriate in the definition of ``lot'' than in the 
definition of ``batch'' because the definition of ``lot'' ``encompasses 
raw material lots better than does the definition of batch'.''
    (Response) FDA disagrees with this comment. The comment is a 
reflection of the problem resulting from the variety of ways in which 
the term ``lot'' is used in manufacturing and also was used in the 
earlier stages of this rulemaking. The concept of ``lots'' of raw 
materials is separate from the concept of ``lot,'' which was used in 
the 1996 proposed rule, and ``production unit,'' which is the term used 
in this interim final rule and is defined in Sec.  106.3. The addition 
of the phrase ``or other material'' to the definition of production 
unit is not appropriate because the production unit does not refer to 
``lots'' of raw materials. Therefore, FDA has not added the phrase ``or 
other material'' to the definition for ``production unit'' in Sec.  
106.3.
    As a result of establishing the new terms ``production aggregate'' 
and ``production unit'' and their definitions, FDA is also making 
technical revisions to two related definitions that the Agency proposed 
in 1996. First, FDA is revising proposed Sec.  106.3(f), the definition 
of ``in-process batch'' and codifying the new term and definition in 
Sec.  106.3 of the interim final rule as follows: ``In-process 
production aggregate means a combination of ingredients at any point in 
the manufacturing process before packaging.'' Similarly, the Agency is 
revising proposed Sec.  106.3(h), the definition of ``lot number, 
control number, batch number,'' and codifying the new term and 
definition in Sec.  106.3 of the interim final rule as follows: 
``Production unit number or production aggregate number means any 
distinctive combination of letters, numbers, symbols, or any 
combination of them, from which the complete history of the 
manufacture, processing, packing, holding, and distribution of a 
production aggregate or a production unit of infant formula can be 
determined.''
2. Major Change (Proposed Sec.  106.3(i))
    The proposed rule defined ``major change in an infant formula'' to 
mean ``any new formulation, or any change of ingredients or processes 
where experience or theory would predict a possible significant adverse 
impact on levels of nutrients or bioavailability \2\ of

[[Page 7946]]

nutrients, or any change that causes an infant formula to differ 
fundamentally in processing or in composition from any previous 
formulation produced by the manufacturer.'' The proposed definition 
provided seven examples of changes resulting in an infant formula that 
would be deemed to differ ``fundamentally in processing or in 
composition.''
---------------------------------------------------------------------------

    \2\ For the purposes of this interim final rule, 
``bioavailability'' (the noun) refers to the degree to which a 
nutrient is absorbed or otherwise becomes available to the body. 
Bioavailability may affect the choice of an ingredient; for example, 
vegetable oil has been substituted for butterfat in infant formulas 
because the latter is not well absorbed by infants. Bioavailability 
may also affect the amount of a substance that must be added to a 
product to ensure adequate delivery of the substance; for example, 
soy-based formula must contain relatively more calcium than a cow 
milk formula because the phytate (a phosphorus compound in soy) 
interferes with the absorption of calcium. ``Bioavailable'' is an 
adjectival form of ``bioavailability.''
---------------------------------------------------------------------------

    (Comment 14) One comment agreed with the proposed definition of 
``major change'' in proposed Sec.  106.3(i) but suggested revised 
language for the example in proposed Sec.  106.3(i)(5). The comment 
suggested that the phrase ``containing a new constituent'' in proposed 
Sec.  106.3(i)(5) should be changed to ``containing a new nutrient'' 
because, the comment asserted, the purpose of the Infant Formula Act is 
to ensure proper nutrition and the term ``nutrient'' is more consistent 
with that purpose. The comment asserted that the term ``constituent'' 
is overbroad, that its use could result in designating as a major 
change the addition of a wholly innocuous new constituent added at 
nominal levels, and that such a result is beyond the basic scope of 
section 412 of the FD&C Act. The comment further argued that this 
interpretation would require formula manufacturers to submit 90 day 
notifications for each of these constituents, which would require both 
the manufacturer and FDA to expend additional resources with no added 
benefit to the consumer.
    (Response) FDA disagrees with this comment and, for two reasons, 
declines to make the suggested revision to the definition of ``major 
change'' in Sec.  106.3 of the interim final rule. First, the use of 
the term ``constituent'' is required by the applicable statute. The 
definition of ``major change'' in proposed Sec.  106.3(i) was based on 
the directive in section 412(c)(2) of the FD&C Act, which states that 
``the term `major change' '' has the meaning given to such term in 
Sec.  106.30(c)(2) of title 21, Code of Federal Regulations (as in 
effect on August 1, 1986), and guidelines issued thereunder.'' The 
guidelines referred to in section 412(c)(2) of the FD&C Act are the 
Guidelines Concerning Notification and Testing of Infant Formulas 
(``the Guidelines'') (Ref. 7). The Guidelines list seven examples of 
changes that cause an infant formula ``to differ fundamentally in 
processing or in composition from any previous formulation produced by 
the manufacturer.'' Accordingly, in proposed Sec.  106.3(i), FDA listed 
the seven examples set out in the Guidelines, including, in proposed 
Sec.  106.3(i)(5), ``Any infant formula manufactured containing a new 
constituent not listed in section 412(i) of the FD&C Act, such as 
taurine or L-carnitine.'' Thus, the language in proposed Sec.  
106.3(i)(5) was drawn directly from the definitional source identified 
in the applicable statute.
    Second, sound policy reasons support use of the term 
``constituent'' in the definition of ``major change'' in Sec.  106.3. 
Constituents other than the nutrients listed in section 412(i) of the 
FD&C Act (``required nutrients'') are added to infant formula (e.g., 
intentionally added microorganisms), and a new constituent other than a 
required nutrient could potentially affect the bioavailability of a 
formula and such nutrients. The Guidelines recognize, and the 
definition of ``major change'' incorporates the recognition, that a new 
constituent other than a required nutrient can potentially affect the 
bioavailability of nutrients in the formula and the formula as a whole. 
Thus, from the standpoint of ensuring the bioavailability of the 
formula matrix as a whole, in addition to the bioavailability of 
individual required nutrients, use of the term ``constituent'' in the 
definition of ``major change'' is appropriate as a matter of policy. 
Therefore, FDA is not revising the definition of ``major change'' in 
response to this comment.
    (Comment 15) Another comment suggested that the conjunction ``and'' 
after proposed Sec.  106.3(i)(6) be changed to ``or.'' The comment 
argued that this revision is appropriate because each of the examples 
in this section is intended to stand alone and, although more than one 
example could be applicable in a given situation, all seven are 
unlikely to occur at the same time.
    (Response) The Agency agrees with this comment. Proposed Sec.  
106.3(i) includes a list of examples of infant formulas, each of which 
differs fundamentally in processing or in composition and thus, each is 
a separate example of a ``major change in an infant formula.'' 
Accordingly, FDA is revising proposed Sec.  106.3(i) by changing the 
conjunction ``and'' to ``or'' before the last example in the definition 
of ``major change'' in Sec.  106.3.
    On its own initiative FDA is removing the words ``for commercial or 
charitable distribution'' from proposed Sec.  106.3(i)(2). This change 
is consistent with the definition of ``manufacturer'' as discussed in 
this document, in which the Agency declined to include the phrase ``for 
commercial or charitable distribution.''
3. Manufacturer (Proposed Sec.  106.3(j))
    The proposed rule (Sec.  106.3(j)) defined ``manufacturer'' as ``a 
person who prepares, reconstitutes, or otherwise changes the physical 
or chemical characteristics of an infant formula or packages or labels 
the product in a container for distribution.''
    (Comment 16) One comment suggested that the definition of 
``manufacturer'' be revised so that ``manufacturer'' means ``a person 
who prepares, reconstitutes, or otherwise changes the physical or 
chemical characteristics of an infant formula or packages or labels the 
product in a container for commercial or charitable distribution 
(emphasis added)'' and asserted that, by including the phrase 
``commercial or charitable,'' parents, child care providers, hospitals, 
and other institutions who prepare formula for infants under their 
direct care would not be considered a ``manufacturer.''
    (Response) FDA believes that this comment raises an important issue 
about the breadth of the proposed definition of ``manufacturer.'' The 
Agency disagrees, however, that including the phrase ``commercial or 
charitable'' as a modifier of the word ``distribution'' would 
sufficiently clarify that those who prepare infant formula for infants 
under their direct care are not ``manufacturers.''
    The Agency recognizes that there are several groups of persons who 
reconstitute powdered or concentrated liquid infant formula or 
otherwise mix formula and provide that formula to an infant for whom 
these persons are providing direct care. These persons include parents, 
daycare providers and other caregivers, and nurses and other healthcare 
personnel. In addition, in some healthcare settings, there is a 
designated institutional unit that performs the formula mixing in place 
of a nurse or other healthcare provider, such as a hospital formula 
room; these staff mix or reconstitute formula for infants under the 
direct care of the hospital or healthcare institution. Whether the 
reconstitution is done by an individual, such as a daycare provider or 
staff in a hospital formula room, the preparation of the infant formula 
is an extension of the care-giving function. FDA does not believe that 
Congress intended that a person who or institution that mixes formula 
for a child as an extension of the care-giving function be considered a 
``manufacturer'' subject to the requirements established under section 
412. Instead, the provisions of section 412 are intended to regulate 
entities that prepare or reconstitute formula for further distribution 
because a manufacturing error by one of these entities has greater 
potential to cause harm by virtue of the broad distribution of its 
products. Also, the activities of a

[[Page 7947]]

hospital formula room or comparable unit are subject to the oversight 
and standards of the hospital or other institution of which it is a 
part. Moreover, as a policy matter, FDA does not believe that it is 
appropriate to interfere with these care-giving relationships by 
requiring a person who mixes formula for an infant under his/her direct 
care to adhere to the types of controls the Agency is establishing in 
this interim final rule.
    FDA affirms, however, that a person or institution that 
reconstitutes formula for subsequent distribution to infants not under 
the direct care of that person or institution is a ``manufacturer'' for 
purposes of the interim final rule. In this situation, the mixing or 
reconstitution and subsequent distribution are separate activities and 
are not simply an extension of the care-giving function.
    Accordingly, FDA is revising proposed Sec.  106.3(j) to clarify 
that the term ``manufacturer'' does not include a person or institution 
employing such person that prepares, reconstitutes, or mixes infant 
formula exclusively for an infant under his/her direct care or the 
direct care of the institution employing such person.
    (Comment 17) One comment suggested that a definition for 
``responsible party'' be added to Sec.  106.3 because the proposed 
definition of ``manufacturer'' would result in overlapping 
responsibilities whenever co-packers are involved in the manufacturing 
of infant formula. This comment suggested defining ``responsible 
party'' as ``the manufacturer of an infant formula when all 
manufacturing steps are performed by a single entity; however, when 
several entities are involved in the manufacture of a given formula, it 
means the manufacturer or other entity that has agreed to assume 
responsibility for ensuring that all requirements for notification and 
assurance under these regulations are satisfied.'' The comment stated 
that for certain requirements, the responsible party would replace the 
manufacturer completely, to avoid duplication and to attribute 
appropriately actual responsibility for other requirements. The comment 
asserted that that duplicate responsibilities for the same activity do 
not serve any purpose in the majority of proposed requirements, and 
therefore, suggested that the concept of ``responsible party'' be 
introduced to eliminate duplication. The comment stated that only for 
``registration'' (see proposed Sec.  106.110) would duplicate 
responsibilities serve FDA's purpose (e.g., for inspections and 
counterfeit formula surveillance).
    (Response) FDA disagrees that a definition for ``responsible 
party'' is needed in the interim final rule because, properly 
understood, the interim final rule will require no duplication of 
effort.
    The Agency believes that the comment did not understand the 
responsibilities under the proposed rule. These obligations are of two 
types: The obligation to conduct certain activities according to the 
requirements of the CGMP regulation and the obligation of certain 
persons to ensure that there is compliance with the rule's requirements 
even if such person is not engaged in the specific activities covered 
by the rule.
    In terms of activities, under the interim final rule, any person 
who satisfies the definition of ``manufacturer'' in Sec.  106.3 must 
comply with all the CGMP requirements that cover activities in which 
such person engages. Thus, if a person conducts all the activities 
necessary to produce an infant formula in its final packaged form 
(i.e., prepares, reconstitutes, or otherwise changes the physical or 
chemical characteristics of a formula, packages the formula, and labels 
the product for distribution), that person must comply with all CGMP 
requirements established by this interim final rule.
    FDA recognizes, however, that in the infant formula industry, a 
person may contract with another to perform some portion of the formula 
production process, such as the packaging and labeling phases of 
manufacture, and there is no legal prohibition to such arrangements. To 
the extent that a contractor performs any of the activities identified 
in the definition of manufacturer in Sec.  106.3, the contractor is a 
``manufacturer'' for purposes of those activities under this interim 
final rule. However, where a person (such as a contractor) performs 
only a part of the complete infant formula manufacturing operation, 
that person is obligated to adhere only to the specific parts of the 
CGMP rule that are relevant to such person's activities. For example, 
if an entity has contracted to act as a spray dryer for a powdered 
infant formula, the spray dryer is an infant formula manufacturer under 
Sec.  106.3 and is responsible for complying with the applicable 
sections of subpart B (CGMPs), subpart D (Conduct of Audits), and 
Subpart F (Records and Reports). The specific responsibilities of a 
given contractor would depend on the terms of the contract. For 
example, a contactor whose duties under the contract are limited to 
spray drying infant formula generally would not be responsible for the 
nutrient testing required under subpart C (Quality Control Procedures), 
subpart E (Quality Factors), or subpart G (Registration, Submission, 
and Notification Requirements).
    Importantly, in addition to the obligation to comply with the parts 
of the CGMP rule that apply to the activities of a particular person's 
operation, the entity who causes the infant formula to be introduced 
into interstate commerce in its final form for distribution to 
consumers has an overarching and ultimate responsibility to ensure that 
all phases of the production of that formula are in compliance with the 
final CGMP regulations and that the formula is lawful in all respects. 
Generally, the person who submits the notification required by section 
412(c)(1)(B) of the FD&C Act is the person with this ultimate 
responsibility. (Under section 201(e) of the FD&C Act (21 U.S.C. 
321(e)), ``person'' includes an individual, partnership, corporation, 
or association.) That is, although a firm can contract out certain 
parts of formula production, the firm cannot, by the same token, 
contract out its ultimate responsibility to ensure that the formula 
that such firm places into commerce (or causes to be placed into 
commerce) is not adulterated and is otherwise lawful. See U.S. v. 
Dotterweich, 320 U.S. 277, 284 (1943) (explaining that an offense can 
be committed under the FD&C Act by anyone who has ``a responsible share 
in the furtherance of the transaction which the statute outlaws''); 
United States v. Park, 421 U.S. 658, 672 (1975) (holding that criminal 
liability under the FD&C Act does not turn on awareness of wrongdoing, 
and that ``agents vested with the responsibility, and power 
commensurate with that responsibility, to devise whatever measures are 
necessary to ensure compliance with the Act'' can be held accountable 
for violations of the FD&C Act). This overarching responsibility flows 
from the FD&C Act's structure. In particular, the FD&C Act prohibits a 
person from introducing or delivering for introduction, or causing the 
delivery or introduction, into interstate commerce an adulterated 
infant formula, 21 U.S.C. 350a(a) and 331(a). Thus, the firm that 
causes an infant formula to be introduced into interstate commerce is 
responsible for ensuring that such formula complies with all the 
requirements under section 412 of the FD&C Act and the interim final 
rule and thus, is not adulterated, regardless of

[[Page 7948]]

who actually carries out the activities covered by the rule.
    In terms of an infant formula firm's obligations relating to the 
use of contractors, FDA notes, as discussed in section X.B, that under 
Sec.  106.110(b)(4), the manufacturer of a new infant formula must 
register with FDA and the registration must list all establishments at 
which the manufacturer intends to manufacture the new formula. FDA 
advises that the list of establishments required by Sec.  106.110(b)(4) 
must include the establishments of all contractors involved in the 
production of the new formula.
4. Microorganisms (Proposed Sec.  106.3(k))
    The proposed rule defined ``microorganisms'' to mean ``yeasts, 
molds, bacteria, and viruses and includes, but is not limited to, 
species having public health significance.''
    (Comment 18) One comment stated that this definition of 
``microorganisms'' is identical to the definition in the food CGMPs (21 
CFR 110.3(i)), which are also applicable to the manufacture of infant 
formulas. Thus, the comment asserted, the definition of 
``microorganism'' should be deleted as it represents a redundancy.
    (Response) The Agency disagrees with this comment. As discussed 
earlier in this preamble, Congress specifically mandated in section 
412(b)(2)(A) of the FD&C Act that the Secretary (and by delegation, 
FDA) establish regulations for ``good manufacturing practices for 
infant formulas, including quality control procedures that the 
Secretary determines are necessary'' to assure that an infant formula 
provides nutrients in accordance with the FD&C Act and is 
``manufactured in a manner designed to prevent adulteration of the 
infant formula.'' Section 412(a)(3) of the FD&C Act provides that an 
infant formula is deemed to be adulterated if the ``processing of such 
infant formula is not in compliance with the good manufacturing 
practices and the quality control procedures prescribed by the 
Secretary'' under section 412(b)(2) of the FD&C Act. FDA is 
establishing a definition of ``microorganisms'' in this interim final 
rule for use with the specific requirements related to such term that 
have been issued under section 412 of the FD&C Act. Therefore, FDA is 
not deleting proposed Sec.  106.3(k) in response to this comment, and 
the definition of ``microorganisms'' is included in Sec.  106.3.
5. New Infant Formula (Proposed Sec.  106.3(l))
    The proposed rule defined ``new infant formula'' to mean ``(1) An 
infant formula manufactured by a person that has not previously 
manufactured an infant formula for the U.S. market, and (2) An infant 
formula manufactured by a person that has previously manufactured 
infant formula and in which there is a major change in processing or 
formulation from a current or any previous formulation produced by such 
manufacturer.''
    (Comment 19) One comment suggested that the definition of ``new 
infant formula'' in proposed Sec.  106.3(l) be changed by replacing the 
word ``means'' with the word ``includes.'' The comment stated that this 
change would make the definition consistent with the FD&C Act and would 
allow for situations not described in this definition. In addition, the 
comment suggested removing the phrase ``for the U.S. market'' from the 
first part of this definition in proposed Sec.  106.3(l). The comment 
argued that the phrase ``for the U.S. market'' does not appear in the 
FD&C Act's definition of new infant formula. Also, the comment asserted 
that, for purposes of proposed Sec.  106.110 (New infant formula 
registration), the phrase would exclude from the definition of ``new 
infant formula'' formulas intended for export only.
    (Response) FDA disagrees with the comment that the term ``means'' 
should be replaced with the term ``includes'' in the definition of 
``new infant formula.'' Although the language in section 412(c)(2) of 
the FD&C Act allows for situations not described in the definition of 
``new infant formula,'' the definition of ``new infant formula'' in 
this rule is limited to the situations described in the definition. An 
infant formula manufacturer must determine whether its formula is a 
``new infant formula'' in order to comply with FD&C Act and its 
implementing regulations. A precise definition of ``new infant 
formula'' will provide these manufacturers with clarity in this area. 
Therefore, FDA is not revising proposed Sec.  106.3(l) to incorporate 
this change.
    However, FDA is removing the phrase ``for the U.S. market,'' from 
the first clause of the definition of ``new infant formula'' as 
suggested in the comment. As the comment suggests, the definition of 
``new infant formula'' in the proposed rule could be interpreted to 
exclude formulas for export only from certain requirements under the 
FD&C Act, e.g. the registration requirements under section 412(c) of 
the FD&C Act. Therefore, FDA is revising proposed Sec.  106.3(l) to 
remove the phrase ``for the U.S. market'' from the first clause of such 
definition.
    In addition, FDA recognizes that a definition of ``new infant 
formula'' without the phrase ``for the U.S. market'' in the first 
clause of the definition could be interpreted to permit a manufacturer 
who has been manufacturing and marketing formula abroad to market the 
same formula that they have been marketing abroad in the United States 
without registering with FDA under section 412(c) of the FD&C Act or 
making a submission under section 412(d) of the FD&C Act, provided that 
the manufacturer made no ``major change'' to the formula. This is 
because the formula would not be a ``formula manufactured by a person 
that has not previously manufactured an infant formula'' in the 
proposed definition of ``new infant formula.'' Even without the removal 
of the phrase ``for the U.S. market'' from the proposed definition, 
such definition could be interpreted to permit certain manufacturers 
who are marketing infant formula abroad to market that formula in the 
United States without making a submission under section 412(c) of the 
FD&C Act. For example, a formula could be considered to be excluded 
from the ``new infant formula'' definition if made by a manufacturer 
that has been marketing that formula abroad, but has also previously 
marketed a different formula in the United States. To avoid any 
ambiguity and to ensure that an infant formula that is being marketed 
in the United States for the first time is classified as a ``new infant 
formula,'' FDA is revising the definition of ``new infant formula'' 
(proposed Sec.  106.3(l)) by inserting at the end of the definition 
``or which has not previously been the subject of a submission under 
section 412(c) of the FD&C Act for the U.S. market.'' With the addition 
of this language, any manufacturer that produces a formula that has not 
been the subject of such a submission will be considered a ``new infant 
formula,'' even if that manufacturer has been continuously 
manufacturing and marketing that formula abroad without making a major 
change. In addition, as explained in response to comment 328, this 
change is consistent with the notification requirements for a 
manufacturer of an infant formula for export only. Although a 
manufacturer of infant formula for export only must still submit a 
notification under section 412(c) of the FD&C Act, the formula is not 
for the U.S. market and the submission requirements in this interim 
final rule for such a formula differ from those required for an infant 
formula intended for the U.S. market. Therefore, the addition of the 
phrase ``for the U.S. market'' in the second clause of the definition 
of ``new infant formula''

[[Page 7949]]

makes it clear that the submission described in section 412(c) of the 
FD&C Act is that which is submitted for infant formula marketed in 
domestic commerce.
    Although the phrase ``or which has not previously been the subject 
of a submission under section 412(c) of the FD&C Act for the U.S. 
market'' does not appear in the definition of ``new infant formula'' 
under the FD&C Act, the inclusion of such a phrase in the definition of 
``new infant formula'' is well within FDA's authority. If the FD&C Act 
is silent or ambiguous with respect to the meaning of ``new infant 
formula,'' the Agency may interpret the term based on a reasonable 
construction of the statute. See Chevron U.S.A. Inc. v. Natural 
Resources Defense Council, 467 U.S. 837, 842-843; FDA v. Brown & 
Williamson Tobacco Corp., 529 U.S. 120, 132 (2000). There is ambiguity 
in the definition of ``new infant formula'' under section 412(c)(2) of 
the FD&C Act. As noted previously in this document, the word 
``includes'' in the definition of new infant formula in section 
412(c)(2) of the FD&C Act indicates that the term ``new infant 
formula'' was meant to encompass situations not described in the 
definition. See NORMAN J. SINGER & J.D. SHAMBIE SINGER, 2A SUTHERLAND 
STATUTORY CONSTRUCTION Sec.  47:7 (7th ed. 2009) (explaining that when 
a statutory definition declares what it ``includes,'' it ``conveys the 
conclusion that there are other items includable, though not 
specifically enumerated''). The situations described in the FD&C Act's 
definition of ``new infant formula'' do not encompass, for example, a 
situation where an infant formula manufacturer who has been 
manufacturing and marketing formula abroad decides to market that 
formula in the United States.
    Because the FD&C Act's definition of ``new infant formula'' is 
ambiguous, the Agency may establish a regulation to fill any gaps in 
that definition so long as it is not ``arbitrary, capricious, or 
manifestly contrary to the statute.'' See Chevron, 467 U.S. at 844. 
Adding to the definition of ``new infant formula'' to account for a 
situation where an infant formula manufacturer who has been 
manufacturing and marketing formula abroad decides to market that 
formula in the United States is clearly consistent with the overall 
purpose of the Infant Formula Act. The Infant Formula Act and the 1986 
Amendments were intended to ensure the ``safety and nutrition'' of 
infant formulas. See Public Law 96-359, 94 Stat. 1190, 1190 (1980). 
Without defining ``new infant formula'' as described previously in this 
document, however, FDA would not be able to ensure the safety and 
nutrition of all infant formulas imported into the United States, 
because a firm that had already been manufacturing and marketing a 
formula abroad would not need to register with FDA or make a submission 
to FDA demonstrating compliance with the applicable U.S. laws.
6. Nutrient (Proposed Sec.  106.3(m))
    The proposed rule defined ``nutrient'' to mean ``any vitamin, 
mineral, or other substance or ingredient that is required in 
accordance with the table set out in section 412(i)(1) of the FD&C Act 
or by regulations issued under section 412(i)(2) or that is identified 
as essential for infants by the Food and Nutrition Board of the 
National Research Counsel through its development of a Recommended 
Dietary Allowance or an Estimated Safe and Adequate Daily Dietary 
Intake range, or that has been identified as essential for infants by 
the Food and Drug Administration through a Federal Register 
publication.''
    (Comment 20) One comment suggested limiting the definition of 
``nutrient'' to ``any vitamin, mineral, or other substance or 
ingredient in infant formula that is required by the act or by 
regulations issued pursuant to the act.'' The comment asserted that the 
intent of the proposed definition is to describe the ways in which 
nutrients can be added to the list of those already required in Sec.  
107.100. The comment stated that it interpreted both the proposed 
language and the suggested revision as applying to ``essential'' 
nutrients, and not to other potential or current ingredients in infant 
formula. On this basis, the comment stated that the regulations should 
not create restrictions on the ability of a manufacturer to include new 
ingredients that are in compliance with existing regulations, nor 
should the regulations affect substances that are being added currently 
in compliance with existing regulations.
    (Response) The proposed definition of ``nutrient'' included ``any 
vitamin or mineral'' or ``other substance or ingredient'' that is (1) 
Required in accordance with the table in section 412(i)(1) of the FD&C 
Act; (2) required by FDA under section 412(i)(2) of the FD&C Act; or 
(3) identified as ``essential'' consistent with the regulations in 
Sec.  107.10(b)(5). FDA believes that the comment confuses the 
declaration of ``required nutrients'' and the declaration of 
``essential nutrients,'' with the use of ``other substances or 
ingredients'' that a manufacturer may add when producing an infant 
formula that are not declared as either ``required'' or ``essential'' 
nutrients. Thus, the Agency provides the following clarification.
    The definition of ``nutrient'' in proposed Sec.  106.3(m) included 
not only vitamins and minerals that may be considered required or 
essential nutrients, but includes the potential for another ``substance 
or ingredient'' that is not a vitamin or mineral to be a required or 
essential nutrient. In the preamble to the 1996 proposal, the Agency 
stated that ``nutrients that are required to be in infant formula under 
Sec.  107.100 will be referred to as 'required nutrients'''(61 FR 36154 
at 36155). Such nutrients include those listed in the table in section 
412(i) of the FD&C Act and those that FDA may require, if FDA revises 
such table by regulation. Importantly, there are currently several 
vitamins and minerals (i.e., selenium, chromium, and molybdenum) that 
are considered ``essential'' nutrients (not ``required'' nutrients) 
based on one of the following: (1) Identified as essential by NAS 
through its development of a recommended dietary allowance or an 
estimated safe and adequate daily dietary intake range; (2) identified 
as essential by the FDA through a Federal Register publication; or (3) 
identified as essential under the 10th edition of the Food and 
Nutrition Board's Recommended Dietary Allowances (RDA), 21 CFR 
107.10(b)(5). Under the proposed definition of ``nutrient,'' a vitamin, 
or mineral, or other substance or ingredient that is ``essential'' may 
be declared on the infant formula label when provided at a level 
considered in the publications as having biological significance, when 
this level is known (Sec.  107.10(b)(5)(ii)). Section 107.10(b)(5) 
limits the label declaration of vitamins and minerals added to in an 
infant formula that are not otherwise required to those that are 
``essential.'' Thus, FDA included, in the proposed definition of 
``nutrient,'' those substances ``determined to be essential by the Food 
and Nutrition Board of the National Research Council or by the FDA'' to 
be consistent with Sec.  107.10(b)(5) on labeling information (61 FR 
36154 at 36157). In the preamble to the final rule implementing section 
Sec.  107.10(b)(5), FDA stated that the ``declaration of nutrients that 
are not required by the Infant Formula Act, not considered to be 
essential by the NAS or FDA, and not at levels considered to have 
biological significance is considered to be a misbranding violation 
under section 403(a)(1) of the FD&C Act . . . because including such 
nutrients in the nutrient table or declaring a nutrient at a level

[[Page 7950]]

that may not have biological significance implies a level of 
significance or usefulness in human nutrition that has not been 
established'' (50 FR 1833 at 1836 (January 14, 1985)). Therefore, under 
the proposed definition of ``nutrient,'' any vitamin, mineral, and 
other substance or ingredient that is not a ``required nutrient'' or an 
``essential nutrient,'' as those terms are used in Sec.  107.10, cannot 
be part of the nutrient declaration of an infant formula. Ingredients 
that may be considered ``nutrients'' but that are not ``required 
nutrients'' or ``essential nutrients'' may be added to infant formula 
provided that the use of the specific chemical form of the ingredient 
is in accordance with the 'Agency's food additive regulations, is 
generally recognized as safe (GRAS), or is authorized by a prior 
sanction. Thus, for these reasons, limiting the definition of 
``nutrient'' to include only substances required under section 412(i) 
of the FD&C Act, or regulations issued under such section is not 
warranted. Accordingly, FDA is not changing the definition for 
``nutrient'' in proposed Sec.  106.3(m) in response to this comment.
    (Comment 21) One comment questioned FDA's authority to ``sub-
delegate'' to the Food and Nutrition Board of the National Research 
Council the 'Agency's authority to establish required nutrients and 
levels for infant formulas.
    (Response) The comment asserting that the Agency is ``sub-
delegating'' its responsibility for establishing required nutrients and 
levels for infant formulas is beyond the scope of this rulemaking 
because current Sec.  107.10(b)(5) establishes the role of the NAS in 
designating nutrients essential for infants, and the Food and Nutrition 
Board is a part of NAS. FDA notes that the NAS Food and Nutrition Board 
is now part of the IOM and that the Food and Nutrition Board has 
replaced ``Recommended Dietary Allowances'' and ``Estimated Safe and 
Adequate Dietary Intake Range'' with ``Dietary Reference Intakes'' 
(Ref. 8). Thus, the Agency is making technical changes to the 
definition of ``nutrient'' in Sec.  106.3 of the interim final rule so 
that ``Institute of Medicine'' replaces ``National Research Council'' 
and ``Dietary Reference Intake (DRI)'' replaces ``Recommended Dietary 
Allowance'' and ``Estimated Safe and Adequate Daily Dietary Intake 
range.''
    Because these same out-of-date references are currently used in 
Sec.  107.10(b)(5), FDA is also making technical revisions to that 
regulation that identify the role of the Food and Nutrition Board of 
the IOM for identifying essential nutrients, and that replace 
``recommended dietary allowance'' and ``estimated safe and adequate 
daily dietary intake range'' with ``Dietary Reference Intake.''
    (Comment 22) One comment requested that the Agency clarify what is 
meant by the phrase ``has been identified as essential for infants by 
the Food and Drug Administration through a Federal Register 
publication,'' and questioned whether nutrients could be identified as 
essential in Federal Register publications that do not constitute 
rulemaking. The comment recommended broadening the definition to 
encompass all FDA rulemaking activities related to infant formula and 
eliminating the last part of the proposed definition (i.e., deleting 
``through a Federal Register publication'').
    (Response) With respect to whether nutrients may be identified as 
essential in Federal Register publications that do not constitute 
rulemaking, this comment is beyond the scope of this rulemaking because 
the process for establishing a nutrient as ``essential'' is set out in 
Sec.  107.10(b)(5) of FDA's regulations. FDA advises that the Agency 
will consider, on a case-by-case basis, the administrative process, 
including Federal Register publication, needed to identify a nutrient 
as ``essential.'' FDA declines to broaden the definition as requested 
by the comment.
7. Quality Factors (Proposed Sec.  106.3(o)) and Requirements for 
Quality Factors (Proposed Sec.  106.96)
    In this portion of the preamble, FDA addresses comments regarding 
the definition of ``quality factors'' in proposed Sec.  106.3(o). 
Because the requirements for quality factors identified in proposed 
Sec.  106.96 are related to the definition of ``quality factors'' in 
proposed Sec.  106.3(o), this portion of the preamble also addresses 
certain comments on proposed Sec.  106.96 that are related to comments 
received on the definition of quality factors.
    The proposed rule defined ``quality factors'' as ``those factors 
necessary to demonstrate that the infant formula, as prepared for 
market, provides nutrients in a form that is bioavailable and safe as 
shown by evidence that demonstrates that the formula supports healthy 
growth when fed as a sole source of nutrition.''
    (Comment 23) Several comments expressed confusion about the role of 
``healthy growth'' as a quality factor compared to a quality factor of 
``normal physical growth.'' ``Normal physical growth'' was identified 
as a quality factor in proposed Sec.  106.96(b).
    (Response) In the 1996 proposal, FDA did not intend to establish 
``healthy growth'' as an individual or separate quality factor 
requirement. Rather, the proposed rule used the broad concept of 
``healthy growth'' to describe what would be achieved when the 
requirements for all quality factors are met. The Agency noted in the 
proposed rule (61 FR 36154 at 36179) that ``healthy growth'' 
encompasses ``all aspects of physical growth and normal maturational 
development, including maturation of organ systems and achievement of 
normal functional development of motor, neurocognitive, and immune 
systems. All of these growth and maturational processes are major 
determinants of an infant's ability to achieve his/her biological 
potential, and all can be affected by the nutritional status of an 
infant.'' Thus, in the 1996 proposal, FDA recognized that the 
nutritional status of an infant can affect the growth and developmental 
process contemplated by the concept of ``healthy growth.'' Currently, 
well-established reference data derived using non-invasive procedures 
are not available to characterize body composition of infants, and 
methods for establishing the requirements for other quality factors 
discussed in the proposed rule that contribute to ``healthy growth'' 
are not available or are impracticable. For this reason, FDA did not 
propose, and is not establishing in this interim final rule, 
requirements for quality factors other than normal physical growth and 
sufficient biological quality of protein. However, as new methodology 
and appropriate reference criteria become available, FDA will consider 
amending this regulation by identifying additional quality factors and 
establishing appropriate requirements to meet the additional quality 
factors.
    (Comment 24) Several comments also expressed confusion about the 
need for quality factors for individual infant formula nutrients as 
well as for the formula as a whole.
    (Response) As explained in section VIII.A, the 1986 Amendments 
revised section 412(b)(1) of the FD&C Act by extending the requirements 
for quality factors to the infant formula as a whole as well to the 
nutrients required by section 412(i) of the FD&C Act (21 U.S.C. 
350a(i)). Thus, by law, FDA must establish requirements for individual 
nutrient quality factors and the formula as a whole to the extent 
possible consistent with current scientific knowledge. To alleviate 
confusion about ``healthy growth'' and ``quality factors,'' and to 
clarify that quality factors apply both to the formula matrix and to 
the

[[Page 7951]]

individual required nutrients, FDA has revised the definition of 
``quality factors.'' Thus, in the interim final rule, ``quality 
factors'' is defined as follows: ``Quality factors means those factors 
necessary to demonstrate the bioavailability and safety of the infant 
formula, as prepared for market and when fed as a sole source of 
nutrition, including the bioavailability of individual nutrients in the 
formula, to ensure healthy growth of infants.''
    In addition to revising the definition of ``quality factors,'' FDA 
is revising the section of the proposed regulation specifying the 
minimum quality factors for infant formulas to clarify the relationship 
between ``healthy growth'' and ``normal physical growth.'' Proposed 
Sec.  106.96 addressed the quality factors for infant formula and 
stated in part: ``All infant formulas shall . . . be of sufficient 
quality to meet the nutritional requirements for healthy growth.'' The 
proposed rule appears to have created some confusion about how to 
comply with such a requirement and how this provision differs from the 
requirements that infant formula be capable of supporting normal 
physical growth and be formulated and manufactured with protein that is 
of sufficient biological quality. A demonstration of ``normal physical 
growth'' is a factor that helps to ensure that the infant formula 
supports ``healthy growth.'' Similarly, a demonstration of sufficient 
biological quality of the protein is a factor that helps to ensure that 
the protein in the infant formula (as opposed the entire formula 
matrix) helps to support healthy growth.
    Consistent with the changes to the definition of ``quality 
factors'' in Sec.  106.3 of the interim final rule, proposed Sec.  
106.96 has been revised by reorganizing Sec.  106.96 to identify the 
two specific quality factors of normal physical growth and sufficient 
biological quality of the protein and to set forth the minimum 
requirements for quality factors for each of the two quality factors. 
Specifically, Sec.  106.96(a) of the interim final rule identifies the 
quality factor of normal physical growth and Sec.  106.96(b) of the 
interim final rule establishes the minimum requirements for that 
quality factor, and Sec.  106.96(e) of the interim final rule 
identifies the quality factor of sufficient biological quality of the 
protein and Sec.  106.96(f) of the interim final rule establishes the 
requirements for this second quality factor. Consistent with FDA's 
original intent, Sec.  106.96 of the interim final rule does not 
identify ``healthy growth'' as a separate quality factor.
    The comments FDA received on the specific quality factor 
requirements of the proposed rule, FDA's responses to those comments, 
and the quality factor requirements as established in this interim 
final rule are addressed in detail in section VIII of this document.
    (Comment 25) One comment requested that FDA delete the reference to 
safety in the definition of ``quality factors'' in proposed Sec.  
106.3(o) to be consistent with the fact that the Infant Formula Act 
does not deal with ``safety'' per se, but rather with nutritional 
adequacy. The comment stated that the omission of a reference to safety 
is consistent with the fact that the FD&C Act ensures safety in many 
ways. Consequently, the comment stated, the additional regulation 
dictated by the Infant Formula Act was only needed to focus on the 
particular reliance of infants on the nutritional aspects of a food 
that might substitute for breast milk as their sole source of 
nutrition.
    (Response) FDA disagrees that the Infant Formula Act, and 
specifically the term ``quality factors,'' does not have aspects 
related to the safety of an infant formula. While it is true that each 
ingredient in infant formula must be approved for use as a food 
additive, be GRAS under the conditions of intended use, or be used in 
accordance with a prior sanction, it is also true that the ingredients 
and the combination of ingredients, i.e., the entire infant formula 
matrix, must be able to support the growth and development of infants. 
The concept of ``bioavailability'' is not separate and distinct from 
the concept of safety. If an infant formula, which is the sole source 
of nutrition for infants, could not support healthy growth of infants, 
FDA would not consider the formula to be safe for use by infants. 
Therefore, FDA disagrees with this comment's request to delete the 
reference to safety in the definition of quality factors and is not 
modifying proposed Sec.  106.3(o) in response to the request.
    (Comment 26) One comment recommended deletion of ``healthy growth'' 
as a quality factor. Another comment requested removal of any reference 
to ``growth'' in the definition of quality factors, asserting that the 
effort to establish ``healthy'' or ``normal'' growth as a quality 
factor is flawed. This comment did not explain the basis for its 
assertion that ``healthy'' or ``normal'' physical growth as a quality 
factor is flawed.
    (Response) As is discussed previously in this document, FDA has 
revised Sec.  106.96 to clarify that ``healthy growth'' is not itself a 
quality factor. Instead, FDA has identified two quality factors, 
``normal physical growth'' and ``sufficient biological quality of 
protein'' and has established in Sec.  106.96 of the interim final rule 
requirements to establish those quality factors. This change has been 
made to clarify that all quality factors in combination help to ensure 
that a formula and the individual nutrients in a formula support 
``healthy growth.'' ``Normal physical growth'' is only one factor that 
helps to ensure healthy growth. As noted previously in this document, 
as science evolves, FDA will consider whether it is appropriate and 
feasible to develop additional quality factors that will help to ensure 
healthy growth and to establish requirements to demonstrate that a 
formula satisfies those additional quality factors.
    FDA disagrees with the comment's claim that the effort to establish 
``normal physical growth'' as a quality factor is flawed. Quality 
factors pertain to the bioavailability of an infant formula and the 
individual nutrients in that formula; demonstrating bioavailability 
helps to ensure that infants will achieve healthy growth when fed the 
formula as a sole source of nutrition. As discussed previously in this 
document, and consistent with the 1996 proposal, FDA considers the 
concept of ``healthy growth'' to be ``broad, encompassing all aspects 
of physical growth and normal maturational development, including 
maturation of organ systems and achievement of normal functional 
development of motor, neurocognitive, and immune systems'' (61 FR 36154 
at 36179). FDA further recognizes that ``all of these growth and 
maturational development processes are major determinants of an 
infant's ability to achieve his/her biological potential, and all can 
be affected by the nutritional status of an infant'' (61 FR 36154 at 
36179). The report of the House Committee on Interstate and Foreign 
Commerce (the 1980 Committee Report) that accompanied the Infant 
Formula Act stated that ``growth of infants during the first few months 
of life is a determining factor for the pattern of development and 
quality of health in adult life'' (Ref. 9). FDA interprets this 
statement as evidence that the Committee recognized the vulnerable 
nature of this period of life and the critical role of diet in 
affecting long-term growth and development during this stage, and that 
healthy growth involves integration of the myriad processes by which an 
infant reaches his/her biological growth potential.
    The concept of ``healthy growth'' in the definition of quality 
factors is not only consistent with the Committee's report, but is also 
consistent with

[[Page 7952]]

discussions of diet and health by several authoritative bodies. For 
example, the preamble to the Constitution of WHO states that ``health 
is a state of complete physical, mental, and social well-being and not 
merely the absence of disease or infirmity'' (http://www.who.int/governance/eb/constitution/en/index.html) (Ref. 10). While FDA's use of 
the term ``healthy growth'' in this regulation does not extend to 
measures of social well-being, it is otherwise consistent with the 
concepts in the WHO definition in that normal development is 
encompassed within the concept of complete physical and mental well-
being. The term ``healthy growth'' is also closely allied with the 
conceptual framework adopted by the Food and Nutrition Board of the 
IOM, which established a comprehensive set of reference values for 
nutrient intakes consistent with the maintenance of good health. For 
example, in revising the dietary reference intakes for the B vitamins, 
the IOM considered risk of developmental abnormalities and chronic 
degenerative disease as well as nutrient functions and their indicators 
(Ref. 8).
    Therefore, FDA is retaining the reference to ``healthy growth'' in 
the definition of ``quality factors'' in Sec.  106.3 of the interim 
final rule, and is retaining normal physical growth as a quality 
factor.
    (Comment 27) One comment agreed with the critical importance of 
ensuring the bioavailability of infant formula and stated that growth 
is clearly an indicator of bioavailability. However, the comment also 
claimed that it would be inappropriate to establish ``healthy growth'' 
or ``normal growth'' as a quality factor and recommended that neither 
be included as a quality factor in proposed Sec.  106.96. The comment 
alleged that there are meaningful scientific weaknesses to establishing 
growth as a quality factor but did not identify those weaknesses.
    The comment also argued that not enough is known about what 
constitutes optimal growth to make it possible to choose the one 
perfect standard against which ``normal'' or ``healthy'' growth should 
be judged and that, as a matter of policy, it would be unwise to depend 
on growth as an outcome. The comment also claimed that focusing on a 
single outcome may cause FDA problems in being even-handed in its 
treatment of manufacturers developing new infant formulas although the 
comment did not explain this assertion.
    (Response) FDA agrees that it would be inappropriate to establish 
``healthy growth'' as an individual quality factor but for reasons 
other than those offered in the comment. As noted previously in this 
document, all quality factors contribute to demonstrating the 
bioavailability and safety of a formula and help to ensure ``healthy 
growth.'' There are many factors that help to ensure ``healthy 
growth,'' one of them being ``normal physical growth'' and another 
being sufficient biological quality of protein. Therefore, because all 
quality factors help to ensure healthy growth, it would be 
inappropriate to establish ``healthy growth'' as a separate and 
distinct quality factor.
    FDA disagrees, however, that it is inappropriate to establish 
``normal physical growth'' as a quality factor. Importantly, FDA does 
not consider ``optimal growth'' to be synonymous with ``normal physical 
growth.'' Demonstrating that a formula supports ``normal physical 
growth'' is a scientifically valid means to contribute to demonstrating 
that the formula (in its entirety) is bioavailable to and safe for the 
infant. Notably, the IOM committee strongly supported studies of normal 
physical growth, recommending ``that growth studies should continue to 
be a centerpiece of clinical evaluation of infant formulas and should 
include precise and reliable measurements of weight and length 
velocity, and head circumference'' (Ref. 4, p. 10).
    Even though there may always be debate in the scientific community 
on what constitutes optimal growth, there is a sufficient knowledge 
base to establish ``normal physical growth'' as a quality factor. It is 
well-established that infants grow steadily and predictably, and there 
are now data to identify what constitutes ``normal physical growth'' 
and how infants should grow. Using worldwide data of how infants grow 
as well as improved statistical procedures, WHO developed new growth 
standards, which are regarded as the most comprehensive standards for 
how infants should grow. The Centers for Disease Control and Prevention 
(CDC) has recommended the use of the WHO growth standards for birth to 
2 years of age since 2009 and CDC's determination was formally 
presented in 2010 (Ref. 11). The 2009 CDC growth charts, based on the 
WHO Child Growth Standards, are available at http://www.cdc.gov/growthcharts/who_charts.htm, and are a valuable clinical tool for both 
health professionals and clinical investigators. The 2009 CDC growth 
charts are incorporated by reference in Sec.  106.160(e) of this 
interim final rule.
    (Comment 28) Several comments addressed the use of ``healthy 
growth'' as a general quality factor (proposed Sec.  106.96(a)). One 
comment stated that it would not be possible to achieve a reasonable 
scientific consensus on what additional functions (in addition to 
anthropometric measurements of physical growth) might constitute 
``healthy growth'' as it is related to nutrition, suggesting that 
``healthy growth'' should not be a quality factor.
    (Response) FDA agrees that ``healthy growth'' should not itself be 
a quality factor and accordingly, the Agency is revising both the 
definition of quality factors in proposed Sec.  106.3(o) and the 
requirements for quality factors in proposed Sec.  106.97 to clarify 
this issue. As noted, ``healthy growth'' is a broad concept, and the 
definition of ``quality factors'' in Sec.  106.3 of the interim final 
rule identifies the achievement of healthy growth as the overall goal 
of all specific quality factors. Importantly, however, FDA has not 
established any requirements for demonstrating ``healthy growth.'' As 
clarified previously in this document, the interim final rule 
identifies two quality factors (``normal physical growth'' and 
``sufficient biological quality of protein'') and establishes 
requirements that relate specifically to those two quality factors. In 
particular, Sec.  106.96(b) of the interim final rule establishes the 
requirements for the quality factor of ``normal physical growth,'' and 
Sec.  106.96(f) of the interim final rule establishes the requirements 
for the quality factor of ``sufficient biological quality of protein.'' 
Meeting the quality factors that are delineated by the Agency, both now 
and in the future, will help to ensure that the individual nutrients in 
an infant formula and the infant formula as a whole support healthy 
growth.
    (Comment 29) Several comments favored requiring normal physical 
growth as a quality factor, and a related comment stated that the only 
practical way of assessing growth is by physical measurement.
    (Response) The Agency agrees with this comment to the extent that 
the comment asserts that the only practical way of measuring normal 
physical growth is by physical measurement. Importantly, it is possible 
that in the future, as science advances, other measures for assessing 
normal physical growth may be identified, and FDA intends to consider 
amending the regulations issued in this interim final rule to 
establish, as appropriate, additional quality factors and associated 
requirements.
    (Comment 30) One comment stated that because of the increasing 
complexity of formula ingredients, it is more relevant to evaluate the 
formula's overall nutrient quality and availability than merely 
assessing selected

[[Page 7953]]

individual nutrients required by the FD&C Act.
    (Response) To the extent this comment asserts that quality factors 
should be established for the complete infant formula, FDA agrees.
    FDA disagrees with the comment, however, to the extent that it 
suggests that evaluation of the formula's overall nutritional quality 
and overall nutrient availability is sufficient or more relevant than 
evaluating the bioavailability of individual nutrients. As explained in 
this document, it is scientifically appropriate to establish quality 
factors both for the complete formula and certain individual formula 
ingredients.
    The 1996 proposal noted that individual nutrient bioavailability is 
especially critical for formula because, for some infants, it serves as 
the sole source of nutrition at a life stage of particular 
vulnerability to harm from nutritional insults (61 FR 36154 at 36179). 
A nutrient is ``bioavailable'' to an infant if it is ``physiologically 
available in sufficient quantities to perform its metabolic 
functions;'' the factors affecting bioavailability are complex and can 
be difficult to predict (61 FR 36154 at 36179). Given the documented 
importance of individual nutrients, it is entirely appropriate that FDA 
consider identifying quality factors for these nutrients.
    Protein is one of the nutrients required to be present in infant 
formula, and the 1996 proposal discussed in detail the complexity of 
protein and its central importance in the infant diet (61 FR 36154 at 
36181). Therefore, at the present time, protein is the only individual 
nutrient for which a quality factor should be established, and thus, 
Sec.  106.96(e) of the interim final rule requires that a formula's 
protein ingredient be of sufficient biological quality. FDA did not 
propose, and is not including in this interim final rule, requirements 
for quality factors for other required nutrients because, for example, 
methods to determine whether such requirements are met are either not 
available, or if available, are impractical because they are invasive, 
technically difficult, or their results cannot be meaningfully 
interpreted.
    A quality factor for the formula's overall nutritional sufficiency 
(i.e., normal physical growth) and a quality factor for the biological 
quality of the formula's protein component (i.e., sufficient biological 
quality) are complementary. Although a growth study can provide an 
assessment of a formula's overall nutritional sufficiency, such a study 
has limitations. In particular, an infant may experience normal 
physical growth in terms of height, weight, and head circumference but 
nevertheless be malnourished because the protein does not contain all 
of the essential amino acids at levels and relative proportions needed 
for healthy growth and development. Said differently, the functional 
outcome from an ingredient, such as protein, may not necessarily be 
immediately reflected by anthropometric measures of physical growth. 
Thus, FDA has concluded that it is scientifically appropriate to 
establish quality factors both for the overall formula and the 
individual formula ingredient, protein. See the discussion in section 
VIII.
    Moreover, section 412(b)(1) of the FD&C Act requires FDA to 
establish, to the extent possible consistent with current scientific 
knowledge, requirements for quality factors for individual ingredients 
and the formula as a whole. Thus, Sec.  106.96 of the interim final 
rule establishes requirements for demonstrating two quality factors: 
normal physical growth and sufficient biological quality of the protein 
ingredient.
    (Comment 31) Several other comments indicated that quality factors 
requirements for infant formulas should demonstrate not only normal 
physical growth but also normal development and health of infants 
during the study period.
    (Response) Physical growth and overall development are both aspects 
of the term ``healthy growth.'' Currently, normal physical growth is a 
readily available method for evaluating the bioavailability of the 
infant formula matrix; however, as science evolves, FDA may add 
additional quality factor requirements that demonstrate that the 
formula ensures that infants achieve healthy growth. The Agency does 
not consider it necessary at this time to include in the four-month 
study period additional quality factors relating to the ``health of 
infants'' or ``normal development,'' nor does the comment explain how 
specifically these additional quality factors would be measured or why 
four months would be a sufficient period of time within which to expect 
measurable changes. Thus, the interim final rule does not identify 
``normal development and health of the infant'' as an additional 
quality factor.
    (Comment 32) One comment agreed with the Agency as to the 
importance of assessing substantive changes in the manufacturing 
process on nutrient bioavailability, but stated that a broad definition 
of growth (healthy growth) would not achieve this objective. Another 
comment requested that FDA put any mention of measurement of 
``healthy'' or ``normal growth'' into a guidance document to identify 
when a clinical demonstration of growth is the most appropriate way to 
demonstrate bioavailability, and that the term ``healthy growth'' be 
changed to ``expected physical growth'' in that guidance. The comment 
also stated that ``expected'' is a more meaningful term and refers to 
the population for whom the formula is intended and can be measured 
objectively.
    (Response) As explained previously in this document, FDA has 
revised proposed Sec.  106.3(o), the definition of ``quality factors,'' 
and is not identifying ``healthy growth'' as an individual quality 
factor in this interim final rule. Further, FDA does not agree that the 
term ``expected physical growth'' should replace the term ``healthy 
growth.'' Unlike the broad concept of ``healthy growth,'' the term 
``expected physical growth'' is too narrow to describe what a 
manufacturer must ensure with respect to the bioavailability and safety 
of the infant formula. The Agency is codifying ``normal physical 
growth'' and ``sufficient biological quality of the protein 
ingredient'' as the two quality factors in this interim final rule. As 
science evolves, FDA will consider amending this regulation by 
identifying additional quality factors.
8. Other Definitions Requested in Comments
    (Comment 33) One comment recommended that the Agency adopt a 
definition of ``minor change,'' and suggested ``any new formulation, or 
any change of ingredients or processes where experience or theory would 
not predict a possible significant adverse impact on nutrient levels or 
nutrient availability. Minor changes may or may not affect whether a 
formula is adulterated under section 412(a) of the FD&C Act; changes 
that affect whether a formula is adulterated under section 412(a) would 
require the manufacturer to notify FDA prior to first processing.'' The 
comment noted that the 1996 proposal did not mention ``minor change,'' 
and claimed that the failure to define ``minor change'' created 
unnecessary confusion. The comment gave several examples of both minor 
changes that would require notification prior to first processing, and 
those that would not require such notification.
    (Response) FDA declines to add a definition for the term ``minor 
change'' because such a definition is unnecessary. Although the comment 
asserts that defining ``minor change'' is needed to dispel confusion, 
the comment does not explain this statement. The pivotal concept for a

[[Page 7954]]

submission required by section 412(d) of the FD&C Act for a new infant 
formula is whether the change is ``major,'' and, in Sec.  106.3, the 
interim final rule includes a definition of ``major change.'' This 
definition of ``major change'' makes clear that only certain changes 
are of a type that require the submission under section 412(d) of the 
FD&C Act; the definition in proposed Sec.  106.3(i) is derived from 
section 412(c)(2)(B) of the FD&C Act, and, the definition of ``major 
change'' in Sec.  106.3 of the interim final rule provides examples of 
changes that would be considered ``major'' because they are changes 
that cause a formula to differ fundamentally in processing or 
composition. Moreover, elsewhere in this preamble, FDA has affirmed 
that not every change to a formula is a ``major change.'' Thus, the 
need for a definition of ``minor change'' has not been established. 
Accordingly, FDA is not persuaded to add a definition for ``minor 
change'' to this interim final rule.
    (Comment 34) A comment suggested adding a definition for the term 
``critical'' in order to limit the scope of ``validation'' (e.g. Sec.  
106.35) to those areas of manufacture that may truly have public health 
significance. The comment suggested that the term ``critical'' be 
defined when describing ``systems or equipment that has been designated 
by the infant formula manufacturer as necessary to control to prevent 
adulteration.'' The comment stated that this definition also emphasizes 
the responsibility of the manufacturer to make a careful determination 
of which areas of the production process may have public health 
significance.
    (Response) FDA is not persuaded to include a definition of 
``critical'' in the interim final rule. Throughout the interim final 
rule, the Agency refers to points, steps, stages, equipment, and 
systems ``where control is necessary to prevent adulteration.'' This is 
the standard in section 412(b)(2)(A), the relevant statutory provision. 
Therefore, it is not appropriate to limit or otherwise modify this 
standard with the term ``critical.'' Accordingly, FDA declines to 
include a definition of ``critical'' in the interim final rule.
    (Comment 35) One comment suggested defining the term 
``specifications.'' The comment stated that FDA should define 
``specifications'' as ``quality control limits or standards for raw 
materials, in-process materials, and finished product, which are 
established by the manufacturer for purposes of controlling quality and 
consistency for infant formula. Failure to meet an established 
specification requires a documented review and material disposition 
decision.'' The comment suggests that in the drug industry, there is 
common acceptance that the term ``specification'' means a predetermined 
value or range for a given parameter, which must be met in order to 
continue the manufacturing process or release the product for 
distribution. Failure to meet a specification triggers special, non-
routine, documented review, not automatic rejection of the product. The 
comment states that this procedure is appropriate because 
specifications, like those in infant formula manufacture, are set well 
within the outer limits that would cause adulteration. In view of this 
definition, the comment suggests deleting the word ``standard'' 
throughout the proposed rule and replacing it with ``specifications.'' 
If FDA opts to define ``specifications'' as the outer acceptability 
limits, the comment strongly recommends that manufacturers be allowed 
to retain the current tighter control range approach and to determine 
whether outer acceptability limits need to be established at each given 
step in the manufacturing process, as opposed to making the 
establishment of outer limits an absolute requirement in every case.
    (Response) FDA agrees that the term ``standards'' does not add 
clarity to the interim final rule because any standard would be 
considered a specification. Thus, the Agency is deleting the term 
``standards'' when used and retaining the term ``specifications.''
    FDA disagrees, however, that the term ``specification'' needs to be 
defined in this interim final rule. The term is commonly used and well-
understood in the context of CGMP. In proposed Sec.  106.6(c), a 
manufacturer would have to establish standards or specifications at any 
point, step, or stage in the production process where control is 
necessary to prevent adulteration. Controls to ensure quality include 
planning processes to determine desired product features or 
characteristics, a system of controls to ensure that the desired 
product will be consistently produced, and making necessary 
improvements to the process (Ref. 12). Manufacturers must plan what 
they intend to produce, institute adequate controls to achieve the 
desired outcome, and ensure that the controls work so that the desired 
outcome is consistently achieved. If the outcome is not consistently 
achieved, one or more corrective actions must be implemented to reach 
the desired outcome.
    This interim final rule embodies the basic concepts of ensuring 
quality through planning, establishing controls, and providing feedback 
to ensure necessary improvements are implemented. An infant formula 
manufacturer must establish controls at all stages of manufacturing to 
ensure that the finished product, as packaged and labeled, meets the 
requirements of the FD&C Act. The controls chosen by a manufacturer may 
include a specific limit (e.g., addition of 60 milligrams (mg) of 
vitamin C) or a range (e.g., product must be held between 35-45 degrees 
F). This interim final rule does not require that a manufacturer set 
specifications at an outer acceptability limit or within a tighter 
control range, as described by the comment. Instead, the manufacturer 
has the flexibility to establish those specifications that are 
necessary to meet the requirements of section 412 of the FD&C Act and 
not adulterate the product under sections 402(a)(1), (a)(2), (a)(3), or 
(a)(4) of the FD&C Act.
    (Comment 36) One comment suggested defining the term ``target 
value.'' The comment also suggests defining the term ``target value'' 
as ``control limits or standards for raw materials, in-process 
materials, and finished product which are established by the 
manufacturer for purposes of targeting the manufacturing process to a 
tight range within broader specifications. Failure to meet an 
established target value shall result in an immediate review and 
adjustment, if necessary, during the manufacturing process. No 
documented review and material disposition is [sic] needed when a 
target value is not met, provided that the established specifications 
are met.'' The comment explained that infant formula manufacturers 
sometimes establish ``target values'' within tight specifications so 
that operators can adjust the process if the target value is exceeded. 
The comment suggested that the term ``target value'' should be not 
defined for purposes of establishing a requirement for them, but, 
instead, to recognize that some infant formula manufacturers use them 
for quality control purposes and to distinguish them from 
specifications because failure to meet a target value should not 
trigger the kind of detailed and documented review prompted by a 
failure to meet specifications.
    (Response) FDA is not persuaded to define the term ``target value'' 
because FDA is not requiring manufacturers to establish target values 
in this interim final rule. Manufacturers who establish ``target 
values'' within their specifications are free to continue this 
practice. Importantly, however, any target value established by a

[[Page 7955]]

manufacturer should be consistent with the manufacturer's 
specifications. FDA agrees that although a failure to meet a 
specification shall prompt a detailed and documented review, such 
review would not be required by the failure to meet a target value that 
does not also serve as a specification.

V. Subpart B--Current Good Manufacturing Practice

    In the 1996 proposed rule, FDA proposed to establish a new subpart 
B in part 106 of title 21 of the CFR to implement section 412(b)(2) of 
the FD&C Act. Section 412(b)(2) of the FD&C Act requires the Secretary 
(and FDA by delegation) to issue regulations to ``establish good 
manufacturing practices for infant formulas, including quality control 
procedures that the Secretary determines are necessary to assure that 
an infant formula provides nutrients in accordance with this subsection 
and subsection (i) and is manufactured in a manner designed to prevent 
adulteration of the infant formula.'' The system proposed by FDA was 
intended to establish a framework in which manufacturing decisions are 
left to the formula manufacturer, but also charges a manufacturer with 
incorporating into its process measures designed to ensure the safety 
and nutritional quality of the formula. The 2003 reopening requested 
comments on all aspects of the 1996 proposal, including proposed 
subpart B. Also, certain provisions of proposed subpart B were the 
subject of FDA's 2006 request for comments.
    FDA received both general comments as well as specific comments on 
proposed subpart B. These comments are summarized in this document 
along with the Agency's responses. In addition to the substantive 
revisions to subpart B noted in this document, FDA is also making minor 
editorial revisions in this subpart.

A. General Comments

    (Comment 37) One comment suggested that the proposed production and 
in-process control system should be called a Hazard Analysis and 
Critical Control Point (HACCP) system because it contains the elements 
of HACCP.
    (Response) The Agency disagrees. In this interim final rule, FDA is 
adopting CGMP requirements for infant formula as mandated by section 
412(b)(2) of the FD&C Act. That statutory provision expressly requires 
that the Secretary establish by regulation good manufacturing practices 
requirements.
    HACCP is a science-based, systematic approach to preventing food 
safety problems through the identification and the assessment of risk 
(likelihood of occurrence and severity), and control of the biological, 
chemical, and physical hazards associated with a particular food 
production process or practice. Application of HACCP requires the food 
producer to develop a plan for the manufacturer's particular production 
process that anticipates food safety hazards and identifies the points 
(critical control points) in such a process where a failure would 
likely result in a hazard being created or allowed to persist.
    HACCP and CGMP share the common goal of a systematic approach to 
food safety. CGMP requires that a manufacturer take all necessary steps 
both to prevent hazards and to ensure that the manufactured product is 
what was established in the manufacturer's specifications. Although 
some requirements of this interim final rule may be consistent with a 
HACCP-based system, this interim final rule establishes CGMP in 
accordance with section 412(b)(2)(A) of the FD&C Act.

B. Current Good Manufacturing Practices (Proposed Sec.  106.5)

    As proposed in 1996, Sec.  106.5(a) stated that the regulations in 
subpart B defined the minimum current good manufacturing practices for 
infant formula and that the provisions of part 113 (21 CFR part 113) 
applied to liquid infant formulas. Under proposed Sec.  106.5(b), the 
failure to comply with any provision of subpart B, or for a liquid 
infant formula, any provision of part 113, would cause the formula to 
be adulterated under section 412(a)(3) of the FD&C Act. The comments 
FDA received on proposed Sec.  106.5 supported the language without 
modification.
    The Agency has recently become aware of an infant formula product 
that satisfies the definition of an ``acidified food'' under Sec.  
114.3(b) (21 CFR 114.3(b)). As an acidified food, this infant formula 
must comply with part 114 (21 CFR part 114). To make Sec.  106.5 a 
comprehensive statement, FDA is, on its own initiative, revising 
proposed Sec.  106.5 to clarify that an infant formula that is an 
acidified food is subject to the requirements of part 114 and that, for 
an infant formula that is an acidified food, the failure to comply with 
any provision of part 114 will cause the formula to be adulterated 
under section 412(a)(3) of the FD&C Act.

C. Production and In-Process Control System (Proposed Sec.  106.6)

    In the 1996 proposal, FDA proposed in Sec.  106.6 to require that 
infant formula manufacturers implement a system of production and in-
process controls designed to ensure that all requirements of subpart B 
are met and that the infant formula is not otherwise adulterated. This 
system would be required to be set out in a written plan extending to 
all stages of processing, from receipt and acceptance of raw materials, 
ingredients, and components, through storage and distribution of 
finished product. For each point at which control is necessary, a 
manufacturer would be required to set specifications, monitor the 
control point, establish a corrective action plan for use when a 
specification is not met, have an individual qualified by education, 
training, or experience evaluate the public health significance of any 
deviation from specifications, and establish recordkeeping procedures.
    The Agency received comments on several aspects of Sec.  106.6, 
which are addressed in this document.
1. Specifications and Failure To Conform to an Established 
Specification
    FDA received comments that addressed ``specifications'' generally 
and did not focus on particular requirements of the proposed rule. 
These comments are relevant to several sections of the proposed rule 
that require a manufacturer to establish, implement, and enforce 
specifications. For purposes of clarity and consistency, FDA addresses 
in this document, in the context of proposed Sec.  106.6, the general 
comments concerning specifications.
    (Comment 38) One comment stated that infant formula manufacturers 
currently establish very tight internal specifications and that, while 
the objective during manufacturing is to produce a product that falls 
within these tight internal specifications, the failure to do so does 
not necessarily mean that the infant formula product is adulterated. 
The comment asserted that a deviation that falls outside the tight 
internal specifications should trigger a formal, documented review and 
a material disposition decision and should not lead to automatic 
rejection of the product. The comment explained that a documented 
review and a material disposition decision is appropriate because 
specifications are customarily well within the outer limits that would 
cause adulteration.
    (Response) The requirement to establish, monitor, and otherwise 
apply specifications was included in several places in the proposed 
rule, including proposed Sec. Sec.  106.6(c), 106.40(d), 106.40(e), and 
106.70. FDA is persuaded by this comment as well as other comments 
received that it is appropriate to make certain revisions to the 
proposed rule's specification requirements.

[[Page 7956]]

    First, FDA is revising proposed Sec.  106.40(d) by removing the 
proposed requirement that an ingredient, container, or closure that 
fails to conform to a specification be automatically rejected for use 
in formula manufacturing and, instead, to provide that such ingredient, 
container, or closure, as well as any affected infant formula, shall be 
subject to a formal, documented review and material disposition 
decision and shall be quarantined pending such review and disposition 
decision. The disposition decision may be to reject the ingredient, 
container, or closure or the affected formula; to reprocess or 
otherwise recondition it; or to approve and release it for use. As 
stated previously in this document, the CGMP procedures in this interim 
final rule are designed to prevent the production of an adulterated 
infant formula. FDA agrees that failure to meet a specification does 
not necessarily mean that the infant formula manufactured using the 
ingredient, container, or closure will be adulterated and thus, the 
ingredient, container, or closure does not need to be automatically 
rejected. Similarly, in such situations, the affected infant formula 
need not be automatically rejected. In order for the revision of Sec.  
106.40(d) to result in adequate public health protection, however, the 
manufacturer must have in place a robust procedure to investigate any 
deviation from its specifications for ingredients, containers, and 
closures so that the manufacturer can credibly determine whether the 
deviation from specifications could result in adulteration of infant 
formula. Such procedure must consist of a documented review of the 
deviation from a specification, records of such documented review, 
including the corrective action taken and the disposition of the 
affected materials, and control of the affected materials pending their 
appropriate disposition. The failure to follow these procedures would 
result in the formula being deemed adulterated under section 412(a)(3) 
of the FD&C Act.
    Specifically, under Sec.  106.40(d) of the interim final rule, any 
deviation from a specification must result in a documented, 
comprehensive, and systematic examination of the affected ingredient, 
container, closure, or of the in-process or finished infant formula in 
which the suspect ingredient, container, or closure was used by an 
individual qualified by education, training, or experience to perform 
such examination. An adequate documented review includes: (1) 
Identification of the specific deviation; (2) a determination of the 
need for an investigation into the cause of the deviation; (3) 
evaluation of the material or product that does not conform to the 
specification to determine whether the deviation has resulted in or may 
lead to adulteration of infant formula; (4) identification of the 
action or actions taken to correct, and prevent a recurrence of, the 
deviation; and (5) documentation of the disposition of the affected 
material and infant formula products, if any.
    Adequate records of the documented review and disposition are 
critical, and the rule requires a manufacturer to establish and 
maintain such records. Specifically, under Sec.  106.100(e)(4) of the 
interim final rule, required records include those showing the identity 
and conclusions of, and followup by, the qualified individual who 
investigated a deviation from a master manufacturing order, a failure 
of a production aggregate or an ingredient of a production aggregate to 
meet manufacturer's specifications, or a failure to meet any 
specification applicable to a production process where control is 
deemed necessary to prevent adulteration.
    Accordingly, proposed Sec.  106.40(d) is revised by deleting the 
requirement to develop written specifications for acceptance or 
rejection of ingredients, containers, and closures used in 
manufacturing infant formula. In its place, FDA is establishing a 
requirement that a manufacturer develop written specifications for 
ingredients, containers, and closures and develop written procedures to 
determine whether such specifications are met. The Agency is also 
establishing a requirement for a documented review and material 
disposition decision by an individual qualified by education, training, 
or experience when an ingredient, container, or closure is determined 
not to meet the manufacturer's specifications.
    Comments on other issues pertaining to proposed Sec.  106.40(d) are 
discussed in section V.H.2.
    Adequate public health protection also requires a manufacturer to 
ensure that any ingredient, container, or closure that does not meet 
the manufacturer's specifications be controlled under a quarantine 
system designed to prevent its use in the manufacturer of an infant 
formula unless and until it is released for such use. Proposed Sec.  
106.40(e) would have required that ingredients, containers, or closures 
be stored in areas clearly designated as ``pending release for use,'' 
``released for use,'' or ``rejected for use.'' In addition, proposed 
Sec.  106.40(e)(3) would have required ingredients, containers, or 
closures that did not meet a manufacturer's specifications to be 
rejected and controlled under a quarantine system to prevent their use 
in the manufacture of infant formula. However, under this interim final 
rule, a disposition decision based on a failure to meet a specification 
is not limited to a decision to reject the material; a decision could 
be made to release the ingredient, container, or closure, or the 
affected infant formula, for use, or to reprocess or recondition it. 
The need to control the ingredient, container, or closure, or the 
affected formula, to prevent its use in the manufacture of infant 
formula, pending a material review and disposition decision, applies 
any time a manufacturer fails to meet a specification. Controlling the 
material under a quarantine system will prevent potentially adulterated 
material from being used, or from co-mingling it with other material, 
in the manufacture of an infant formula. Comments discussed elsewhere 
in this preamble requested clarification with respect to methods that 
could be used to control and segregate material. Section 106.40(e) 
describes the ways a manufacturer may quarantine material that has not 
been released for use due to failure to meet a specification, or that 
has been rejected for use in the manufacture of an infant formula.
    Comments on other issues pertaining to Sec.  106.40(e) are 
discussed in section V.H.2. Consistent with the changes in Sec.  
106.40(d) and (e) of the interim final rule, Sec.  106.40(f) requires a 
manufacturer to quarantine an ingredient, container, or closure and to 
conduct a documented review and make a material disposition decision if 
the ingredient, container, or closure has been, or may have been, 
exposed to conditions that may adversely affect it.
    Comments on other issues pertaining to Sec.  106.40(f) are 
discussed in section V.H.3.
    Similarly, under Sec.  106.50(f) of the interim final rule, failure 
to meet a specification does not result in automatic rejection. A 
manufacturer must control, under a quarantine system, in-process 
material that does not meet specifications pending a material review 
and disposition decision by a qualified individual. In-process material 
that does not meet a manufacturer's specifications could potentially 
adulterate an infant formula, if used. If an affected in-process 
material is reprocessed or otherwise reconditioned, it must be 
controlled under a quarantine system, pending a documented review and 
material disposition decision. Any in-process material that is rejected 
must also be

[[Page 7957]]

controlled under quarantine system to prevent its use in infant formula 
manufacturing and processing operations.
    Finally, at the final production stage, a manufacturer must 
determine whether the production aggregate may be released for use or 
distribution. Pending a decision by the manufacturer to release the 
production aggregate for use or distribution, proposed Sec.  106.70(a) 
would have required that the manufacturer ``hold, or maintain under its 
control,'' each production aggregate until the manufacturer determines 
certain criteria are met. This language was proposed in order to ensure 
that adulterated formula would not be released (see 61 FR 36154 at 
36174). For consistency with changes made to Sec. Sec.  106.40 and 
106.50 related to the need to establish a quarantine system pending a 
documented review and material disposition decision by a qualified 
individual, and options to reject, reprocess or otherwise recondition, 
or approve and release affected material, FDA is making corresponding 
changes to Sec.  106.70 of the interim final rule.
    For purposes of consistency with the changes in Sec. Sec.  
106.40(d), (e), and (f), 106.50(f), and 106.70(a), (b), and (c), FDA is 
revising Sec.  106.6(c)(4) to state that the review conducted shall be 
a documented review resulting in a material disposition to reject, 
reprocess or otherwise recondition, or approve and release the affected 
article. Likewise, FDA is inserting a new Sec.  106.6(d) that states 
the requirement to establish a quarantine system pending a documented 
review and material disposition decision for any article that fails to 
meet a specification.
    These revisions reflect CGMP and are necessary to prevent 
adulteration of an infant formula, provide consistency across 
requirements, and clarify, in response to comments, that a failure to 
meet a specification does not necessarily result in automatic rejection 
at each stage of the manufacturing process, i.e., for an ingredient, 
container or closure, for an in-process material, or for a finished 
infant formula.
    FDA also received comments on specific aspects of proposed Sec.  
106.6. These comments are discussed in this document.
    (Comment 39) One comment regarding specifications focused on 
proposed Sec.  106.70. This comment expressed support for the intent of 
this provision, which the comment characterized as preventing the sale 
and consumption of a formula that is nutritionally or microbiologically 
inadequate. The comment asserted, however, that the rejection or 
reprocessing of a batch (production aggregate) of infant formula that 
falls outside a manufacturer's specifications is an overly prescriptive 
means of achieving this objective, and explained that a manufacturer 
assesses deviations from specifications on a case by case basis and 
that, once reported, all deviations are evaluated by suitably trained 
personnel who consider the nutritional and public health significance 
of the deviation. The comment proposed alternative language for 
proposed Sec.  106.70(b).
    (Response) As noted, FDA has revised several provisions of the 
interim final rule that concern specification deviations, including 
proposed Sec.  106.70(b). Although FDA declines to adopt the 
alternative language offered by this comment, the Agency believes that 
the revisions to proposed Sec.  106.70(b), which clarify the 
responsibilities of a manufacturer when a production aggregate does not 
conform to its specifications, respond to the issues raised by the 
comment.
2. Establishment and Implementation of a Control System (Proposed Sec.  
106.6(a))
    (Comment 40) One comment suggested that instead of requiring in 
proposed Sec.  106.6(a) a system to cover all stages of processing, the 
production and in-process control system should extend to those stages 
of processing, storage, and distribution that are under the 
manufacturer's control because, the comment contended, a manufacturer 
cannot be expected to be responsible for ensuring proper distribution 
practices. In addition, the comment asserted that, for co-packers, the 
scope of responsibility of the co-packer is necessarily limited to the 
specific aspect of manufacturing, storage, or distribution that the co-
packer has agreed by contract to handle.
    (Response) FDA believes that this comment misunderstands the 
responsibilities of manufacturers under the interim final rule. As 
discussed in the response to Comment 17, there are two types of 
responsibilities under the interim final rule: The obligation to 
conduct certain activities according to the requirements of the CGMP 
regulations and the obligation of certain persons to ensure compliance 
with the rule's requirements even if such person is not engaged in the 
specific activities covered by the rule. The degree to which a 
manufacturer must adhere to the interim final rule's CGMP requirements 
is determined by the specific activities in which such manufacturer is 
engaged: Under the interim final rule, a manufacturer must comply with 
all the CGMP requirements that cover activities in which such 
manufacturer actually engages. Thus, a firm that packages an infant 
formula is a ``manufacturer'' as defined in Sec.  106.3 and must comply 
with all requirements applicable to the operations it performs. For 
example, a firm that packages an infant formula is responsible for 
having a production and in-process control plan for that operation. 
Conversely, the firm that packages the formula is not responsible for 
production and in-process control requirements that are not related to 
packaging operations, such as those related to the receipt of raw 
materials.
    For the foregoing reasons, FDA is not persuaded to change Sec.  
106.6(a) in response to this comment and, with the exception of minor 
editorial changes, Sec.  106.6(a) is included in this interim final 
rule as proposed.
3. Elements of the Production and In-Process Control System (Proposed 
Sec.  106.6(c))
    (Comment 41) Another comment objected to the requirement in 
proposed Sec.  106.6(c) that the manufacturer take certain actions at 
any point, step, or stage in the production process where control is 
necessary to prevent adulteration. The comment argued that ``any point, 
step, or stage'' could refer to every conceivable manufacturing 
activity and there are few manufacturing activities that could not, 
theoretically, give rise to a finding of ``technical'' adulteration. 
The comment stated that it is impractical to fulfill the requirements 
of proposed Sec.  106.6(c) for every conceivable manufacturing activity 
and suggested that the regulation be revised to focus on the 
manufacturing steps most important or critical to ensuring that a 
product is free from actual adulteration. The comment claimed that this 
would also make proposed Sec.  106.6(c) consistent with the 
recordkeeping requirements in proposed Sec.  106.100(e)(3). The comment 
also emphasized that it is the responsibility of the manufacturer to 
identify the critical points.
    (Response) FDA does not intend that the control procedures 
established under Sec.  106.6(c) would address every theoretical risk 
of technical adulteration. Importantly, however, a manufacturer has a 
responsibility, as part of CGMP, to ensure quality in the finished 
product on a consistent basis. The way to ensure quality is to identify 
controls needed at various steps in the production process so that, in 
its final form, the formula complies with all requirements.

[[Page 7958]]

    FDA agrees with the comment to the extent that it asserts that 
certain actions (e.g., the establishing of specifications) are not 
required at every step in the manufacturer's process. Instead, it is 
the responsibility of a manufacturer to identify those points at which 
control is necessary to prevent adulteration of infant formula 
products. A manufacturer must consider all possible risks likely to 
occur with its products and determine how these risks will be 
controlled. These risks include insanitary conditions that may 
contaminate formula or may render a formula injurious to health, not 
just conditions that do, in fact, contaminate the formula or render it 
injurious to health. A formula product that has been held under 
insanitary conditions whereby it may become contaminated with filth or 
it may be rendered injurious to health is deemed adulterated under 
section 402(a)(4) of the FD&C Act.
    In addition, a manufacturer must determine the controls that are 
necessary to prevent adulteration during the production of each formula 
based on the manufacturer's individual operations. Failure to establish 
specifications under Sec.  106.6(c) at any point, step, or stage where 
control is necessary to prevent adulteration would cause the product to 
be adulterated under section 412(a)(3) of the FD&C Act for failure to 
follow CGMP, including quality control procedures, required by FDA. 
Accordingly, FDA is not persuaded to make the revisions requested in 
this comment.
    (Comment 42) One comment requested that FDA consider the meaning of 
the term ``specification'' in proposed Sec.  106.6(c)(1), which 
requires that infant formula manufacturers establish standards or 
specifications to be met at any point, step, or stage in the production 
process where control is necessary to prevent adulteration.
    The comment presented several objections to setting specifications 
at the outer limits. The comment stated that a manufacturer should be 
encouraged to impose tight control over its manufacturing process to 
produce infant formula of consistent quality and noted that infant 
formula manufacturers set their specifications well within the outer 
limits that would cause adulteration. The comment noted that, in most 
cases, manufacturers have not identified every extreme outer limit for 
every process and product parameter that would result in rejection.
    (Response) The Agency believes that this comment misreads the 
proposed rule. The comment seems to suggest that proposed Sec.  
106.6(c)(1) would require a manufacturer to establish a specification 
at a particular level or range that, if not met, would cause the infant 
formula to be adulterated. The Agency disagrees with this reading of 
proposed Sec.  106.6(c)(1). The purpose of Sec.  106.6(c) is to ensure 
that each manufacturer examines its infant formula production processes 
and addresses those points, steps, and stages where control is needed 
to ensure that the process will produce the formula the manufacturer 
intends to produce. Proposed Sec.  106.6(c)(1) stated that a 
specification must be established where control is necessary to prevent 
adulteration but does not specify the range or magnitude of the 
specification. Also, as discussed in section V.C.1, although proposed 
Sec.  106.40(d) stated that specifications shall be set for the 
acceptance or rejection of ingredients, containers, and closures; FDA 
is revising proposed Sec.  106.40 so that when a formula ingredient, 
container, or closure fails to conform to specifications, an individual 
qualified by education, training, or experience must conduct a 
documented review to determine whether such failure could result in an 
adulterated infant formula, and thereafter, must make and document a 
material disposition decision to reject, reprocess or otherwise 
recondition, or approve and release the material or the affected infant 
formula for use. Additionally, as discussed in section V.I, FDA is 
revising Sec.  106.50 so that if any in-process material fails to meet 
a specification established under Sec.  106.6(c)(1), an individual 
qualified by education, training, or experience must conduct a 
documented review and make a material disposition decision to reject, 
reprocess or otherwise recondition, or approve and release the in-
process material. Therefore, a manufacturer may choose to establish a 
level or range as a specification that must be met in order to produce 
a formula that is not actually adulterated but is not compelled or 
encouraged to set its specifications at the outer limits. In fact, a 
manufacturer may establish a specification within a narrow range to 
ensure a larger margin of error for some or all of its processes.
    In addition, FDA notes that, as discussed in section IV, the Agency 
is revising, in response to a comment, proposed Sec.  106.6(c)(3) to 
delete the words ``standard or'' (see subpart A).
    (Comment 43) Several comments suggested changes to proposed Sec.  
106.6(c)(3), which would require a manufacturer to establish a 
corrective action plan to use when a specification, established in 
accordance with Sec.  106.6 (c)(1), is not met. One comment suggested 
establishing standard operating procedures (SOPs) for use when a 
specification is not met as an alternative to a corrective action plan. 
The comment objected to the language in the preamble to the 1996 
proposal that ``the best way to ensure that a corrective action is 
appropriate is to determine the action in advance,'' asserting that 
while it may often be feasible to establish corrective action plans in 
advance, a manufacturer cannot be expected to foresee all future 
circumstances that may require reliance on a corrective action plan and 
to predict how it will operate and that many circumstances may have a 
different set of elements to be considered, thus requiring a case-by-
case analysis. The comment stated that a manufacturer could include 
potential corrective actions in an SOP, but a corrective action should 
not be mandated when irrelevant to the facts of a given situation.
    (Response) FDA is not persuaded to change Sec.  106.6(c)(3) for the 
following reasons. First, a corrective action plan is one type of SOP 
that addresses corrective actions. Therefore, a manufacturer may use a 
SOP as its corrective action plan. Second, although FDA acknowledges 
that a manufacturer may not foresee all circumstances in which a 
corrective action will be necessary, such a plan is needed only to 
respond to the failure to meet a specification. Under Sec.  
106.6(c)(1), a manufacturer must set specifications only for those 
points, steps, or stages in the production process where the 
manufacturer has determined that control is necessary to prevent 
adulteration. Thus, the manufacturer should have some familiarity with 
the circumstances in which a correction action would be required.
    Moreover, having in place a corrective action plan for those 
situations that the manufacturer can anticipate will enable the 
manufacturer to react more promptly when the anticipated control 
failure occurs. Even if it is a general mechanism or policy, it is 
appropriate for a manufacturer to establish a corrective action plan to 
anticipate the response to a deviation from specifications; the plan 
should identify what steps should be taken in response to a deviation 
and by whom. For example, the manufacturer may decide that for certain 
deviations from a specification, a designated person should stop the 
production process until a documented review and material disposition 
decision can be made. In addition, the corrective action plan should 
include a procedure for the manufacturer's documented review and 
material disposition decision for the

[[Page 7959]]

deviation, but does not need to specify in advance a decision for a set 
of facts not yet known.
    (Comment 44) In response to the 2003 request for comments, one 
comment stated that corrective actions are based on scientific judgment 
and past experiences and that if each specification needs to be tested 
to the point of failure, the cost would be huge and would prevent or 
severely limit new product development. Given the complex and multi-
factorial aspects of infant formula production and the occasional 
failure of finished products to meet specifications, the comment 
questioned whether such speculative actions would provide applicable 
guidance in a specific instance. Instead, if scientific judgment 
supported by empirical evidence were allowed to determine which 
specifications should be challenged, some corrective action procedures 
might be identified in advance, but they would be limited to those 
situations that manufacturers would reasonably expect to encounter.
    (Response) As discussed in response to the previous comment, a 
corrective action plan is needed only to respond to the failure to meet 
a specification, and such specifications are not unlimited. That is, 
under Sec.  106.6(c)(1), a manufacturer is required to set 
specifications only for those points, steps, or stages in the 
production process where the manufacturer has determined that control 
is necessary to prevent adulteration. Thus, FDA does not agree with the 
comment that the costs of establishing corrective action plans will be 
overwhelming.
    The Agency does agree that a manufacturer cannot predict in advance 
the outcome of a documented review and material disposition decision 
for every deviation. However, as the comment recognizes, a manufacturer 
can anticipate certain corrective actions. For these anticipated 
deviations, the corrective action plan required under Sec.  106.6(c)(3) 
will provide a procedure in advance for what, if any, action is needed 
when a specification is not met, who should take such action, and the 
process for the documented review and material disposition decision. A 
manufacturer is expected periodically to revise and include additional 
relevant information, as appropriate, to a corrective action plan for 
the identified specifications.
    (Comment 45) Several comments were received on proposed Sec.  
106.6(c)(4), which requires review of the results of monitoring of 
production and in-process control points, steps, or stages where 
control is necessary to prevent adulteration and evaluation of the 
public health significance of any deviations from established 
specifications. These comments noted that not all deviations from 
specifications involve concerns of public health significance; for 
example, shipper cartons that are found with a printing color that 
differs slightly when compared to the color standard would not justify 
a public health significance evaluation. The comments agreed, however, 
that if a deviation has potential public health significance, a 
qualified individual must make a documented review and material 
disposition decision.
    (Response) These comments appear to misunderstand the proposed 
rule. Proposed Sec.  106.6(c)(1) would require a manufacturer to 
establish specifications only at those points, steps, or stages in the 
production process where control is necessary to prevent adulteration. 
The Agency recognizes that a manufacturer may establish specifications 
that are not related to preventing product adulteration, such as the 
shade of ink on shipper cartons. Unless the manufacturer determines 
that a particular specification is necessary to prevent product 
adulteration, it would not be a specification established under Sec.  
106.6(c)(1) and, thus, would not be subject to review under Sec.  
106.6(c)(4). For this reason, FDA is not revising Sec.  106.6(c)(4) in 
response to these comments.

D. Controls To Prevent Adulteration by Workers (Proposed Sec.  106.10)

    In the 1996 proposal, FDA proposed in Sec.  106.10 general 
standards to help ensure that workers involved in the production of 
infant formula do not cause the formula to become adulterated. The 
proposed provisions address sufficiency and training of personnel, 
personal hygiene of production personnel, and safeguarding formula from 
microbial contamination from production personnel. The Agency received 
comments on several aspects of proposed Sec.  106.10, which comments 
are addressed in this document.
    (Comment 46) One comment suggested eliminating Sec.  106.10(a) 
because it is overly prescriptive. The comment stated that the only 
standard by which one can demonstrate that ``sufficient personnel 
qualified by training and experience, to perform all operations'' have 
been employed by the manufacturer is by demonstrating that an 
unadulterated infant formula can be routinely manufactured. In 
addition, the comment argued, because other provisions of the existing 
and proposed regulations already require that unadulterated products be 
routinely manufactured, compliance with CGMP requirements should be 
adequate without the Agency's evaluation of internal staffing matters. 
The same comment stated that if this section is not deleted, it should 
be made clear that it is the manufacturer's responsibility to determine 
what is meant by ``sufficient'' personnel.
    (Response) FDA disagrees with this comment and declines to delete 
Sec.  106.10(a) from the interim final rule. It is critical that a 
manufacturer of infant formula employ an adequate number of qualified 
personnel to staff the manufacturing operation, and the requirement in 
Sec.  106.10(a) ensures that a manufacturer will provide sufficient 
trained personnel to achieve compliance with CGMP.
    FDA does not believe that Sec.  106.10(a) is overly prescriptive. 
In fact, the Agency agrees that it is the manufacturer's responsibility 
to determine what constitutes ``sufficient'' personnel to perform fully 
all operations necessary to produce the infant formula in compliance 
with CGMP. The proposal identified no specific number of workers that 
must be employed, expressly noting that the Agency ``is proposing a 
general standard for determining how many employees are necessary [but] 
is leaving the determination of the actual number of employees 
necessary to the manufacturer's discretion.'' (61 FR 36154 at 36159). 
To clarify that the decision regarding sufficiency of personnel is both 
within the manufacturer's authority as well as an obligation of the 
manufacturer, FDA is revising proposed Sec.  106.10(a) to emphasize 
that the ``A manufacturer shall employ sufficient personnel,'' rather 
than retaining the somewhat ambiguous language of the proposal.
    (Comment 47) Another comment stated that it was unrealistic to 
demand that all individuals be fully trained and experienced in infant 
formula manufacturing because training must be carried out on the job. 
The comment suggested that some form of licensing of infant formula 
manufacturing may be appropriate and suggested that at least one 
licensed person be present during each shift of infant formula 
manufacture.
    (Response) FDA believes that this comment misinterprets proposed 
Sec.  106.10(a). FDA proposed that production personnel be qualified by 
training and experience to ensure that all operations are correctly and 
fully performed. This provision would simply require an infant formula 
manufacturer to have, at all times, sufficient numbers of employees in 
both

[[Page 7960]]

supervisory positions and non-supervisory positions who are 
knowledgeable and qualified to perform the functions necessary to 
manufacture an infant formula so that the formula is not adulterated. 
Employees may obtain the necessary knowledge and qualifications through 
training (which may include formal training and on-the-job training), 
experience, or a combination of these. FDA recognizes that a new 
employee may be trained in the manufacture of infant formula on the 
job, for example, when that new employee is under the supervision of a 
person trained and experienced in the operation that the new employee 
is asked to perform. FDA is revising proposed Sec.  106.10(a) to 
clarify that training may include both education and on-the-job 
training and to clarify that an employee may be qualified by any 
combination of education, training, or experience.
    Finally, FDA does not currently require any type of licensure for 
individuals involved in the manufacture of infant formula. The Agency 
is not aware of any problems that have resulted from of the absence of 
a licensure requirement and is not aware of the particular benefits 
that would result from such requirement. The comment did not identify 
either particular problems or specific benefits related to such 
licensure. Therefore, FDA is not persuaded to modify Sec.  106.10(a) in 
response to this comment.

E. Controls To Prevent Adulteration Caused by Facilities (Proposed 
Sec.  106.20)

    In the 1996 proposal, FDA proposed in Sec.  106.20 to require that 
an infant formula manufacturer implement a system of controls designed 
to prevent adulteration caused by an infant formula facility. These 
controls would cover buildings, storage areas, lighting, air filtration 
systems, appropriate storage of certain chemicals, water quality, 
plumbing and toilet and hand-washing facilities for employees. FDA 
received no comments on proposed Sec.  106.20(a), (e), and (g), and 
those provisions are included in the interim final rule as proposed. 
The Agency did receive comments on several other aspects of proposed 
Sec.  106.20, which are addressed in this section.
1. Systems of Separation (Proposed Sec.  106.20(b))
    (Comment 48) Several comments on the 1996 proposal objected to 
proposed Sec. Sec.  106.20(b) and 106.40(e), which would require an 
infant formula manufacturer to designate separate areas for holding or 
storing raw materials (ingredients, containers, and closures), in-
process materials, and final infant formula product pending release for 
use, after rejection for use and before disposition, and after release 
for use. The comments agreed that each manufacturer must establish an 
effective system to identify and control materials and finished product 
before and after release for use, but argued that physical separation 
of materials was not practical. The comments suggested that we allow 
separation of materials by a means other than physical separation of 
materials, including computerized inventory controls and adequately 
marked pallets. As a result of these comments, in the 2003 reopening, 
FDA specifically requested additional comment on this issue.
    (Response) Based on the comments, FDA is persuaded to revise Sec.  
106.20(b) to allow materials to be segregated by means other than 
physically separate storage areas. It may be desirable to have separate 
storage areas for holding or storing raw materials, in-process 
materials, and final infant formula product pending release for use, 
after rejection for use and before disposition, and after release for 
use. However, use of physically separate storage areas is not necessary 
if other systems, such as computerized inventory controls or automated 
systems of separation, can adequately segregate materials to prevent 
accidental mixups or co-mingling of materials. A computerized inventory 
system utilizes technical advances and allows tracking of materials 
through the use of bar codes and radio frequency identification tags 
that identify items in a firm's inventory. An inventory system could 
also employ bar codes to identify and track the material in the 
production facility; for example, a bar code could identify the 
material, the item's storage location, when it arrived at its 
designated storage location, and could be used to reorder the item.
    FDA disagrees, however, that marked pallets alone would be adequate 
to prevent mix-ups of these materials because there is no assurance 
that specific materials will stay associated with a particular pallet 
without additional arrangements. For example, unless additional 
measures are taken to avoid mixups such as physical attachment of the 
material to the pallet (e.g., materials are shrink-wrapped in plastic 
to the pallet), there is a risk that the separated materials will 
accidentally become co-mingled with other materials. The objective of 
this proposed CGMP requirement is to avoid the mix-up of different 
materials (or different lots of the same material) and ensure the 
continuing integrity of such materials through the use of systematic 
storage methods. Use of shrink-wrapped pallets would be an acceptable 
storage system so long as the integrity of a pallet's contents is 
reestablished by rewrapping following penetration of the shrink-wrap.
2. Holding of Rejected Materials (Proposed Sec.  106.20(b)(2))
    (Comment 49) One comment objected to proposed Sec.  106.20(b)(2), 
which would require separation of raw materials, in-process materials, 
and final product infant formula after rejection for use in infant 
formula and before disposition. The comment suggested removing the 
phrase ``before disposition'' because once a decision is made 
concerning disposition, the requirement for proper status designation 
should not end. The comment also suggested that the need for separation 
of rejected or released finished infant formula also should be 
acknowledged in proposed Sec.  106.20(b)(2) and (b)(3).
    (Response) The Agency agrees that the phrase ``before disposition'' 
is not necessary. Any time such materials or formula are rejected, the 
materials should remain segregated until disposition is completed to 
avoid co-mingling of rejected and released materials.
    FDA also agrees with the comment that the interim final rule should 
acknowledge that finished infant formula product should be segregated. 
Therefore, FDA is revising proposed Sec.  106.20(b)(2) to state ``After 
rejection for use in, or as, infant formula.'' However, FDA is not 
adding the phrase ``or as'' to Sec.  106.20(b)(3) of the interim final 
rule, because the need to segregate released final product is already 
acknowledged in this provision.
    FDA is also making corresponding revisions to Sec.  106.40(e) of 
the interim final rule.
3. Lighting (Proposed Sec.  106.20(c))
    (Comment 50) One comment objected to Sec.  106.20(c) and 
recommended that this provision be deleted, asserting that it is 
redundant with food CGMP, Sec.  110.35(b)(5).
    (Response) Although this comment refers to Sec.  110.35(b)(5), FDA 
believes the correct reference to food CGMP is Sec.  110.20(b)(5). The 
comment did not criticize the substance of proposed Sec.  106.20(c) and 
did not claim that its more specific requirements were inappropriate 
for infant formula manufacture. While FDA agrees that the requirements 
in part 110 (the CGMP for manufacturing, packing and holding human 
food) apply to infant formula manufacture, redundancy, in and of

[[Page 7961]]

itself, is not a reason to eliminate this provision. Indeed, given the 
nature of infant formula, the manufacturing process is necessarily a 
more specific and highly sophisticated operation, and all lighting must 
be adequate for each specific area. Accordingly, Sec.  106.20(c) is 
included in the interim final rule as proposed.
4. Air Filtration Systems (Proposed Sec.  106.20(d))
    (Comment 51) Several comments objected to the requirement of 
proposed Sec.  106.20(d) that air filtration systems, including 
prefilters and particulate matter air filters, be used on air supplies 
to production areas where ingredients or infant formula are directly 
exposed to the atmosphere and suggested that Sec.  106.20(d) be 
deleted. One comment stated that proposed Sec.  106.20(d) was overly 
prescriptive and that CGMP for foods in current Sec.  110.20(b)(6) 
should be sufficient for infant formula manufacturing facilities. 
Current Sec.  110.20(b)(6) requires the plant and facilities to 
``provide adequate ventilation or control equipment to minimize odors 
and vapors (including steam and noxious fumes) in areas where they may 
contaminate food; and locate and operate fans and other air-blowing 
equipment in a manner that minimizes the potential for contaminating 
food, food-packaging materials, and food-contact surfaces.''
    (Response) FDA agrees that the requirements in current Sec.  
110.20(b)(6) are appropriately applied to infant formula manufacturing 
facilities. However, the Agency is not persuaded that the requirements 
of current Sec.  110.20(b)(6) are completely sufficient because current 
Sec.  110.20(b)(6) does not address air filtration. As stated in the 
preamble to the 1996 proposal (61 FR 36154 at 36160-36161), proposed 
Sec.  106.20(d) is designed to improve air quality in formula 
production areas and thus reduce the potential for contamination by 
air-borne sources such as spores, molds, and bacteria that may be 
carried on dust or other air-borne contaminants. The presence of such 
spores, molds, and bacteria may lead to severe illness, particularly in 
the vulnerable population consuming infant formula.
    Importantly, however, because of differences in plant design, 
location, and other unique features, the manufacturer can best 
determine which air filtration system or systems are needed to prevent 
contamination by air-borne sources in a specific plant. Therefore, FDA 
is persuaded that the interim final rule does not need to require 
specific types of filters or prescribe when filters are necessary to 
prevent air-borne contamination. Accordingly, as revised, the interim 
final rule requires a manufacturer to identify the parts of the 
production facility in which there is potential for airborne 
contamination of ingredients, in-process product, finished product, 
packing materials, and infant formula contact surfaces, and use air 
filtration as necessary to prevent contamination of these materials.
    (Comment 52) One comment noted that although the Agency referenced 
the drug CGMP as a formative source for the 1996 proposal, the phrase 
in the drug CGMP regulations, ``when appropriate,'' was not included in 
the infant formula CGMP proposed rule. This comment suggested 
alternative language for the CGMP provision, such as ``when there is 
reason to believe that the air in a particular area of the plant might 
result in adulteration of the product, measures should be taken to 
prevent such adulteration, by air filtration or some other means.''
    (Response) FDA believes that the revision to proposed Sec.  
106.20(d), which incorporates the concept of ``as appropriate,'' 
responds to this comment.
    (Comment 53) Another comment stated that proposed Sec.  106.20(d) 
would require complete air filtration and cooling to be used for all 
production rooms and maintenance of positive air pressure at all times 
in these rooms. This comment recommended that air filtration should be 
required only in areas where there is direct contact between the air 
and formula, such as in dryers and dehumidifiers.
    (Response) FDA believes that this comment misunderstands proposed 
Sec.  106.20(d). Proposed Sec.  106.20(d) would not have mandated air 
cooling and positive air pressure in all production rooms; it would 
have expressly limited prefilters and particulate matter air filters to 
those production areas where ingredients and infant formula would be 
directly exposed to the atmosphere. Moreover, as noted, the comments 
have persuaded FDA to delete the proposed requirement for specific 
types of filters or when filters are necessary to prevent 
contamination. Accordingly, Sec.  106.20(d) of the interim final rule 
requires a manufacturer to identify the parts of the production 
facility in which there is potential for airborne contamination of 
ingredients, in-process product, finished product, packing materials, 
and infant formula contact surfaces and use air filtration as necessary 
to prevent contamination of these materials.
    (Comment 54) In the 2003 reopening, FDA requested comments on types 
and costs of air filtration systems used by infant formula 
manufacturers and the costs of making changes to these systems. One 
comment stated that manufacturers use different filters in different 
areas of a facility and that prefilters and particulate matter air 
filters are used on air supplies to production areas and areas where 
formula may be exposed to the atmosphere. The comment stated that the 
proposed provision would not result in the expenditure of any 
additional funds and that a more detailed account of the types and 
costs of air filtration systems would be wasteful and an undue burden 
on industry when no public interest would be served by insisting on 
specific changes in this arena.
    (Response) FDA considered the information provided in this comment 
and, as noted previously in this document in response to Comment 51, 
the requirement of proposed Sec.  106.20(d) that prefilters and 
particulate matter filters be used in formula manufacturing facilities 
is not included in Sec.  106.20(d) of the interim final rule. Thus, the 
interim final rule will not necessarily result in specific changes to 
the air filtration systems of infant formula manufacturing facilities.
    (Comment 55) Another comment stated that one manufacturer currently 
has air filtration systems in all areas of the manufacturing plant 
where infant formula or raw materials may be exposed to the atmosphere. 
These mechanisms filter all incoming air using pleated filters or bag 
filters to remove particulate matter. The comment states that FDA 
should consider the prohibitive cost and level of disruption 
encountered in changing air filtration systems to meet an increased 
specification in comparison to systems currently performing to an 
appropriate standard and posing no risk of contamination of infant 
formula products.
    (Response) FDA believes that the revisions to the interim final 
rule will avoid the costs and disruptions raised as a concern in this 
comment. As noted, as revised, Sec.  106.20(d) does not require the use 
of particular filtration measures (such as prefilters and particulate 
matter air filters). Instead, the interim final rule requires a 
manufacturer to employ ``appropriate measures'' to reach the goal of 
minimizing the potential for contamination of materials in the 
manufacturing facility. Such measures may, but are not required to, 
include the use of air filtration or the location and operation of fans 
and other air-blowing equipment.

[[Page 7962]]

5. Potable Water (Proposed Sec.  106.20(f))
    (Comment 56) Several comments objected to the requirement in 
proposed Sec.  106.20(f)(1) that the fluoride level of the water used 
in infant formula manufacturing be as low as possible. The comments 
asserted that this requirement is vague, potentially prohibitively 
costly, and not needed to address a public health concern. The comments 
stated that manufacturers strive to produce infant formula products 
with low fluoride levels utilizing a variety of technologies. One 
comment suggested that the requirement that fluoride removal equipment 
be used for fluoridated water would be sufficient. Another comment 
suggested that the regulation be modified to state that the water used 
in infant formula manufacturing must ``not be fluoridated or shall be 
defluoridated prior to use.'' The comment stated that this change more 
accurately reflects current technology and industry practice.
    (Response) In the 1996 proposed rule, the Agency noted that infant 
formulas are currently manufactured without using fluoridated water and 
recommended that manufacturers continue their practice of not using 
fluoridated water in the manufacture of infant formula (61 FR 36154 at 
36161). Also as noted in the proposed rule, the NAS recommends a safe 
and adequate intake of 0.1 to 0.5 mg/day fluoride for infants from 0 to 
6 months. Accordingly, the Agency is not persuaded that a requirement 
that the water used in infant formula manufacturing must ``not be 
fluoridated or shall be defluoridated prior to use'' is consistent with 
the recommendations of the NAS/IOM. The purpose of this requirement is 
to reduce fluoride levels in water used to produce infant formula and, 
thereby, reduce the likelihood that fluoride intake of infants 
consuming finished infant formula product will exceed the tolerable 
upper intake level of 0.7 mg fluoride/day that has been established by 
the IOM for infants 0 to 6 months of age (Ref. 8). The glossary of the 
Environmental Protection Agency (EPA) includes a definition of 
``defluoridation,'' which is ``The removal of excess fluoride in 
drinking water to prevent the mottling (brown stains) of teeth'' (Ref. 
13). Importantly, the EPA definition does not specify an upper fluoride 
limit for ``defluoridated'' water. However, the requirement for the 
fluoride level should better reflect industry practices and, therefore, 
FDA is clarifying in Sec.  106.20(f) that water used in the manufacture 
of infant formula shall either be free of fluoride or defluoridated to 
a level as low as possible. FDA disagrees that requiring a manufacturer 
to defluoridate water to achieve a level of fluoride ``as low as 
possible'' is vague. The Agency is providing some flexibility for the 
manufacturer to determine the level of fluoride the manufacturer can 
achieve in its operations to keep such level ``as low as possible,'' 
should the manufacturer choose to defluoridate water rather than to use 
water that is not fluoridated.
6. Steam (Proposed Sec.  106.20(h))
    (Comment 57) One comment suggested that proposed Sec.  106.20(h) 
require that only culinary steam in compliance with 3-A Sanitary 
Standards be used at infant formula product contact points.
    (Response) Proposed Sec.  106.20(h) would require that steam in 
direct contact with infant formula be ``safe.'' FDA has considered this 
comment and agrees that the interim final rule should require that only 
culinary steam in compliance with 3-A Sanitary Standards should be used 
for steam that comes in contact with infant formula product. The 
interim final rule incorporates by reference at Sec.  106.160 the 
current 3-A Sanitary Standard for culinary steam, 3-A Sanitary 
Standards, No. 60903: Method of Producing Steam of Culinary Quality 
(November 2004) (Ref. 14). The 3-A standard is more specific than the 
standard of the proposed rule (``safe.''). The standard is a method for 
producing steam of culinary quality that is accepted practice for 
systems used to process perishable foods and it will ensure that the 
steam that comes in contact with infant formula will not contaminate 
the formula. Accordingly, the Agency is revising proposed Sec.  
106.20(h) to include the 3-A Sanitary Standard as a requirement for 
steam that comes into direct contact with infant formula.
7. Employee Toilet Facilities (Proposed Sec.  106.20(i))
    (Comment 58) One comment suggested that proposed Sec.  106.20(i) 
should be deleted because it is redundant with the food CGMP, Sec.  
110.37(d) and (e). The comment stated that if proposed Sec.  106.20(i) 
were retained, it should be revised to include ``air dryers'' as an 
alternative to single-service sanitary towels in the toilet facility.
    (Response) For the reasons discussed in the response to Comment 1, 
FDA disagrees with the suggestion to delete proposed Sec.  106.20(i) 
due to redundancy with the food CGMP regulation, Sec.  110.37(d) and 
(e). FDA agrees that air dryers are an equally acceptable alternative 
to single-service sanitary towels in the toilet facility. In the 
preamble to the 1996 proposal, FDA stated its view that proposed Sec.  
106.20(i) would be consistent with the Agency's food CGMP (Sec.  
110.37(d)) and drug CGMP (Sec.  211.52). Importantly, under both the 
food CGMP and the drug CGMP, air dryers are permitted as an alternative 
to single service towels in employee toilet and hand washing 
facilities. Thus, it is reasonable to include air dryers as an 
alternative in infant formula manufacturing facilities, and Sec.  
106.20(i) has been revised accordingly, along with several minor 
editorial changes.

F. Controls To Prevent Adulteration Caused by Equipment or Utensils 
(Proposed Sec.  106.30)

    In 1996, FDA proposed in Sec.  106.30 to require that an infant 
formula manufacturer implement a system of controls designed to prevent 
adulteration caused by equipment and utensils. The proposed provisions 
addressed the design, installation, and maintenance of infant formula 
manufacturing equipment. Specific proposed provisions addressed the 
accuracy of instruments used in such manufacturing (including their 
calibration), appropriate time and temperature for storage and 
processing, and the use of compressed gases in infant formula 
production operations. The Agency received comments on several aspects 
of proposed Sec.  106.30, which are addressed in this section. In 
addition to revisions made in response to comments, FDA has made minor 
editorial revisions in proposed Sec.  106.30.
1. Design, Cleaning, and Sanitizing of Equipment and Utensils (Proposed 
Sec.  106.30(b))
    (Comment 59) One comment suggested that this section be deleted 
because it is redundant with FDA's CGMP for food (Sec.  110.35(d)). The 
comment further stated that if Sec.  106.30(b) was not removed then a 
clarification to proposed Sec.  106.30(b) was needed. Section 106.30(b) 
would require that all surfaces that contact ingredients, in-process 
materials, or infant formula be cleaned, sanitized, and maintained to 
protect infant formula from being contaminated by any source. The 
comment argued that there are some areas where wet cleaning is neither 
practical nor desirable (e.g., in the infant formula powder 
manufacturing process) because frequent exposures to moisture should be 
avoided to reduce the likelihood of microbiological contamination. The 
comment acknowledged that this proposed

[[Page 7963]]

regulation could be interpreted to allow for these unique 
circumstances, but suggested that a statement, such as ``as 
necessary,'' be added to this section.
    (Response) For the reasons discussed in the response to Comment 1, 
FDA disagrees with the suggestion to delete proposed Sec.  106.30(b) 
due to redundancy with the food CGMP regulations, Sec.  110.35(d). 
Further, FDA did not intend that proposed Sec.  106.30(b) would be 
interpreted to specify wet cleaning as the most appropriate cleaning 
method for equipment or utensils used to manufacture infant formula. As 
the comment notes, proposed Sec.  106.30(b) would permit cleaning and 
sanitizing of powdered infant formula equipment or utensils by means 
other than a wet cleaning method. However, FDA does recognize that it 
may not be necessary to sanitize a contact surface for which wet 
processing is not used. Therefore, FDA is modifying this provision to 
require that surfaces be cleaned and sanitized, ``as necessary,'' and 
be maintained to protect infant formula from being contaminated by any 
source.
    In addition, FDA is deleting the last sentence of proposed Sec.  
106.30(b), which states ``Sanitizing agents used on food-contact 
surfaces must comply with Sec.  178.1010.'' The Food Quality Protection 
Act of 1996 (Pub. L. 104-170) and the Antimicrobial Regulation 
Technical Corrections Act of 1998 (Pub. L. 105-324) clarified which 
sanitizing agents are under the jurisdiction of EPA and which are under 
the jurisdiction of FDA. For example, a sanitizing agent that is used 
on a semi-permanent or permanent food contact surface (excluding food 
packaging) is a ``pesticide chemical'' subject to the regulatory 
purview of EPA (section 201(q)(1)(B)(i)(III) of the FD&C Act (21 U.S.C. 
321(q)(1)(B)(i)(III)). Most sanitizers used on equipment or utensils to 
which Sec.  106.30(b) of the interim final rule applies would be 
sanitizers under EPA's regulatory purview as ``pesticide chemicals.'' 
To the extent that a sanitizer that a manufacturer uses is a food 
additive or a GRAS ingredient, such substance is subject to FDA's 
regulatory purview and such use must comply with applicable FDA laws 
and regulations. FDA modified proposed Sec.  106.30(b) in view of this 
change in regulatory authority, in response to the foregoing comments, 
and with the addition of several editorial changes.
2. Use of Lubricants and Coolants in Infant Formula Manufacture 
(Proposed Sec.  106.30(c))
    (Comment 60) One comment requested that proposed Sec.  106.30(c) be 
clarified to state that lubricants or coolants that would render the 
infant formula adulterated if they came in contact with the formula 
must not come in contact with closures prior to the closing/sealing 
operation. The comment stated that the requirement is probably implied 
in proposed Sec.  106.30(c), but requested an explicit statement that 
the reference to containers and closures means prior to the closing/
sealing operation when the hermetic seal is formed. The comment also 
suggested that the phrase ``in a manner not permitted by applicable 
food additive regulations'' be added to the end of this proposed 
requirement to make it consistent with applicable food additive 
regulations.
    (Response) FDA agrees that lubricants and coolants that would 
render the infant formula adulterated if they came in contact with the 
formula must not be allowed to come in contact with containers and 
closures before the closing/sealing operation. Additionally, such 
lubricants and coolants must not be allowed to come in contact with 
containers and closures even after sealing as this may lead to 
contamination when the container is opened for use. Further, it is not 
clear that all lubricants that may be used would be necessarily subject 
to the food additive regulation in 21 CFR 178.3570 for lubricants with 
incidental food contact. Consequently, FDA is replacing the phrase ``if 
they contaminated the formula'' with ``if such substances were to come 
in contact with the formula'' in Sec.  106.30(c). In this way, if a 
particular lubricant is not subject to a food additive regulation, 
e.g., it is GRAS under certain conditions of use, the requirement would 
cover all such substances.
3. Controlling Parameters at Points Where Control Is Deemed Necessary 
To Prevent Adulteration (Proposed Sec.  106.30(d)(1))
    (Comment 61) One comment requested that FDA clarify in proposed 
Sec.  106.30(d)(1) that the infant formula manufacturer is responsible 
for determining the points where control is deemed necessary to prevent 
adulteration and the routine intervals necessary for calibration of 
instruments. The comment did not object to the requirement for the 
calibration of instruments, but noted that it could prove unduly 
burdensome if the Agency applied ``drug'' type compliance standards. 
The comment stated that including the qualification that infant formula 
manufacturers bear the final responsibility for determining the 
frequency and scope of testing would help assure that the standard 
applied to infant formula is appropriate.
    (Response) FDA observes that the comment did not explain what would 
constitute ``unduly burdensome, `drug' type compliance standards.'' 
Moreover, the Agency is not persuaded that the requested clarification 
is necessary because proposed Sec.  106.30(d)(1) specifically states 
that instruments and controls shall be calibrated at routine intervals, 
as specified in writing by the manufacturer of the instrument or 
control or as otherwise deemed necessary to ensure the accuracy of the 
instrument (emphasis added). Thus, the Agency affirms that proposed 
Sec.  106.30(d)(1) does provide a formula manufacturer with discretion 
to determine the calibration frequency for controls and instruments 
that is required to ensure that these instruments or controls are 
operating within the correct parameters.
    (Comment 62) One comment explained that because of the number of 
instruments to which this rule will apply, it is possible that certain 
of the instruments requiring calibration may need to be in use while 
they are being calibrated. Thus, the comment suggested adding the words 
``on or before first use'' to describe the timing of the initial 
certification (calibration).
    (Response) FDA agrees with this suggestion. Calibrating an 
instrument against a known reference standard at the time the 
instrument is first used will be sufficient to ensure the accuracy of 
testing subsequently done with the instrument to establish that certain 
specifications are met. Thus, FDA is revising Sec.  106.30(d)(1) in the 
interim final rule by adding the phrase ``at the time of or.''
    (Comment 63) In response to FDA's 2003 comment period reopening and 
request for comments on calibration, one comment stated that U.S. 
formula manufacturers have established calibration and preventative 
maintenance schedules for appropriate pieces of equipment, that 
priorities for calibrations and preventative maintenance are linked to 
``criticality in regard to product quality and safety,'' and that 
procedures and schedules are aligned according to the criticality 
assessments, which vary from company to company, and are often based on 
the recommendations of the instrument supplier. The comment asserted 
that the regulation should simply require that calibrations and 
preventative maintenance be performed on pre-established schedules and 
according to written procedures as the formula manufacturer determines, 
based on information from the equipment

[[Page 7964]]

supplier where applicable and that a requirement that all instruments 
need to be calibrated routinely, regardless of function, would result 
in either the removal of all instruments that the manufacturer deems 
not critical or the addition of significant new personnel and extensive 
systems to coordinate and track the calibration program.
    (Response) FDA believes that this comments misunderstands the 
calibration requirement in proposed Sec.  106.30(d)(1) in two important 
ways. First, only certain instruments and controls used in an infant 
formula manufacturing operation are subject to calibration under 
proposed Sec.  106.30(d)(1); that is, not all instruments and controls 
used in formula manufacturing are required to be calibrated. 
Specifically, proposed Sec.  106.30(d)(1) requires only those 
instruments and controls at points where ``control is deemed necessary 
to prevent adulteration'' to be accurate and maintained, including by 
calibration. Second, the proposed rule would require a calibration 
schedule based on the written specifications of the instrument or 
control manufacturer or that is otherwise necessary to ensure 
instrument or control accuracy. Although the comment does not define 
``criticality,'' FDA believes that ``criticality'' and the proposed 
standard of Sec.  106.30(d)(1) (where ``control is deemed necessary to 
prevent adulteration'') are comparable. Thus, the Agency believes that 
proposed Sec.  106.30(d)(1) is consistent with the comment. 
Accordingly, FDA is making no revisions in the interim final rule in 
response to this comment.
    (Comment 64) Another comment in response to the 2003 reopening 
stated that because more specificity is required and that infant 
formula is the sole source of nutrition for a high risk population, 
calibration needs to be high and frequent. The comment stated that this 
frequency is necessitated by the ubiquity of microbes and formula's 
status as an ideal medium for bacterial growth.
    (Response) FDA notes that this comment did not explain the 
additional ``specificity'' required, or the relationship between 
instrument calibration and microbial contamination.
    The requirement to calibrate is limited to those instruments and 
controls used in the manufacture of an infant formula for measuring, 
regulating, or controlling those parameters where control is deemed 
necessary to prevent adulteration, such as mixing time and speed, 
temperature, pressure, moisture, or water activity. To the extent that 
this comment asserts that calibration should be performed as necessary 
to prevent microbial contamination that would result in adulteration of 
an infant formula, FDA agrees with the comment. However, this comment 
does not require a revision of proposed Sec.  106.30(d)(1). Therefore, 
in light of the foregoing Sec.  106.30(d) is included in the interim 
final rule as proposed with minor editorial changes.
4. Areas of Cold Storage (Proposed Sec.  106.30(e)(2))
    Several comments questioned the across-the-board storage 
temperature requirement of 40 [deg]F (4.4 [deg]C) in proposed Sec.  
106.30(e)(2).
    (Comment 65) One comment argued that instead of requiring that cold 
storage compartments be maintained at a temperature of 40 [deg]F (4.4 
[deg]C) or below, FDA allow manufacturers to establish the appropriate 
temperature for cold storage compartments that would assure the quality 
and safety of in-process materials. The comment recommended that the 
regulations simply state the end point to be achieved, e.g., ``cold 
storage will be maintained at temperatures that prevent growth of 
harmful microorganisms.'' The comment acknowledged that in some 
situations (e.g., the long-term storage of aqueous solutions of 
nutrients that might support microbial growth), the use of 40 [deg]F as 
a storage temperature is well-established as appropriate. But, the 
comment asserted, many materials stored at low temperatures in infant 
formula plants do not require the use of 40 [deg]F to ensure stability.
    (Response) FDA disagrees with this comment. The Agency proposed 40 
[deg]F as the maximum temperature for cold storage compartments because 
a temperature of 40 [deg]F (4.4 [deg]C) is considered to be an 
appropriate temperature to minimize the growth of pathogens (Ref. 15) 
and the deterioration of liquid ingredients, nutrients, and the 
formulated product. The comment did not provide any data, authoritative 
research, or other material to contradict the information supporting 
the proposed standard of 40 [deg]F (4.4 [deg]C). Thus, the proposed 
temperature limit remains appropriate.
    (Comment 66) One comment stated that defining cold storage only as 
40 [deg]F or lower is incompatible with the manufacture of quality 
infant formula. Another comment argued that in some cases, the use of 
temperatures this low may create quality problems for the infant 
formula, such as mix destabilization and non-homogeneity, which could 
theoretically result in the final product being adulterated.
    (Response) FDA agrees in part with this comment. The Agency is 
aware that storing some in-process and final formulas at too low a 
temperature may create quality problems that risk causing a formula to 
be adulterated. Importantly, however, these problems of precipitation 
and instability do not exist in all infant formula materials (such as 
raw ingredients.) Indeed, as noted in Comment 65 there are certain 
infant formula materials that must be stored at lower temperatures, 
such as the 40 [deg]F storage temperature originally proposed, in order 
to maintain quality and safety.
    Accordingly, FDA is revising proposed Sec.  106.30(e)(2) to provide 
infant formula manufacturers with some flexibility in terms of cold 
storage conditions. Specifically, Sec.  106.30(e)(2) of the interim 
final rule permits a manufacturer to store in-process material and 
final formula product (those items that, according to the comments, are 
susceptible to destabilization or loss of homogeneity) for a limited 
period of time at a temperature not greater than 45 [deg]F (7.2 
[deg]C), provided that the manufacturer has data and other information 
to demonstrate both that such materials cannot be stored at 40 [deg]F 
(4.4 [deg]C) without risking an adverse effect on their quality and 
that the storage conditions (i.e., the time and temperature) used by 
the manufacturer are sufficient to ensure the safety of the stored 
product.
    It is well-recognized that the microbial load of a substance, the 
length of time a product is held at a particular temperature, and the 
nature of the product (e.g., product pH) must be considered when 
determining safe storage conditions. The maximum temperature of 45 
[deg]F (7.2 [deg]C) for cold storage compartments will prevent 
significant growth of microorganisms of public health significance 
under certain conditions specific to the product composition and the 
processing step. (Product composition is a factor in how well a 
particular formulation will support microbial growth.) For this reason, 
Sec.  106.30(e)(2)(ii) of the interim final rule requires a 
manufacturer to have data and other information to demonstrate that the 
time and temperature conditions are sufficient to ensure product 
safety. That is, the manufacturer must determine whether a temperature 
not greater than 45 [deg]F (7.2 [deg]C) will be sufficient for the cold 
storage of an in-process formula or a final infant formula for the 
storage period contemplated by the manufacturer. Because the nature of 
the product will affect the extent of microbial growth, this 
determination must be product-

[[Page 7965]]

specific. FDA will consider the conditions of cold storage (i.e., time 
and temperature) to be sufficient for a particular product at a 
particular product stage, provided that there is no significant growth 
of microorganisms of public health significance during the period of 
storage. Significant growth is considered to be growth of one or more 
log colony forming units (CFUs) (Refs. 16 and 17).
    (Comment 67) Another comment maintained that the short period of 
time the materials are held does not justify the use of a 40 [deg]F 
storage temperature and thus, mandating an absolute maximum temperature 
of 40 [deg]F for all purposes is not justifiable to protect public 
health and would require additional capital investments for cooling 
capacity that would not add value to the product.
    (Response) FDA believes that the revision of proposed Sec.  
106.30(e)(2) is responsive to this comment. That revision is based in 
part on the recognition that all infant formula materials do not 
require identical cold storage conditions and thus, the revision 
provides a manufacturer with some flexibility in terms of permissible 
cold storage conditions. In addition, Sec.  106.30(e)(2) of the interim 
final rule reflects the point made implicitly by the comment that 
storage time, as well as temperature, is an important factor in 
ensuring safety of formula materials.
    (Comment 68) One comment noted that if it were necessary to ensure 
that the temperature never rose above 40 [deg]F, the materials would 
have to be held at even lower temperatures most of the time in order to 
allow a ``margin.''
    (Response) FDA disagrees with this comment. In addition to 
specifying a maximum holding temperature and an alternative, proposed 
Sec.  106.30(e) would require a manufacturer to have in place 
safeguards to help ensure appropriate storage temperature, including 
monitoring cold compartment temperatures at appropriate frequencies and 
equipping such compartments with easily readable, accurate temperature-
indicating devices. These provisions are included in Sec.  106.30(e) of 
the interim final rule. The comment did not explain why these 
requirements would not be sufficient to ensure that the maximum holding 
temperature of 40 [deg]F would be achieved without the use of a 
``margin.'' Moreover, as discussed previously in this document, FDA 
recognizes that, in certain circumstances, the 40 [deg]F (4.4 [deg]C) 
holding temperature could adversely affect product quality. Thus, FDA 
has revised proposed Sec.  106.30(e)(2) to provide some flexibility in 
terms of the maximum holding temperature for certain in-process and 
finished infant formulas.
    (Comment 69) Another comment suggested that the maximum temperature 
of 45 [deg]F (7.2 [deg]C) for cold storage would be appropriate and 
consistent with Sec.  110.80(b)(3)(i), the Grade ``A'' Pasteurized Milk 
Ordinance, industry practice, and equipment design capabilities.
    (Response) FDA believes that the revision of proposed Sec.  
106.30(e)(2) is responsive to this comment. That revision is based in 
part on the recognition that all infant formula materials do not 
require identical cold storage conditions and thus, the revision 
provides a manufacturer with some flexibility in terms of permissible 
cold storage conditions. In particular, Sec.  106.30(e)(2) of the 
interim final rule will permit certain formula materials to be stored 
at a temperature not greater than 45 [deg]F (7.2 [deg]C) as long as the 
formula manufacturer has data and other information to demonstrate an 
adverse effect on the quality of the product if held at 40 [deg]F or 
below and to demonstrate that there is no significant growth of 
microorganisms of public health significance during the period of 
storage.
5. Thermal Processing and Temperature-Recording Devices (Proposed Sec.  
106.30(e)(3))
    (Comment 70) One comment stated that the thermal processing 
recording device requirement in proposed Sec.  106.30(e)(3)(ii) is 
either redundant or in conflict with part 113 (Thermally Processed Low-
Acid Foods Packaged in Hermetically Sealed Containers). The comment 
observed that proposed Sec.  106.30(e)(3)(ii) requires that a thermal 
processing temperature-recording device reflect the true temperature, 
and that Sec.  113.40(e)(2) requires a bias so that the temperature-
recording device reads ``as nearly as possible with, but to be in no 
event higher than, the known accurate mercury-in-glass thermometer.'' 
The comment stated that part 113 more accurately reflects the needs of 
a thermal processing system, and suggested that the infant formula CGMP 
simply refer to the regulations in part 113.
    (Response) FDA agrees with these comments and is revising and 
consolidating certain provisions of proposed Sec.  106.30(e), as 
discussed in detail in this document.
    First, FDA is revising proposed Sec.  106.30(e)(1) to clarify that 
the requirements in parts 108 and 113 (21 CFR parts 108 and 113) apply 
to thermally-processed infant formula. This is simply restating an 
existing requirement. In light of this revision, FDA is deleting the 
language in proposed Sec.  106.30(e)(3)(ii) that ``Thermal processing 
equipment shall be equipped with temperature-recording devices that 
will reflect the true temperature on a continuing basis.'' Thus, Sec.  
106.30(e)(1) of the interim final rule states: ``Equipment and 
procedures for thermal processing of infant formula packaged in 
hermetically sealed containers shall conform to the requirements in 21 
CFR parts 108 and 113.''
    Second, FDA is revising the portion of proposed Sec.  106.30(e)(1) 
that would require, among other things, that thermal processing 
equipment used at points where temperature control is necessary to 
prevent adulteration ``be monitored with such frequency as is necessary 
to ensure that temperature control is maintained,'' and redesignating 
it in the interim final rule as Sec.  106.30(e)(5). Under Sec.  
108.35(c)(2), thermal processing monitoring frequency would be included 
in the information required to be submitted in the process filing for 
the scheduled process. Thus, Sec.  106.30(e)(5) of the interim final 
rule states that ``Such monitoring shall be at such frequency as is 
required by regulation or is necessary to ensure that temperature 
control is maintained.''
    (Comment 71) A comment stated that it was unnecessary to require in 
proposed Sec.  106.30(e)(3)(ii) that ``[c]old storage compartments must 
be equipped with either temperature-recording devices that will reflect 
the true temperature, on a continuing basis, within the compartment or, 
in lieu of a temperature-recording device, a high temperature alarm or 
a maximum-indicating thermometer that has been verified to function 
properly'' because cold storage temperature monitoring can be 
acceptably achieved through periodic manual recordings with sufficient 
frequency to ensure proper temperature control. The comment explained 
that the large volume liquid mixes in the infant formula manufacturing 
process do not demonstrate significant temperature changes over time, 
and therefore, do not warrant the increased capital investment of 
recording devices and temperature alarms. The comment argued that 
manual recordings at predetermined intervals are adequate to monitor 
cold temperature storage conditions.
    (Response) FDA agrees that an appropriate method of ensuring that 
cold storage temperature control is maintained is by manual monitoring 
compartment temperature on a temperature-indicating device and

[[Page 7966]]

recording this temperature in a record with such frequency as is 
necessary to ensure that temperature control is maintained. The goal of 
proposed Sec.  106.30(e)(3)(ii) is to ensure adequate control of cold 
temperatures. It is feasible to accomplish manually what can also be 
achieved automatically; in this case, establishing a plan to monitor 
cold temperatures, monitoring and recording the temperature, and doing 
so at appropriate intervals, can provide the same assurance as an 
automatic temperature monitoring system. Accordingly, FDA is adding 
such manual monitoring to the options originally provided in proposed 
Sec.  106.30(e)(3)(ii). Thus, an infant formula manufacturer will have 
four choices for monitoring the temperature of a cold storage 
compartment: (1) The temperature may be monitored manually using a 
temperature-indicating device and manually recording the temperature at 
an appropriate frequency; (2) the compartment may be equipped with a 
temperature-recording device that will reflect the true temperature, on 
a continuing basis, within the compartment; (3) the compartment may be 
equipped with a high temperature alarm that has been verified to 
function properly and the temperature may be manually recorded at an 
appropriate frequency; or (4) the compartment may be equipped with a 
maximum-indicating thermometer that has been verified to function 
properly and the temperature may be manually recorded at an appropriate 
frequency.
    Additionally, Sec.  106.30(e)(3)(ii) of the interim final rule 
includes information about making and retaining records. Section 
106.30(e)(3)(iii) of the interim final rule takes into account the 
option to manually monitor temperatures, by stating that ``the 
manufacturer shall, in accordance with Sec.  106.100(f)(3), make and 
retain records of the temperatures recorded in compliance with Sec.  
106.30(e)(3)(ii).'' Because Sec.  106.30(e)(3)(iii) of the interim 
final rule contains the requirement that ``the manufacturer shall, in 
accordance with Sec.  106.100(f)(3), make and retain records of the 
temperatures recorded in compliance with Sec.  106.30(e)(3)(ii),'' FDA 
is making conforming changes to proposed Sec.  106.100(f)(3). Section 
106.100(f)(3) of the interim final rule includes ``records in 
accordance with Sec.  106.30(e)(3)(iii).''
    (Comment 72) One comment suggested that proposed Sec.  106.30(e)(4) 
be deleted because the requirement that thermal process recording 
devices be biased to not read higher than the calibrated temperature-
indicating device is redundant with part 113. Another comment asserted 
that proposed Sec.  106.30(e)(3)(ii) and proposed Sec.  106.30(e)(4) 
conflict with one another.
    (Response) As noted, FDA is revising proposed Sec.  106.30(e)(1) to 
clarify that the requirements in parts 108 and 113 apply to thermally-
processed infant formula. The requirement of proposed Sec.  
106.30(e)(4) is incorporated into Sec.  106.30(e)(1) of the interim 
final rule by virtue of the reference to the application of the 
requirements in parts 108 and 113 to thermally-processed formula. 
Accordingly, in Sec.  106.30(e)(4) of the interim final rule, FDA is 
deleting the language referring to thermal process recording devices 
not reading ``higher than the calibrated temperature-indicating device 
for thermal processing equipment.''
    (Comment 73) A comment argued that the bias in proposed Sec.  
106.30(e)(4) relating to cold storage temperature recorders was 
inappropriate because a slight temperature deviation of the cold 
storage compartment would have a very small impact on the growth of 
microorganisms. The comment contended that the proposal appears to 
equate the importance of a very slight temperature deviation for the 
sterilization process with a very slight temperature deviation of the 
cold storage compartment when the two situations are radically 
different. The comment explained that a one degree Fahrenheit drop in 
the sterilization temperature could have a significant effect on the 
process lethality and could result in a failure to meet commercial 
sterility, whereas a one degree Fahrenheit increase in the temperature 
of a cold storage compartment would have a very small impact on the 
growth of microorganisms.
    (Response) FDA disagrees with this comment. The purpose of proposed 
Sec.  106.30(e)(4) is to ensure that a temperature-recording device for 
a cold storage compartment reflects the actual temperature of the 
compartment and will not overstate the conditions in the compartment. 
The accuracy of a temperature-recording device is important given that 
the record in this rulemaking establishes that a temperature of 
40[deg]F (4.4[deg]C) in cold storage compartments will prevent the 
growth of harmful microorganisms and will prevent spoilage and 
deterioration of nutrients, all of which could lead to adulteration of 
the infant formula. Moreover, as noted previously in this document, the 
impact of temperature variation, including a one degree Fahrenheit 
increase in temperature, will vary depending upon the initial microbial 
load of the chilled product, the time the product is held at the 
elevated temperature, and other product characteristics, such as 
product hydrogen-ion concentration (pH) (Refs. 16 and 17).
    Accordingly, in light of the foregoing comments, Sec.  106.30(e)(4) 
of the interim final rule provides that ``When a manufacturer uses a 
temperature-recording device for a cold storage compartment, such 
device shall not read lower than the reference temperature-indicating 
device.''
    (Comment 74) One comment objected to the recommendation in the 1996 
preamble that ``manufacturers should calibrate thermometers for cold 
storage temperature measurements at least at the beginning and end of 
each production day . . ..'' The comment argued that FDA is 
recommending a calibration frequency that is far more stringent than 
measurement devices for thermal food processing, which is a process of 
critical importance. The comment asserted that the frequency for 
calibration of cold storage temperature measurement devices should be 
determined by the manufacturer based on the volume, hold time, and 
location in the manufacturing process.
    (Response) FDA agrees with this comment to the extent that the 
comment asserts that calibration frequency should be determined by the 
manufacturer based on variables of the manufacturer's process. In 
addition, in determining the appropriate calibration frequency, a 
manufacturer should consider the calibration frequency recommended by 
the manufacturer of the equipment in question.
6. Maintenance of Equipment and Utensils at Regular Intervals (Proposed 
Sec.  106.30(f))
    A number of comments objected to the requirements in proposed Sec.  
106.30(f) relating to cleaning, sanitizing, and maintaining equipment 
and utensils. These comments indicate that there is confusion about 
what would be required by proposed Sec.  106.30(f).
    FDA intended that the requirements of proposed Sec.  106.30(f) 
would extend to all equipment and utensils used in the production of 
infant formula, including storage tanks, equipment and utensils used in 
the ingredient weighing area, in-process and processing equipment and 
utensils, and container filling, closure, and container packaging 
equipment. All of the equipment and utensils used in producing infant 
formula have some potential to cause adulteration of the formula and 
thus, all must be appropriately cleaned, sanitized, and maintained. 
Although every piece of equipment and each utensil is not likely

[[Page 7967]]

to require the same cleaning, sanitizing, or maintenance, all must be 
subject to such activities at intervals that will prevent such 
adulteration.
    (Comment 75) One comment questioned whether the requirement of 
``regular intervals of cleaning, sanitizing, and maintenance'' would 
apply when a production line that ordinarily requires daily cleaning 
and sanitizing is taken out of service. The comment requested that the 
Agency clarify that it is the equipment and utensils used in an 
operating production line for the manufacture of infant formula that 
must be cleaned, sanitized, and maintained at regular intervals.
    (Response) FDA disagrees with this comment. Contrary to the 
comment's suggestion, these requirements apply equally to the equipment 
and utensils of an operating production line and to the equipment and 
utensils of a production line that is taken out of service. FDA 
recognizes that entire production lines, along with their associated 
equipment and utensils, may be taken out of service, sometimes for 
prolonged periods. However, manufacturers must establish cleaning, 
sanitizing, and maintenance procedures that include a schedule for 
cleaning and sanitizing, as necessary, and maintaining dormant 
equipment, including production lines and utensils, prior to 
reactivating their use.
    (Comment 76) Another comment requested that FDA clarify whether the 
requirement in proposed Sec.  106.30(f) to maintain equipment and 
utensils and to check and retain records on this maintenance would 
apply only to major equipment or would include every minor action that 
is taken to maintain equipment (e.g., changing an ``O'' ring). The 
comment argued that if minor actions were included, the requirement 
would be extensive. The comment also suggested that the terms 
``maintained'' and ``maintenance'' be deleted from this section.
    (Response) As stated previously in this document, because all 
equipment and utensils used in producing infant formula have the 
potential to cause adulteration of the formula, all must be 
appropriately cleaned, sanitized, and maintained. Although every piece 
of equipment and each utensil is not likely to require the same degree 
of cleaning, sanitizing, or maintenance, all must be subject to such 
activities at intervals that will prevent such adulteration. Thus, FDA 
disagrees with the comment suggesting that the requirement to maintain 
equipment and utensils, to have a qualified individual check all 
cleaning, sanitizing, and maintenance, and to make and retain records 
of such activities should apply only to major equipment.
    The requirements of proposed Sec.  106.30(f) include both routine 
and required maintenance of all equipment as well as any unplanned 
correction or repair of equipment. Manufacturers generally document the 
routine servicing of production equipment as part of a preventative 
maintenance program that identifies the work to be performed and its 
frequency. Changing an ``O'' ring, an example given in the comment, may 
be documented in a preventative maintenance program simply by noting 
the time, date, and employee involved if changing the ``O'' ring 
represents routine, scheduled equipment maintenance. If, however, this 
activity is an unplanned correction or equipment repair, more detailed 
documentation would likely be required, including an evaluation of 
whether the ``O'' ring failure may have resulted in product 
adulteration.
    The comment did not explain why the words ``maintain'' and 
``maintenance'' should be deleted from proposed Sec.  106.30(f). 
Maintaining production equipment and utensils is, like cleaning and 
sanitizing, an essential part of ensuring that formula does not become 
adulterated due to equipment and utensils. In fact, changing an ``O'' 
ring, an example of ``minor'' maintenance mentioned in the comment, may 
be critically important if, for example, the ``O'' ring is used in pipe 
connections of the processing system where a defective ring could 
result in a loss of sterility or allow contaminants to enter the 
product stream and thus, cause a formula to be adulterated. For these 
reasons, FDA declines to delete ``maintain'' and ``maintenance'' from 
Sec.  106.30(f) of the interim final rule.
    (Comment 77) One comment requested that FDA clarify the meaning of 
``regular intervals'' in the requirement that equipment and utensils 
used in the manufacture of infant formula be cleaned, sanitized, and 
maintained ``at regular intervals.'' This comment also requested that 
FDA clarify that the manufacturer determines the appropriate ``regular 
interval'' for cleaning, sanitizing, and maintaining equipment and 
utensils to prevent adulteration of the infant formula.
    (Response) FDA agrees that under proposed Sec.  106.30(f), the 
manufacturer would determine the intervals between cleaning, 
sanitation, and maintenance activities that are needed to prevent 
adulteration of the infant formula. Specifically, a manufacturer is 
responsible for identifying the ``regular interval'' for cleaning, 
sanitizing, and maintaining equipment and utensils that is appropriate 
to prevent adulteration of the formula. In the preamble to the 1996 
proposal, FDA acknowledged that equipment cleaning, sanitizing, and 
maintenance will vary from plant to plant, concluding that ``[e]ach 
manufacturer should study its own plant and develop a procedure that is 
tailored to that plant's needs and circumstances.'' (61 FR 36154 at 
36165).
    In determining the appropriate interval for these activities, a 
manufacturer should consider the type and nature of the product being 
manufactured (e.g., soy-based, milk-based, liquid, powder), the length 
of production runs, the length of time between equipment and utensil 
use and their cleaning, and the period of time between cleaning and 
subsequent use of the equipment and utensils. Because a ``regular 
interval'' will generally be plant-specific or operation-specific, FDA 
declines to specify further the meaning of ``regular intervals'' in 
proposed Sec.  106.30(f).
    (Comment 78) Another comment objected to the requirement in 
proposed Sec.  106.30(f) that all cleaning, sanitizing, and maintenance 
be checked by a qualified individual to ensure that such activities 
have been satisfactorily completed. The comment asserted that utensils 
should be cleaned and maintained on an ``as needed'' basis and that a 
requirement to check the satisfactory completion would be overly 
burdensome. Thus, the comment suggested changing proposed Sec.  
106.30(f) to only require checking of the cleaning, sanitizing, and 
maintenance of equipment (not utensils). Another comment suggested that 
records should be required to document equipment cleaning but not 
cleaning of utensils.
    (Response) FDA disagrees that the requirement that a qualified 
individual confirm proper cleaning, sanitizing, and maintenance should 
apply only to equipment and not to production utensils. This 
requirement is designed to confirm that cleaning, sanitizing, and 
maintenance have been properly executed. Unless properly cleaned, 
sanitized, and maintained, utensils, like equipment, can be a source of 
adulteration. For example, a utensil that is not properly cleaned, 
sanitized and dried can be a source of microbial contamination.
    FDA notes that this review of utensils is not required to be 
performed immediately after cleaning or sanitizing, as this is left to 
the manufacturer to address in its procedures. For example, a 
manufacturer could conclude that, in its operation, it would be 
sufficient for a qualified individual to check utensils for cleanliness 
immediately before use.

[[Page 7968]]

The Agency agrees that a manufacturer does not need to maintain records 
of utensil cleaning, sanitizing, and maintenance; proposed Sec.  
106.100(f)(4) did not require such records for utensils.
    (Comment 79) Another comment proposed that this section be revised 
to state that only documentation relating to equipment cleaning, 
sanitizing, and maintenance would need to be reviewed to ensure that 
those activities have been completed satisfactorily rather than include 
microbial or other testing required for this verification.
    (Response) FDA is not persuaded to revise proposed Sec.  106.30(f) 
as requested to clarify that a review of records of equipment cleaning, 
sanitizing, and maintenance alone is sufficient to verify that these 
activities have been properly completed. Although review of 
documentation relating to such activities provides some assurance that 
the activities occurred, such records do not provide evidence that such 
efforts have been adequately performed. Only physical examination of 
the equipment and utensils by a qualified individual will provide the 
necessary level of assurance that cleaning, sanitizing, and maintenance 
have been satisfactorily completed. This assessment may or may not 
include the need for microbial or other testing. FDA advises that it is 
the manufacturer's responsibility to determine the specific means 
needed to verify that production equipment and utensils have been 
properly cleaned, sanitized, and maintained in accordance with 
established procedures.
    For all of the foregoing reasons, FDA is not revising proposed 
Sec.  106.30(f) in response to these comments and is making only minor 
editorial changes to this requirement.
7. Use of Compressed Gases in the Manufacture of Infant Formula 
(Proposed Sec.  106.30(g))
    (Comment 80) One comment suggested that proposed Sec.  106.30(g) be 
deleted because it was redundant and is already unlawful under existing 
regulations to introduce indirect additives or adulterants into infant 
formulas by way of gases or by any other means.
    (Response) For the reasons discussed in section IV.A (response to 
Comment 1), FDA disagrees with the suggestion to delete proposed Sec.  
106.30(g) due to redundancy with other existing regulations. The 
purpose of this rule is to establish CGMP and quality control 
requirements designed to prevent the adulteration of infant formula, 
including controls to prevent adulteration under section 402(a)(1), 
(a)(2), (a)(3), and (a)(4) of the FD&C Act. In the preamble to the 1996 
proposal, the Agency explained that compressed gases may be 
contaminated with oil, filth, or microbes, and the comment did not 
dispute that explanation. Accordingly, FDA is not persuaded that this 
requirement relating to compressed gases is unnecessary, and is making 
only minor editorial changes in Sec.  106.30(g) of the interim final 
rule.

G. Controls To Prevent Adulteration Due to Automatic (Mechanical or 
Electronic) Equipment (Proposed Sec.  106.35)

    In 1996, FDA proposed in Sec.  106.35 to require that an infant 
formula manufacturer implement a system of controls designed to prevent 
adulteration due to automatic (mechanical or electronic) equipment. The 
proposal defined the terms ``hardware,'' ``software,'' ``system,'' and 
``validation'' for purposes of proposed Sec.  106.35, and proposed 
requirements for the design, installation (including validation), 
testing, and maintenance of such automatic equipment. The Agency 
received comments on several aspects of proposed Sec.  106.35, which 
are addressed in this document.
    Several comments suggested that the proposed definition of 
validation and the validation requirements be stricken from the rule.
    (Comment 81) One comment requested that proposed Sec.  106.35 be 
deleted and recommended that FDA and members of the infant formula 
industry form a task force to define the scope and content of 
validation of automated systems used in the production or quality 
control of infant formula. The comment stated that through such a task 
force, FDA would be able to assess the cost impact, the degree of 
industry resources, and time necessary to attain compliance with 
proposed Sec.  106.35. The comment further recommended that, until this 
task force has completed these tasks, Sec.  106.35 be removed from part 
106.
    (Response) FDA is not persuaded to remove proposed Sec.  106.35 
from part 106, nor is the Agency persuaded to delay finalizing Sec.  
106.35 until a joint FDA-industry task force can discuss the details of 
systems validation for production and quality control of infant 
formulas. The comment asserted that the purpose of a joint task force 
would be to allow FDA to acquire information to assess the cost impact, 
the degree of industry resources, and time necessary to attain 
compliance with proposed Sec.  106.35. In FDA's view, the comment 
periods in this rulemaking serve the same purpose: they have provided 
an opportunity for interested persons (including the infant formula 
industry) to submit to FDA relevant information about the provisions of 
the proposed rule, including details about the effect of the validation 
provisions of proposed Sec.  106.35. Thus, the infant formula industry 
had opportunities to submit such information in comments both at the 
time of the 1996 proposal and in response to the 2003 reopening. In 
fact, in the notice reopening the comment period in 2003, the Agency 
expressly requested information on validation practices in the infant 
formula industry. Accordingly, a joint task force is not necessary and 
the implementation of Sec.  106.35 need not be delayed. For these 
reasons, FDA is not removing Sec.  106.35 from the interim final rule 
in response to this comment.
    (Comment 82) Another comment suggested that FDA merely require that 
processing equipment be ``designed, installed, tested, and maintained 
in a manner that will ensure that it is capable of performing its 
intended function and of producing or analyzing infant formula.''
    (Response) Systems validation is critical to ensuring that 
manufacturing processes for infant formula do not result in the 
production of adulterated formula and thus, FDA disagrees with this 
comment. The comment does not dispute that validation of systems and 
revalidation of modified systems is a basic tenant of CGMP nor does the 
comment explain why system validation is not necessary either generally 
or specifically in the case of infant formula manufacture (Ref. 18). In 
fact, systems validation is broadly recognized as essential to ensuring 
that a product meeting established specifications can be consistently 
produced under a manufacturer's system. Thus, FDA declines to adopt the 
suggestion of this comment.
    (Comment 83) One comment asserted that it is unnecessary to rely on 
validation because the Infant Formula Act requires finished product 
testing for specific nutrients in each batch of infant formula.
    (Response) FDA believes that this comment confuses system 
validation and system verification. System validation is the process by 
which a manufacturer ensures that a system, if operating properly, is 
capable of producing, on a consistent basis, a product (e.g., an infant 
formula) that meets the manufacturer's specifications. In contrast, 
verification is an on-going determination that the validated system is 
performing as necessary to produce a product that conforms to 
specifications. Nutrient testing is a form of verification of a 
system's proper operation. To the

[[Page 7969]]

extent that such testing shows that a particular production aggregate 
of infant formula does not meet specifications, the operation of the 
manufacturing system is not verified and the validation of the system 
is called into question. Given this distinction between validation and 
verification, FDA disagrees that finished product testing for nutrients 
eliminates the need for system validation.
    (Comment 84) One comment claimed that FDA has proposed an all-
encompassing definition of ``validation'' that is well beyond the scope 
applied even in the drug industry. The comment explained that drug 
validation must be precise because it is imperative that drugs contain 
the precise amount of active ingredient to achieve efficacy in treating 
illness. Because the margin of safety for drugs can be so critical, 
their manufacture requires far more critical tolerances than do infant 
formulas. The comment stated that requiring strict ``drug-like'' 
validation and revalidation of systems for infant formula would be 
extremely costly, unnecessarily burdensome, and a disincentive for 
process improvements.
    (Response) FDA disagrees that the proposed definition of 
``validation'' is overly broad. In the 1996 preamble (61 FR 36154 at 
36166), FDA explained the basis of the definition of ``validation'' in 
proposed Sec.  106.35(a)(4) as follows: The proposed definition is 
derived from the ISO International Guideline ISO-9000-3, (which defines 
``validation'' as ``the process of evaluating software to ensure 
compliance with specified requirements''); the IEEE Standard 610.12-
1990, which (defines it as ``the process of evaluating a system or 
component during or at the end of the development process to determine 
whether it satisfies specified requirements'''); and FDA's ``Glossary 
of Computerized System and Software Development Terminology,'' which 
defines it as ``establishing documented evidence which provides a high 
degree of assurance that a specific process will consistently produce a 
product meeting its predetermined specifications and quality 
characteristics'' (Ref. 19).
    All three sources of the proposed definition have in common the 
concept that ``validation'' involves the evaluation of a system or a 
system component to ensure that it meets established specifications or 
requirements. The ISO definition was revised shortly after FDA issued 
the 1996 proposal. The current ISO definition of validation (ISO 
8402:1994) is ``a step beyond verification to ensure the user needs and 
intended uses can be fulfilled on a consistent basis.'' The other two 
sources of the proposed definition of validation, IEEE Standard 610.12-
1990 (Ref. 19) and FDA's ``Glossary of Computerized System and Software 
Development Terminology'' (Ref. 20), are unchanged.
    The proposed definition of ``validation'' is largely derived from 
FDA's guidance, ``Glossary of Computerized System and Software 
Development Terminology.'' This document is intended to serve as a 
glossary applicable to software development and computerized systems in 
all FDA regulated industries. As such, the guidance document's 
definition of ``validation'' applies equally to all product areas 
regulated by FDA, including human drugs. Thus, FDA disagrees with the 
comment's claim that the proposed definition of ``validation'' is 
``well beyond the scope applied even in the drug industry.''
    Moreover, the comment does not dispute the importance of systems 
validation. As noted, validation of systems and revalidation of 
modified systems is a basic principle of CGMP, one that is essential to 
ensuring that a consistent product can be produced under the 
manufacturer's system. Like drug manufacturing systems, the system used 
to produce infant formula must be able to produce a product that meets 
the manufacturer's specifications and all applicable regulatory 
requirements.
    Finally, although the comment claims that validating all systems 
used to manufacture infant formula before first use would be extremely 
costly, unnecessarily burdensome, and create a disincentive for process 
improvements, the comment does not explain the basis of these 
assertions. Indeed, the comment merely asserted that the proposed 
validation requirements would be costly but did not provide any data or 
other information to support these assertions. FDA notes that in the 
2003 reopening, the Agency expressly requested cost information 
relating to systems validation but no such data were submitted in 
response to that request.
    Accordingly, FDA is not revising the definition of ``validation'' 
in proposed Sec.  106.35(a)(4), and thus, Sec.  106.35(a)(4) is 
included in this interim final rule as proposed.
    FDA received a number of comments addressing the scope of the 
validation requirements.
    (Comment 85) Several comments asserted that FDA's validation 
requirements are overly burdensome, and other comments suggested 
specific changes to the scope of validation. One comment suggested that 
the requirements of proposed Sec.  106.35 be limited to the validation 
of ``critical'' systems (i.e., proposed Sec.  106.35(b)(1), (b)(3), 
(b)(4), and (b)(5)) and ``critical'' hardware and software (i.e., 
proposed Sec.  106.35(b)(2) and (b)(5)). Another comment stated that 
although an indiscriminate and across-the-board validation requirement 
is unnecessarily burdensome, validation of critical systems can be a 
valuable quality assurance tool for the infant formula manufacturer and 
that infant formula manufacturers are already validating systems and 
procedures based upon a risk-based criticality assessment. The comment 
requested that FDA consider a tiered approach to validation, including 
such other concepts as verification, qualification, capability studies, 
challenge testing, and operational testing. For example, HACCP involves 
both a risk-based criticality assessment and other documented levels of 
control. The comment suggested that each company should be permitted to 
decide the levels of validation required, based upon the degree of 
criticality of each system to assuring the safety and quality of the 
infant formula produced.
    (Response) FDA disagrees that the proposed validation requirements 
are overly burdensome and declines to limit the scope of these 
requirements by adding ``critical'' to the description of systems and 
of hardware and software.
    Although FDA agrees that the process for validation is necessarily 
related to the level of risk that each component of the system 
presents, the Agency does not agree that validation should be limited 
to ``critical'' systems. A ``system'' is composed of multiple, 
interdependent parts, and the proper functioning of the system requires 
that all system elements are working as intended. Importantly, the 
comment did not explain how to distinguish ``critical'' from 
``noncritical'' systems used in the manufacture of infant formula. 
Infant formula is a sophisticated mixture of ingredients that is 
intended for use by a vulnerable population as the sole source of 
nutrition during critically important developmental stages. Given the 
nature of the product and its intended consumers, it is difficult, if 
not impossible, to identify a part of the system that is not critical.
    Accordingly, all parts of the ``system'' must be validated-- not 
simply the ``critical'' pieces--to ensure that the system as a whole 
operates properly. This approach is consistent with the Agency's 
position as described in its Guide to Inspections of Computerized 
Systems in the Food Processing Industry (http://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm074955.htm), which states that ``as 
long as the

[[Page 7970]]

computerized system controls or records are part of or the entirety of 
a manufacturing process, the manufacturer is responsible for 
establishing that the computerized system functions as it was intended 
to function'' (Ref. 21).
    FDA agrees that a manufacturer must determine how to validate its 
systems to ensure that the system will consistently produce a product 
meeting predetermined specifications and quality characteristics. The 
Agency recognizes that the validation process may be more complex for 
systems that are integral to controlling or affecting those points, 
steps, or stages where control is necessary to prevent adulteration. 
Thus, FDA is not specifying how each manufacturer must validate its 
systems. It is, however, appropriate to require that a manufacturer 
ensure that any system used to manufacture infant formula is validated 
by having documented evidence that provides a high level of assurance 
that the system will produce infant formula that meets applicable 
specifications and requirements.
    (Comment 86) One comment suggested that proposed Sec.  106.35(b)(5) 
be changed to require revalidation only after a major functional change 
to a system. The comment explained that this change will avoid 
unnecessary revalidation as a result of documented operator interface 
changes that do not change the functionality of the control system.
    (Response) FDA disagrees with this comment that seeks to limit the 
circumstances in which a manufacturer must revalidate a system used to 
manufacture infant formula. By revalidation, FDA means that the 
manufacturer must re-establish that, following a modification to a 
system, the system is functioning as intended. Validation and 
revalidation of a manufacturer's systems are both fundamental concepts 
of CGMP applicable to many different types of products, and both are 
essential to ensuring consistent production of the intended product. 
Thus, a manufacturer must conduct a validation analysis to determine 
the extent and impact of the change on the system in response to any 
change to the system. In fact, a ``major functional change'' requires 
more extensive revalidation than a change that does not change the 
functionality of the control system. Nevertheless, revalidation after a 
change other than a ``major functional change'' is necessary to provide 
assurance that the system, as changed, will continue to produce 
consistently a product that satisfies established specifications and 
quality characteristics. Moreover, FDA advises that the manufacturer 
must not only analyze the need to validate the individual change but 
also the validation status of the entire system to ensure that the 
change did not affect other parts of the system. Based on the 
validation analysis, the manufacturer should conduct an appropriate 
level of regression testing to demonstrate that unchanged but 
vulnerable portions of the system have not been adversely affected.
    For these reasons, FDA is not revising proposed Sec.  106.35(b)(5) 
(recodified as Sec.  106.35(b)(4) in the interim final rule) in 
response to this comment, and is making only minor editorial changes to 
this requirement.
    (Comment 87) Another comment requested that if FDA intends to 
require validation of all mechanical and electronic processes used in 
the manufacture of infant formula, this requirement should not apply 
retrospectively to processes that have been used successfully for many 
years. Instead, the comment asserted, validation should apply only to 
significant changes to equipment or processes that are critical to 
manufacturing formula in the future. The comment also stated that the 
manufacturer is in the best position to determine what testing is 
appropriate for specific pieces of equipment and whether this equipment 
is critical to infant formula manufacture.
    (Response) FDA's response to the previous comment explains why the 
Agency declines to limit the validation requirement to critical 
equipment. Similarly, FDA disagrees with the suggestion that validation 
should not apply retrospectively to systems and processes in place for 
many years. Although this comment claimed that certain systems have 
been ``used successfully for many years,'' the comment provided no data 
or other information to support this assertion. Validation requires a 
systematic evaluation of a process or system and the development of 
evidence to show that a system will consistently produce a product 
within predetermined specifications. The mere operation of a system for 
a lengthy period without apparent problems is neither systematic nor 
``documented evidence'' of adequate function. The manufacturer must 
ensure that the system it creates (including software and hardware) 
functions in the way intended and therefore is capable of producing 
what the manufacturer intends according to required specifications. As 
noted, FDA is not specifying in the interim final rule how each 
manufacturer must validate its systems, but is requiring that such 
systems be validated. This requirement applies to all systems, whether 
such systems were in place prior to the interim final rule or are 
established after the effective date of the interim final rule.
    (Comment 88) One comment suggested that proposed Sec.  106.35(b)(4) 
be revised to require that only software-controlled equipment be 
validated. The comment further stated that this requirement should be 
changed to require only that the equipment be designed, installed, 
tested, and maintained in a manner that will ensure that it is capable 
of performing its intended function and of producing or analyzing 
infant formula.
    (Response) FDA disagrees with this comment. Although various 
components of a system may, and should, be tested separately, the 
entire ``system'' (i.e., collection of components, including software 
and hardware, organized to accomplish a specific function or set of 
functions in a specified environment) must be validated to ensure that 
the system, as it is configured and used in the production of infant 
formula, consistently performs within the pre-established operational 
limits and consistently produces formula that meets established 
specifications and quality characteristics. FDA notes that, as defined 
in proposed Sec.  106.35(a)(3), a ``system'' is the collection of all 
mechanical and electronic components, as well as all other components, 
including manual components (such as a manually operated crank), and 
the operation of such manual components would be evaluated as part of 
the required validation of the system. The ability of a system to 
produce the intended product on a consistent basis depends upon the 
proper functioning of all system components. Thus, system validation 
encompasses all equipment, including mechanical and electronic 
equipment (which includes computer software.) Therefore, FDA is not 
revising proposed Sec.  106.35(b)(4) in response to this comment.
    (Comment 89) Several comments objected to proposed Sec.  
106.35(b)(4) and (b)(5), which would require that all systems be 
validated before their first use to manufacture commercial product or, 
in the case of a modified system, before use of the modified system to 
manufacture commercial product. The comments noted that while most 
system validation work is conducted prior to the production of infant 
formula, the first commercial batch should be produced as part of the 
validation process.

[[Page 7971]]

    (Response) FDA agrees that a production aggregate of infant formula 
that is produced as part of the initial validation process of a system 
may be commercially distributed, provided that the manufacturer 
determines before release that the production aggregate meets the 
manufacturer's specifications and otherwise complies with the FD&C Act 
and FDA's regulations. Similarly, FDA agrees that a production 
aggregate of infant formula that is produced as part of the 
revalidation of a system may be commercially distributed, provided that 
the manufacturer determines before release that the production 
aggregate meets the manufacturer's specifications and otherwise 
complies with the FD&C Act and FDA's regulations. Accordingly, FDA is 
revising proposed Sec.  106.35(b)(4) and (b)(5), which are recodified 
as Sec.  106.35(b)(3) and (b)(4) in the interim final rule and include 
minor editorial revisions, to require that infant formula be produced 
as part of the validation process.
    In addition to the comments relating to validation, FDA received 
comments on several other aspects of proposed Sec.  106.35.
    (Comment 90) One comment suggested that the Agency delete the 
requirement in proposed Sec.  106.35(b)(2) that hardware be routinely 
calibrated. The comment argued that calibration applies to 
instrumentation, not hardware.
    (Response) FDA disagrees with this comment. The word ``hardware'' 
was defined in proposed Sec.  106.35(a)(1) as ``all automatic 
equipment, including mechanical and electronic equipment (including 
computers) that is used in the production or quality control of a 
infant formula.'' As defined, hardware would include any automated 
instrumentation that can be calibrated. Thus, it is appropriate that 
proposed Sec.  106.35(b)(2) would require the calibration of hardware. 
Accordingly, FDA is not deleting the requirement from proposed Sec.  
106.35(b)(2) that hardware be routinely calibrated, but is clarifying 
that calibration applies to hardware that is capable of being 
calibrated. Thus, Sec.  106.35(b)(1) of the interim final rule reads 
``A manufacturer shall ensure that hardware that is capable of being 
calibrated is routinely calibrated according to written procedures, and 
that all hardware is routinely inspected and checked according to such 
procedures.''
    (Comment 91) One comment suggested that the statement ``nutrient 
test results should be used to substantiate the adequacy of the checks 
required by this section'' be added to proposed Sec.  106.35(b)(3).
    (Response) FDA is not persuaded to add this statement to proposed 
Sec.  106.35(b)(3). Nutrient test results alone may not be sufficient 
to substantiate the adequacy of all checks required by this provision. 
Although meeting specifications for nutrients may be a part of input/
output verification, other factors, such as levels of microorganisms or 
other contaminants and achieving adequate temperature, may also be a 
part of verification of the production system.
    Assessing the adequacy of can seam measurements illustrates the 
limitations of nutrient test results for this purpose. A formula 
manufacturer may use a computerized system to measure and determine the 
adequacy of container seams. If the system is not confirmed as 
accurate, errors could be generated by this system and the product 
could become adulterated due to inadequate container seams. 
Importantly, nutrient testing could not determine the accuracy of 
results from this seam measurement system because such testing 
evaluates the nutritional adequacy of the formula and does not address 
the adequacy of a formula's packaging. Further, the systems covered by 
proposed Sec.  106.35 are the automated systems used in the quality 
control testing of an infant formula. Automated systems used in quality 
control of an infant formula must also be validated before accurate 
nutrient test results can be obtained. Thus, FDA declines to add 
``nutrient test results should be used to substantiate the adequacy of 
the checks required by this section'' to Sec.  106.35(b)(3) in the 
interim final rule because this would erroneously suggest that nutrient 
testing is all that is necessary to substantiate the adequacy of the 
validation required by Sec.  106.35(b)(3).
    (Comment 92) One comment suggested that FDA revise the part of 
proposed Sec.  106.35(b)(3) that states ``the degree and frequency of 
input/output verification shall be based on the complexity and 
reliability of the system and the level of risk associated with the 
safe operation of the system.'' The comment stated that the 
verification must be based on the manufacturer's assessment of the 
complexity and reliability of the system and the level of risk 
associated with the safe operation of the system.
    (Response) FDA disagrees with this comment because inserting the 
phrase, ``based on the manufacturer's assessment,'' does not further 
clarify what is being required. The ultimate purpose of the 
verification required by proposed Sec.  106.35 is to confirm that 
formula manufacturing systems will produce a formula that is not 
adulterated. Although the verification process for more complex systems 
and systems that operate to control potentially high levels of risk are 
likely to require more diligence by the manufacturer to ensure the safe 
operation of the system, the degree and frequency of verification that 
the manufacturer employs must be sufficient to ensure that the final 
product is not adulterated. Therefore, FDA is revising proposed Sec.  
106.35(b)(3) to clarify the level of effort required. Section 
106.35(b)(2) of the interim final rule states ``A manufacturer shall 
check and document the accuracy of input into, and output generated by, 
any system used in the production or quality control of an infant 
formula to ensure that the infant formula is not adulterated.'' Adding 
this phrase clarifies that the manufacturer must ensure that the system 
is able to meet established specifications for any point, step, or 
stage in the production process where control is necessary to prevent 
adulteration.
    (Comment 93) Regarding proposed Sec.  106.35(c), one comment 
requested that FDA limit the recordkeeping requirements to critical 
automatic equipment, as opposed to all automatic equipment.
    (Response) As stated in response to Comment 85, FDA declines to 
limit the validation requirements of the interim final rule to 
``critical'' systems, hardware, and software.
    In addition to the revisions to proposed Sec.  106.35 in response 
to comments, the Agency has made minor editorial revisions in Sec.  
106.35 of the interim final rule.

H. Controls To Prevent Adulteration Caused by Ingredients, Containers, 
and Closures (Proposed Sec.  106.40)

    In 1996, FDA proposed in Sec.  106.40 to require that an infant 
formula manufacturer implement a system of controls designed to prevent 
adulteration caused by ingredients, containers, and closures. The 
proposed provisions included standards for ingredients, containers, and 
closures used for infant formulas, as well as requirements for 
identification, rejection and acceptance, and storage of these 
materials.
    The Agency received comments on several aspects of proposed Sec.  
106.40, which are addressed in this document. In addition to the 
revisions made in response to comments that are discussed in this 
document, FDA has made minor editorial revisions in Sec.  106.40 of the 
interim final rule.

[[Page 7972]]

1. Food Ingredients and Food Contact Substances (Proposed Sec.  
106.40(a) and (b))
    (Comment 94) One comment asserted that proposed Sec.  106.40(a) 
should be deleted as redundant because, under current law and 
regulations, it is illegal to use an ingredient in an infant formula 
that is not GRAS, an approved food additive, or prior-sanctioned for 
such use.
    (Response) As discussed in the response to Comment 1, the Agency is 
not making changes to Sec.  106.40(a) in response to this comment, and 
has only made minor editorial changes in Sec.  106.40(a) of the interim 
final rule.
    (Comment 95) Several comments asserted that proposed Sec.  
106.40(b) was unnecessarily restrictive in terms of the substances that 
would be permitted for use in infant formula packaging, including 
containers and closures. One comment expressed concern that proposed 
Sec.  106.40(b) would appear to exclude the use of substances in infant 
formula packaging that are not ``food additives'' within the meaning of 
section 201(s) of the FD&C Act (i.e., substances that are not 
reasonably expected to become a component of food when used as 
intended). In addition, the comment expressed concern that proposed 
Sec.  106.40(b) would prohibit the use of substances reviewed under 21 
CFR 170.39 for use in food-contact material and exempted from the 
requirement of a food additive regulation. This comment also contended 
that all packaging materials authorized by a prior sanction issued by 
the U.S. Department of Agriculture (USDA) should be allowed in infant 
formula packaging.
    (Response) FDA did not intend to limit permissible infant formula 
packaging to substances regulated as food additives. To the extent that 
use of a food packaging material for infant formula packaging is exempt 
under Sec.  170.39, FDA agrees such substance would be permissible in 
infant formula packaging. Similarly, although FDA is not aware of any 
prior sanction issued by USDA for a substance that could be used in 
infant formula packaging, if a prior sanction exists, a substance used 
in accordance with such prior sanction would be lawful. Also, to the 
extent that a substance in food packaging is not reasonably expected to 
become a component of food, the substance is not a food additive under 
section 201(s) of the FD&C Act and thus, could be lawfully used in 
infant formula packaging without prior approval. Finally, proposed 
Sec.  106.40(b) recognized that a substance authorized for use as an 
``indirect food additive'' could be lawfully used in infant formula 
packaging. As a result of amendments made to section 409 of the FD&C 
Act by the Food and Drug Administration Modernization Act (FDAMA) (Pub. 
L. 105-115), food packaging materials are generally now regulated as 
``food contact substances.'' Thus, FDA agrees that the rule should 
recognize that a food contact substance that is the subject of an 
effective notification under section 409(h) of the FD&C Act may be 
lawfully used in packaging for infant formula.
    Thus, in response to these comments and the FDAMA amendments, FDA 
is clarifying proposed Sec.  106.40(b) to identify all substances that 
may lawfully be used for infant formula containers, closures, and 
packaging. Section 106.40(b) of the interim final rule lists all 
substances that may lawfully be used in food packaging for infant 
formula.
    (Comment 96) One comment suggested that FDA list in Sec.  106.40(b) 
substances that are exempted from the requirement of a food additive 
listing regulation under Sec.  170.39.
    (Response) FDA does not agree that the Agency should list in Sec.  
106.40(b) of the interim final rule those substances that FDA has 
exempted from the requirement of a food additive listing regulation 
under Sec.  170.39. This information is continually changing, and FDA's 
Web site has current lists of the substances exempted under Sec.  
170.39, http://www.fda.gov/Food/FoodIngredientsPackaging/FoodContactSubstancesFCS/ucm093685.htm, and the food contact substances 
that are the subject of an effective notification, http://www.fda.gov/Food/FoodIngredientsPackaging/FoodContactSubstancesFCS/ucm116567.htm.
2. Written Specification for Ingredients, Containers, and Closures 
(Proposed Sec.  106.40(d))
    Several comments objected to proposed Sec.  106.40(d), which would 
require an infant formula manufacturer to develop written 
specifications for the acceptance or rejection of ingredients, 
containers, and closures (``the materials'') to be used in infant 
formula manufacturing.
    (Comment 97) One comment objected to several statements in the 1996 
proposal, including FDA's statement that ``indigenous'' nutrients 
should be included in ingredient specifications and standards for 
acceptance or rejection (61 FR 36154 at 36167). The comment argued that 
testing for endogenous nutrients in these cases is not for acceptance 
or rejection of the ingredient, but to determine the actual nutrient 
levels that can be factored into specific batch formulations.
    (Response) As discussed previously in this document in section 
V.C.1, FDA is persuaded by the comments to revise Sec.  106.40(d) in 
the interim final rule to delete the requirement that any ingredient, 
container, or closure that does not conform to specifications must 
automatically be rejected. The Agency believes that this change 
responds, at least in part, to the comment objecting to statements in 
the 1996 preamble that manufacturers must establish, and test for, 
levels of endogenous nutrients in formula ingredients.
    FDA disagrees with this comment to the extent that it objects to 
the requirement that the proposed rule would require a formula 
manufacturer to establish specifications for the nutrient content of 
formula ingredients and a process to assess whether such specifications 
have been met. These procedures may include reliance on a supplier's 
guarantee or certification that an article conforms to specifications 
or a laboratory analysis by the formula manufacturer that demonstrates 
that the article conforms to established specifications. Even where a 
formula manufacturer relies on a guarantee, FDA expects that the 
ingredient will conform to the specifications set by the manufacturer 
and that the manufacturer has a means to evaluate the guarantee or 
certification, such as periodic chemical analysis of the ingredient.
    A manufacturer's specifications should include specifications for 
endogenous nutrients in formula ingredients because such specifications 
are one method of ensuring both that the required nutrients will be 
present in the infant formula at or above the established minimum level 
and that any nutrient for which there is an established maximum level 
is not present in the formula at a level that would cause the product 
to be adulterated. Chemical analysis for such endogenous nutrients is 
the means by which a manufacturer is able to determine the nutrient 
levels actually present, which information may be factored into a 
specific production aggregate's formulation.
    Although there is no requirement that the manufacturer test every 
ingredient for all nutrients as suggested in the comment, section 
412(b)(3)(B) of the FD&C Act requires that manufacturers test each 
nutrient premix for each nutrient that the manufacturer expects to be 
supplied by the premix to ensure that the premix complies with its 
specifications or the certification by the

[[Page 7973]]

premix supplier. Accordingly, the FD&C Act requires that a manufacturer 
test each nutrient premix, but the FD&C Act does not require testing 
the premix for nutrients not intended to be supplied by the premix.
    (Comment 98) One comment asserted that infant formula manufacturers 
have an extensive history in the use of condensed skim milk such that 
they can predict endogenous nutrient levels within a narrow range. The 
comment argued that because of this experience with this ingredient and 
the fact that the condensed skim milk can provide 100 percent of 
several of the final product's nutrients, there is no need to assay the 
ingredients for specific batch formulations. The comment also argued 
that because all nutrients required to be present in infant formula are 
tested and assured in each batch as required by the Infant Formula Act, 
any problems would be detected through routine, legally mandated in-
process and finished product testing.
    (Response) Section 106.40(d) of the interim final rule does not 
specify which nutrients in which formula ingredients must be the 
subject of manufacturer specifications and does not require that 
ingredients be tested for endogenous nutrients. FDA agrees with the 
comment that an infant formula manufacturer's history of use of an 
ingredient may help determine what endogenous nutrients should be 
included as an ingredient specification and when testing is necessary 
to confirm a supplier's assurance that the manufacturer's ingredient 
specifications are met. FDA views endogenous nutrient specifications as 
one method of ensuring both that the required nutrients will be present 
in the infant formula at the appropriate level and that nutrients that 
have maximum levels under Sec.  107.100 will not be present in the 
formula at levels that would cause the product to be adulterated. 
Testing of endogenous nutrients can serve to confirm that the nutrients 
are in the ingredient in the amount anticipated by the manufacturer and 
to ensure that the infant formula will have the required levels of 
nutrients. The example given in the preamble to the 1996 proposal (61 
FR 36154 at 36167) was the level of sodium determined in the protein 
ingredient, sodium caseinate. The maximum level of sodium that can 
legally be in an infant formula is 60 mg/100 kilocalorie (kcal). The 
level of sodium in the sodium caseinate will affect how much sodium can 
be added to the formula from other sources before this legally mandated 
sodium limit is violated.
    Although the interim final rule does not require testing 
ingredients for endogenous nutrient levels, it is very useful for 
manufacturers to know the endogenous nutrient content of the 
ingredients so that the infant formula is manufactured with all the 
required nutrients within required ranges and adjustments that may be 
needed during processing may be better anticipated. Use of routine in-
process and finished product testing is valuable because it can help 
detect problems with the levels of required nutrients prior to 
distribution. Testing for endogenous ingredients may reduce the need 
for adjustments during processing, which can provide the manufacturer 
with added efficiency, reduced costs, and more robust adherence to 
CGMP. Indeed, a manufacturer may find through experience that the best 
way to ensure that the final product will meet all specifications is to 
measure certain nutrients in ingredients before using them in the 
production of infant formula.
    (Comment 99) One comment stated requiring that ingredients be 
tested for all endogenous nutrients would have a significant impact on 
laboratory space, manpower, operating costs, and potentially quality, 
with no increased assurance of benefit to infants consuming the final 
product.
    (Response) As noted previously in this document, FDA is requiring 
under Sec.  106.40(d) of the interim final rule that any failure to 
meet specifications be investigated to ensure that the failure does not 
lead to the release into the marketplace of an adulterated infant 
formula. FDA is not requiring that the manufacturer test all formula 
ingredients for all endogenous nutrients. Importantly, however, 
endogenous nutrient testing is one means to limit final product 
rejection, reformulation, or reprocessing and thus, the costs of such 
testing must be balanced by potential costs of rejection, 
reformulation, or reprocessing. That is, a manufacturer should consider 
that the costs of formula adjustments during or at the end of 
processing might be avoided by chemical analysis of ingredients because 
such an approach may offset possible costs related to testing the 
endogenous nutrient content.
    (Comment 100) One comment also objected to the suggestion in the 
preamble to the 1996 proposal that included testing for contaminants in 
the ingredient specifications and standards for acceptance or rejection 
of the material except as provided in compendial standards such as 
United States Pharmacopeia (USP) (http://www.usp.org). The comment 
argued that this suggestion is inappropriate and unworkable and that 
there are significant questions to be considered, such as the selection 
of contaminants to test for in each ingredient, the determination of 
acceptable/unacceptable levels, and detection versus quantification 
scenarios. The comment further argued that even if one were to address 
these questions, the inclusion of routine contaminant testing would be 
grossly impractical due to the sophistication of the testing involved 
and the exorbitantly high costs associated with compliance. The comment 
stated that the testing requirements for ingredients, containers, and 
closures should be determined by the manufacturer.
    (Response) As explained in section V.C.1 of this document, FDA has 
revised proposed Sec.  106.40(d) by removing the proposed requirement 
that an ingredient, container, or closure that fails specifications 
shall be automatically rejected for use in formula manufacturing and, 
instead, to provide that an ingredient, container, or closure that 
fails to meet a specification, as well as any formula that could be 
affected by the deviation, shall be quarantined pending a formal, 
documented review and material disposition decision. The Agency 
recognizes that a failure to conform to a specification does not 
necessarily mean that the infant formula manufactured using the 
ingredient, container, or closure will be adulterated and thus, should 
not be automatically rejected for use in formula manufacturing. In the 
interim final rule, FDA has made additional revisions to the proposed 
provisions to ensure that deleting the automatic rejection provision 
will nevertheless result in adequate public health protection by 
requiring that each manufacturer establish a robust procedure to 
investigate any deviation from specifications so that the manufacturer 
can credibly determine whether the deviation from specifications will 
result in adulteration of infant formula. The revisions to the proposed 
requirements will ensure that there is a documented review of the 
deviation, that records of such documented review are established and 
maintained, and that affected materials are quarantined pending a 
decision about their appropriate disposition. Therefore, this comment 
has been addressed to the extent that it relates to the need for a 
specification to determine ``acceptance or rejection'' of ingredients, 
containers, and closures.
    FDA agrees with the comment that the infant formula manufacturer is 
responsible for determining whether contaminant testing of formula

[[Page 7974]]

ingredients is warranted and if so, for which contaminants. In the 1996 
proposal, FDA did not specify the contaminants for which a manufacturer 
must test or when such testing must occur because the Agency believes 
that formula manufacturers are likely to be more aware of which 
contaminants may be present in their particular ingredients and that 
may adulterate or lead to adulteration of formula.
    (Comment 101) One comment suggested that FDA add the phrase ``as 
components'' and the phrase ``and packaging'' to proposed Sec.  
106.40(d) to require manufacturers to develop written specifications 
for ingredients, containers, and closures used as components in infant 
formula manufacturing and packaging.
    (Response) FDA declines to adopt the suggestion in this comment 
because the Agency considers that it is understood that the 
ingredients, containers, and closures referred to in proposed Sec.  
106.40 for which the manufacturer must develop written specifications 
are those used by such manufacturer in its formula production 
operation. Indeed, this is a reasonable interpretation because these 
are the ingredients, containers, and closures over which the 
manufacturer exercises control, including the authority and obligation 
to establish and apply specifications for such materials.
    (Comment 102) One comment suggested that proposed Sec.  
106.40(e)(3) should be revised to permit the reconditioning, under 
certain conditions, of materials that have been rejected for use in 
infant formula production. The comment did not specify under what 
conditions it thought reconditioning should be allowed.
    (Response) As discussed previously in this document in response to 
Comment 38, Sec.  106.40(d) of the interim final rule establishes 
reconditioning of an ingredient, container, or closure that fails to 
meet a specification as one of the three alternative dispositions that 
may result from the documented review that is required when any such 
material does not conform to a manufacturer's specifications.
3. Option To Reject Ingredients, Containers, or Closures (Proposed 
Sec.  106.40(f))
    (Comment 103) One comment requested that proposed Sec.  106.40(f) 
be modified to permit rejection of ingredients, containers, or closures 
that fail to meet a specification as well as for the retesting or 
reexamination of such deviant materials.
    (Response) As discussed in response to comment 38, Sec.  106.40(f) 
of the interim final rule requires a documented review and material 
disposition decision and such decision may be to reject an ingredient, 
container, or closure that does not conform to the manufacturer's 
specifications, to reprocess or otherwise recondition and then test or 
reexamine such material to determine whether it should be approved and 
released for use, or simply to approve and release for use without 
reconditioning.
    (Comment 104) Another comment agreed that the requirement to retest 
or reexamine any ingredient, container, or closure, if it is found by 
the infant formula manufacturer to have been exposed to adverse storage 
conditions, is reasonable. However, the comment contended that this 
requirement should only apply when the manufacturer has knowledge of 
the potentially adverse conditions. The comment suggested that to 
document control of all storage areas, additional recording charts 
might be needed to provide continuous monitoring.
    (Response) Consistent with changes elsewhere in the interim final 
rule and discussed in section V.C.1, FDA has revised proposed Sec.  
106.40(f) to provide for a documented review and material disposition 
decision in the circumstances covered by this provision. Also, the 
Agency is not persuaded that the requirement of proposed Sec.  
106.40(f) should only apply when the manufacturer has actual knowledge 
of potentially adverse conditions affecting an ingredient, container, 
or closure. A manufacturer has a responsibility, as part of CGMP, to 
quarantine an ingredient, container, or closure when that manufacturer 
has a reasonable basis to believe that the ingredient, container, or 
closure may have been exposed to adverse conditions. For example, a 
manufacturer must quarantine and conduct a documented review and make a 
material disposition decision when the manufacturer has information 
relating to where and when such materials were held, which information 
reasonably suggests that the integrity of the materials may have been 
compromised. A formula manufacturer has the overarching responsibility 
to ensure that its infant formula is not adulterated, which 
responsibility includes ensuring that ingredients, containers, or 
closures are not exposed to conditions that may result in the 
production of an adulterated formula product. After a documented review 
and material disposition decision to release, these ingredients, 
containers, and closures must remain suitable for use in the 
manufacture of infant formula so that when such materials are used in 
formula production, the materials continue to conform to the 
manufacturer's specifications. In response to this comment, the Agency 
is revising proposed Sec.  106.40(f) to clarify that an ingredient, 
container, or closure must also be quarantined when a manufacturer 
reasonably believes that an ingredient, container, or closure may have 
been exposed to adverse conditions.

I. Controls To Prevent Adulteration During Manufacturing (Proposed 
Sec.  106.50)

    In 1996, FDA proposed to require in Sec.  106.50 that an infant 
formula manufacturer implement a system of controls designed to prevent 
adulteration during the production of infant formula. The proposed 
provisions included requirements for use of a written master 
manufacturing order; for control and examination of raw and in-process 
ingredients; for identification of the contents of compounding and 
storage containers; processing lines and major equipment; for controls 
to ensure required nutrient levels and to prevent contamination of 
formula; for equipment monitoring; and for control of rejected in-
process materials.
    The Agency received comments on several aspects of proposed Sec.  
106.50, which are addressed in this document. In addition to the 
changes discussed in this document made in response to comments, Sec.  
106.50 of the interim final rule includes minor editorial revisions.
1. Identification of the Contents of Storage Containers, Processing 
Lines, and Major Equipment (Proposed Sec.  106.50(c))
    Several comments requested clarification of proposed Sec.  
106.50(c), which would require a manufacturer to identify the contents, 
including the processing stage and the lot or batch number of a batch 
of infant formula, of all compounding and storage containers, 
processing lines, and major equipment used during the production of a 
batch (production aggregate) of an infant formula.
    (Comment 105) One comment requested clarification of the meaning of 
``identify'' in proposed Sec.  106.50(c). The comment objected to 
physically labeling these items because, the comment asserted, infant 
formula manufacturers use multitudes of equipment and lines in the 
production of infant formula and physical labeling would require a 
significant increase in manpower to apply and remove labels several 
times

[[Page 7975]]

daily to accomplish this task with no benefit to the operation. 
However, the comment stated that it would be reasonable to require a 
system that would permit determination of the location and movement of 
each batch of infant formula. The comment suggested alternative 
language that would require a manufacturer to establish a system that 
permits the manufacturer to determine the major equipment systems used 
during the production of a batch of infant formula.
    (Response) FDA considers that it is necessary to clarify the 
purpose of proposed Sec.  106.50(c). The Agency did not intend the term 
``identify'' in proposed Sec.  106.50 to require that a manufacturer 
physically place a label identifying the contents, processing stage, 
and production aggregate number on each piece of equipment used to 
manufacture a particular production unit of infant formula. Although 
FDA agrees that this method would satisfy the requirements of proposed 
Sec.  106.50(c), it is not the only means by which a manufacturer could 
comply with proposed Sec.  106.50(c). To clarify this requirement, the 
Agency has revised Sec.  106.50(c) in the interim final rule to require 
that a manufacturer establish a system (i.e., a collection of 
components organized to accomplish a specific function or set of 
functions in a specified environment) of identification for the 
contents of all compounding and storage containers, processing lines, 
and major equipment used during the manufacture of a production unit or 
a production aggregate of an infant formula. As such, this provision 
gives a manufacturer flexibility to design its production tracking 
system. Thus, the requirement in Sec.  106.50(c) could be met, for 
example, by establishing a computerized system that makes it possible 
to track a particular production unit or production aggregate of infant 
formula throughout all stages of the manufacturing process, permitting 
the identification of the contents of all compounding and storage 
containers, processing lines, and major equipment used during the 
manufacturing of a specific production aggregate of infant formula. As 
noted, the comment agreed that it is reasonable to require 
establishment of a system that permits determination of the location 
and movement of each production aggregate.
    FDA declines to adopt the alternative language proposed by this 
comment because it does not accurately capture the purpose of the 
proposed requirement. The purpose of proposed Sec.  106.50(c) is to 
require a manufacturer to establish a system to identify the contents 
of compounding and storage containers, processing lines, and various 
pieces of equipment used during the manufacture of a particular 
production aggregate of infant formula and not to identify the major 
equipment systems used during a particular production run. This purpose 
was recognized in the preamble of the 1996 proposal: ``[Proposed Sec.  
106.50(c)] will enable the manufacturer to accurately determine the 
status of all batches of infant formula during all stages of the 
manufacturing process, will help to prevent mix-ups in the addition of 
ingredients to the formula, and will facilitate prompt action by the 
manufacturer if any problems in processing are identified. For example, 
identifying that a particular storage container contains a batch of 
formula that has not yet had all ingredients added to it will prevent a 
manufacturer from inadvertently final-stage packaging the product and 
thus will help to ensure that adulterated product is not introduced 
into interstate commerce'' (61 FR 36154 at 36169).
    (Comment 106) One comment stated that it should be necessary to 
identify the processing lines used in the manufacture of infant formula 
only if the manufacturing facility is processing different types of 
infant formula or non-infant formula products simultaneously because 
there is increased potential for cross-contamination or comingling of 
different products. In such circumstances, the comment argued, 
processing lines should be identified.
    (Response) FDA disagrees with the comment that the requirement of 
proposed Sec.  106.50(c) should apply only when a firm is 
simultaneously manufacturing more than one type of infant formula 
product or a formula product and a non-formula product. The purpose of 
the requirement to establish an identification system is to ensure that 
both finished product and in-process material can be fully identified, 
including by the unique number associated with its production 
aggregate. This will ensure that if a problem develops with a formula 
product necessitating a recall, the affected product can be 
specifically identified and the recall structured as narrowly as 
possible. A narrowly targeted recall is more readily managed by a 
formula company and overseen by FDA and also reduces the likelihood of 
a product shortage from an overly broad recall.
    Moreover, as noted in the preceding comment, infant formula 
processing facilities often contain a multitude of equipment, storage 
tanks, and processing lines; those processing lines may include liquid 
component lines, in-process lines, and finished product lines, as well 
as ancillary lines such as cleaning solution lines, steam lines, and 
water lines. Regardless of whether a facility processes different types 
of infant formulas, processes non-formula products simultaneously with 
infant formula, or processes only one type of infant formula, the 
content of these lines, tanks, and equipment must be identified in some 
way to ensure that such contents are not mishandled or misused. The 
example from the 1996 preamble cited in the response to the preceding 
comment illustrates clearly why content identification is essential 
even when a facility produces only a single type of formula. 
Importantly, under Sec.  106.50(c) of the interim final rule, a 
manufacturer has the discretion to select its content identification 
system.
2. Controls To Ensure the Nutrient Levels and Lack of Contaminants in 
Formulas (Proposed Sec.  106.50(d))
    (Comment 107) One comment agreed that the intent of proposed Sec.  
106.50(d) is sound and is rightfully a part of the CGMP regulations for 
infant formula but objected to what it characterized as the 
prescriptive nature of proposed Sec.  106.50(d)(1) through (d)(4) and 
requested that these specific paragraphs be deleted. The comment argued 
that FDA should allow individual manufacturers to determine the best 
and most economical approach to producing high quality infant formulas 
that meet the nutrient requirements of Sec.  107.100 and do not contain 
contaminants. The comment contended that FDA only needs to define the 
goal and general intent of this section and not specify exact 
parameters that a manufacturer must follow. The comment expressed 
concern that defining exact parameters could unintentionally prevent 
manufacturers from using other production methods that could result in 
an acceptable product. The comment suggested that the manufacturer 
should document its intended approach, as well as compliance with its 
own designated control systems.
    (Response) FDA disagrees that the requirements in proposed Sec.  
106.50(d)(1) through (d)(4) are overly prescriptive. Indeed, one 
benefit of this interim final rule is that it informs new infant 
formula manufacturers of the controls that must be established in a 
proper infant formula manufacturing operation. The points identified in 
proposed Sec.  106.50(d)(1), (d)(2), (d)(3), and (d)(4) are those at 
which control is necessary to produce a formula that is homogeneous, 
that is not contaminated, that will not undergo nutritional

[[Page 7976]]

deterioration, and the containers of which will remain properly sealed. 
Controls at these points are essential to the production of any formula 
to ensure that it is not adulterated, a conclusion not disputed by the 
comment. Importantly, however, the manufacturer has the authority, 
responsibility, and flexibility to determine the parameters for each 
control point, and these parameters are, in part, based on the 
manufacturer's knowledge and experience. Thus, the manufacturer has the 
flexibility to determine the specific time, temperature, and speed for 
mixing; the steps needed in a spray-drying process to prevent microbial 
and other contamination; the extent of air removal needed from finished 
product to prevent nutrient deterioration; and procedures for ensuring 
proper seal of containers. Because the comment did not explain why 
control is not necessary at the points identified in proposed Sec.  
106.50(d)(1) through (d)(4), FDA is not revising proposed Sec.  
106.50(d) in response to this comment.
3. Removal of All Air From Containers of Infant Formula (Proposed Sec.  
106.50(d)(3))
    (Comment 108) One comment objected to proposed Sec.  106.50(d)(3), 
which requires ``the removal of air from the finished product to ensure 
that nutrient deterioration does not occur.'' The comment explained 
that it is not technically feasible to remove all ``oxygen'' to ensure 
that nutrient deterioration does not occur, and suggested that this 
provision be revised to require ``the removal of oxygen from the 
finished product to a level that will avoid deterioration below an 
acceptable level of nutrients throughout the shelf life of the 
product.'' Another comment stated that if a manufacturer could package 
an infant formula without the removal of air and still meet the 
nutritional and quality factors throughout the shelf-life of the 
product, FDA should permit this approach.
    (Response) The Agency recognizes that it may not be possible to 
remove all of the air from finished product containers. Importantly, 
however, the manufacturer must remove or control the amount of air in 
the container to prevent deterioration of nutrients. When the 
requirement of proposed Sec.  106.50(d)(3) is read in conjunction with 
the stability testing requirements of proposed Sec.  106.91(b), air 
removal must be sufficient to ensure that the nutrients continue to 
meet the levels required by section 412(i) of the FD&C Act throughout 
the shelf life of the product. Each manufacturer must decide the extent 
to which air must be removed from its finished product containers to 
ensure nutrient stability. Further, proposed Sec.  106.50(d)(3) is 
consistent with the regulations on thermally processed low-acid foods 
packaged in hermetically sealed containers (part 113), which require 
that the ``exhausting of containers for the removal of air shall be 
controlled so as to meet the conditions for which the process was 
designed'' (Sec.  113.81(d)). Liquid infant formulas that are low-acid 
canned foods must comply with part 113; one purpose of the process for 
such liquid formulas is to ensure stability of a formula's nutrients 
throughout the shelf-life of the formula. Accordingly, FDA is not 
modifying proposed Sec.  106.50(d)(3) in response to these comments, 
and Sec.  106.50(d)(3) is included in this interim final rule as 
proposed.
4. Controls on Rejected In-Process Materials (Proposed Sec.  106.50(f))
    (Comment 109) One comment suggested deleting or revising proposed 
Sec.  106.50(f)(3), which would require a manufacturer to establish 
controls to ensure that rejected in-process materials meet the 
appropriate specifications, if reprocessed, before being released for 
use in infant formula. The comment argued that this section could be 
deleted if the definition of specifications suggested in the comment 
were adopted by the Agency because the proposed definition of 
specifications addresses the situation described in proposed Sec.  
106.50(f)(3). The comment recommended the following definition of 
``specifications:'' ``Specifications means quality control limits or 
standards for raw materials, in-process materials, and finished 
product, which are established by the manufacturer for purposes of 
controlling quality and consistency for infant formula. Failure to meet 
an established specification requires a documented review and material 
disposition decision.''
    (Response) The response to Comment 35 addresses the request that 
the rule include a definition of ``specifications.'' For the reasons 
stated in that response, FDA declines to add a definition of 
``specifications'' to the interim final rule. Because the request to 
delete proposed Sec.  106.50(f)(3) relies on a separate suggested 
change that FDA declines to make, Comment 109 has been addressed.
    (Comment 110) One comment asserted that proposed Sec.  106.50(f)(3) 
could be interpreted as requiring that all out-of-specification in-
process materials be rejected.
    (Response) As discussed previously in this document, FDA did not 
intend all out-of-specification in-process materials to be rejected and 
has revised proposed Sec.  106.50(f) to be consistent with revisions 
made elsewhere in the interim final rule, including Sec. Sec.  
106.6(c), 106.40(d), 106.40(e), 106.40(f), and 106.70, related to a 
failure to meet a specification.
    The distinction between ``out-of-specification material'' and 
``rejected material'' is clear in light of the revisions made elsewhere 
in the interim final rule. As noted previously in this document, the 
interim final rule revises Sec.  106.6(c)(4) to require that, where 
there is a failure to meet any specification established under Sec.  
106.6(c)(1), an individual qualified by education, training, or 
experience conduct a documented review and make a material disposition 
decision to reject the affected article (i.e., material or product), 
reprocess or otherwise recondition the affected article, or approve and 
release the article for use or distribution. Thus, one possible outcome 
is that the out-of-specification in-process material is not rejected 
and is released for use in formula without the need for reprocessing or 
other reconditioning. Another possible outcome of the documented review 
and material disposition decision is that the non-conforming article is 
rejected. Additionally, if appropriate, the out-of-specification 
material may be reprocessed, and if successfully reprocessed, could be 
used in an infant formula. Thus, under the terms of the interim final 
rule, out-of-specification material is not necessarily required to be 
rejected. However, if in-process material is rejected following the 
documented review and material disposition decision required by Sec.  
106.6(c), Sec.  106.50(f)(4) requires that any such material be clearly 
identified as rejected and be quarantined. Likewise, under Sec.  
106.50(f)(2) of the interim final rule, in-process materials that are 
pending a documented review and disposition decision must be clearly 
identified as such and be controlled under a quarantine system to 
prevent their use prior to any disposition decision. Additionally, if 
an in-process material is reprocessed, it must undergo another 
documented review and material disposition decision to determine 
whether the in-process material that has been reprocessed may be 
released for use in infant formula.
    Accordingly, to clarify the required controls for in-process 
material that fails to meet specifications, including controls for 
rejected in-process material, FDA is revising proposed Sec.  106.50(f) 
as discussed previously in this document in section V.C.1.

[[Page 7977]]

J. Controls To Prevent Adulteration From Microorganisms (Proposed Sec.  
106.55)

    In 1996, FDA proposed to require that infant formula manufacturers 
establish controls to prevent the adulteration of formula from 
microorganisms. Specifically, proposed Sec.  106.55(a) would have 
required that a manufacturer of liquid infant formula comply with the 
procedures in part 113 (Thermally Processed Low-Acid Foods Packaged in 
Hermetically Sealed Containers). Proposed Sec.  106.55(b) would have 
required that a manufacturer of powdered infant formula test 
representative samples of every batch (production aggregate) at the 
final product stage and before distribution to ensure that the formula 
meets microbiological quality standards, which standards were set out 
in proposed Sec.  106.55(c). Proposed Sec.  106.55(c) would have 
established seven microbiological standards: aerobic plate count (APC), 
coliforms, fecal coliforms, Salmonella, Listeria monocytogenes, 
Staphylococcus aureus, and Bacillus cereus. Under proposed Sec.  
106.55(c), if the M value (defined as the maximum allowable number of 
organisms present in 1 g of dry formula, expressed as ``colony forming 
unit per gram'' (CFU/g) or ``most probable number'' (MPN/g)), for the 
microbe was exceeded, the infant formula would have been considered 
adulterated under sections 402 and 412 of the FD&C Act. Proposed Sec.  
106.55(d) would have required a manufacturer to make and retain records 
relating to the testing of infant formulas for microbial contamination.
    Thereafter, in 2003, FDA reopened the comment period to receive new 
information based on the 2002 and 2003 meetings of the FAC and two of 
its subcommittees that considered, among other issues, microbiological 
standards for E. sakazakii (Cronobacter spp.) \3\ and other 
microorganisms in powdered infant formula (68 FR 22341). At that time, 
the Agency requested comments on whether the final rule should include 
a microbiological standard for E. sakazakii (Cronobacter spp.) and if 
so, what that standard should be. Concerns about Cronobacter spp. 
stemmed from the 2001 death of one of ten infants made ill from 
consuming formula consisting of sterile water and contaminated powdered 
infant formula (68 FR 22341 at 22342). The Agency also requested 
comments on additional changes to the microbiological standards 
proposed in 1996 and on whether formula for preterm and newborn infants 
should be subject to more strict microbiological requirements.
---------------------------------------------------------------------------

    \3\ As noted previously in the document, in 2008, the taxonomy 
of Enterobacter sakazakii was reclassified to include all the 
species that were pathogenic into a new genus named Cronobacter spp. 
(Ref. 1).
---------------------------------------------------------------------------

    FDA subsequently reopened the comment period in 2006 to consider 
the recommendations from an FAO/WHO expert consultation, the report of 
which included a risk assessment model and data used for that model 
that became available after the 2003 reopening. The Agency announced 
that, based on its review of the expert reports, it had tentatively 
determined to establish a standard for Cronobacter spp.; that the 
appropriate standard for Cronobacter spp. would be negative in 30 x 10 
g samples and, for Salmonella spp., negative in 60 x 25 g samples; that 
manufacturers would be required to test representative samples of each 
production aggregate (batch) of powdered infant formula for the two 
pathogens; and that testing for aerobic plate count (APC) and the five 
remaining microorganisms identified in the 1996 proposal (coliforms, 
fecal coliforms, Listeria monocytogenes, Staphylococcus aureus, and 
Bacillus cereus) would not be required. The Agency specifically 
requested comments on two issues related to the microbiological quality 
of powdered infant formula: whether FDA should establish a standard for 
Cronobacter spp. in powdered infant formula of negative in 30 x 10 g 
samples and whether FDA should finalize microbiological standards for 
APC, coliforms, fecal coliforms, Listeria monocytogenes, Staphylococcus 
aureus, and Bacillus cereus.
    The Agency received comments on microbiological controls in 
response to the 1996 proposal and in response to the 2003 and 2006 
reopenings. This section addresses those comments.
1. Microbiological Requirements for Liquid Infant Formula (Proposed 
Sec.  106.55(a))
    FDA received no comments opposing this proposed provision. On its 
own initiative, FDA is revising proposed Sec.  106.55(a) to clarify 
that liquid infant formulas that are acidified foods are required to 
comply with the regulations in part 114 (``Acidified foods''). In 
addition, for clarity and consistency with the remainder of the interim 
final rule, FDA is making minor editorial changes and is redesignating 
proposed Sec.  106.55(a) in this interim final rule as Sec.  106.55(b) 
to state: ``A manufacturer of liquid infant formula shall comply, as 
appropriate, with procedures specified in part 113 of this chapter for 
thermally processed low-acid foods packaged in hermetically sealed 
containers and part 114 of this chapter for acidified foods.''
    FDA notes that Sec.  106.55(a) of the interim final rule is 
discussed in section J.2.a.ii.
2. Microbiological Requirements for Powdered Infant Formula (Proposed 
Sec.  106.55(b) and (c))
    As a result of the reopening of the comment period in 2003 and 
2006, the Agency's tentative conclusions about appropriate 
microbiological testing requirements (proposed Sec.  106.55(b) and (c)) 
have been substantially revised and are discussed in this document.
    a. General comments.
    i. Final product stage testing.
    (Comment 111) Several comments suggested that FDA re-evaluate the 
need for finished product microbiological testing of all lots 
(production aggregates) of infant formula to determine whether such 
testing will provide significantly enhanced safety when an effective 
in-process control system is in place.
    (Response) FDA disagrees with the suggestion of this comment.
    First, the comment appears to misunderstand the proposed 
requirements for microbiological testing of finished product at the 
final product stage. In particular, liquid infant formulas 
(concentrates and ready-to-feed formulas) must comply with the 
requirements for thermally processed, low-acid foods packaged in 
hermetically sealed containers (in part 113) or with requirements for 
acidified foods (in part 114), which do not require final product stage 
microbiological testing. Part 113 focuses on ensuring that commercial 
sterility \4\ is achieved in thermal processing and packaging; part 114 
ensures that commercial sterility is achieved through acidification, 
thermal processing, and packaging. Processing an infant formula 
consistent with part 113 or part 114 ensures the destruction of 
vegetative pathogens, including Cronobacter spp. and Salmonella spp.
---------------------------------------------------------------------------

    \4\ FDA's regulations on acidified foods, 21 CFR 114.80 states 
that ``acidified foods shall be thermally processed to an extent 
that is sufficient to destroy the vegetative cells of microorganisms 
of public health significance and those of non-health significance 
capable of reproducing in the food under the conditions in which the 
food is stored, distributed, retailed and held by the user.'' As 
used in this interim final rule, the term ``commercial sterility'' 
includes an acidified food that has been thermally processed to an 
extent that is sufficient to destroy the vegetative cells of 
microorganisms of public health significance and those of non-health 
significance capable of reproducing in the food under the conditions 
in which the food is stored, distributed, retailed and held by the 
user.
---------------------------------------------------------------------------

    Second, FDA acknowledges that proposed Sec.  106.55(b) would have

[[Page 7978]]

established microbiological standards for powdered infant formulas and 
would have required representative samples from every production 
aggregate of powdered infant formula to be tested, at the final product 
stage and before distribution, to ensure that the production aggregate 
meets the established standards. The comment included no data or 
information to support its suggestion that an effective in-process 
control system would eliminate the need for end-product testing. The 
purpose of final product stage testing is to ensure the microbiological 
safety of each production aggregate of infant formula. In addition, 
however, final product stage testing serves to verify that the 
manufacturer's food safety control system is operating effectively to 
prevent microbial contamination of formula during processing because, 
to the extent that such testing shows finished product contamination, 
the manufacturer is put on notice that its system of controls is not 
functioning effectively.
    (Comment 112) One comment stated that based on knowledge of factors 
associated with E. sakazakii (Cronobacter spp.) infections (such as 
abusive temperatures and poor storage conditions), relying on end-
product microbiological testing as a control strategy for this 
microorganism is not a dependable approach to preventing illness. 
Several other comments suggested that education concerning formula 
preparation and handling, or additional labeling, is more likely to 
reduce the risk of infection than finished product testing. One comment 
suggested that FDA issue guidelines on the correct preparation of 
formula.
    (Response) FDA disagrees with these comments to the extent that 
they suggest that education concerning formula preparation and handling 
should replace final product stage testing. First, the comment does not 
dispute that powdered infant formula itself can be a source of 
Cronobacter spp. contamination. Although the data on surveys of 
Cronobacter spp. in powdered infant formula show that the percent of 
samples found positive for the pathogen have decreased over the past 
years as manufacturers have implemented stricter controls in the 
processing environment (Ref. 3, Table 4), the risk that the organism 
will be present in finished formula still exists.
    Cronobacter spp. have been described as ``a severe hazard for 
restricted populations, [resulting in] life threatening or substantial 
chronic sequelae of long duration'' by the International Commission for 
Microbiological Specifications for Foods (ICMSF 2002) (Ref. 22). 
Cronobacter spp. have been identified as the etiological agent in 
neonatal meningitis, septicemia, and necrotizing enterocolitis, and are 
considered emerging opportunistic pathogens (Ref. 23 and 24). 
Cronobacter spp. have caused meningitis resulting in brain abscess and 
ventriculitis (inflammation of the cerebral ventricles) with a very 
high associated mortality rate in neonates and infants (Refs. 23 and 
25). Survivors of Cronobacter-induced meningitis suffer life-long 
mental and physical developmental delays (Ref. 23). Although there has 
been continued study of this pathogen and further characterization, the 
dose required to cause infection has yet to be determined (Ref. 24). 
Given the absence of a documented infectious dose and the severity of 
Cronobacter spp. infections in infants, even a low risk of such 
contamination of infant formula from the production environment must 
not be tolerated.
    An important objective of CGMP is to identify points in product 
processing where there is a risk of adulteration and implementing 
controls to prevent contamination that adulterates the product. This 
objective is captured generally in Sec.  106.6(b) of the interim final 
rule and specifically in Sec.  106.55(a), which, as discussed in this 
document, has been added to Sec.  106.55 of the interim final rule. 
Implementing a standard for Cronobacter spp., which includes testing of 
the final production aggregate, complements these efforts directed at 
system control by providing a separate mechanism to verify that food 
safety measures and system process controls are producing an infant 
formula that is not adulterated.
    It is also important to note that there have been multiple efforts 
by various external groups to alert consumers and health professionals 
about the risk of illness from Cronobacter spp. and powdered infant 
formulas contaminated with this pathogen. For example, in 2011, the 
American Dietetic Association (ADA) published an updated book titled 
``Infant Feedings: Guidelines for Preparation of Formula and Breastmilk 
in Health Care Facilities'' (Ref. 26). The International Formula 
Council (IFC) published a pamphlet for health professionals, which was 
based on the ADA book; the IFC guidelines are available at 
www.infantformula.org/for-health-professionals (Ref. 27). The American 
Academy of Pediatrics (AAP) also published an article on infant formula 
safety that provides recommendations on food safety practices for 
powdered infant formula (Ref. 28). Manufacturers of powdered infant 
formula have developed educational materials for consumers and made 
changes to their labels to include directions for the safe preparation 
and storage of infant formula. In addition, the USDA provides guidance 
to participants in the USDA Women, Infants, and Children (WIC) program 
on safe preparation and storage of infant formula www.nal.usda.gov/wicworks/Topics/FG/Chapter4_Infantformulafeeding.pdf (Ref. 29, p. 
91).\5\ All of these programs contribute to the overall food safety 
efforts to prevent foodborne illness from contaminated powdered infant 
formula.
---------------------------------------------------------------------------

    \5\ Significantly, according to the USDA, Economic Research 
Service, WIC participants now account for over half of all infant 
formula sold in the United States (Ref. 30), and WIC participants 
use powdered infant formula almost exclusively.
---------------------------------------------------------------------------

    (Comment 113) Some comments suggested that point-of-use 
contamination from poor preparation practices represents the most 
significant risk of E. sakazakii (Cronobacter spp.) infection for 
infants consuming formula.
    (Response) FDA is not aware of data that would refute or 
corroborate this point. Moreover, the comment did not provide any data 
to support this assertion. There is always a potential risk that 
microbial contamination may occur during food handling. However, that 
possibility does not mean that there is no need to ensure that a 
packaged infant formula product does not exceed microbial limits before 
distribution from the processing plant. The responsibility for food 
safety falls at every point along the food chain, which begins with 
manufacturing. Better controls used by the manufacturer to minimize 
contamination during processing contribute substantially to reducing 
the risk of illness at point of use.
    (Comment 114) One comment stated that the need for end-product 
microorganism testing should be determined by the manufacturer.
    (Response) FDA disagrees with this comment. Infant formula is 
intended for consumption by a vulnerable population and, as discussed 
previously in this document, infants are at risk of significant 
morbidity or mortality from an infection caused by Cronobacter. Illness 
caused by Salmonella spp. (salmonellosis) has long been associated with 
contaminated dried milk products. Non-typhoidal serovars (NTS) of 
Salmonella, such as Salmonella enterica, have also been found in infant 
formulas and are capable of causing invasive disease. In the reported 
outbreaks of Salmonella infection associated with powdered infant 
formula, the organism was found at low

[[Page 7979]]

levels in the unreconstituted powdered formula. The incidence of 
salmonellosis among infants is higher than in all other age groups and 
is considered a public health problem (Ref. 31). Infants younger than 1 
year of age are reported to have an infection rate of 120/100,000 
population in the United States (Ref. 32). The symptoms associated with 
salmonellosis range from dehydration to bloody diarrhea requiring 
hospitalization, sepsis, and death. Complications from NTS include 
bacteremia (bacterial bloodstream infection), enterocolitis 
(inflammation of the mucus membrane of the small intestine or colon), 
meningitis (inflammation of the membranes covering the brain or spinal 
cord), and osteomyelitis (inflammation of bone due to an infection). 
Indeed, the threat to the health of infants from consuming powdered 
infant formula contaminated with these pathogens has been recognized 
not only by the FDA, but by the international community as well. 
Accordingly, due to the severity of illness associated with 
contamination, FDA has concluded that the frequency and degree of end-
product testing must be prescribed by the Agency in the interim final 
rule and not simply left to the discretion of each formula 
manufacturer. However, because the testing specified in Sec.  106.55 of 
the interim final rule is the minimum necessary, a formula manufacturer 
is free to conduct additional microbiological testing. FDA notes that, 
if such additional testing is conducted, the Agency expects that the 
manufacturer would monitor such testing and act appropriately on the 
results.
    (Comment 115) Some comments stated that the proposed regulations 
encompass a HACCP-type approach but the requirement for routine end 
product testing for certain micro-organisms is contradictory to the 
HACCP concept. However, these comments suggested that if end-product 
testing is required, FDA should issue guidelines on the number and size 
of samples to be tested to ensure that lots (production aggregates) of 
powdered infant formula do not contain pathogens.
    (Response) FDA disagrees with this comment. The purpose of this 
interim final rule is to establish CGMP for infant formula. Thus, the 
premise of the comment is erroneous.
    Moreover, FDA does not agree that end-product testing is 
contradictory to the HACCP concept. Although the HACCP concept may 
emphasize process controls, finished product testing at the final 
product stage, before distribution, is an important means of verifying 
that process controls are being continuously applied and effective. As 
discussed in response to Comment 116, testing representative samples of 
final production aggregates can serve as a final check on both the food 
safety controls and process designed to prevent microbial contamination 
during processing and on the microbiological safety of the infant 
formula prior to distribution.
    The Agency is not issuing guidance on a sampling plan for microbial 
testing, as requested in the comment, because the number and size of 
formula samples for testing from each production aggregate are 
specified in Sec.  106.55(e) of the interim final rule. As discussed in 
section V.J.2.c., by specifying the number and size of the samples for 
testing finished product, FDA ensures that there is sufficient 
statistical confidence to support the validity of results showing that 
the finished product meets the specified microbiological standards.
    (Comment 116) Some comments asserted that there is no need to 
establish a standard for E. sakazakii (Cronobacter spp.) because the 
safety of infant formula would be better assured by hazard analysis 
critical control plans (HACCP), environmental monitoring, labeling, and 
education.
    (Response) FDA disagrees with these comments. In the 2006 
reopening, FDA noted that comments in response to the 1996 proposal 
suggesting that alternatives to end-product testing would provide 
sufficient assurance of safety (e.g., HACCP plans and environmental 
monitoring, labeling, and education on formula preparation and 
handling) had not submitted any data or other information to support 
such assertions with respect to Cronobacter spp. All of the approaches 
mentioned in these comments may contribute to a total food safety plan, 
but essential to the plan is verifying the effectiveness of the process 
control established to ensure the microbial safety of the finished food 
product. Testing final production aggregates for Cronobacter spp. is 
one way that the manufacturer can verify the production process and the 
safety of the product prior to distribution and marketing. Further, FDA 
did not receive any information or data in response to the 2006 
reopening that contradicts its tentative conclusion regarding 
microbiological testing of powdered infant formula for Cronobacter spp.
    ii. Microbiological specifications and powdered infant formula.
    (Comment 117) One comment questioned the practicality of including 
specific microbiological specifications in the CGMP given the length of 
time required to pass or change such regulations. The comment suggested 
that, in the future, when FDA encounters emerging pathogens of concern, 
it could establish interim requirements through such mechanism as a 
guidance document, which would be less burdensome than establishing the 
CGMP regulations.
    (Response) FDA disagrees with the comment to the extent that it 
suggests that the Agency issue guidance instead of establishing 
standards for microbiological contamination for any future emerging 
pathogens of concern. In many cases, guidance is not a long-term 
substitute for a binding regulation. FDA's Good Guidance Practices 
(GGPs) (21 CFR 10.115) state that guidance represents the Agency's 
current thinking on a topic and does not create or confer any rights 
for or on any person and does not operate to bind FDA or, more 
importantly in this case, the public, including infant formula 
manufacturers. As discussed in response to Comment 116, the population 
for whom infant formula is manufactured and the risks for that 
population from microbial contamination require that FDA establish 
legally binding requirements. Because the process for issuing guidance 
is somewhat simpler than the process for promulgating a regulation, the 
Agency acknowledges that it may be appropriate, in some circumstances, 
to use guidance to communicate FDA's current thinking on specifications 
for an emerging pathogen of concern.
    (Comment 118) One comment asserted that although manufacturers can 
take proactive measures to reduce the level, frequency, and incidence 
of E. sakazakii (Cronobacter spp.) in powdered infant formula, total 
eradication of the microorganism from powdered infant formula is not 
currently technologically possible given the nature of food powder 
manufacturing. The comment stated that manufacturers are currently 
attempting to further define and reduce, to the extent possible, any 
potential risk posed by contaminated powdered infant formula.
    (Response) Even if the total eradication of Cronobacter spp. may 
not be technologically feasible, that limitation does not alter the 
Agency's conclusion that a strict microbiological standard, such as 
that required by the interim final rule (less than one organism in 300 
grams of powdered formula) is necessary to reduce the risk of illness 
associated with Cronobacter spp. in infants. Powdered infant formula 
cannot undergo a post-packaging thermal process that is required for 
liquid ready-to-feed or concentrated

[[Page 7980]]

products. This fact supports the need for a microbiological standard 
for powder formula to ensure that the safest product possible is 
available to infants. Under Sec.  106.6(b) of the interim final rule, a 
manufacturer must take responsibility to establish appropriate controls 
and monitor those manufacturing processes where adulteration could 
occur, and Sec.  106.55(a) of the interim final rule requires a 
manufacturer specifically to establish a system of process and controls 
to ensure that infant formula does not become adulterated due to the 
presence of microorganisms in the formula or in the processing 
environment.
    b. Need for a Cronobacter spp. (E. sakazakii) microbiological 
standard for powdered infant formula.
    i. Need for a standard for formula for term infants.
    (Comment 119) One comment asserted that, given infant formula's 
excellent safety record since the passage of the Infant Formula Act, 
there is no need for additional microbiological requirements.
    (Response) FDA disagrees with this comment. Cronobacter spp. have 
been documented as responsible for infant illnesses such as bacteremia, 
sepsis, and meningitis, with a reported mortality rate as high as 40 to 
80 percent (Ref. 33). These cases of Cronobacter spp. infections have 
been associated both directly with powdered infant formula and 
epidemiologically (Refs. 33, 34, and 35). The existence of outbreaks 
associated with powdered infant formula contaminated with Cronobacter 
spp., such as the one that occurred in Tennessee (Ref. 34), attests to 
the ability of this pathogen to cause significant illness and death. 
Accordingly, the safety record for infant formula does not obviate the 
need for the microbiological requirements of this interim final rule.
    (Comment 120) Several comments noted that there are data 
demonstrating that the industry has taken measures to achieve increased 
control over potential contamination of powdered infant formula overall 
and that since July 2003, there has been a reduction in the level of E. 
sakazakii (Cronobacter spp.) found in powdered infant formula.
    (Response) FDA agrees that available data appear to suggest that 
the risk of Cronobacter spp. contamination of powdered infant formula 
has decreased. One of the earliest surveys of powdered infant formula 
samples for Cronobacter spp. was conducted in 1988 by Muytjens and co-
workers (Ref. 36). The investigators reported that 14 percent of 
samples of powdered infant formula that had been collected from 13 
countries contained the pathogen at levels that ranged from 0.36 to 66 
CFU/100 g. A more recent analysis of 82 powdered infant formulas by 
Iversen and Forsythe (2004) documented Cronobacter spp. in 
approximately 2.4 percent of samples (Ref. 37). Although these two 
investigations appear to reflect a reduction in the percent of formula 
contaminated with Cronobacter spp., the risk of potentially fatal 
illness will persist as long as the pathogen can survive in the 
environment and in powdered formula. To the extent the comment is 
suggesting that there is no need to establish a standard for this 
organism given the reduction in the percent of formula contaminated 
with Cronobacter spp., the Agency disagrees. Given the severe 
consequences of a Cronobacter spp. infection in an infant, protection 
of the public health requires that the Agency establish a standard for 
this organism in powdered infant formula and require sampling and 
testing to achieve that standard.
    (Comment 121) One comment asserted that there have been no reported 
cases linking powdered infant formula to illness caused by E. sakazakii 
(Cronobacter spp.) in healthy term infants except when there was 
positive evidence of external contamination or abuse of reconstituted 
formula. Another comment argued that, based on the lack of evidence 
linking Cronobacter spp. to outbreaks in term infants, FDA's current de 
facto standard of zero tolerance of Cronobacter spp. in term infant 
formulas is not warranted.
    (Response) FDA disagrees with these comments because the available 
scientific evidence demonstrates that term infants are at risk of 
foodborne illness associated with powdered infant formula contaminated 
with Cronobacter spp., including the risk of severe morbidity and 
mortality. FDA notes that powdered infant formula is not intended to 
be, nor is it, a sterile product. Because term infants are more likely 
to receive powdered formula rather than liquid formula that is 
commercially sterile, they risk being exposed to Cronobacter spp.
    Reports in the published literature document the existence of this 
risk for term infants. For example, in 1989, Biering et al. reported 
three cases of neonatal meningitis associated with Cronobacter spp. in 
three infants fed powdered milk formula where two of the three infants 
were term infants (Ref. 38). The Cronobacter spp. isolated from the 
term neonates was indistinguishable from the 22 strains grown from the 
powdered infant formula. Muytjens et al. (1983) reported on one term 
infant infected with Cronobacter spp. infection who died from 
bacteremia (Ref. 39).
    Additionally, FDA and CDC have both received reports through the 
agencies' electronic adverse event reporting systems or otherwise of 
several cases of healthy term infants becoming ill from Cronobacter 
spp. infection (Ref. 40). In each case, contaminated powdered infant 
formula was the suspect vehicle. Although followup investigations of 
these cases were unable to determine the source of contamination that 
caused the illness, these reports demonstrate nonetheless that healthy 
term infants continue to be at risk of life-threatening illness from 
Cronobacter spp. infections. Importantly, illnesses from Cronobacter 
spp. are not required to be reported to the CDC (Ref. 41). Detection of 
the pathogen and the disorders has been identified through surveillance 
surveys. This suggests that the actual number of cases of Cronobacter 
spp. infection in infants is under-reported.
    Although infant age is not protective, infant age may be associated 
with particular presentations of Cronobacter spp. illness. That is, CDC 
data suggest that infants who develop meningitis tend to be near term 
in gestational age and birth weight (Ref. 33). Consistent with this 
observation are conclusions from the FAO/WHO expert consultation that 
identified the two risk groups as ``preterm infants who develop 
bacteraemia outside of the neonatal period, with most, but not all, 
cases occurring in infants under two months, and term infants who 
develop meningitis during the neonatal period.'' (Ref. 3) Importantly, 
the FAO/WHO report further notes that ``any infant may develop either 
syndrome at any age.''
    FDA also notes that the comment incorrectly asserted that the 
Cronobacter spp. standard is a zero tolerance standard. In fact, this 
is not the case, as explained in the discussion of the standard and the 
sampling plan (section V.J.2.c).
    (Comment 122) One comment argued that the low risk among healthy 
term infants is supported by the low number of reported cases among 
healthy term infants in comparison with the estimated 100,000 infants 
who have been exposed to contaminated formula in the past 15 years.
    (Response) FDA agrees that the number of reported cases of illness 
in term infants with Cronobacter spp. infection is less than those of 
preterm infants but notes that the comment does not dispute the 
Agency's conclusion that term infants have been afflicted with serious 
illness caused by Cronobacter spp. infections. Term infants have been 
reported ill from contaminated powdered infant formula

[[Page 7981]]

(Refs. 35 and 38), and several cases of term infants seriously affected 
by Cronobacter spp. infections, without a clear association to powdered 
infant formula, have been reported to FDA and CDC (Refs. 40 and 41). As 
described in the response to Comment 112, extremely serious health 
conditions, such as meningitis, bacteremia, seizures, brain abscess, 
hydrocephalus, developmental delay, and death associated with infection 
from Cronobacter spp. have been reported in the scientific literature 
(Refs. 33 and 42) and directly to FDA or the CDC (Ref. 40). Thus, in 
light of the consequences of an infection from Cronobacter spp., even a 
``low risk'' of such infection in healthy infants is unacceptable and 
is appropriately compared to what is essentially a zero risk of a 
Cronobacter spp. infection in breast-fed infants.
    (Comment 123) One comment suggested that products clearly labeled 
for infants six months of age or older should be exempt from the E. 
sakazakii (Cronobacter spp.) microbiological standard because there is 
no evidence powered infant formula has caused any cases of E. sakazakii 
(Cronobacter spp.) infection in older infants.
    (Response) FDA disagrees with this comment for several reasons. 
First, although Cronobacter spp. infections are less frequently 
reported in infants six months of age and older than in younger 
infants, older infants are nevertheless at risk of Cronobacter spp. 
infections and the scientific literature includes reports of such 
infections in older infants. In 2003, a case of Cronobacter spp. 
infection in a healthy eight month old infant was reported directly to 
the FDA and CDC (Ref. 40). The patient was healthy prior to consuming 
powdered infant formula a few hours before the onset of symptoms of 
illness. Likewise, in its expert review of multi-country data on the 
risk of illness from Cronobacter spp., FAO/WHO reported that of 120 
individually documented cases among infants and young children up to 3 
years of age, six occurred in infants aged 6 to 11 months and two cases 
in children 12 to 36 months (Ref. 43). Importantly, the FAO/WHO report 
also noted that there are few data available on the prevalence of the 
Cronobacter spp. pathogen in formulas specifically intended for infants 
ages 6 to 11 months (so-called ``follow-up formula''), a situation 
attributed to the absence of mandatory testing for Cronobacter spp. 
(Ref. 43).
    Second, a food that is capable of causing severe illness is 
adulterated within the meaning of section 402(a)(1) of the FD&C Act 
because the presence of a microorganism, and labeling to restrict the 
food's use to certain subpopulations cannot make that unlawful food 
lawful.
    Third, section 201(z) of the FD&C Act defines ``infant formula'' as 
``a food that purports to be or is represented for special dietary use 
solely as a food for infants.'' FDA's regulations (21 CFR 105.3(3)) 
define ``infant'' as a person not more than 12 months of age. 
Accordingly, the U.S. regulatory system does not distinguish between 
formula for infants less than 6 months of age and formula intended for 
infants older than 6 months. (The latter is often referred to as 
``followup'' formula.) Thus, all infant formula for infants ages 0 to 
12 months must meet the same microbiological standards and requirements 
under this interim final rule.
    For these reasons, FDA declines to adopt the suggestion of this 
comment.
    (Comment 124) One comment asserted that formula labeled for infants 
6 months of age and older should be exempt from the E. sakazakii 
(Cronobacter spp.) standard. The comment noted that in 2003, the FAC 
defined the at-risk population as preterm infants born at less than 36 
weeks gestational age up to a post term age of 4-6 weeks, 
immunocompromised infants at any age, and term infants. The comment 
asserted that the FAC did not identify healthy-term infants as at risk.
    (Response) FDA does not disagree that preterm and immunocompromised 
infants are at greater risk of infection from Cronobacter spp. compared 
to term infants and infants six months of age and older. However, as 
demonstrated by the evidence discussed in the previous responses, term 
infants are still at risk of infection from Cronobacter spp.; these 
infections are very serious and can lead to life-long disability or 
death. The FAO/WHO 2008 report on the risk of illness from this 
pathogen in powdered follow-up formula made several significant 
observations: (1) Six cases of illness from Cronobacter spp. were 
identified in infants between the ages of 6 and 11 months; (2) 
globally, there are few surveillance data for Cronobacter spp. related 
illness; (3) because there is no universal mandate for testing followup 
formula for this pathogen, there are few data available on the 
prevalence of the pathogen in these products intended for older 
infants; and (4) there are data to demonstrate that followup formula is 
consumed by infants less than 6 months of age and sometimes consumed by 
infants less than 1 month (Ref. 43). To exempt followup formula from 
the CGMP microbiological standards in this interim final rule would be 
to ignore the very real potential for serious illness in this older 
group of infants consuming these formulas, as well as infants less than 
six months of age that may be consuming these formulas.
    Accordingly, FDA declines to exempt ``follow-up formula'' from the 
interim final rule's standard for Cronobacter spp.
    (Comment 125) One comment asserted that although the available 
scientific evidence does not permit a comprehensive risk assessment, 
the available evidence does permit the rather straightforward 
conclusion, such as that reached by the Food Advisory Committee, that 
whatever the risk powdered infant formula may pose to term infants by 
virtue of the presence of Cronobacter spp., that risk is not only lower 
than that which is associated with premature infants, but also is 
unquantifiable.
    (Response) FDA disagrees in part and agrees in part with this 
comment. Importantly, as discussed in detail in this document, a 
scientifically sound quantitative risk assessment can be, and has been, 
conducted of the potential for Cronobacter spp. infection in infants. 
As noted in its response to Comment 114, FDA does agree that the 
incidence of illness from Cronobacter spp. infection is lower in term 
infants than in premature infants. Nonetheless, as also explained 
previously in this document, it is appropriate to establish a 
Cronobacter spp. standard for all infant formula, including formula for 
older infants. Accordingly, FDA is not revising Sec.  106.55 in 
response to this comment.
    ii. Issues related to the standards for Cronobacter spp.
    (Comment 126) One comment, which questioned the proposed standard, 
stated that a research study by Health Canada, in which a suckling 
mouse was used as a model to study E. sakazakii, found that this 
organism has low infectivity, and that large numbers of organisms are 
needed to cause infection, even with the most virulent strains.
    (Response) As discussed in this document, this study does not 
demonstrate that the Cronobacter spp. organism has low infectivity.
    The research by Health Canada identified in the comment was 
designed to study virulence factors and pathogenesis of E. sakazakii 
(Cronobacter) using the suckling mouse assay (Ref. 44). The animals 
were challenged both by oral and intraperitoneal routes with clinical 
and food isolates of the pathogen. The investigators reported that one 
strain of the pathogen (MNW2), which was administered orally, was 
lethal to suckling mice at 10\8\ CFU per mouse,

[[Page 7982]]

while others were lethal at doses greater than 10\8\ CFU per mouse. In 
a more recent animal study, Richardson et al. (2009) evaluated the 
infectivity and lethality of the MNW2 strain of Cronobacter spp. in 
three different strains of neonatal mice to determine whether neonatal 
mice could be used as a model for Cronobacter spp. infection in 
premature infants (Ref. 45). The investigators found that one of the 
three mouse strains was the most susceptible to the pathogen and had 
the lowest infectious dose (10\2\ CFU) and the lowest lethal dose 
(10\2\ CFU) (Ref. 45). The investigators noted that there was not a 
clear dose-dependent response after treatment with the pathogen.
    FDA finds that the contradictory results of these two studies 
demonstrate that more research is needed to identify an appropriate 
animal model, or specific strain of animal, for Cronobacter spp. 
research. Neither study clearly established the relationship between 
growth of the pathogen in mice and growth of the pathogen in an infant. 
The results of these studies do show that Cronobacter spp. is an 
infectious and lethal pathogen. As noted, this organism has a 40-80 
percent lethality in infant illness (Ref. 45).
    (Comment 127) One comment argued that infections are primarily 
associated with foods in which the pathogen has significantly 
multiplied, but there is scant to no evidence to suggest that ingestion 
of small numbers (<100 CFU) of E. sakazakii (Cronobacter spp.) or 
Listeria monocytogenes causes illness in high risk populations. The 
comment added that because of the presence of both pathogens in the 
environment, there is the potential for contamination of foods during 
at-point-of-use preparation as well as the potential for growth during 
subsequent storage. Thus, the comment asserted that high-risk processed 
foods initially free of the pathogens can become contaminated and 
abused by the food preparer resulting in a dangerously unsafe product. 
The comment stated that establishing a zero tolerance for these 
pathogens in high-risk foods will not address the issue.
    (Response) As discussed in section V.J.2.e, FDA has determined that 
the interim final rule will not include a standard for Listeria 
monocytogenes. Thus, the Agency's response to this comment addresses 
the issues in the comment only from the perspective of Cronobacter spp.
    FDA disagrees with this comment for several reasons. First, the 
Agency is aware that the available data are not adequate to identify 
with certainty the infectious dose for Cronobacter spp. Importantly, 
however, FDA disagrees that the absence of information on the 
infectious dose supports the conclusion that these organisms pose 
little or no risk of illness in high risk populations when ingested in 
small numbers.
    Second, the available evidence demonstrates that post-processing 
contamination is not required for there to be an illness outbreak as 
illustrated by the investigation of the 2001 Tennessee outbreak of 
Cronobacter spp. infection. As part of the follow-up investigation, 
hospital personnel reviewed Neonatal Intensive Care Unit (NICU) 
infection-control practices, policies, and procedures for preparation, 
storage, and administration of powdered infant formula (Ref. 34), and 
no breaches in infection control were identified. The investigation 
determined that the formula was prepared in the NICU according to 
manufacturer's instructions and that the powdered formula was mixed 
with sterile water, immediately refrigerated, and used within 24 hours 
of preparation. The infant that developed Cronobacter spp. meningitis 
was given formula by continuous administration; administration or 
``hang'' time (i.e., the amount of time the contents of a formula bag 
are fed to a patient) did not exceed 8 hours. A second outbreak in a 
Belgian hospital NICU also documented that infections associated with 
powdered infant formula may occur in high-risk infants despite proper 
formula preparation. In this instance, formula powder that was 
apparently contaminated was prepared and administered according to NICU 
protocol, and resulted in serious illnesses (including two deaths) of 
12 premature infants (Ref. 46).
    Finally, although there is potential for contamination of foods 
during preparation and subsequent storage, that fact does not negate 
the need to establish a tolerance. FDA disagrees that establishing a 
tolerance (claimed by the comment to be a zero tolerance) for these 
pathogens in high-risk foods will not address the illness issue. One 
purpose of the CGMPs in this interim final rule is to focus on 
manufacturing controls to help eliminate the potential for microbial 
contamination of formula during processing and thus reduce the risk of 
potential illness from powdered infant formula contaminated, even at 
low levels, with harmful microorganisms. The Agency also disagrees that 
the microbial standard for Cronobacter spp. established in Sec.  106.55 
of the interim final rule is a ``zero tolerance'' standard, and we 
respond to this comment in section V.J.2.c.
    iii. Issues related to alternatives to testing for Cronobacter spp.
    (Comment 128) One comment suggested that the addition of E. 
sakazakii (Cronobacter spp.) inhibitors to formula, such as 
antimicrobials inhibitory to E. sakazakii (Cronobacter spp.) that are 
presently approved for use in foods, provide a more effective means of 
preventing the growth of E. sakazakii (Cronobacter spp.) that may occur 
under conditions of abuse. Importantly, however, the comment stated 
that use of such antimicrobials would require that the formula not have 
an initial level of contamination that would be considered unsafe.
    (Response) FDA disagrees with the suggestion of this comment for 
two reasons. First, the use of antimicrobials was not suggested as an 
alternative to finished product testing. Rather, the comment proposed 
that such inhibitors be used to manage the risk of post-rehydration 
abuse. Thus, the comment does not provide a basis for rejecting the 
Agency's tentative conclusion that testing finished powdered infant 
formula is necessary to control contamination from Cronobacter spp. 
before rehydration. Second, as noted in the 2006 reopening, the comment 
suggesting the use of inhibitors to Cronobacter spp. in powdered 
formula did not provide data to demonstrate the effectiveness of such 
ingredients to control this pathogen in a powdered infant formula 
matrix. For these reasons, FDA concludes that the use of antimicrobials 
is not an alternative to establishing a standard for Cronobacter in 
finished infant formula products.
    (Comment 129) Several comments suggested that instead of requiring 
testing for E. sakazakii (Cronobacter spp.), FDA should instead require 
stricter testing for indicator organisms, such as Enterobacteriaceae 
(which include E. sakazakii (Cronobacter spp.)). A second comment 
recommended testing for the presence or absence of Enterobacteriaceae, 
rather than requiring a quantitative analysis. The second comment 
further suggested that a standard for Enterobacteriaceae of zero 
organisms in a ten gram sample would provide an appropriate level of 
assurance and that this criterion should be applied to all formulas, 
including exempt formulas.
    (Response) FDA disagrees with the comments that support testing 
powdered infant formula for the presence or absence of an indicator 
organism, specifically Enterobacteriaceae, as an alternative to testing 
directly for Cronobacter spp. The Agency also notes that this interim 
final rule does not extend to exempt infant

[[Page 7983]]

formulas. Thus, this response does not address the comment regarding 
the appropriateness of testing exempt formula.
    Cronobacter spp. is a member of the Enterobacteriaceae family. 
Detection and identification of the organism have presented 
methodological difficulties, which difficulties were considered when 
determining the finished product standard. Baumgartner et al., (2009) 
reported that some methods for the detection of Enterobacteriaceae may 
not effectively identify or otherwise be used to determine the presence 
of Cronobacter spp. (Ref. 47). The standard methods of isolation for 
Enterobacteriaceae are not specific for Cronobacter spp., and detection 
of the Cronobacter organism is further complicated by the sensitivity 
of a number of Cronobacter spp. strains to certain chemicals used in 
isolation and detection media for Enterobacteriaceae (Refs. 37, 48, and 
49). Studies have shown that specially modified enrichment media are 
needed for the detection of this pathogen (Refs. 48, 50, and 51) and 
are described on the FDA Web site (http://www.fda.gov/Food/ScienceResearch/LaboratoryMethods/ucm114665.htm). In addition, the 
primary microbial populations found in powdered infant formula are 
Bacillus species and other gram-positive bacteria, which bacteria may 
have an adverse affect on the enrichment and isolation of 
Enterobacteriaceae (Ref. 52).
    Detection, identification, and specificity of Cronobacter spp. are 
critical to effective management of this pathogen. Enterobacteriaceae 
may not function effectively as in indicator of the presence of 
Cronobacter spp. because testing for Enterobacteriaceae may produce a 
negative result for Enterobacteriaceae even though Cronobacter spp. is 
present. Because powdered infant formula is not a sterile product, any 
post-heat treatment contamination with Cronobacter spp. may be from a 
source where Enterobacteriaceae are not present but Cronobacter are. 
These same observations and conclusions were reported by Paoli and 
Hartnett (2006) in their article ``Overview of a risk assessment model 
for Enterobacter sakazakii in powdered infant formula'' (Ref. 53). 
Following a statistical evaluation of the relationship between 
Enterobacteriaceae and Cronobacter spp., the investigators concluded 
the data indicated that a strong positive relationship between the 
concentrations of the pathogens could not be inferred and that the 
absence of Enterobacteriaceae in a powdered infant formula sample did 
not necessarily mean that Cronobacter spp. were not present. Thus, 
relying on testing for Enterobacteriaceae to identify Cronobacter spp. 
could produce a false negative finding, resulting in the release of 
product for distribution that is contaminated with Cronobacter spp.
    For these reasons, FDA declines to require the use of 
Enterobacteriaceae as an indicator organism to identify the presence of 
Cronobacter spp. in powdered infant formula as an alternative to a 
specific standard for Cronobacter spp. The interim final rule's 
standard for Cronobacter spp. is discussed in detail in section 
V.J.2.c.
    iv. The microbial risk assessment.
    (Comment 130) One comment requested that FDA make available to the 
public a risk assessment or risk profile analysis to support its 
Cronobacter spp. standard.
    (Response) The comment requesting public disclosure of a risk 
assessment or risk profile analysis was submitted prior to several 
important actions related to microbial contamination of powdered infant 
formula. These subsequent activities have effectively responded to the 
comment's request.
    In particular, as discussed previously in this document, FAO/WHO 
organized two expert consultations (2004 and 2006) on Cronobacter spp. 
contamination of powdered infant formula. The second consultation 
culminated in the 2006 FAO/WHO report, Enterobacter sakazakii and 
Salmonella in Powdered Infant Formula, which report included a 
quantitative risk assessment of Cronobacter spp. contamination of such 
formula (Ref. 3). In the 2006 reopening, FDA summarized the FAO/WHO 
risk assessment model and announced the Agency's tentative decision to 
rely on that assessment to support the Agency's risk management 
decision as reflected in the proposed Cronobacter spp. standard. At the 
time of the 2006 reopening, a pre-publication copy of the 2006 FAO/WHO 
report was made available for review at FDA's Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852 (Ref. 3). The final FAO/WHO report is 
also available at FDA's Division of Dockets Management and also at the 
following Web site: http://www.who.int/foodsafety/publications/micro/mra10.pdf. FDA notes that another document providing additional insight 
into the 2006 risk assessment is ``Overview of a Risk Assessment Model 
for Enterobacter sakazakii in Powdered Infant Formula'' (Ref. 53). This 
document is likewise available at the Division of Dockets Management 
and on the FAO/WHO Web site at www.who.int/foodsafety/micro/jemra/r_a_overview.pdf.
    The Agency's review of the data and quantitative risk assessment 
model as applied to Cronobacter spp. led to its tentative conclusions 
to establish a standard for this pathogen. Since the 2006 reopening, 
there have been no further scientific data made available to cause the 
Agency to change its tentative conclusions.
    Accordingly, FDA has responded to this comment.
    (Comment 131) One comment expressed concern that the risk 
assessment model relied upon by the Agency to propose a standard for E. 
sakazakii (Cronobacter spp.) lacks sufficient supporting evidence, 
particularly dose-response data.
    (Response) FDA disagrees with this comment for several reasons.
    First, one reason that quantitative risk assessment methodology has 
been developed is to allow assessment of risk even where data are 
limited; such methodology generally anticipates further refinements as 
more data become available. The FAO/WHO Guidelines on ``Exposure 
assessment of microbiological hazards in foods'' (Ref. 54) discuss the 
characteristics of data used in an exposure assessment and note that 
the iterative nature of an exposure assessment is ``concerned with the 
fact that initial attempts to model a process are likely to utilize 
data with a high degree of uncertainty. This process can be used to 
identify where the greatest uncertainty lies, allowing targeted data 
collection for subsequent model updating'' (Ref. 54).
    Second, the Agency acknowledges that there are no complete dose-
response data for infants who consumed powdered infant formula and 
developed Cronobacter infections. Similarly, as discussed previously in 
this document, there are as well insufficient data in animals to 
characterize a dose-response relationship. It is unlikely that 
sufficient empirical data in infants will be developed even to 
establish an infectious dose, i.e., the lowest dose of the pathogen 
required to cause illness, for Cronobacter, because the illness is 
relatively rare and such research would present significant ethical 
problems. If and when an appropriate animal model is identified, more 
research can perhaps be done to try to develop data on an infectious 
dose and a dose-response curve in order to gain a better understanding 
of the infectivity of Cronobacter spp. in infants.
    Even in the face of limited data (Refs. 33, 34, and 46), the 
severity of the public health risk from Cronobacter spp.

[[Page 7984]]

infections requires action by FDA. In this instance, the available tool 
is a risk assessment grounded in well-considered, conservative 
estimates; as more data become available and are applied to the model, 
the levels of uncertainty will be reduced. Although the FAO/WHO risk 
assessment was based on several estimates, the expert committee was 
fortunate to receive data on the initial levels of Cronobacter spp. 
contamination of infant formula from formula manufacturers worldwide. 
It is also important to note that the technical experts at the 2006 
FAO/WHO meeting in Rome, including representatives from FDA and CDC, 
reviewed and endorsed the risk assessment, finding it to be ``accurate 
and valid, based on the approach taken, the assumptions made and the 
interpretation of data'' (Ref. 2, p. xvi) (see http://www.who.int/foodsafety/publications/micro/mra10.pdf).
    For these reasons, FDA concludes that the FAO/WHO risk assessment 
model is sound and an extremely valuable tool for managing the risk 
presented by Cronobacter contamination of infant formula in the United 
States.
    (Comment 132) One comment asserted that there is no ``nominated 
dose-response'' used to support the arguments, that a risk model is a 
measure of relative rather than actual risk, and that caution is needed 
when determining criteria to use to support a standard.
    (Response) It is not clear what this comment means by ``nominated 
dose-response.'' In the absence of an appropriate animal model, it is 
not possible to establish a level of Cronobacter spp. in powdered 
infant formula that, when consumed by infants, will result in illness. 
It is reasonable, therefore, for FDA to employ a well-considered, 
conservative estimate of the probable level of pathogen required to 
cause illness.
    In the absence of specific dose-response information, the exposure 
assessment model used by the FAO/WHO expert group assumed that one 
colony-forming unit of Cronobacter spp. per gram (1 CFU/g) powdered 
infant formula was capable of causing illness (Ref. 53). In the 
application of the model, this level was adjusted to take into account 
any growth or decline that may occur due to the conditions of use.
    The hazard characterization portion of the 2006 FAO/WHO risk 
assessment model was used to evaluate the probability that illness 
would result from powdered infant formula contaminated with Cronobacter 
spp.; this probability of illness was assessed using an exponential 
dose-response model in which an initial contamination level of 1 CFU/g 
of Cronobacter spp. was assumed to cause illness (Ref. 53). The risk 
assessors explained that this initial level of 1 CFU/g per serving was 
``adjusted to take into account any growth or decline that may occur 
due to the conditions of preparation, holding and feeding to give an 
estimate of the dose ingested'' (Ref. 53). Because there were no data 
available at the time of the risk assessment to estimate the value of 
the model's dose-response parameter, six options were presented to 
represent the baseline dose-response parameter. It was assumed that the 
dose-response parameter would likely be specific for each of the infant 
groups considered in the model. The risk assessment used a value of 1 
for the dose-response multiplier, which enables a direct comparison of 
the impact of the assumptions regarding the value of the dose-response 
parameter and the relative susceptibility of the infant groups in terms 
of the estimates of risk (Ref. 53).
    For these reasons, the absence of an empirical dose-response does 
not preclude managing the risk presented by Cronobacter ssp. in 
powdered infant formula by relying on the FAO/WHO quantitative risk 
assessment.
    (Comment 133) One comment argued that the risk assessment used an 
incorrect premise that healthy newborns should be grouped with 
premature infants.
    (Response) FDA disagrees with this comment. The risk assessment 
appropriately grouped together healthy terms infants and preterm 
infants. The report of the 2006 risk assessment explains this approach, 
which FDA endorses. Specifically, the expert consultants reviewed the 
available outbreak data and noted that the cases could be grouped into 
two risk groups in terms of age at which the illness occurred: 
``premature infants who developed bacteraemia outside of the neonatal 
period, with more, but not all, cases occurring in infants under 2 
months; and term infants who develop meningitis during the neonatal 
period.'' http://www.who.int/foodsafety/publications/micro/mra10.pdf, 
(Ref. 54, p. 14). These experts further observed, however, that the 
differences in timing of infection onset may have been related to 
differences in timing of exposure to the pathogen rather than to 
differences in susceptibility. They concluded that any infant may 
develop either syndrome (i.e., bacteraemia or meningitis) at any age 
(Ref. 54, p. 14).
    FDA agrees with the FAO/WHO expert consultants that the outbreak 
data support the observation that both preterm and term infants are at 
risk of illness from consuming powdered infant formula contaminated 
with Cronobacter spp. and that the impact of illness from this pathogen 
is significant for the term infant and the premature infant alike. 
Because both premature and term infants are susceptible, at different 
times in their lives, to illness from this pathogen and may be fed 
powdered formula, it was reasonable and appropriate for the two cohorts 
to be grouped together in the risk assessment.
    c. Microbiological standards for powdered infant formula for 
Cronobacter spp. and Salmonella spp.
    In the 2006 reopening, FDA tentatively concluded that it was 
appropriate to establish a standard for E. sakazakii (Cronobacter spp.) 
of negative in 30 x 10 g samples (71 FR 43392 at 43395). The Agency 
suggested no change to the proposed standard for Salmonella spp. of 
negative in 60 x 25 g samples.
    i. The sampling plan--Cronobacter spp.
    (Comment 134) Several comments agreed with the need to establish a 
microbiological standard for E. sakazakii (Cronobacter spp.), but did 
not suggest a specific standard. Several other comments agreed with FDA 
regarding the proposed microbiological standard and the proposed 
sampling plan for Cronobacter spp. (negative in 30 x 10 g samples.) 
Other comments requested that FDA provide an explanation of the number 
and sample sizes required to test finished formula product for 
contamination.
    (Response) To place in context FDA's tentative decision to 
establish a standard of negative in 30 x 10 g samples for Cronobacter, 
it is useful to understand the outlines of the risk assessment and risk 
management processes both generally and specifically with respect to 
Cronobacter contamination of powdered infant formula.
    Risk assessment and risk management are two separate, though 
related, parts of the process to address a hazard. At the risk 
assessment stage, the nature and probability of an adverse event is 
calculated. Often, this calculation is an estimate based on a less than 
complete set of empirical data. At the risk management stage, the risk 
manager determines the tolerable level of risk (or the level of 
protection) and the desirable level of confidence that the level of 
protection will be achieved.
    In the case of Cronobacter contamination of powdered infant 
formula, a quantitative risk assessment model was developed as part of 
the FAO/WHO expert consultation (Ref. 3).

[[Page 7985]]

This model estimates the risk of Cronobacter illness to infants 
consuming powdered infant formula and ``provides the means to evaluate 
microbiological criteria and sampling plans in terms of the risk 
reductions achieved and the percentage of product [production 
aggregates] rejected.'' (Ref. 3, p. xii). All told, the model was used 
to project risk reduction and product rejection rates for 162 different 
scenarios (Ref. 3, pp. 46-47). Importantly, the FAO/WHO expert group 
did not select a specific approach to managing the Cronobacter hazard; 
instead, the 2006 Rome Report recommended that each country manage this 
risk using the risk assessment model (Ref. 3, p. xiv-xv).
    Accordingly, using the information from and applying the FAO/WHO 
risk assessment model, FDA subsequently engaged in the risk management 
phase of addressing the Cronobacter hazard. Specifically, the Agency 
identified both the appropriate level of protection (i.e., the level of 
contamination below which we would not expect in a Cronobacter 
infection to occur) and the level of desired certainty that such level 
of protection would be achieved (i.e., the confidence level). In making 
these determinations, FDA sought to balance the risk of illness and the 
likely percentage of production aggregates of formula that would be 
rejected due to a finding of the presence of Cronobacter spp., and 
tentatively determined that a sampling plan of 30 samples of 10 g each 
per production aggregate would appropriately manage the risk of 
Cronobacter infections from powdered infant formula. According to the 
FAO/WHO risk assessment model, the 30 x 10 g sampling plan (that is, 
negative for Cronobacter in 30 x 10 g or 300 g total) would result in 
approximately 20 percent fewer cases of Cronobacter illness each year 
and the rejection of 1.4 percent of production aggregates of powdered 
infant formula.
    (Comment 135) One comment stated that FDA's regulatory sample size 
of 30 x 10 g samples would not provide a high level of assurance that 
the lot (production aggregate) was not contaminated because unlike 
chemicals which may be uniformly dispersed throughout a powdered 
formula, bacteriological contamination is likely to be unevenly 
distributed in the final lot (production aggregate). The comment 
asserted that because microbiological contamination present in finished 
powdered infant formulations produced in inadequately controlled 
systems are likely to be uneven and at low levels, sample size would 
have to reach excessive levels (at a minimum ten percent of the lot 
(production aggregate)) to ensure meaningful results.
    (Response) FDA disagrees with this comment. The Agency notes that 
the comment did not provide any data to support its assertion that, to 
ensure meaningful results, the proposed sample size would have to reach 
a minimum of 10 percent of the production aggregate. FDA agrees that 
microbiological contamination of powdered infant formula may be 
unevenly dispersed in the production aggregate, particularly when there 
is low level contamination. However, even where the pathogen is 
unevenly dispersed, an appropriately designed and executed sampling 
plan can help to address the variability and uncertainty created by 
such conditions. In addition to establishing a limit for the pathogens 
of concern, microbiological criteria include the testing method 
employed, the sampling plan (size and number of samples to be 
examined), and the actions to be taken when the microbiological limits 
are exceeded (Ref. 54, p. 62).
    The sampling plan for Cronobacter spp. is intended to help 
manufacturers identify unacceptable production aggregates at the 
finished product stage, i.e., those production aggregates not complying 
with the established limits, before release for distribution. To 
establish an appropriate sampling plan, it is necessary to consider, 
for any production aggregate, the likely level of contamination and the 
variability within the production aggregate in order to evaluate the 
likelihood that a sample will be positive for the pathogen (Ref. 55). 
Because there will be variability between and among production 
aggregates, the true concentration of the pathogen in a production 
aggregate cannot be determined with 100 percent accuracy. Thus, the 
average of the concentrations of the pathogen across all production 
aggregates and the ``between production aggregate variability'' among 
production aggregates is used to determine the percentage of production 
aggregates likely to be rejected by a particular sampling plan. This 
statistical approach is commonly used to establish microbiological and 
chemical contaminant sampling plans for regulatory purposes.
    With any sampling plan in which there is variability in the 
concentration and dispersion of the contaminant, there is the 
likelihood that some ``good'' production aggregates may be rejected by 
the sampling plan (false positives) and that some ``bad'' production 
aggregates (false negatives) may be deemed acceptable. In a public 
health environment, FDA is most concerned about the risk to infants by 
the acceptance of false negative (``bad'') production aggregates by the 
sampling plan.
    As noted previously in this document in response to Comment 134, 
the FAO/WHO risk utilized a large body of data on the initial levels of 
Cronobacter spp. contamination of infant formula from formula 
manufacturers worldwide. Relying on these data, the proposed sampling 
plan for Cronobacter spp. of 30 x 10 g samples took into consideration 
the low levels of contamination and variability of contamination 
between and among production aggregates. The statistical design of the 
proposed sampling plan seeks to minimize false positives and false 
negatives and to maximize true findings of positive and negative, 
within a 95 percent confidence interval. As discussed in the 2006 
reopening, based on the FAO/WHO risk assessment, the 30 x 10 g sample 
plan is expected to provide a relative annual risk reduction of 20 
percent fewer cases (assuming a mean log 10 concentration of 
pathogen of -5 CFU/g) and 37 percent (assuming a mean log 10 
concentration of -3 CFU/g) of illness from Cronobacter spp. than would 
be the case if there were no powdered infant formula sampling plan in 
place (71 FR 43392 at 43394-43395). Thus, the greater the contamination 
of the powdered infant formula, the greater the sampling can reduce the 
risk of illness, because as the level of contamination increases, the 
rejection rate of production aggregates increases and the relative risk 
reduction increases. If manufacturers focus on ensuring that the 
overall mean log concentration of the pathogen is low and that 
variation between lots (production aggregates) is controlled, the 
potential for rejection of the lot (production aggregate), and the risk 
of illness, are both reduced (71 FR 43392 at 43395).
    (Comment 136) One comment argued that based on a lack of evidence 
linking Cronobacter spp. to outbreaks in term infants, FDA's de facto 
standard of zero tolerance for this pathogen in term infants is not 
warranted. Another comment contended that because high risk foods 
initially free of E. sakazakii (Cronobacter spp.) can become 
contaminated and abused by the food preparer resulting in a dangerously 
unsafe product, establishing a zero tolerance for the pathogen in high 
risk foods will not address the issue.
    (Response) FDA notes that the Agency's response to the comment 
about term infants is addressed in Comment 121 (section V.J.2.b.i) and 
the comment regarding post-processing

[[Page 7986]]

contamination is addressed in Comment 127 (section V.J.2.b.ii).
    For two reasons, FDA disagrees with the comment that the standard 
for Cronobacter spp. is zero. First, the sampling plan for Cronobacter 
spp. proposed in the 2006 reopening and established in this interim 
final rule is not zero; rather it is negative in a composite sample of 
300 g (30 x 10 g samples) taken from a single production aggregate of 
finished product. In other words, the standard is the absence of the 
organism in a defined volume of powdered infant formula sampled from 
the production aggregate, which is not the same as the absence of the 
organism from the entirety of the production aggregate. This means that 
when the production aggregate is sampled and the composite is tested, 
if the pathogen is not detected, the manufacturer has a 95 percent 
level of confidence that there would be <1 CFU Cronobacter spp. in 100 
g powder. The statistical validity of the sampling plan, based on an 
analysis of industry data, is discussed in detail in response to 
Comment 134 in this section. Not finding Cronobacter spp. analytically 
does not mean that the pathogen may not be present in the production 
aggregate; it could be present but at an extremely low level (<1 CFU/
100 g). When the pathogen is present in the powdered formula, the 
sampling plan approach accounts for a widely dispersed and, typically, 
low level of contamination. For manufacturers who adhere to strict food 
safety controls during processing, the standard will have little impact 
on the number of production aggregates that would be rejected because 
of a positive finding for the organism.
    Second, the limit of detection of FDA's Cronobacter spp. analytical 
method in the Agency's Bacteriological Analytical Manual (BAM) is 1 
CFU/100 g (Ref. 56). This means that the lowest level of the pathogen 
that can be detected is 1 CFU; not zero.
    For these reasons, FDA disagrees that the standard in Sec.  
106.55(e) of the interim final rule for Cronobacter spp. is a zero 
tolerance.
    (Comment 137) One comment stated that it has been well documented 
in the literature that using small sample sizes of finished product 
will provide no assurance of product safety. The comment contended 
that, in the case of infant formula, to achieve ninety-nine percent 
assurance that the finished product does not contain a pathogen (e.g., 
Salmonella spp., Listeria monocytogenes) that is subject to a ``zero'' 
tolerance level, the manufacturer would have to randomly select 
hundreds of sample throughout the production aggregate, which would 
require significant financial resources.
    (Response) FDA notes that in the 2006 reopening, the Agency 
tentatively decided to eliminate the proposed standard for Listeria 
monocytogenes (71 FR 43392 at 43396), and this interim final rule 
affirms that tentative decision. Thus, this response addresses the 
comment only to the extent that it concerns Salmonella spp.
    The Agency disagrees that the proposed standard for Salmonella is 
zero tolerance for reasons that parallel those presented in response to 
comments regarding the standard for Cronobacter spp (see the response 
to Comment 135). In general, the sampling plan for Salmonella is based 
on the category of food in which it may be present. FDA's BAM describes 
three categories of foods (http://www.fda.gov/Food/ScienceResearch/LaboratoryMethods/BacteriologicalAnalyticalManualBAM/default.htm). Of 
these, Category I Foods (defined as ``foods that would not normally be 
subjected to a process lethal to Salmonella between the time of 
sampling and consumption and are intended for consumption by the aged, 
the infirm, and infants'') includes powdered infant formula. The 
current standard for Category I foods is negative in 60 x 25 g samples 
(i.e., a total composite sample of 1500 g). When FDA tests a sample for 
the presence of Salmonella following the BAM method, four 375 g 
subsamples are removed from the 1500 g composite and tested for the 
pathogen as specified in the method. If no Salmonella are detected 
using the 60 X 25 g sampling, there is a 95 percent level of confidence 
that the pathogen, if present in the production aggregate, is < 1 CFU/
500g of product. This sampling plan has been validated statistically 
and has been used to analyze many foods similar to powdered infant 
formula where the pathogen of interest is likely to be widely dispersed 
and at low concentration. This same sampling plan would provide the 
same level of confidence when used by a formula manufacturer to test 
final production aggregates. A finding of no Salmonella spp. in a 60 X 
25 g composite of the manufacturer's powdered infant formula 
demonstrates, with 95 percent confidence, that the pathogen is present 
in the production aggregate at <1 CFU/500 g of product.
    FDA notes that manufacturers may choose to do more intensive 
testing, such as testing using larger sample sizes or more samples, to 
enhance the confidence of the testing results. Further, the BAM 
analytical method for Salmonella has a limit of detection of 1 CFU/25 g 
and, for some products, 1 CFU/375 g; it cannot establish a total 
absence of the pathogen (``zero'').
    Based on the foregoing comments, Sec.  106.55(b) of the interim 
final rule requires that manufacturers test representative samples of 
each production aggregate of powdered infant formula at the final 
product stage, before distribution, to ensure that each production 
aggregate meets the microbiological quality standard of negative in 30 
x 10 g samples for Cronobacter spp. and negative in 60 x 25 g samples 
for Salmonella spp.
    (Comment 138) One comment suggested that the level of 0.36 CFU/100 
g should be considered safe for the term infant population, a level 
that the comment characterized as the limit of detection.
    (Response) FDA notes that the limit of detection of the analytical 
method the Agency uses to detect the presence of Cronobacter spp. is 1 
CFU/100 g of powdered infant formula. The Agency will consider an 
infant formula to be adulterated under sections 402(a)(1), 402(a)(4), 
and 412(a)(3) of the FD&C Act if the pathogen is detected at this level 
or higher using the analytical method required by this interim final 
rule for determining compliance with the M value in Sec.  106.55(e).
    For the following reasons, FDA declines to adopt the suggestion of 
this comment. First, this comment predates FDA's announcement of its 
tentative decision in the 2006 reopening to establish a microbiological 
standard for Cronobacter spp. of negative (i.e., no organisms) in 30 X 
10 g. As discussed previously in this document, this standard should 
protect both premature and term infants. Although it proposes a 
slightly different standard, the comment does not directly challenge 
the interim final rule's standard of 30 X 10 g. Second, on a 100 g 
basis, FDA's final microbiological standard for Cronobacter spp. 
(negative in 30 X 10 g) is slightly higher than the standard suggested 
in this comment (0.36/100 g). FDA has determined that a standard of 30 
X 10 g is adequate to protect all infants.
    ii. Other issues regarding the sampling plan.
    (Comment 139) Several comments asked for clarification about 
whether the ``30 x 10 g'' refers only to the sampling plan, and that 
the testing required would consist of one test of a composited sample.
    (Response) FDA is clarifying that the 30 individual samples of 10 g 
each are to be combined, for purposes of testing, into one 300 g sample 
composite. FDA emphasizes that that when sampling, a

[[Page 7987]]

manufacturers must collect 30 individual samples of 10 g each randomly 
from each production aggregate of finished product and may not take a 
single sample of 300 g because a single sample consisting of 300 g 
would not be considered representative of the production aggregate.
    (Comment 140) One comment stated that while sampling large batches 
of product can be problematic, and product sterility cannot be 
absolutely assured, all powdered formula should be E. sakazakii 
(Cronobacter spp.) free.
    (Response) FDA believes that this comment does not fully understand 
the standard proposed for Cronobacter spp. The standard that FDA 
proposed in the 2006 reopening is negative for Cronobacter in 300 g (30 
x 10 g samples) of composited formula. This means that there must be 
less than one CFU in the 300 g sample. Said differently, a sample will 
be considered positive (and the production aggregate of infant formula 
will be considered adulterated) if one or more CFUs of Cronobacter are 
found in the 300 g sample.
    The Agency agrees that, based on current technologies, it is not 
possible to produce a sterile powdered infant formula. For this reason, 
the interim final rule does not establish a zero tolerance for 
Cronobacter spp. However, by sampling and testing final production 
aggregates, as required in this interim final rule, product 
contamination with this pathogen will be minimized and public health 
protection maximized.
    (Comment 141) One comment stated that the sampling plan proposed in 
the 2006 reopening is designed for use on large batches in continuous 
process manufacturing, that, in contrast, exempt infant formulas are 
often produced in small distinct batches, and that select sampling and 
testing programs that are relevant to exempt infant formulas to ensure 
the safety of the finished exempt formulas are preferable.
    (Response) FDA notes that the requirements in this interim final 
rule, including the microbiological testing and sampling requirements, 
do not govern the manufacturing of exempt infant formulas. Elsewhere in 
this issue of the Federal Register, FDA is publishing a notice of 
availability of a draft guidance that addresses recommendations 
concerning how these CGMP should be applied to the exempt infant 
formulas.
    d. A microbiological standard for Cronobacter spp. for powdered 
infant formula consumed by premature and newborn infants.
    Some of the following comments were addressed in the 2006 reopening 
(71 FR 43392 at 43394).
    (Comment 142) Some comments urged FDA to adopt the same standard 
for formulas intended for term infants and formulas intended for 
premature infants because a risk of E. sakazakii (Cronobacter spp.) 
infection exists in both populations.
    (Response) FDA agrees with the comments that, with respect to non-
exempt infant formula, consumption of powdered infant formula by 
infants of any age poses a risk of illness from Cronobacter spp. and 
therefore, all such formula should be subject to the same 
microbiological standards.
    (Comment 143) Some comments addressed the need for a 
microbiological standard for exempt infant formulas, as defined in 
Sec.  107.3, and asserted that, due to FDA's statutory authority under 
section 412(h)(2) of the FD&C Act to establish terms and conditions for 
the exemption of formulas intended for infants who are low birth weight 
or who have unusual medical problems, any effort to establish stricter 
microbiological requirements for these formulas should be done with a 
separate notice and comment rulemaking.
    (Response) FDA notes that exempt infant formulas are not required 
to comply with this interim final rule. The Agency further notes that 
many exempt formulas are liquids and are already required to comply 
with part 113 because they are thermally processed low-acid foods 
packaged in hermetically sealed containers or part 114 because they are 
acidified foods. As such, these liquid formulas are commercially 
sterile products. However, there are a few exempt infant formulas that 
are powdered products, such as those for inborn errors of metabolism, 
which are not sterile. Because the risk of contaminated powder exists 
with these products, elsewhere in this issue of the Federal Register, 
FDA is publishing a notice of availability of a draft guidance that 
addresses recommendations concerning how these CGMP should be applied 
to the exempt infant formulas.
    (Comment 144) One comment stated that there is no need to establish 
a more stringent standard for formula intended for premature or newborn 
infants as it would be impractical to differentiate between formulas as 
many of them are consumed by both full term and premature infants. 
Another comment recommended that the standards regarding powdered 
formula be the same for premature and term infants. The comment 
contended that the absolute risk of serious illness, even to term 
infants, is not zero. The comment also asserted that powdered formula 
products should not be consumed by premature infants before 44 weeks 
gestational age, or by any immunocompromised child, and that, with few 
exceptions (amino acid and metabolic formulas), ``commercially'' 
sterile liquid products are available for these populations. The 
comment noted, however, that it is not possible to eliminate completely 
powdered human milk fortifiers fed to premature infants, because many 
premature infants are unable to tolerate the added volume of liquid 
fortifier.
    (Response) To the extent that the comment is referring to non-
exempt infant formulas, FDA agrees that, as a practical matter, it 
would be difficult to limit formula consumption by certain infant 
subgroups to a specific type of formula unless the infants are directly 
under medical supervision because powdered infant formula intended for 
newborns and term infants may also be fed to premature infants. Thus, 
it is essential that non-exempt powdered formulas, whether fed to 
newborns, term infants, or premature infants, meet the same 
microbiological standards. As noted, the data clearly implicate 
powdered infant formula, a potential source of contamination from 
Cronobacter spp. and Salmonella spp. for all infant groups (see 
discussions in section V.J.2.b). The standard established by this 
interim final rule will be protective of infants consuming non-exempt 
infant formulas, regardless of gestational age.
    The Agency notes, however, that infant formulas, including human 
milk fortifiers, that are represented and labeled as being for infants 
with inborn errors of metabolism, low birth weight, or infants with 
other unusual medical or dietary problems are exempt infant formulas 
and, as such, are not subject to the CGMP in this interim final rule. 
Although many of the exempt infant formulas are commercially sterile 
liquids, some are, as noted in the comment, powdered formulas and are 
not commercially sterile. As noted, elsewhere in this issue of the 
Federal Register, FDA is publishing a notice of availability of a draft 
guidance that addresses how these CGMP should be applied to exempt 
infant formulas.
    (Comment 145) Some comments contended there should be a heightened 
standard for formulas intended for certain sub-populations of infants, 
including infants who are premature, of low birth weight, ill, or among 
a group described as vulnerable hospitalized infants. Several of these 
comments argued that there should either be no

[[Page 7988]]

standard or a lower standard for formulas intended for other infants.
    (Response) To the extent that this comment is referring to 
standards for exempt infant formulas (i.e., formulas represented and 
labeled for use by infants who have an inborn error of metabolism, low 
birth weight, or unusual medical or dietary problems), such products 
are not, as noted previously in this document, subject to the 
requirements of these CGMP FDA is publishing a notice of availability 
of a draft guidance that addresses how to apply these CGMP, including 
microbial testing standards, to such formulas. FDA notes that it is 
possible that a number of subgroups of infants, including those term 
infants who are ill or hospitalized, may be fed a non-exempt infant 
formula, and that the microbiological standards in this interim final 
rule are sufficiently protective of such subgroups of infants.
    FDA disagrees with the comment that suggested no standard or a 
lower standard for formulas intended for ``other infants,'' to the 
extent that ``other infants'' refers to ``term infants,'' for the 
reasons discussed in section V.J.2.b.i.
    (Comment 146) One comment asserted that formulas for premature 
infants or infants with gastrointestinal medical conditions should 
receive specific and elevated testing. The comment argued that although 
microbiological testing by formula manufacturers has generally been 
sufficient for such infant populations in the past, there have been 
changes in the infant population consuming powdered formula. In 
particular, the comment claimed that premature infants are now viable 
at ``micro weights'' and extreme prematurity of less than 23 weeks 
gestation; these infants are more susceptible to microbial infection. 
The comment asserted that a more rigorous standard may be needed for 
powdered products designed for feeding low birth weight infants or some 
vulnerable hospitalized infants, although even in these cases, 
mishandling of formula during reconstitution, feeding, and storage may 
increase the risk of disease.
    (Response) FDA notes that this comment preceded the 2006 reopening 
and the Agency's tentative determination to establish a standard for 
Cronobacter spp. in powdered infant formula. Thus, the comment was not 
directly challenging the adequacy of the microbiological standards 
proposed at that time.
    The Agency acknowledges the comment's concerns about the safety of 
formula fed to very low weight premature infants but, as explained in 
Comment 143, the formulas that are subject to this rulemaking are the 
non-exempt infant formulas (i.e., formulas that are not represented and 
labeled for infants that have an inborn error of metabolism, low birth 
weight, or other unusual medical or dietary problem.) FDA is aware that 
some premature infants may be fed the same powdered infant formulas 
that are consumed by term infants and thus, are vulnerable to infection 
from Cronobacter spp. and Salmonella spp., if these organisms are 
present in the formula. The microbiological standards established in 
Sec.  106.55(e) of the interim final rule for non-exempt infant 
formulas are designed to provide and will provide adequate protection 
for both premature and term infants who consume them. To the extent 
that this comment concerns exempt infant formulas, FDA notes that such 
powdered exempt formulas are not subject to the standards of this 
interim final rule. While it may be appropriate at some future date to 
propose a separate standard for some or all exempt infant formulas, the 
Agency declines to do so at this time. As noted, the agency is 
concurrently issuing draft guidance on how the CGMPs should apply to 
exempt infant formulas.
    FDA has carefully considered all of the comments that support two 
standards for non-exempt infant formulas--one standard for formula 
intended for premature and newborn infants and one for formula intended 
for infants beyond the newborn period and finds that it is neither 
necessary nor feasible to establish a more stringent Cronobacter spp. 
standard or a more stringent Salmonella spp. standard for non-exempt 
powdered infant formula consumed by premature and newborn infants. For 
the reasons cited previously in this document, FDA concludes that the 
standards established in Sec.  106.55(e) of the interim final rule for 
Cronobacter spp. and for Salmonella spp. apply to all non-exempt 
powdered formulas intended for infants from birth to 12 months of age 
and that both such standards are sufficiently protective of such 
infants.
    (Comment 147) A few comments asserted that formulas for premature 
infants or infants with gastrointestinal medical conditions should be 
labeled to inform families and practitioners that the product is not 
sterile. One comment added that the label should state that the product 
should not be given to immunocompromised babies.
    (Response) Comments regarding the labeling of formula for premature 
or immunocompromised infants are beyond the scope of this interim final 
rule. Importantly, however, FDA notes that a variety of educational and 
other outreach programs have been established to communicate the proper 
use, preparation, and handling of powdered infant formula, including 
outreach by the AAP and ADA to their members.
    e. Elimination of microbiological standards for Aerobic Plate 
Count, Coliforms, Fecal Coliforms, Listeria monocytogenes, 
Staphylococcus aureus, and Bacillus cereus.
    In the original 1996 proposal, FDA proposed to establish seven 
microbiological quality standards for powdered infant formula: APC, 
coliforms, fecal coliforms, Listeria monocytogenes, Staphylococcus 
aureus, Bacillus cereus, and Salmonella spp. At the time of the 
proposal, the microorganisms for which FDA proposed standards were 
those of known public health significance or were viewed as indicators 
that a formula was prepared, packed, or held under insanitary 
conditions (62 FR 36154 at 36170).
    Subsequently, in the 2003 reopening, the Agency requested comment 
on the need for a standard for Cronobacter spp., an emerging pathogen 
associated with severe illness in certain formula-fed infants. 
Thereafter, in the 2006 reopening, FDA announced the Agency's tentative 
conclusion not to finalize the microbiological testing regime proposed 
in 1996 and to limit required final product testing of powdered infant 
formula to only two microorganisms, Cronobacter spp. and Salmonella 
spp. Based on the available evidence, including the 2004 and 2006 FAO/
WHO expert consultations, the Agency tentatively concluded that only 
Cronobacter spp. and Salmonella spp. had been associated with infant 
illness related to microbiological contamination of powdered infant 
formula (Ref. 2). In the 2006 reopening, FDA also explained that 
testing for an indicator organism, such as Enterobacteriaceae, can be 
beneficial to manufacturers in monitoring their overall process and 
production sanitation (71 FR 43392 at 43396) but the Agency's tentative 
decision was not to require such testing.
    Several comments supported the Agency's tentative determination to 
establish microbiological standards only for Cronobacter spp. and 
Salmonella spp. in finished powdered infant formula product. One 
comment noted that Listeria monocytogenes and Staphylococcus aureus 
have not been problems for the U.S. formula industry. In addition, 
several comments made in response to the 1996 proposal challenged the 
proposed requirement to test each batch (production aggregate) of

[[Page 7989]]

powdered infant formula at the final product stage for the 
microorganisms listed in proposed Sec.  106.55(c) and thus, indirectly 
supported FDA's tentative determination not to finalize certain of the 
proposed standards. Other comments objected to FDA's tentative plans to 
revise proposed Sec.  106.55.
    (Comment 148) One comment questioned FDA's tentative conclusion in 
the 2006 reopening that only E. sakazakii (Cronobacter spp.) and 
Salmonella spp. are of concern in infant formula.
    (Response) FDA is confirming its tentative decision announced in 
the September 2006 reopening not to finalize the proposed 
microbiological standards for APC, coliforms, fecal coliforms, Listeria 
monocytogenes, Staphylococcus aureus, and Bacillus cereus. FDA notes 
that this comment provided no data or other information to contradict 
the Agency's tentative conclusion that protection of the public health 
does not require establishing microbiological standards and testing for 
organisms other than Cronobacter spp. and Salmonella spp. The basis for 
the decision not to finalize all of the proposed requirements is 
discussed in detail in this document.
    Aerobic Plate Count, Coliforms, and Fecal Coliforms: The 1996 
proposed rule would have required infant formula manufacturers to 
conduct tests for APC, coliforms, and fecal coliforms. In the proposal, 
FDA noted that these three microbiological standards had a specific 
purpose: an M value exceeding the proposed standard would imply that 
the formula was produced under insanitary conditions whereby the 
formula may have been rendered injurious to health and thus, the 
formula could be adulterated under section 402(a)(4) of the FD&C Act. 
(Such use of microbiological testing is often referred to as 
``indicator organism'' testing.) The Agency acknowledged that all three 
tests were capable of identifying both pathogenic and non-pathogenic 
microorganisms, and the proposal did not specifically identify any 
evidence that pathogenic organisms that would be identified by these 
three tests had previously been linked to formula-borne illness in 
infants.
    FDA has concluded that, on balance, it is not necessary or 
appropriate to finalize standards for APC, coliforms, and fecal 
coliforms because in the context of the complete interim final rule, 
including the required microbiological testing scheme, these tests are 
not essential and the proper interpretation of the results of such 
testing is not at all clear.
    As discussed in section V.C. 2, Sec.  106.6 of the interim final 
rule requires a manufacturer to implement a system of production and 
in-process controls designed to prevent adulteration, including 
adulteration due to insanitary conditions. The decision to conduct 
``indicator organism'' testing (such as APC and testing for coliforms 
and fecal coliforms) is best made on a facility-by-facility basis and 
in the context of a manufacturer's entire production and in-process 
control system. Thus, to the extent that a particular manufacturing 
process requires or would otherwise benefit from the application of 
indicator organism testing, such as APC or testing for coliforms or 
fecal coliforms, as a means to control adulteration from insanitary 
conditions, the manufacturer's plan may, and should, include such 
testing. Accordingly, FDA declines to finalize standards for APC, 
coliforms, and fecal coliforms that would apply to all manufacturers 
regardless of the process control systems. Not finalizing the 
requirements for APC and coliforms and fecal coliforms testing will not 
increase the risk of illness to infants. As noted, the three tests do 
not distinguish between pathogenic and non-pathogenic microorganisms so 
they cannot be used to identify organisms that theoretically could 
contaminate powdered infant formula with pathogens.
    Moreover, as discussed in detail previously in this document, the 
interim final rule mandates that each production aggregate of finished 
infant formula be analyzed for the two pathogenic organisms that have a 
documented association with powdered infant formula, Cronobacter spp. 
and Salmonella spp. Thus, the interim final rule requires specific 
controls to prevent the direct microbiological contamination of formula 
with these pathogens. Although a variety of Enterobacteriaceae have 
been isolated from powdered infant formula, including Citrobacter 
koseri, Klebsiella pneumoniae, Klebsiella oxytoca, Pantoea agglomerans, 
and Enterobacter cloacae, and are capable of causing illness, none have 
been demonstrated to have done so (Ref. 2). In contrast, Salmonella 
enterica (Ref. 57), Salmonella virchow (Ref. 58), and Cronobacter spp. 
are associated with illness in infants (Refs. 24, 34, 59). Also, to the 
extent that testing for Cronobacter spp. or Salmonella spp. documents 
contamination of a production aggregate of finished formula, as 
discussed in this document, other provisions of the interim final rule 
require controls to prevent microbial contamination that would 
adulterate the infant formula.
    Section 106.6(c) of the interim final rule requires that a 
manufacturer establish specifications at any point, step, or stage in 
the production process where control is necessary to prevent 
adulteration. Therefore, a manufacturer that determines that a 
specification for indicator organism testing results is a necessary as 
part of its system of production and in-process controls in order to 
prevent adulteration is required to establish such a specification. If 
a manufacturer's testing of its facility documents levels of APC, 
coliforms, or fecal coliforms under circumstances that establish the 
presence of insanitary conditions in the facility that would adulterate 
the infant formula, and the manufacturer has either not included 
indicator organism testing in its plan under Sec.  106.6(a) of the 
interim final rule or has not established specifications for such 
indicator organisms, the presence of such organisms at such levels and 
the absence of established specifications for such organisms would be a 
violation of Sec.  106.55(a) of the interim final rule.
    Moreover, the interim final rule requires investigation and 
evaluation of the circumstances that result in a failure to meet 
specifications, including the microbiological standards of the interim 
final rule. Specifically, Sec.  106.70(b) of the interim final rule 
requires quarantine of the contaminated formula and a documented review 
and a material disposition decision for the formula. Similarly, Sec.  
106.100(e)(4)(iii) of the interim final rule requires a manufacturer to 
maintain a record of the investigation and follow-up of such failure. 
FDA expects that part of a manufacturer's investigation and follow-up 
to a finding of actual contamination of formula will be the evaluation 
of the manufacturing environment to determine whether insanitary 
conditions may have contributed to the microbiological contamination of 
the production aggregate and the identification and implementation of 
appropriate corrective actions.
    For these reasons, FDA declines to finalize the proposed 
requirements for APC and for coliforms and fecal coliforms testing in 
proposed Sec.  106.55(c).
    Listeria monocytogenes, Staphylococcus aureus, and Bacillus cereus: 
Proposed Sec.  106.55(c) would have required infant formula 
manufacturers to conduct tests of finished powdered infant formula for 
Listeria monocytogenes, Staphylococcus aureus, and Bacillus cereus. In 
the proposal, FDA noted that ``health concerns may arise due to the 
presence of any

[[Page 7990]]

detectable . . . Listeria or S. aureus bacteria in infant formula or 
due to levels of B. cereus that exceed 1,000 `colony-forming units' 
(CFU's) per gram (g) of a powdered formula.'' (61 FR at 36170). In 
making this statement, the Agency did not cite specific data or other 
information documenting the contamination of powdered infant formula 
with any of these microorganisms.
    More recently, in the 2006 reopening, FDA tentatively concluded, 
based on the data developed during the FAO/WHO expert consultations, 
that testing for these three organisms was not warranted to ensure 
microbiological safety of powdered infant formula (Ref. 3). The report 
of the 2004 FAO/WHO expert consultation sorted the microorganisms of 
possible concern in infant formula into three categories; Listeria 
monocytogenes, Staphylococcus aureus, and Bacillus cereus were placed 
in the category ``causality less plausible or not yet demonstrated'' 
because the organisms had not been identified in powdered formula 
(Listeria monocytogenes, Staphylococcus aureus) or because no causal 
association between the organism and illness from powdered formula had 
been demonstrated (Bacillus cereus) (Ref. 2). The report of the 2006 
expert consultation affirmed this categorization (Ref. 3). Moreover, 
FDA is not aware of any data or other information showing that these 
organisms are present in powdered infant formula or, if present, have 
been associated with infant illness.
    Several comments supported FDA's tentative determination to not 
finalize the microbiological standards for Listeria monocytogenes, 
Staphylococcus aureus, and Bacillus cereus, with one comment noting 
that Listeria monocytogenes and Staphylococcus aureus, have not been 
problems for the U.S. formula industry. However, as noted, one comment 
objected to FDA's proposal to delete microbiological standards for 
Listeria monocytogenes, Staphylococcus aureus, and Bacillus cereus 
although no data were submitted to support this objection.
    (Comment 149) Several 1996 comments argued that testing for 
Listeria monocytogenes was unnecessary because this organism does not 
pose a significant health concern in infant formula.
    (Response) FDA agrees with this comment and, as noted, is not 
finalizing the proposed Listeria monocytogenes microbiological standard 
for powdered infant formula. The Agency's decision on this point is 
supported by the conclusions of the recent FAO/WHO expert consultation.
    (Comment 150) One 1996 comment requested that FDA change the M 
value for Bacillus cereus to 1,000 most probable number/g (MPN/g) 
because there is no health concern associated with the proposed level 
of 100 MPN/g.
    (Response) FDA is not finalizing the proposed microbiological 
standard for Bacillus cereus in powdered infant formula. As noted, the 
recent FAO/WHO expert consultation concluded that there is no 
documented association between Bacillus cereus and illness from 
consumption of powdered infant formula, a conclusion with which the 
Agency agrees. Thus, the suggestion that the M value for Bacillus 
cereus be revised is moot.
    (Comment 151) One comment requested that FDA replace the standards 
for coliforms and fecal coliforms with one for E. coli due to the 
possibility of improper interpretation of coliform and fecal coliform 
tests.
    (Response) As noted, FDA is not finalizing the proposed 
microbiological standard for coliforms and fecal coliforms in powdered 
infant formula because the Agency has determined that the decision to 
use certain organisms as indicators of insanitary conditions, including 
coliforms and fecal coliforms, should be made on a case-by-case basis 
by each manufacturer in the context of the manufacturer's overall plan 
to control adulteration and baseline data developed for the facility. 
Thus, the suggestion that a test for E. coli be substituted for the 
coliforms and fecal coliforms testing is moot.
    (Comment 152) One comment recommended an Enterobacteriaceae 
standard of 3.0 MPN/g as a substitute for coliforms.
    (Response) FDA notes that the comment did not provide the reasoning 
to support the use of this standard. The Agency is not finalizing the 
proposed microbiological standard for coliforms in powdered infant 
formula. Thus, the suggestion that a standard for Enterobacteriaceae of 
3.0 MPN be substituted for the coliforms standard is moot.
    (Comment 153) Several comments expressed concern about the Agency's 
interpretation of ``unhygienic conditions'' and adulteration with 
respect to a positive finding for a microorganism other than 
Cronobacter spp. and Salmonella spp. The comments asserted that 
language in the 2006 reopening (71 FR 43392 at 43397) advised that the 
presence of any level of the identified organism would be sufficient to 
conclude that a formula is adulterated. Thus, one comment suggested 
that ``unhygienic conditions'' be defined through guidance criteria. 
Another comment asserted that, in the absence of any standard for these 
other microorganisms, FDA was establishing a zero tolerance for these 
microorganisms and that elimination of all organisms is not be feasible 
at this time.
    (Response) FDA is restating its views on microbiological test 
results and conclusions about insanitary conditions that lead to 
adulteration of food.
    As noted in the comment, in the 2006 reopening, FDA stated that 
``the presence of these microorganisms in an infant formula reflects 
that the formula was prepared, packed, or held under insanitary 
conditions whereby it may have been rendered injurious to health and 
therefore is adulterated under section 402(a)(4) of the FD&C Act.'' 
This statement appears to suggest that the violation of one of the 
proposed microbiological standards (i.e., APC, coliform, fecal coliform 
test, Listeria monocytogenes, Staphylococcus aureus, Bacillus cereus, 
or Enterobacteriaceae) would categorically establish adulteration under 
section 402(a)(4) of the FD&C Act.
    In fact, FDA generally considers any microbiological test results 
as well as any other CGMP observations when considering whether a food 
has been processed under insanitary conditions. Moreover, as noted in 
the 2006 reopening, the tests for several of these organisms (APC, 
coliforms, fecal coliforms, and Enterobacteriaceae) do not distinguish 
between pathogenic and non-pathogenic organisms (71 FR 43392 at 43396) 
so it is difficult to interpret the meaning of any positive results in 
the absence of baseline data, either for the infant formula industry 
generally or specific to individual infant formula production 
facilities. Accordingly, FDA has no current plans to define 
``unhygienic conditions'' in an Agency guidance document.
    Finally, for reasons comparable to those stated in the response to 
Comment 121, FDA does not agree that the Agency is setting a zero 
tolerance for any microorganism either in infant formula or in the 
formula processing environment. Accordingly, FDA has no current plans 
to define ``unhygienic conditions'' in an Agency guidance document.
    (Comment 154) One comment suggested that FDA not repeat the 
statement regarding adulteration as written in the 2006 reopening (71 
FR 43392 at 43397), which referred to adulteration in the context of 
finding any of the other pathogens present, and suggested the following 
statement ``the presence of certain food borne pathogens in an infant 
formula at levels (concentrations) known to be of public

[[Page 7991]]

health significance establishes that the formula may have been 
prepared, packed or held under insanitary conditions whereby it may 
have been rendered injurious to health and therefore is adulterated.''
    (Response) In responding to Comment 148, FDA has clarified its 
views on the significance of the presence of microorganisms other than 
Cronobacter spp. and Salmonella spp. in powdered infant formula and the 
infant formula processing environment and adulteration under section 
402(a)(4) of the FD&C Act. Accordingly, it is unnecessary to adopt the 
statement suggested in the comment and FDA declines to do so.
    f. Comments on testing methodology.
    (Comment 155) One comment expressed concern with the provision in 
proposed Sec.  106.55(c) that states that the Agency will determine 
compliance based on the methods cited in the Bacteriological Analytical 
Manual. The comment stated that a comparison of the BAM and a method 
used by the USDA for the determination of Listeria monocytogenes 
concluded that neither method provided a greater detection of 
efficiency for isolating Listeria monocytogenes from all types of 
foods. However, the comment recommended that FDA consider the use of 
other official, recognized methods, such as the USDA method, to reduce 
the testing time and consequent costs without detriment to compliance.
    (Response) As discussed previously in this document, FDA has 
determined that the interim final rule need not contain a 
microbiological standard for Listeria monocytogenes in final product 
powdered infant formula. Thus, this comment no longer requires a 
response.
    (Comment 156) One comment pointed out that AOAC International 
Association of Official Analytical Chemists should be changed to AOAC 
International, in proposed Sec.  106.55(c).
    (Response) Section 106.55 of the interim final rule does not refer 
to the AOAC and thus, there is no need to update the organization's 
name as requested.
    g. Microbiological standard to ensure the safety of powdered infant 
formula if microorganisms are intentionally added to the formula.
    (Comment 157) Several comments discussed the effect of 
intentionally added microorganisms (``probiotics'') on the testing for 
compliance with microbiological standards. One comment asserted that it 
is not clear that the addition of beneficial organisms would have any 
negative impact on the proposed microbiological requirements and that 
while it is possible that some infant formulas supplemented with 
probiotics might exceed the APC, others, such as those containing 
anaerobic bacteria, would not. Thus, the comment suggested that FDA 
exempt formulas containing these organisms from the APC limit as long 
as the manufacturer employed sanitation indicative testing, such as 
testing for Enterobacteriaceae. Other comments suggested that for these 
probiotic-containing formulas, FDA require automatic testing for 
organisms such as B. cereus that is usually only required when the 
formula exceeds the APC. One comment claimed that this additional 
testing would be similar to the currently recommended evaluation of 
cultured dairy products. Another comment requested that any final 
regulation acknowledge that probiotic formulas would require exemption 
for APC limits or any other proposed criteria for assessing insanitary 
conditions. One comment suggested that, to ensure that a high APC is 
caused by the added probiotic organism and not by contamination of the 
formula, there would need to be a two-stage testing procedure: Prior to 
addition of the probiotic organism, the bulk product would have to be 
sampled and the APC measured, and then selective microbiological test 
regimes would have to be carried out on final packaged product.
    (Response) In the 2006 reopening, FDA stated it was not aware of 
any marketed infant formula in the United States that contained 
intentionally added microorganisms and tentatively decided not to 
consider requirements related to such formula (71 FR 43392 at 43396). 
Since that time, powdered infant formulas containing intentionally 
added microorganisms have entered the U.S. market.
    As discussed earlier in this section, FDA has decided not to 
finalize the requirement for an APC count in proposed Sec.  106.55(c). 
Under Sec.  106.55(a) of the interim final rule, a manufacturer of a 
formula to which microorganisms have been intentionally added must 
ensure that the formula does not become adulterated due to the presence 
of microorganisms or in the processing environment. In addition, as 
discussed previously in this document, under Sec.  106.6(c) of the 
interim final rule, a manufacturer must establish specifications where 
control is necessary to prevent adulteration, including a specification 
for intentionally added microorganisms. Thus, a manufacturer would need 
to evaluate the potential for any intentionally added organisms to 
interfere with the ability to detect Cronobacter spp. and Salmonella 
spp., and should have data to demonstrate the absence of such 
interference in order to establish that the formula meets the 
microbiological standards in Sec.  106.55 of the interim final rule. 
Moreover, manufacturers would have to ensure that the presence of 
microorganisms is due to the intentional addition of such 
microorganisms, based on the master manufacturing order, and not to 
contamination.
    (Comment 158) One comment stated that manufacturers should do 
specific culturing and identification of the intentionally added 
bacteria, not just plate counts.
    (Response) Although FDA is not finalizing the requirements for APC 
testing, FDA emphasizes that a manufacturer needs to know the identity 
and quantity of any microorganism that it is adding to a formula. FDA 
agrees that any microorganism intentionally added to an infant formula 
should be identified by genus, species, and strain through testing of 
the final production aggregate to confirm that the organism present is 
the organism added and is present in the intended amounts. For example, 
if Bifidobacterium lactis strain Bb12 is added during production, 
testing must demonstrate that the final production aggregate contains 
the microorganism in the intended amount.
    (Comment 159) One comment stated that testing would need to be 
specific for the type of organism added and requested that ``any final 
regulation acknowledge that validated methods for testing probiotic 
formulas will need to be decided between the manufacturer and FDA as 
part of the pre-market review process.''
    (Response) As stated in the response to Comment 158, FDA agrees 
that testing needs to be specific to the type of microorganism 
intentionally added to a formula. In subpart C (see section VI.A.1 of 
this preamble), FDA addresses the use of ``validated'' test methods for 
nutrient testing. It is appropriate to apply a similar construct to the 
use of microbiological test methods used to confirm the identity and 
amount of intentionally added microorganisms. A manufacturer may use 
any method that is accurate, precise, and specific for its intended 
purpose, and thus, methods for intentionally added microorganisms 
should not be restricted to FDA official BAM methods or other methods 
formally validated in a multi-laboratory collaborative study.
    (Comment 160) One comment suggested that because sampling and 
testing for microbiological endpoints continue to lead to variability, 
and thus

[[Page 7992]]

uncertainty of results, FDA should define sampling and testing methods 
in association with establishing microbiological specifications as 
proposed by International Commission on Microbiological Specifications 
for Foods (ICMFS), and recognized by Codex, as an option.
    (Response) FDA disagrees with this comment. First, the comment did 
not explain how testing for microbiological endpoints would continue to 
lead to variability and uncertainty of results. Second, the Agency does 
expect that a manufacturer's sampling plan for an intentionally added 
microorganism will have an appropriate statistical basis and will take 
into account any variability in distribution of the microorganism in 
the production aggregate. FDA has no objection to the use by a 
manufacturer of a testing method proposed by ICMFS for intentionally 
added microorganisms as long as the method is valid, that is, the 
methods are scientifically sound, accurate, precise, and specific for 
its intended use. Accordingly, FDA is not defining in this interim 
final rule the specific sampling and analytical method(s) that should 
be used for intentionally added microorganisms. Intentionally added 
microorganisms have to meet the specifications set by manufacturers for 
such ingredients, as would any ingredient added to an infant formula. 
As discussed earlier in this preamble, manufacturers must characterize 
the formula that they intend to produce, institute adequate controls to 
produce that formula, and ensure that the controls work so that the 
desired formula is consistently produced and is not adulterated.
    (Comment 161) Several comments questioned the safety of 
intentionally added microorganisms. One comment expressed concern 
particularly with the use of these substances in formula intended for 
preterm infants with underdeveloped gastrointestinal barriers. Another 
comment suggested the need for a large clinical trial on both term and 
preterm infants to uncover unwanted side effects. One comment expressed 
opposition to the addition of Bifidobacterium and Streptococcus 
intended for use in infant formulas for infants over the age of four 
months because of concern about the GRAS status of these 
microorganisms, the risk-benefits, and the unknown biological effects 
of these organisms on the microflora in the infants' intestines. This 
comment also expressed concern regarding the unknown effects of 
manipulation of the infants' intestines and how these organisms might 
affect the infants' developmental processes. The comment further stated 
that although there have been reported beneficial effects of these 
microorganisms, the mechanisms of these effects are not known nor have 
long-term adverse effects been entirely excluded. The comment also 
stated that there is a risk that infants not in the intended use group 
would receive this formula as there is presently no formula on the 
market that is only intended for infants over four months of age.
    (Response) Comments relating to the safety of microorganisms added 
to infant formula are beyond the scope of this rule. As discussed 
previously in this document, the safety of ingredients of all 
substances added to food, including microorganisms intentionally added 
to infant formula, is governed by sections 409 and 201(s) of the FD&C 
Act, and FDA expects that a formula manufacturer will ensure that the 
safety of any formula ingredient is appropriately established prior to 
using the ingredient in a formula product. FDA emphasizes that it is 
the manufacturer's responsibility to ensure the safety of the all food 
ingredients, including microorganisms added to infant formula.

K. Controls To Prevent Adulteration During Packaging and Labeling 
(Proposed Sec.  106.60)

    In 1996, FDA proposed in Sec.  106.60 to require that an infant 
formula manufacturer implement specific controls designed to prevent 
adulteration during the packaging and labeling of infant formula. The 
proposed provisions included requirements for the examination of 
packaged and labeled formula, label design and application, and 
packaging of multiple container units of formula.
    The Agency received comments on several aspects of proposed Sec.  
106.60, which are addressed in this document. Section 106.60 of the 
interim final rule includes minor editorial revisions as well as the 
changes discussed in this document that are made in response to 
comments.
1. Labels Designed To Remain Legible and Attached During Use (Proposed 
Sec.  106.60(b))
    (Comment 162) Several comments requested that the phrase ``and 
use'' be deleted from proposed Sec.  106.60(b), which would require 
that labels be designed, printed, and applied so that the labels remain 
legible and attached during the conditions of processing, storage, 
handling, distribution, and use. These comments noted that some infant 
formula product labels are designed to be removed by the end user 
because the backs of the labels are printed with use information (such 
as use instructions in a foreign language) or coupons. One comment 
contended that this proposed requirement would prohibit providing 
useful information to the consumer.
    (Response) The purpose of proposed Sec.  106.60(b) is to ensure 
that a formula label is designed and applied so that the label cannot 
easily become detached during processing, storage, handling, 
distribution, and use. Importantly, however, FDA would not object to a 
label that is designed and applied to a formula product so that a 
consumer could purposefully remove the label, so long as the label is 
otherwise designed and applied to remain attached to the infant formula 
container under reasonably expected conditions of use. FDA is concerned 
that removing the phrase ``and use'' from proposed Sec.  106.60(b) 
would permit a manufacturer to design and apply a label that would not 
remain attached or legible under reasonably expected conditions of use. 
For example, with the suggested revision, a manufacturer could use a 
label adhesive that dissolves when dampened. For this reason and in 
light of the foregoing clarification, FDA declines to modify Sec.  
106.60(b) in the interim final rule in response to these comments.
2. Multiple Container Packages (Proposed Sec.  106.60(c))
    Several comments objected to proposed Sec.  106.60(c), which would 
require that all infant formula held in a single package be the same 
product bearing the same code. In the preamble to the proposal, FDA 
explained how these proposed packaging requirements would make it more 
difficult for counterfeit formulas, or formula with counterfeit labels, 
to be shipped in interstate commerce (61 FR 36154 at 36173).
    (Comment 163) One comment requested that FDA make a distinction in 
the preamble to the final rule between counterfeiters and diverters. 
The comment explained that diverters are part of the normal 
distribution channel for infant formula and are not counterfeiters. The 
comment stated that diverters generally purchase formula products in a 
geographic area where a special allowance or deal is being offered and 
then resell the products in an area where the deal is not offered. In 
such circumstances, the comment explained, the immediate formula 
containers retain the original manufacturer labels but several lots of 
the same product may be consolidated to fill a single shipping 
container. The comment requested that FDA remove all references to 
diverters in the proposal.

[[Page 7993]]

    (Response) FDA did not intend to stymie distribution of formula or 
prohibit wholesaling or other legitimate marketing practices, including 
those of legitimate diverters as described in the comment. However, to 
ensure that, in the event of a product recall, all affected formula can 
be readily identified, it is imperative that all infant formula 
packaged in a single shipping container be completely and accurately 
identified. Only with such identification will recalled formula be 
traceable. As discussed in response to Comment 164, FDA is revising 
proposed Sec.  106.60(c) to permit, in certain limited circumstances, 
mixed lot packages of infant formula.
    (Comment 164) Several comments asserted that proposed Sec.  
106.60(c) would prohibit manufacturers from making discharge packages 
or ``kits'' that contain samples of different products with different 
codes. One comment explained that these packages, which are commonly 
used by the infant formula industry to familiarize new parents with 
infant formula prior to an infant's discharge from the hospital, are 
designed to hold samples of different products and thus, necessarily 
contain products with different manufacturing codes. According to this 
comment, individual discharge packages are assigned a unique lot number 
for traceability purposes. The comment concluded by asserting that 
FDA's intention is not to eliminate discharge kits, which would be a 
disservice to consumers and hospitals and would have a substantial 
impact on the marketing programs of formula manufacturers.
    (Response) In proposing Sec.  106.60(c), FDA did not intend to 
prohibit manufacturers from preparing and distributing hospital 
discharge packages of infant formula. The comments state that these 
discharge kits are labeled with a unique identification number. Under 
certain limited conditions, traceability can be assured even with a 
mixed-lot container of formula, such as a discharge kit. Therefore, FDA 
is revising proposed Sec.  106.60(c) to allow infant formula to be 
packaged, in certain limited circumstances, in mixed-lot shipping 
packages and in hospital discharge packages. Importantly, however, 
these mixed-lot container packages will be required to bear complete 
and accurate identification about all infant formulas in the package or 
be labeled with a unique identification number that is linked to a 
record that identifies the product code required under Sec.  106.80 for 
each container of infant formula product in the multiple container 
package.

L. Controls on the Release of Finished Infant Formula (Proposed Sec.  
106.70)

    In 1996, FDA proposed to require in Sec.  106.70 that infant 
formula manufacturers establish controls on the release of finished 
infant formula. In particular, the controls would require the 
manufacturer to hold or otherwise maintain control of finished formula 
until it was determined to conform to all specifications of the 
manufacturer. In addition, proposed Sec.  106.70(b) would require any 
out-of-specification formula to be rejected, and any rejected formula 
that was reprocessed would be required to conform to all specifications 
before release. Finally, proposed Sec.  106.70(c) would require an 
individual qualified by training or experience to investigate any out-
of-specification finding.
    FDA received comments on proposed Sec.  106.70, specifically on 
Sec.  106.70(b). The Agency has addressed these comments in section 
V.C.2, and proposed Sec.  106.70 has been revised as described 
previously in this document.

M. Traceability (Proposed Sec.  106.80)

    In 1996, FDA proposed to require that infant formula manufacturers 
ensure traceability of their products by coding the finished products. 
Adequate coding will ensure product recovery in case of a formula 
recall. The Agency received no comments specifically on proposed Sec.  
106.80, and to the extent other comments (such as those on proposed 
Sec.  106.60) indirectly raised concerns about proposed Sec.  106.80, 
the Agency has addressed those comments earlier in this preamble.
    Since publication of the proposed rule in 1996, FDA has acquired 
additional information about the production of infant formula. For 
example, the Agency has learned that liquid formula may be produced 
over more than a single day and that many formula manufacturers use a 
``continuous process'' manufacturing approach for their formula 
products regardless of the final form of the product (e.g., liquid or 
powered). Thus, some parts of proposed Sec.  106.80 are no longer 
appropriate. Accordingly, FDA has revised Sec.  106.80 in the interim 
final rule to update this provision in light of current manufacturing 
methods in the formula industry. The provisions of Sec.  106.80 of the 
interim final rule do not distinguish between infant formula that has 
been produced during a single day, and infant formula that has been 
produced over more than a single day. In addition to being more 
current, these changes will have the advantage of requiring the 
application of the same coding protocol to all forms of a 
manufacturer's products, resulting in more consistent coding for all 
products of the same brand or line.

N. Audits of Current Good Manufacturing Practice (Proposed Sec.  
106.90)

    In 1996, FDA proposed to require that infant formula manufacturers 
conduct regularly scheduled audits of a firm's compliance with CGMP and 
stipulated that such audits be performed by a person with knowledge of 
all aspects of infant formula production and FDA's CGMP regulations but 
who has no direct responsibility for the matters being audited. The 
Agency received several comments on proposed Sec.  106.90, which are 
addressed in this document.
    (Comment 165) One comment stated that requiring that the auditor be 
knowledgeable in ``all'' aspects of infant formula production is a 
lofty expectation given the complexities of an infant formula 
production environment. The comment suggested that the auditor should 
possess a general knowledge of the areas being audited, but not the 
depth and extent implied by the word ``all.''
    (Response) This comment does not fully understand the personnel 
qualification requirement of proposed Sec.  106.90. The objective of an 
audit required under proposed Sec.  106.90 would be to determine 
whether the manufacturer has complied with current good manufacturing 
practice. As with any audit, to be valid and effective, the auditor 
must have well-developed knowledge of the focus of his audit. In this 
case, this means that the individual conducting the audit must have in-
depth knowledge of infant formula production as well as the regulations 
governing that process. FDA disagrees that this is a ``lofty'' 
expectation.
    Importantly, however, the CGMP audit of a firm's infant formula 
production would not be required to be conducted by a single 
individual. Thus, a manufacturer may choose to utilize a team of 
auditors, each of whom has general knowledge of the formula production 
process as well as more detailed knowledge of a specific facet or 
facets of that process so that, collectively, the auditing team is 
knowledgeable in ``all'' aspects of infant formula production. Where a 
team of auditors is used to conduct a CGMP audit, the team member 
assigned to audit a specific facet or facets of the process must 
possess specialized, detailed knowledge of both that aspect of the 
process and the Agency regulations that apply to such facet or facets. 
Importantly, however, where one person conducts a manufacturer's

[[Page 7994]]

CGMP audits, that individual must possess comprehensive knowledge of 
all aspects of infant formula production and of the applicable CGMP 
regulations. The Agency is revising Sec.  106.90 in the interim final 
rule to expressly allow a team of individuals to conduct an audit. In 
addition, the Agency is changing ``education, training, and 
experience'' to ``education, training, or experience'' because the 
Agency considers that each of these can independently provide an 
adequate basis for an auditor have the necessary knowledge and skills 
to perform an audit.
    (Comment 166) Another comment agreed with the proposed requirement 
that an auditor must not have direct responsibility for the matters 
being audited, but took exception to the preamble statement that the 
auditor must have no ``past involvement in the activities being 
audited.'' The comment contended that this requirement presents a 
dilemma if the auditor must have knowledge of infant formula 
production, but could have no past involvement where knowledge might 
have been gained. The comment recommended that a reasonable time (1 
year) be established after which any concern about potential bias would 
dissipate and an auditor could evaluate an area of previous employment.
    (Response) As explained in this document, FDA agrees in part with 
this comment. In order to be meaningful and function as an appropriate 
oversight tool for CGMP compliance, any audit, including an audit 
conducted under proposed Sec.  106.90, must be as objective as 
possible. Thus, FDA proposed to require in Sec.  106.90 that the 
individual conducting an audit (including an auditor who is an employee 
of the company) have no direct responsibility for the matters being 
audited. As FDA noted in the preamble to the 1996 proposal, ``The 
requirement that the audit be performed by an individual who has no 
direct responsibility for the matters being audited is one way to 
ensure the objectiveness of the audit process. The person should be 
free of any past involvement in the activities being audited because 
the audit is intended to uncover any problems or shortcomings in the 
manufacturer's procedures. A person who has been involved may feel that 
finding problems will reflect poorly on his or her work'' (61 FR 36154 
at 36175).
    FDA is persuaded, however, that there may be certain circumstances 
in which an auditor with prior involvement in the activities being 
audited could still perform an unbiased audit. Each situation must be 
evaluated on a case-by-case basis by the formula manufacturer to ensure 
that that the audit will be objective and free from bias. A 
manufacturer should determine that a proposed auditor is able to be 
objective and to exercise independent judgment and thus, should 
consider such factors as the scope of the employee's previous 
responsibilities, the time elapsed between the reassignment of the 
former responsibilities and the audit, and whether the audit will be 
conducted by this single individual or a team. Evaluating these types 
of factors can provide a manufacturer with reasonable assurance that an 
audit conducted by this individual will be independent of bias.
    (Comment 167) One comment contended that firms would have to hire 
auditors from outside their company to perform audits since an 
individual could not audit his or her own area and it would be unlikely 
that one person would be knowledgeable in all areas of plant 
operations. The comment points out that hiring an outside auditor would 
be an added expense and suggests that auditing could be conducted as 
effectively by in-house auditors trained in auditing practices.
    (Response) FDA disagrees that a firm would have to hire auditors 
from outside its company to perform audits. First, section 
412(b)(2)(B)(iv) of the FD&C Act, which requires that audits ``be 
conducted by appropriately trained individuals who do not have any 
direct responsibility for the manufacture or production of infant 
formula,'' would not preclude an auditor being an employee of the 
manufacturer. Moreover, as noted in the responses to Comments 165 and 
166, a manufacturer may employ a team approach to ensure that an audit 
is staffed by individuals with comprehensive knowledge of the infant 
formula production process and also, in certain circumstances, a 
manufacturer may utilize an individual to audit an area of his/her 
prior responsibility so long as the manufacturer determines that an 
audit by such individual would be objective and free of bias.
    The Agency notes that proposed Sec.  106.90 addressed both audit 
scheduling and audit personnel requirements. For clarity, FDA is 
dividing Sec.  106.90 of the interim final rule into two sections. 
Section 106.90(a) of the interim final rule establishes the regularly 
scheduled audit requirement, and Sec.  106.90(b) of the interim final 
rule establishes the requirements for auditing personnel. The Agency is 
also clarifying that audits must be performed frequently enough to 
ensure compliance with the regulations in subpart B.

VI. Subpart C--Quality Control Procedures

    As noted in the introductory section of this preamble, in 1982, FDA 
established subpart B of part 106, Infant Formula Quality Control 
Procedures (47 FR 17016 April 20, 1982). These regulations were 
authorized by section 412 of the FD&C Act as it existed at that time. 
Section 412 of the FD&C Act was subsequently amended in 1986 (Pub. L. 
99-570). Thereafter, in 1996, the Agency proposed to redesignate, 
revise, or remove parts of the current quality control procedures 
regulations. The proposed requirements related to nutrient testing, 
stability testing, quality control records, and quality control audits. 
In proposing these changes, the Agency sought to establish the minimum 
practices that infant formula manufacturers must implement to ensure 
that all batches (production aggregates) of infant formula that they 
produce contain the required nutrients at the required levels 
throughout the shelf life of the product.
    FDA received several comments on proposed subpart C. These comments 
are summarized in this document along with the Agency's responses. In 
addition to the revisions to subpart C, FDA is making minor editorial 
revisions in this subpart. These editorial revisions include deleting 
the titles from the paragraphs in Sec.  106.91, a change that will make 
Sec.  106.91 of the interim final rule consistent with the rest of part 
106.

A. General Quality Control (Proposed Sec.  106.91)

1. Nutrient Testing on Each Production Aggregate of Infant Formula 
(Proposed Sec.  106.91(a)) \6\
---------------------------------------------------------------------------

    \6\ In the following discussion, FDA uses the term ``nutrient'' 
as defined in Sec.  106.3(k) of the interim final rule (i.e., as 
``any vitamin, mineral, or other substance or ingredient that is 
required in accordance with the table set out in section 412(i)(1) 
of the FD&C Act or by regulations issued under section 412(i)(2) or 
that is identified as essential for infants by the Food and 
Nutrition Board of the Institute of Medicine through its development 
of a Dietary Reference Intake (DRI), or that has been identified as 
essential for infants by FDA through a Federal Register 
publication.'') This was also the proposed rule's definition of 
``nutrient'' with a few minor editorial revisions.
---------------------------------------------------------------------------

    In 1996, the Agency proposed to require nutrient testing at four 
separate stages during the production of formula. Specifically, FDA 
proposed to require the following testing: (1) Testing of any nutrient 
premix used by a manufacturer to ensure compliance with specifications; 
(2) testing of each production aggregate of the infant formula product 
for an indicator nutrient (as defined in proposed Sec.  106.3) either 
during the manufacturing

[[Page 7995]]

process, after addition of the premix, or at the final product stage 
and before distribution; (3) testing of the final product stage and 
before distribution for vitamins A, E, C, and thiamin; and (4) testing 
during manufacturing or at the final product stage and before 
distribution for all required nutrients as well as for any added 
nutrient for which the manufacturer has not previously tested.
    (Comment 168) One comment requested that FDA delete proposed Sec.  
106.91(a)(1), which would require the testing of any nutrient premix 
used by a manufacturer. The comment contended that FDA should eliminate 
the requirement for premix testing and require only end-product testing 
for infant formula.
    (Response) FDA disagrees with the suggestion to eliminate premix 
testing because such revision would be inconsistent with section 
412(b)(3)(B) of the FD&C Act. Section 412(b)(3)(B) of the FD&C Act 
requires that each nutrient premix used in the manufacture of an infant 
formula be tested for each nutrient required by section 412(i) of the 
FD&C Act that is contained in such premix and that the manufacturer 
relies on the premix to supply to ensure that such premix is in 
compliance with its specifications or any certification by a premix 
supplier. Moreover, ``nutrient'' is defined in Sec.  106.3 as any 
vitamin, mineral, or other substance or ingredient that is set out in 
the table of required nutrients in section 412(i) of the FD&C Act, that 
is set out in such table as revised by FDA by regulation, or that is 
identified as ``essential'' for infants by FDA or the Food and 
Nutrition Board of the IOM. Thus, a manufacturer that adds a 
``nutrient'' not otherwise required under section 412(i) of the FD&C 
Act would have been required to test for such nutrient under proposed 
Sec.  106.91(a), if the nutrient is added as part of a nutrient premix 
and the manufacturer is relying on the premix to provide that nutrient. 
Accordingly, the Agency declines to revise proposed Sec.  106.91(a)(1) 
in response to the comment. For increased clarity regarding the 
nutrients that must be tested, however, FDA is making a minor revision 
as reflected in Sec.  106.91(a)(1) in the interim final rule by adding 
the parenthetical phrase ``(required under Sec.  107.100 or otherwise 
added by the manufacturer)'' after the words ``shall be tested'' in 
Sec.  106.91(a)(1). The Agency is also deleting the title in proposed 
Sec.  106.91(a) to make this section consistent with the rest of part 
106.
    (Comment 169) One comment also objected to proposed Sec.  
106.91(a)(3), which would require that, because they are susceptible to 
degradation, vitamins A, C, E, and thiamin be tested at the final batch 
(production aggregate) stage. The comment asserted that these vitamins 
are not always susceptible to degradation because susceptibility of a 
particular vitamin to degradation is affected by formula pH and 
processing techniques and that when using an aseptic or dry mix 
process, vitamins A, E, and thiamin also degrade very slowly. The 
comment contended that use of a premix with appropriate levels of 
vitamins A, C, E, and thiamin, and analytical verification at final 
product stage by a premix tracer (i.e., an indicator nutrient) is 
sufficient to ensure compliance with required nutrient levels without 
analyzing for these vitamins at the final product stage. The comment 
further asserted that requiring 100 percent analytical testing at the 
batch (production aggregate) stage is burdensome because of the 
increased paperwork, the additional time required for analysis, and the 
need to hold the finished product pending the analytical results and 
that such testing will be extremely expensive, the cost of which will 
need to be passed on to the consumer.
    (Response) FDA is not persuaded by this comment to revise proposed 
Sec.  106.91(a)(3) because such revision would be inconsistent with 
section 412(b)(3)(A) of the FD&C Act. Section 412(b)(3)(A) of the FD&C 
Act requires that at the final product stage, each production aggregate 
(batch) of infant formula be tested for four specific vitamins 
(vitamins A, C, E, and B1 (thiamin)) to ensure that the formula is in 
compliance with section 412(b) and (i) of the FD&C Act. There are no 
exceptions for this testing requirement for formulas that arguably 
degrade more slowly due to product pH or the means by which the product 
is manufactured. Moreover, the comment did not assert that the testing 
required for vitamin C be stricken, apparently because the comment 
could not credibly argue that vitamin C degrades slowly. Accordingly, 
the Agency declines to revise proposed Sec.  106.91(a)(3) in response 
to the comment, and proposed Sec.  106.91(a)(3) is included in this 
interim final rule as proposed.
    (Comment 170) One comment stated that the proposed regulation 
requires that all nutrients required to be in infant formula by Sec.  
107.100 must be tested at the final batch (production aggregate) stage, 
even though the nutrient premixes already would have been analyzed for 
all the nutrients that the manufacturer is relying on the premix to 
supply.
    (Response) This comment appears to relate to proposed Sec.  
106.91(a)(4) and seems to suggest that this proposed provision should 
be modified. FDA is not persuaded by this comment to revise the 
proposed provision. Proposed Sec.  106.91(a)(4) is directly authorized 
by section 412(b)(3)(C) of the FD&C Act (21 U.S.C. 350a(b)(3)(C)). 
Section 412(b)(3)(C) of the FD&C Act requires that during the 
manufacturing process or at the final product stage and before 
distribution, an infant formula be tested for all nutrients required by 
section 412(i) of the FD&C Act to be in the formula for which testing 
has not been done under section 412(b)(3)(A) or (b)(3)(B) of the FD&C 
Act. There are no exceptions from this testing requirement. A nutrient 
that is not otherwise tested as part of testing the premix or is 
required to be tested at the final product stage under Sec.  
106.91(a)(3) of the interim final rule is required to be assayed either 
during the manufacturing process or during the final product stage. 
Accordingly, the Agency declines to revise proposed Sec.  106.91(a)(4) 
in response to this comment.
    (Comment 171) One comment suggested that FDA modify proposed Sec.  
106.91(a)(4) to require that quality control testing be conducted using 
validated nutrient test methods to ensure the accuracy and precision of 
test results to determine compliance with the FD&C Act.
    (Response) It is important to distinguish between ``validated'' 
test methods and ``valid'' test methods. The process of method 
validation is a formal process for demonstrating that an analytical 
procedure is suitable for its intended use. In contrast, a ``valid'' 
method is a method that is suitable for or capable of consistently 
achieving the intended results.
    Typical validation characteristics include accuracy, precision, 
specificity, detection limit, quantitation limit, linearity, range, and 
robustness. Methods, such as AOAC International methods, are validated 
in collaborative studies using several laboratories under identical 
conditions; these methods are often described as ``official [validated] 
methods.'' Method validation may also be conducted in a single 
laboratory by repeating the same test multiple times. Many analytical 
methods have been formally validated. However, other scientifically 
valid methods have not been subject to the formal validation process. 
For example, a test method not validated by a collaborative study using 
multiple laboratories may nonetheless be scientifically valid because 
it is, in fact, suitable for its intended purpose

[[Page 7996]]

and capable of consistently producing accurate results.
    FDA disagrees with the comment's specific recommendation that 
proposed Sec.  106.91(a)(4) be revised to require that quality control 
testing be conducted using validated nutrient test methods. It is 
scientifically sound to permit nutrient tests to use any method that is 
accurate, precise, and specific for its intended purpose and thus, 
permitted methods should not be restricted to official AOAC methods or 
other methods formally validated in a multi-laboratory, collaborative 
study.
    Although FDA does not agree with the comment's specific 
recommendation, in light of the foregoing comment, it is appropriate to 
stipulate in the interim final rule a standard for nutrient testing 
methods. Accordingly, in this interim final rule, FDA is redesignating 
proposed Sec.  106.91(c) ``Quality control records'' as Sec.  
106.91(d), and adding a new Sec.  106.91(c) ``Use of scientifically 
valid nutrient test methods.'' Section 106.91(c) of the interim final 
rule states that ``All quality control testing shall be conducted using 
appropriate, scientifically valid test methods.''
    (Comment 172) One comment suggested revising proposed Sec.  
106.91(a)(4) to require that during the manufacturing process or at the 
final product stage, before distribution, each batch (production 
aggregate) be tested for ``each nutrient'' instead of for ``all 
nutrients'' required to be included in such formula under Sec.  
107.100.
    (Response) FDA declines to make the revision proposed by this 
comment because the Agency is not persuaded that there is a sound 
reason to replace the reference to ``all nutrients'' by the phrase 
``each nutrient'' in proposed Sec.  106.91(a)(4). The comment provides 
no reason for this suggested change. The proposed requirement is 
consistent with the language in the statute in that section 
412(b)(3)(C) of the FD&C Act requires testing for ``all nutrients'' 
required to be included in an infant formula for which testing had not 
been completed earlier in the manufacturing process. On this basis, FDA 
is not revising Sec.  106.91(a)(4) in response to this comment.
    (Comment 173) One comment requested that FDA delete the requirement 
in proposed Sec.  106.91(a)(4) and (b) that the manufacturer test ``for 
any nutrient added by the manufacturer'' in addition to testing for the 
nutrients required by Sec.  107.100. The comment contended that this 
testing requirement is without added benefit.
    (Response) FDA disagrees. Nutrients are unique compounds and are 
needed at certain levels by the body for normal health. If an infant 
formula contains too little of a nutrient, a deficiency may occur in 
infants consuming the formula. Conversely, if an infant formula 
contains too much of a nutrient, toxic effects may occur.
    Testing for nutrients not required under Sec.  107.100 in each 
production aggregate of infant formula is consistent with CGMP and 
quality control procedures that are required to be established by 
section 412(b)(2)(A) of the FD&C Act. The preamble to the 1996 proposal 
explained why testing for these added nutrients is necessary for proper 
formulation of a formula as follows: ``[I]t is important that the level 
of these added nutrients be controlled, and that the level of the added 
nutrient be consistent from batch to batch [production aggregate to 
production aggregate] and be uniform throughout the batch [production 
aggregate] of infant formula. The level of a nutrient needs to be 
controlled because some nutrients can be toxic to an infant if given at 
too high a level. Controlling the level of the added nutrient for 
consistency from batch to batch [production aggregate to production 
aggregate] and in a particular batch [production aggregate] of infant 
formula will ensure that the infant receives the essential nutrient on 
a consistent basis and will also ensure that the infant does not 
receive too high, or too low, a level of the nutrient because the 
nutrient was not uniform through the batch [production aggregate] of 
infant formula'' (61 FR 36154 at 36176).
    The comment does not dispute the reasoning of the 1996 preamble 
that supports the need to test formula at the final product stage to 
confirm the presence and level of a nutrient that is not legally 
required in but added to formula by the manufacturer. Furthermore, if 
health professionals or parents are selecting a particular infant 
formula because it contains a particular nutrient that is declared in 
the statement of nutrient amounts in the labeling and not currently 
required by Sec.  107.100, it is important that the nutrient is present 
in the infant formula at the level stated in the product's labeling.
    The concern about the testing for nutrients added but not required 
under Sec.  107.100 is not simply theoretical. Infant formula 
manufacturers have voluntarily added the nutrient, selenium, to their 
infant formulas even though this nutrient is not currently required by 
Sec.  107.100. Selenium has been identified by the IOM of the NAS as an 
essential nutrient for infants (61 FR 36154 at 36176) and, if added, 
may be declared in the statement of nutrient amounts in the formula 
labeling (Sec.  107.10(b)(5)). Selenium is necessary for health but is 
toxic at high doses (Ref. 60). Characteristics of morbidity resulting 
from both deficient and excess intakes were summarized in 2000 by the 
IOM (Ref. 60). Keshan disease, a cardiomyopathy that occurs almost 
exclusively in children, has been linked to selenium deficiency. 
Chronic selenium toxicity (selenosis) has also been observed in humans. 
Reported characteristics of such toxicity include gastrointestinal 
upsets, hair and nail brittleness and loss, skin rash, garlic breath 
odor, fatigue, irritability, and nervous system abnormalities. Although 
acute selenium toxicity is rare, the literature contains a few reports 
of acute fatal or near fatal selenium poisoning resulting from 
accidental or suicidal ingestion of selenium (Ref. 60). Given the 
adverse effects of too little or too much selenium, the IOM has 
established an adequate intake level and a tolerable upper intake level 
of selenium for infants.
    As the sole source of nutrition for many infants, infant formula 
must provide appropriate amounts of all nutrients in the formula. 
Testing each production aggregate of infant formula for each nutrient 
at the final product stage will help to ensure that an infant formula 
consistently contains an appropriate amount of each nutrient.
    For additional consideration of selenium in infant formula, see 
Comment 295 in section VIII.
    For these reasons, FDA is not revising Sec.  106.91(a)(4) in the 
interim final rule in response to this comment.
    Similarly, FDA is not persuaded to make the requested change in 
proposed Sec.  106.91(b). Proposed Sec.  106.91(b) would establish 
testing requirements to ensure that the nutrients in infant formula 
products remain stable throughout the shelf-life of the products. The 
provisions of proposed Sec.  106.91(b) implement section 
412(b)(2)(B)(ii) of the FD&C Act. The reasons to conduct in-process and 
finished product testing to confirm the presence and levels of all 
nutrients apply to stability testing as well, a point not disputed by 
the comment. Thus, FDA is not revising Sec.  106.91(b) in the interim 
final rule in response to this comment. Additional comments on proposed 
Sec.  106.91(b) are addressed in this document.
    (Comment 174) One comment suggested that proposed Sec.  
106.91(a)(4) be revised to state that each batch (production aggregate) 
of infant formula must be tested for all nutrients required to be 
included in such formula under Sec.  107.100 ``if the presence of that 
nutrient in the batch (production

[[Page 7997]]

aggregate) has not been confirmed pursuant to testing'' conducted for 
compliance with Sec.  106.91(a)(1) (premix testing) or (a)(3). The 
comment suggested substituting this language for that in the proposal 
to convey better that a manufacturer may rely on testing under Sec.  
106.91(a)(1) instead of requiring that finished product be retested for 
nutrients confirmed to be a part of a premix used in the infant 
formula. This comment also suggested that Sec.  106.91(a)(2) (testing 
for an indicator nutrient for each nutrient premix) be added as another 
means of testing that would exclude the need to test for a nutrient 
under proposed Sec.  106.91(a)(4). The comment stated that testing 
under Sec.  106.91(a)(2) should be included in the list of prior 
testing recognized as a substitute for finished product testing because 
testing under proposed Sec.  106.91(a)(1) would only confirm that a 
nutrient is present at the appropriate level in the premix and not 
establish that the nutrient is present at the appropriate level in the 
infant formula.
    (Response) FDA is not persuaded by this comment to revise proposed 
Sec.  106.91(a)(4). Section 106.91(a)(4) of the interim final rule 
parallels the statutory language of section 412(b)(3)(C) of the FD&C 
Act, which requires that each batch (production aggregate) of infant 
formula be tested for all required nutrients for which testing has not 
been conducted under sections 412(b)(3)(A) (final product stage 
testing) and 412(b)(3)(B) (premix testing) of the FD&C Act. Under 
proposed Sec.  106.91(a)(4), a manufacturer is permitted to rely on 
testing under Sec.  106.91(a)(1) (premix testing for relied upon 
nutrients) and thus, would not be required to test a production 
aggregate of finished infant formula for each relied upon nutrient that 
has been evaluated under Sec.  106.91(a)(1), unless testing of the 
nutrient is also required at the final product stage by section 
412(b)(3)(B) of the FD&C Act (i.e., vitamins A, C, E, and thiamin).
    In addition, proposed Sec.  106.91(a)(4) would already provide for 
an exemption for nutrients tested as indicator nutrients under proposed 
Sec.  106.91(a)(2). Specifically, any indicator nutrient testing under 
proposed Sec.  106.91(a)(2) would be conducted during the manufacturing 
process after the addition of the premix, or at the final product 
stage. If so tested, the manufacturer would have satisfied, for that 
indicator nutrient, the requirement in proposed Sec.  106.91(a)(4). 
Therefore, if the nutrient used as the indicator nutrient in tests 
conducted under proposed Sec.  106.91(a)(2) is a required or added 
nutrient, the manufacturer would have met testing requirements 
established for the nutrient under proposed Sec.  106.91(a)(4). If the 
indicator nutrient is tested under proposed Sec.  106.91(a)(2) and is 
also a nutrient that is required to be tested under proposed Sec.  
106.91(a)(1), the nutrient would need to be tested twice during 
manufacturing. However, as the comment recognizes, the nutrient testing 
under proposed Sec.  106.91(a)(1) and (a)(2) have separate and distinct 
purposes and both types of testing are necessary to ensure that the 
infant formula contains the nutrients it is intended to contain.
    On its own initiative, FDA is making minor editorial changes in 
Sec.  106.91(a)(4) of the interim final rule and is also clarifying 
that the phrase ``for which testing is not conducted for compliance 
with paragraphs (a)(1) or (a)(3) of this section'' applies both to 
required nutrients and any nutrient not required but added by the 
manufacturer, except that the latter would not have been tested under 
Sec.  106.91(a)(3) of the interim final rule.
2. Testing of Packaged Finished Product To Confirm the Presence of the 
Nutrients Required Under Sec.  107.100 and Any Nutrients Added by the 
Manufacturer (Proposed Sec.  106.91(b))
    The Agency received a number of comments objecting to the stability 
testing requirements in proposed Sec.  106.91(b). This proposed 
provision would implement section 412(b)(2)(B)(ii) of the FD&C Act, 
which was part of the 1986 amendments, and would revise and replace 
current Sec.  106.30(b)(3). Proposed Sec.  106.91(b) differs from the 
current stability analysis requirements in three principal ways: it 
would require the collection of representative samples every three 
months; it would require that stability testing of a formula assess all 
nutrients (both required and those added by the manufacturer); and it 
would expressly require that stability testing be performed on the 
collected samples at the beginning, the midpoint, and the end of the 
shelf life of the product. The 1996 preamble noted that quarterly 
testing of infant formulas for nutrient stability was the current 
practice of the industry and that FDA was not aware of any problems 
resulting from this frequency of testing. In addition, the Agency 
expressly requested comment on the appropriateness of the 3-month 
frequency for stability testing sample collection.
    (Comment 175) One comment argued that proposed Sec.  106.91(b) 
inappropriately combines requirements for periodic analyses and 
stability testing. The comment suggested establishing separate 
requirements for periodic analyses and stability testing because these 
two testing regimens serve different purposes. The comment explained 
that periodic analysis confirms on a quarterly basis the proper 
operation of the controls used by a manufacturer to ensure the presence 
of all required nutrients within required ranges in the finished infant 
formula. In contrast, the comment further explained, stability testing 
serves as a check that labeled nutrients present in the infant formula 
at the finished product stage do not, over the shelf life of the 
formula, degrade below minimum levels.
    (Response) FDA believes that the comment results in part from the 
lack of clarity in proposed Sec.  106.91, which did not separately 
identify requirements for periodic testing and stability testing. The 
Agency does, however, agree with the comment's description of the 
nature and purpose of stability testing and also agrees that one 
purpose of periodic testing can be to confirm the proper operation of 
the controls used by a manufacturer.
    FDA has considered this comment and has carefully analyzed the 
various quality control testing requirements in proposed Sec.  106.91. 
The Agency has concluded that the testing required by Sec.  106.91(a) 
of the interim final rule can serve as final product testing of each 
production aggregate and also fulfill the purpose of periodic testing 
by serving as a check on the proper operation of the controls used by a 
manufacturer to ensure the presence and proper concentration of all 
nutrients. As discussed previously in this document, Sec.  106.91(a)(1) 
of the interim final rule requires the manufacturer to test each premix 
before manufacture of an infant formula to ensure that each premix 
meets its specifications; Sec.  106.91(a)(2) of the interim final rule 
requires the manufacturer to test, during the manufacture of the infant 
formula, after addition of the premix, or at the final product stage, 
for at least one indicator nutrient for each nutrient premix used in 
the infant formula to confirm that the appropriate amount of each 
premix is present in the production aggregate of infant formula; Sec.  
106.91(a)(3) of the interim final rule requires the manufacturer to 
test each production aggregate for the labile vitamins (vitamins A, C, 
E, and thiamin) at the final product stage, before distribution; and 
Sec.  106.91(a)(4) of the interim final rule requires the manufacturer 
to test during the manufacturing process, or at the final product 
stage, each production aggregate for all nutrients required to be in 
the formula under Sec.  107.100 of this

[[Page 7998]]

chapter and for any nutrient added by the manufacturer, for which 
testing was not conducted for compliance with paragraphs (a)(1) or 
(a)(3). When the manufacturer conducts these tests as required by Sec.  
106.91(a) of the interim final rule, the results will show whether all 
nutrients required under 21 CFR 107.100 and any other nutrient added by 
the manufacturer are present and at the proper concentration. These 
collective results can also be used to evaluate whether the 
manufacturer's production controls are functioning properly because any 
nutrient not identified in the production aggregate or not found at the 
correct concentration would be evidence that the production controls 
may not be functioning properly. In such circumstances, the 
manufacturer would need to address the production aggregate shown to be 
out of compliance and would also need to evaluate the production 
controls to determine where the error occurred. Because the testing in 
Sec.  106.91(a) of the interim final rule not only confirms the 
presence and concentration of the nutrients in the particular 
production aggregate, but can also serve to demonstrate the proper 
functioning of the manufacturing controls, FDA concludes that specific 
requirements for periodic testing in Sec.  106.91 of the interim final 
rule are not necessary.
    (Comment 176) One comment suggested that periodic analysis requires 
that quarterly, a manufacturer test a finished batch (production 
aggregate) of each form of infant formula (from each facility) for all 
nutrients not analyzed directly in the immediate analysis of that batch 
(production aggregate).
    (Response) As discussed in the response to the preceding comment, 
the Agency has determined that the testing requirements of Sec.  
106.91(a) of the interim final rule will satisfy the requirement in 
section 412(b)(2)(B)(iii) of the FD&C Act, which requires that the 
manufacturer test finished products to confirm that in-process controls 
(i.e., CGMP) are operating properly and thereby, are preventing the 
production of adulterated infant formula. That is, because Sec.  
106.91(a) of the interim final rule requires each production aggregate 
to be tested for the presence and level of all nutrients in the final 
formula product, testing conducted to satisfy Sec.  106.91(a) of the 
interim final rule can also be used to determine whether a 
manufacturer's production controls are operating properly.
    (Comment 177) One comment suggested permitting an appropriate 
sampling and testing program for infant formulas produced less 
frequently than every three months.
    (Response) Because the interim final rule will not require periodic 
testing, no response to this comment is required. Importantly, however, 
an infant formula that is produced infrequently must still comply with 
the nutrient testing requirements of Sec.  106.91(a) of the interim 
final rule and the stability testing requirements of Sec.  106.91(b) of 
the interim final rule.
    (Comment 178) Several comments argued that the stability testing 
requirements in proposed Sec.  106.91(b) are excessive. One comment 
asserted that the proposed stability testing requirements require an 
excessive number of infant formulas and nutrients to be routinely 
analyzed and proposed that infant formula manufacturers continue to 
follow the requirements of the current Sec.  106.30(b)(3), which 
requires a manufacturer to conduct a stability analysis, using 
representative samples collected from finished product batches 
(production aggregates), for selected nutrients with sufficient 
frequency to substantiate the maintenance of nutrient content 
throughout the shelf life of the product.
    (Response) The Agency disagrees that proposed Sec.  106.91(b) would 
require an excessive number of infant formulas to be routinely tested. 
It is well-recognized that nutrient stability is affected by several 
factors, including the form of the infant formula (powder, ready-to-
feed, or concentrate), the matrix of the formulation, processing 
techniques, and packaging (Ref. 61). Given the impact of these 
variables, it is scientifically sound to require that stability testing 
be performed on each production aggregate of each physical form 
(powder, ready-to-feed, or concentrate) of each infant formula from 
each manufacturing facility because different forms of the product may 
contain different ingredients, and the various forms of infant formula 
are subjected to manufacturing conditions and processing procedures 
that are specific to the product and to the manufacturing facility. As 
noted, each of these factors could affect the stability of the product.
    The stability analysis required by the current regulation (21 CFR 
106.30(b)(3)) is not adequate given the range of factors that are known 
to affect nutrient stability. For example, Sec.  106.30(b)(3) requires 
analysis only for selected nutrients and does not specify the frequency 
of such testing to substantiate the maintenance of nutrient content 
throughout the shelf life of the product.
    Therefore, it is entirely reasonable to require that stability 
testing include the analyses stipulated in proposed Sec.  106.91(b). As 
explained in this document, the Agency is revising the proposed 
stability testing provisions to distinguish between the comprehensive 
stability testing of the first production aggregate of a new infant 
formula (Sec.  106.91(b)(1) of the interim final rule) and the routine 
stability testing of subsequent production aggregates of the same 
formula (Sec.  106.91(b)(2) of the interim final rule).
    Specifically, under Sec.  106.91(b)(1) of the interim final rule, 
the manufacturer must demonstrate the appropriateness of the proposed 
shelf life by completing the comprehensive testing of the first 
production aggregate of the new infant formula every three months 
during the proposed shelf-life and such testing must substantiate the 
shelf life established for the product. If the testing conducted under 
Sec.  106.91(b)(1) of the interim final rule does not substantiate the 
chosen stability date, the manufacturer is required by Sec.  
106.91(b)(3) of the interim final rule to repeat the comprehensive 
stability testing under Sec.  106.91(b)(1) of the interim final rule to 
confirm that the infant formula provides, throughout the shelf life of 
the infant formula, appropriate levels of both required nutrients and 
any nutrients added by the manufacturer. Alternatively, the 
manufacturer may choose to revise the shelf life date for the formula 
so that it is substantiated by the results of the comprehensive 
stability testing. Additionally, where the testing under Sec.  
106.91(b)(1) of the interim final rule fails to support the shelf life 
date, the manufacturer must take appropriate action with regard to any 
distributed formula bearing such unsubstantiated shelf life date.
    In addition to comprehensive stability testing, the manufacturer is 
required by Sec.  106.91(b)(2) of the interim final rule to conduct 
routine stability testing of each production aggregate of a formula at 
the beginning, midpoint, and end of its shelf life. If the results of 
this routine testing show that any required nutrient is not present in 
a production aggregate at the level required by Sec.  107.100 or that 
any nutrient added by the manufacturer is not present at the level 
declared on the formula's label, the manufacturer must take steps to 
understand these results. Specifically, Sec.  106.91(b)(4) of the 
interim final rule requires the manufacturer to investigate the cause 
of a variance in the level of any nutrient; to evaluate the 
significance of the results for other production aggregates of the same 
formula that have been released for distribution; to determine which 
production aggregates are implicated by the results and address those 
production aggregates as appropriate; and to determine whether

[[Page 7999]]

it is necessary to repeat the comprehensive stability testing required 
by Sec.  106.91(b)(1) of the interim final rule.
    (Comment 179) One comment suggested that stability ``testing every 
three months for vitamins and minerals should be used only when a new 
product is introduced and until a history for that product is 
established. After 2 years of experience is acquired, then stability 
testing should be only at the beginning, middle, and end of shelf 
life.''
    (Response) FDA agrees in part with this comment. As such, Sec.  
106.91(b) of the interim final rule focuses on stability testing and 
differentiates between the initial comprehensive stability testing 
required for the first production aggregate of a new infant formula 
(Sec.  106.91(b)(1) of the interim final rule) and the routine 
stability testing of subsequent production aggregates of that new 
formula (Sec.  106.91(b)(2) of the interim final rule). For example, as 
applied to a new infant formula in liquid form first produced in 
January and initially labeled with a 1-year shelf life, the 
requirements of Sec.  106.91(b) of the interim final rule would require 
testing in the following months: ``First production aggregate: January, 
April, July, October, and December. Subsequent production aggregates: 
January, July, and December.''
    Thus, routine stability testing at the beginning, midpoint, and end 
of a product's shelf life should be retained for all formula products 
after the completion of the comprehensive stability testing of the 
initial production aggregate; these are the formulas with which the 
manufacturer has had previous experience. Stability testing at the 
beginning of the shelf life shows that the formula is in compliance 
with the nutrient requirements of the FD&C Act when it is released for 
distribution. (FDA notes that in some circumstances, the results from 
the testing required under Sec.  106.91(a)(4) of the interim final rule 
could also be used to meet the requirements for initial stability 
testing of a particular production aggregate at the beginning of the 
shelf-life and thereby reduce duplicative analyses.) Testing at the end 
of the shelf life confirms that the formula contains all the nutrients 
needed to comply with the FD&C Act throughout its shelf life and will 
provide continued justification for the predicted shelf life. Testing 
at the midpoint of the shelf-life will provide an early indicator when 
nutrient concentrations are decreasing more rapidly than anticipated, 
based on previous experience.
    (Comment 180) Another comment argued that the proposed level of 
quality control testing is appropriate for new infant formulas to guard 
against unexpected changes in the formula, but is inappropriate for an 
experienced infant formula manufacturer.
    (Response) The Agency agrees with the comment to the extent that 
the comment suggests that a new infant formula, as defined in Sec.  
106.3 of the interim final rule, requires more frequent testing than 
products with which the manufacturer has experience, and Sec.  
106.91(b)(1) of the interim final rule reflects this principle. The 
1986 amendments refer to ``regularly scheduled testing.'' With respect 
to what constitutes ``regularly scheduled testing'' for each nutrient 
in the infant formula, the Agency agrees that the stability testing of 
the initial production aggregate of a ``new infant formula'' needs to 
be more frequent because the infant formula manufacturer will have had 
very limited or no experience with the stability of all nutrients in 
the particular formula matrix.
    FDA emphasizes that it is important that the stability testing be 
conducted on the new infant formula product manufactured for the 
marketplace, i.e., the formulation, processing, and packaging of the 
marketed product. In the past, some infant formula manufacturers have 
used pilot production aggregates that differed from the marketed 
product in formulation, processing, or packaging to assess the 
stability of the product and to assign the shelf-life. For these 
reasons, the Agency is requiring that the first production aggregate of 
a ``new infant formula,'' as defined in Sec.  106.3 of the interim 
final rule, for distribution be tested every three months during its 
predicted shelf-life.
    (Comment 181) Several comments objected to the stability testing 
requirements proposed in Sec.  106.91(b)(2), which would require 
quality control testing of an infant formula that has been changed in 
formulation or in processing in a way that does not make it a new 
infant formula but that may affect whether it is adulterated under 
section 412(a) of the FD&C Act. These comments suggested that the 
manufacturers should determine whether stability testing needs to be 
conducted for such a change. One comment contended that quality control 
testing on changed infant formulas only needs to be conducted for each 
nutrient that has been or may have been significantly and adversely 
affected by the change.
    (Response) FDA has considered these comments and has significantly 
revised proposed Sec.  106.91(b)(2). Under Sec.  106.91(b) of the 
interim final rule, a reformulated infant formula is subject to the 
comprehensive stability testing of Sec.  106.91(b)(1) of the interim 
final rule only if the change in the formula causes the formula to be a 
``new infant formula'' within the meaning of Sec.  106.3 of the interim 
final rule. Utilizing the concept of a ``new infant formula'' is a 
reasonable basis for distinguishing when the comprehensive testing of 
Sec.  106.91(b)(1) of the interim final rule and the routine testing of 
Sec.  106.91(b)(2) of the interim final rule would be required. The 
Agency believes that this revision responds to the concern expressed by 
the comment.
    (Comment 182) One comment stated that confirming the presence of a 
mineral throughout the formula product's shelf life is not necessary 
because minerals do not degrade.
    (Response) FDA agrees that minerals do not undergo degradation and 
will remain stable throughout the shelf-life of an infant formula. 
Although it is critical to test for the presence and level of minerals 
in the finished product, as required by Sec.  106.91(a) of the interim 
final rule, the Agency agrees that subsequent analysis as a part of 
stability testing for the presence and level of minerals is not needed 
because these ingredients do not degrade. Therefore, Sec.  106.91(b)(5) 
of the interim final rule exempts all required minerals (calcium, 
phosphorus, magnesium, iron, iodine, zinc, copper, manganese, sodium, 
potassium, and chloride), as well as any mineral added to the formula 
by the manufacturer, from the requirements for stability testing in 
Sec.  106.91(b)(1) and(b)(2) of the interim final rule.
    (Comment 183) One comment suggested that the proposal be revised to 
require stability testing of only labile nutrients. (A labile nutrient 
is one that readily or frequently undergoes chemical or physical 
change.)
    (Response) FDA does not agree that only labile nutrients should be 
the subject of stability testing as such approach would not address the 
concerns that resulted in the 1986 amendments.
    Although section 412(b)(2)(B)(ii) of the FD&C Act, added by the 
1986 amendments, does not specify which nutrients must be tested to 
ensure stability of the infant formula, the Agency proposed to require, 
under its authority to establish quality control procedures, that all 
nutrients be tested in a stability testing program. Infant formula is 
very often the sole source of nutrition for infants during a critical 
developmental period. As noted previously in this document, it is well

[[Page 8000]]

established that the absence or inappropriate amount of any of the 
nutrients listed in Sec.  107.100 may cause adverse effects, many of 
which may be life-threatening or result in life-long impairments (Refs. 
62, 63, 64, 65, and 66). Without testing for the stability of all 
nutrients, a manufacturer cannot know whether the level of a particular 
nutrient has declined. (As noted in the preceding comment, FDA 
recognizes that because minerals do not degrade, it is entirely 
reasonable that stability testing not extend to such substances.) Thus, 
it is both essential and reasonable to require stability testing of all 
nutrients, both required and added (except minerals), in an infant 
formula.
    (Comment 184) One comment suggested that the title of proposed 
Sec.  106.91(b) be changed from ``Stability testing'' to ``Testing of 
packaged, finished product to confirm that the infant formula provides 
nutrients in accordance with sec. 107.100.''
    (Response) As noted, to make Sec.  106.91 of the interim final rule 
consistent with the rest of part 106, FDA is deleting the titles from 
the paragraphs in this section, including Sec.  106.91(b).
    (Comment 185) Several comments stated that the manufacturer should 
determine the frequency of stability testing, if deemed necessary.
    (Response) The Agency agrees in part with the comment that 
recommended that the manufacturer determine the frequency of stability 
testing. The Agency disagrees that the manufacturer should be allowed 
to test less frequently than required under Sec.  106.91(b)(1) or 
(b)(2) of the interim final rule. The Agency views this testing 
frequency as the minimum required to ensure nutrient stability over the 
shelf-life of the product. However, if a manufacturer wishes to test 
more frequently than required under Sec.  106.91(b)(1) or (b)(2) of the 
interim final rule, FDA would not object to additional testing by the 
manufacturer.

B. Audits of Quality Control Procedures (Proposed Sec.  106.92)

    In 1996, FDA proposed to require in Sec.  106.92 that infant 
formula manufacturers conduct regularly scheduled audits of a firm's 
compliance with those quality control procedures that are necessary to 
ensure that a formula provides nutrients in accordance with section 
412(b) and (i) of the FD&C Act, and is manufactured in a manner 
designed to prevent adulteration of the infant formula. Proposed Sec.  
106.92 would also have required that such audits be performed by a 
person with knowledge of all aspects of infant formula production and 
FDA's quality control regulations but who had no direct responsibility 
for the matters being audited. The Agency received several comments on 
proposed Sec.  106.92, which are addressed in this document.
    FDA notes that proposed Sec.  106.90 (Audits of current good 
manufacturing practice) and proposed Sec.  106.92 (Audits of quality 
control procedures) would have imposed similar requirements for the two 
types of audits. As a result, several comments FDA received addressed 
both proposed Sec.  106.90 and proposed Sec.  106.92. For this reason, 
the discussion that follows references the responses to certain 
comments on proposed Sec.  106.90 (section V.N).
    (Comment 186) One comment stated that requiring that the auditor be 
knowledgeable in ``all'' aspects of infant formula production is a 
lofty expectation given the complexities of an infant formula 
production environment. The comment suggested that the auditor should 
possess a general knowledge of the areas being audited, but not the 
depth and extent implied by the word ``all.''
    (Response) As noted previously in this document in section V.N 
(Comment 165), FDA disagrees that the standard in proposed Sec.  
106.92(b) is a ``lofty'' expectation. As with any audit, to be valid 
and effective, the auditor must have well-developed knowledge of the 
focus of his audit. In this case, this means that the individual 
conducting the audit must have in-depth knowledge of infant formula 
production as well as the regulations governing that process. In 
responding to Comment 165, the Agency explained that using a team of 
individuals is a permissible approach to audits of infant formula 
manufacturing, and is one way that the necessary breadth of expertise 
can be assembled for an audit.
    (Comment 187) Another comment agreed with the Agency that an 
auditor must not have direct responsibility for the matters being 
audited, but took exception to the preamble statement that the auditor 
must have no ``past involvement in the activities being audited.'' The 
comment contended that this requirement presents a dilemma if the 
auditor must have knowledge of infant formula production, but could 
have no past involvement where knowledge might have been gained. The 
comment recommended that a reasonable time (1 year) be established 
after which any concern about potential bias would dissipate and an 
auditor could evaluate an area of previous employment.
    (Response) As noted previously in this document in section V.N, in 
order to be meaningful and function as an appropriate oversight tool 
for quality control compliance, an audit, including one conducted under 
proposed Sec.  106.92, must be as objective as possible although, as 
noted, the Agency is persuaded that there may be certain circumstances 
in which an auditor with prior involvement in the activities being 
audited could still perform an unbiased audit. In designating an 
individual to conduct an audit under Sec.  106.92(b), the manufacturer 
should consider the factors identified in the response to Comment 166 
and determine that the proposed auditor is able to be objective and to 
exercise independent judgment.
    (Comment 188) One comment contended that firms would have to hire 
auditors from outside their company to perform audits since an 
individual could not audit his or her own area and it would be unlikely 
that one person would be knowledgeable in all areas of plant 
operations. The comment pointed out that hiring an outside auditor 
would be an added expense and suggested that auditing could be 
conducted as effectively by in-house auditors trained in auditing 
practices.
    (Response) As discussed previously in this document in section V.N, 
FDA disagrees that a firm would have to hire auditors from outside its 
company to perform audits regardless of whether the audits are CGMP or 
quality control audits. First, section 412(b)(2)(B)(iv) of the FD&C Act 
would not preclude an auditor being an employee of the manufacturer. In 
addition, as noted, a manufacturer may utilize a team approach to 
ensure an audit is conducted by individuals, whether employees of the 
manufacturer or otherwise, with comprehensive knowledge of the infant 
formula production process and may also utilize an individual to audit 
an area of his/her prior responsibility so long as the manufacturer 
determines that an audit by such individual would be objective and free 
of bias. Thus, FDA disagrees that the audit provisions of proposed 
Sec.  106.92 would require a manufacturer to hire individuals from 
outside the firm to conduct audits.
    (Comment 189) One comment suggested that the language of proposed 
Sec.  106.92 be changed to clarify that it is the manufacturer's 
responsibility to determine what will constitute ``regularly scheduled 
audits'' and to establish SOPs for that purpose. To achieve this goal, 
the comment suggested that proposed Sec.  106.92 be revised to state 
that the manufacturer must conduct audits ``according to its 
established practice.''

[[Page 8001]]

    (Response) FDA disagrees that proposed Sec.  106.92 should be 
revised to make the established practice of the manufacturer the only 
basis for the conduct of ``regularly scheduled'' audits.
    The 1986 amendments to section 412 of the FD&C Act reflect a 
Congressional determination that greater control over the formulation 
and production of infant formula was needed. A total quality control 
program for the manufacture of infant formula is necessary to ensure 
that each production aggregate of formula is uniform in composition and 
conforms to the nutrient requirements for infants. Under section 
412(b)(2)(B)(iv) of the FD&C Act, a manufacturer is required to conduct 
audits at regularly scheduled intervals. Thus, in response to this 
comment, FDA advises that ``regularly scheduled'' means that a 
manufacturer shall conduct, at each manufacturing facility, audits at a 
frequency that is required to ensure compliance with such regulations, 
with additional audits as needed, to determine whether the manufacturer 
has complied with the quality control procedures regulations.
    For clarity, FDA is dividing proposed Sec.  106.92 into two 
sections. Section 106.92(a) of the interim final rule establishes the 
regularly scheduled audit requirement, and Sec.  106.92(b) of the 
interim final rule establishes the audit personnel requirement.

VII. Subpart D--Conduct of Audits

Audit Plans and Procedures (Proposed Sec.  106.94)

    Three separate sections of the interim final rule address audits. 
Section 106.90 of the interim final rule establishes the requirement to 
conduct audits of compliance with CGMP, and Sec.  106.92 of the interim 
final rule establishes the requirement to conduct audits of compliance 
with quality control procedures. These provisions both implement 
section 412(b)(2)(B)(iv) of the FD&C Act. Subpart D (Sec.  106.94 of 
the interim final rule) establishes requirements for audit plans and 
procedures.
    In the 1996 proposal, FDA proposed in Sec.  106.94 to require that 
infant formula manufacturers develop and follow a written audit plan. 
The audit plan would be required to set out the method used to 
determine whether the firm is operating in compliance with CGMP, 
including quality control procedures, and would include evaluation of 
the firm's production and in-process controls, a comparison of the 
written plan to the observed process, and review of certain records, 
including monitoring records, specification deviation investigations, 
and a representative sample of all records maintained under proposed 
Sec.  106.100(e) and (f).
    The Agency received comments on several aspects of Sec.  106.94, 
which are addressed in this document. Although FDA declines to make any 
of the revisions to subpart D in response to the comments received, the 
Agency is making minor editorial revisions in this subpart.
    (Comment 190) One comment objected to proposed Sec.  
106.94(c)(1)(i) which would require observation of the production of 
infant formula and comparison of the observed process to the written 
production and in-process control plan. The comment stated that this 
proposal could be interpreted as requiring observation of every single 
manufacturing operation, from ingredient receipt through manufacturing, 
holding, and distribution, and that such detail during an audit would 
make the auditing process an extremely tedious and unwieldy endeavor 
and would result in overly prolonged audits. The comment proposed that 
the actual observation portion of the audit be devoted to the critical, 
product/line specific steps of the process as defined by the 
manufacturer.
    (Response) FDA disagrees with this comment. The requirement that a 
manufacturer conduct regularly scheduled audits to assess compliance 
with CGMP, including quality control procedures, derives from section 
412(b)(2)(B)(iv) of the FD&C Act, which mandates that CGMP and quality 
control procedures regulations include requirements for regularly 
scheduled audits by a formula manufacturer to determine whether the 
manufacturer has complied with such regulations. Thus, the scope of a 
manufacturer's audits, and the audit plans and procedures established 
under proposed Sec.  106.94(c)(1)(i), is determined by the breadth of 
the CGMP and quality control procedure requirements. Section 106.6(a) 
of the interim final rule requires a manufacturer to establish a system 
of production and in-process controls that covers all stages of 
processing, from the receipt and acceptance of the raw materials, 
ingredients, and components through the storage and distribution of the 
finished product, and Sec.  106.6(b) of the interim final rule requires 
a written plan of such system. To assess compliance adequately, an 
audit must extend to all of these areas of production. Thus, it is 
appropriate that the audit plan required under proposed Sec.  
106.94(c)(1)(i) include observation of each element of the 
manufacturing operation, from ingredient receipt through manufacturing, 
holding, and distribution. Accordingly, FDA is not revising Sec.  
106.94(c)(1)(i) in the interim final rule in response to this comment.
    (Comment 191) One comment claimed that proposed Sec.  
106.94(c)(1)(i) would require additional trained personnel to complete 
this type of audit, and that this requirement would interfere 
unnecessarily with the focus on high quality production.
    (Response) FDA notes that this comment did not explain its 
assertion that additional personnel would be required to complete an 
audit under proposed Sec.  106.94(c)(1)(i). Nor did the comment explain 
how this proposed requirement would interfere with high quality 
production. Without such details, FDA cannot respond to the comment. 
Moreover, in its response to comments on the requirement to conduct 
audits of compliance with CGMP and compliance with quality control 
procedures, FDA addressed similar comments about the need for 
additional trained personnel to conduct the audits that would be 
required by proposed Sec. Sec.  106.90 and 106.92. In short, the audit 
provisions (proposed Sec. Sec.  106.90. 106.92, and 106.94) provide 
ample flexibility in terms of audit personnel.
    For the foregoing reasons, Sec.  106.94(c)(1)(i) is included in 
this interim final rule as proposed.
    (Comment 192) One comment suggested revising proposed Sec.  
106.94(c)(1)(ii), which requires that the audit procedures include 
reviewing records of the monitoring of points, steps, or stages where 
control is necessary to prevent adulteration. The comment noted that 
the 1996 preamble to this proposed section stated that the review of 
``production and in-process control records'' contemplated by this 
section must involve ``all batches produced in a given period of time'' 
(61 FR 36154 at 36178). The comment recommended that the required audit 
procedures be revised to include a review of records of representative 
batches, over multiple days of production, of the monitoring of points, 
steps, or stages where control is critical to prevent adulteration, 
asserting that such audits would be more thorough and beneficial if the 
records reviewed covered a wider span of time (i.e., months), but 
extended only to ``representative'' batches, not ``all'' batches, and 
to ``representative'' records of only the most important control points 
(i.e., ``critical points'').

[[Page 8002]]

    (Response) As discussed in this document, FDA declines to make the 
revisions requested in this comment.
    The purpose of an audit is to identify conditions related to 
production and in-process controls that may result in the manufacture 
of an adulterated infant formula. The Agency agrees with the comment 
that an effective production and in-process control system audit may be 
based on a ``representative sample'' (as defined in Sec.  106.3), of 
production aggregates covering several months, and proposed Sec.  
106.94 provides flexibility to the manufacturer as to the period of 
production specified for review in the manufacturer's audit plan. 
Importantly, however, the audit plan developed by the manufacturer 
under proposed Sec.  106.94 must ensure that the audit covers a 
sufficient number of products over a sufficient period of time so that 
the manufacturer is able to determine whether its operations are in 
compliance with CGMP, including quality control procedures required by 
this interim final rule, to ensure that its infant formula provides the 
required and added nutrients at the appropriate levels and is 
manufactured in a manner designed to prevent adulteration. The audit 
plan should provide a reasonable probability that any discrepancies in 
the process can be identified. The audit plan must also provide a 
mechanism whereby the manufacturer can identify any production 
practices or in-process controls that require revision to ensure 
compliance with all requirements for infant formula. FDA disagrees, 
however, with the comment to the extent that it asserts that an audit 
should be limited to ``representative records of the most important 
control points.'' As discussed in the response to Comment 190, an 
effective audit must be co-extensive with the production and in-process 
controls established under Sec.  106.6 of the interim final rule. 
Similarly, in order for such audit to be effective, an audit must 
extend to the records of all points, steps, or stages where control is 
necessary to prevent adulteration for each production aggregate in the 
representative sample of an infant formula audited.
    Importantly, under Sec.  106.6 of the interim final rule, a 
manufacturer has both the responsibility and the flexibility to 
identify in its own production process those points, steps, or stages 
in the process where control is necessary to prevent adulteration of 
formula. Any point, step, or stage identified by the manufacturer as a 
focus for control under Sec.  106.6 of the interim final rule is, by 
definition, ``critical'' to producing an infant formula that is not 
adulterated. Thus, it is essential that all of these points, steps, or 
production stages be audited, including through a review of the records 
related to such points, steps, or production stages, to confirm that 
the relevant controls are functioning properly and ensuring that no 
adulterated formula is produced. Moreover, as noted previously in this 
document, audits by infant formula manufacturers are required by 
section 412(b)(2)(B)(iv) of the FD&C Act, and a requirement that a 
manufacturer's audits be limited to a review of the ``most important 
control points'' would not allow a manufacturer to determine whether it 
has complied with the CGMP, including quality control procedures, 
regulations as mandated by section 412(b)(2)(B)(iv) of the FD&C Act. 
Thus, it is entirely appropriate that the audit plan established under 
Sec.  106.94(c) of the interim final rule require the review of the 
records relating to all of the points, steps, or stages of the 
production process where control is deemed necessary to prevent 
adulteration.
    For these reasons, FDA declines to revise proposed Sec.  
106.94(c)(1)(ii), and this provision is included in this interim final 
rule as proposed.
    (Comment 193) One comment suggested that proposed Sec.  
106.94(c)(1)(iii), which would require reviewing records of the 
handling of deviations from any standard or specification at points, 
steps, or stages where control is deemed necessary to prevent 
adulteration should be revised by adding the phrase ``to assure that 
the review was complete.'' The comment noted that the 1996 preamble 
states that the auditor must review these records to determine 
``whether the conclusions and follow-up of these investigations are 
appropriate for each failure to meet the specification or standard'' 
(61 FR 36154 at 36178), and asserted that it is unrealistic to expect 
an auditor to have the background and breadth of technical knowledge to 
assess whether the dispositions were ``appropriate.'' The comment 
claimed that such disposition decisions may involve multiple 
disciplines in a company, and it would be more reasonable to expect the 
auditor's review to confirm the completeness and sufficiency of such 
investigations, rather than to expect the auditor to determine whether 
the conclusions and follow-up were appropriate.
    (Response) Although FDA agrees that an audit should confirm the 
completeness and sufficiency of the review of deviations from any 
standard or specification, this action would not fulfill all of the 
purposes of an audit. Because an audit serves as a manufacturer's 
follow-up mechanism to provide independent evaluation of a firm's 
management of deviations from specifications, a comprehensive audit 
must also include an evaluation of how the manufacturer responded to 
any deviation and whether the disposition decision was appropriate.
    In terms of the comment's concern that an auditor may not have the 
requisite expertise to evaluate the response and disposition to a 
deviation, the Agency clarified in the response to Comment 165 that 
audits may be conducted by a single individual or by a team of 
individuals, each qualified to evaluate a particular portion or 
portions of the production process. In fact, the use of a team for 
audits is one way to ensure that an audit is comprehensive. Thus, 
proposed Sec.  106.94(c)(iii) is not unrealistic and FDA is not 
persuaded to make the revision suggested by this comment.
    (Comment 194) One comment objected to the requirement in proposed 
Sec.  106.94(c)(1)(iii) that the review of all deviations from the 
manufacturer's standards or specifications at points, steps, or stages 
where control is necessary to prevent adulteration be a part of 
regularly scheduled audits. The comment suggested that instead of 
requiring the auditor to review all deviations, review of a random 
sample of deviations should be sufficient.
    (Response) FDA disagrees that review of a ``random sample'' of 
deviations from a manufacturer's specifications would constitute a 
sufficient audit. The purpose of a quality control audit is to identify 
recurring problems and detect any weaknesses or flaws in the system. In 
order to maximize the likelihood of identifying a pattern of repeated 
failures, an audit must include the review of all deviations from 
specifications. As discussed previously in this document, the fact that 
a manufacturer fails to meet a specification requires prompt 
investigation to determine whether the manufacturing process is under 
control. A subsequent audit evaluates the handling of all such 
occurrences and assesses whether the appropriate material disposition 
decisions were made. Thus, a review of all deviations as a part of the 
audit will identify failures that occur and show how these failures are 
handled by the manufacturer.
    For these reasons, FDA is not revising proposed Sec.  
106.94(c)(1)(iii) in response to this comment, and, with the exception 
of minor editorial revisions, Sec.  106.94(c)(i)(iii) is included in 
this interim final rule as proposed.

[[Page 8003]]

VIII. Subpart E--Quality Factors

    In Subpart E, ``Quality Factors,'' comments often referred to both 
proposed Sec.  106.96 and proposed Sec.  106.97 because the subjects of 
these two proposed provisions are closely related. The interim final 
rule reorganizes and consolidates into a single section (Sec.  106.96 
of the interim final rule) most of the content of proposed Sec.  106.96 
and proposed Sec.  106.97 related to requirements for infant formula 
quality factors. In addition, Sec.  106.121 of the interim final rule, 
which is discussed in section X.D., specifies the assurances for the 
established quality factors that a manufacturer is required to submit 
in a new infant formula submission or in a submission made under 
section 412(d)(3) of the FD&C Act. For these reasons, this portion of 
the preamble is generally organized by topic rather than by section of 
the proposed codified.
    FDA notes that the Agency received several comments in response to 
proposed Sec.  106.96 and Sec.  106.97 that raised issues beyond the 
scope of this rulemaking. In particular, FDA received comments 
expressing concern about the safety of particular ingredients used in 
infant formula. Because the safety of particular infant formula 
ingredients is not at issue in this rulemaking, FDA is not responding 
to these comments.

A. Quality Factors: Legal Authority

    Section 412(b)(1) of the FD&C Act, which was added to the statute 
by the 1986 amendments, requires that the Secretary ``. . . establish 
requirements for quality factors for infant formulas to the extent 
possible consistent with current scientific knowledge, including 
quality factor requirements for the nutrients required by subsection 
(i).''
    Section 412(a)(2) of the FD&C Act deems an infant formula that does 
not meet the quality factors requirements established by the Secretary 
to be adulterated.
    (Comment 195) One comment asserted that there is no basis in the 
plain language of the statute or in its legislative history to support 
an interpretation of ``normal growth'' as a quality factor, which would 
establish a requirement that applies to the infant formula as a whole. 
The comment cited to legislative statements and FDA testimony 
concerning the Infant Formula Act or the 1986 amendments to the Infant 
Formula Act as support for its assertion that Congress intended quality 
factors to be limited to individual components in the infant formula, 
and that the Infant Formula Act does not authorize FDA to require 
clinical studies for new infant formulas, including those that have 
undergone a major change.\7\
---------------------------------------------------------------------------

    \7\ The comment cites to floor statements in the Senate Record 
that describe the 1986 amendments as providing testing for ``each 
essential nutrient'' and as further describing ``the quality factor 
of nutrient content requirements of the law, as demonstrated by the 
testing called for in the amendments.'' 132 Cong. Rec. S26775, 26777 
(daily ed. Sept. 27, 1986). The comment also cites to a statement by 
then Commissioner of Food and Drugs Jere E. Goyan stating that the 
proposed legislation required ``tests, including clinical tests, 
where appropriate.'' See Nutritional Quality of Infant Formula: 
Hearings on H.R. 6590, H.R. 6608, H.R. 5836, and H.R. 5839 Before 
the Subcomm. on Health and the Environment of the H. Comm. on 
Interstate and Foreign Commerce, 96 Cong. 132, 74 (1980). The 
comment notes that this statement by Commissioner Goyan was 
responded to by Representative Mottl, who replied that ``I am 
speaking of analysis in the chemical and nutritional laboratories, 
and I am not referring to clinical trials.'' Id. at 120.
---------------------------------------------------------------------------

    (Response) FDA disagrees with the suggestion that the Infant 
Formula Act does not support an interpretation of ``normal growth'' as 
a quality factor, or does not provide authority to require a well-
controlled growth monitoring study to ensure that a formula will 
support normal physical growth. Such reasoning is flawed. Legislative 
silence on an issue is not persuasive when determining the meaning of a 
statute. Central Bank v. First Interstate Bank, 511 U.S. 164, 187 
(1994) (stating that ``Congressional inaction lacks persuasive 
significance''). Clearly, just as Congress is not expected to express 
``every single evil sought to be corrected'' in a grant of authority to 
issue a rule, it cannot be expected to articulate every requirement 
that is within an Agency's delegated authority. American Trucking 
Assoc. v. United States, 344 U.S. 298, 309-10 (1953).
    In addition, the various legislative statements and Agency 
testimony that the comment cites to support its assertion as to the 
meaning of ``quality factors'' are not on point. First, the 
congressional statements the comment cites to support its assertion 
that FDA lacks the authority to require testing of the infant formula 
as a whole (see footnote 1) discuss testing in the context of 
laboratory analysis of required nutrients; the statements in question 
do not relate to quality factors. Additionally, the Agency testimony 
cited by the comment, stating that Congress did not intend the use of 
clinical testing, comes from a discussion of the Infant Formula Act's 
recall provisions. Second, even if these congressional statements and 
FDA testimony were relevant, such isolated statements are not 
sufficient evidence of congressional intent. See Weinberger v. Rossi, 
456 U.S. 25, 34-35 (U.S. 1982) (rejecting the argument that a single 
statement of a sponsor taken out of context should be determinative of 
congressional intent); Regan v. Wald, 468 U.S. 222, 237 (1984) 
(explaining that testimony of Senators and Representatives and 
witnesses can seldom be expected to be as precise as the language of 
the enacted bill, and should not later be permitted to undermine the 
bill).
    FDA disagrees that there is no basis under the infant formula 
provisions of the FD&C Act to require a well-controlled growth 
monitoring study that demonstrates normal physical growth. Under 
section 412(a) of the FD&C Act, Congress stipulated that infant formula 
``shall be deemed to be adulterated if . . . such infant formula does 
not meet the quality factor requirements prescribed by the Secretary . 
. . .'' Section 412(b)(1) of the FD&C Act further provides that ``[t]he 
Secretary shall by regulation establish requirements for quality 
factors for infant formulas to the extent possible consistent with 
current scientific knowledge, including quality factor requirements for 
the nutrients required by subsection (i).''
    In construing the meaning of the term ``quality factors,'' FDA is 
confronted with two questions. First, has Congress directly and 
unambiguously spoken to the precise question at issue (``Chevron step 
one'') Chevron U.S.A. Inc. v.Natural Resources Defense Council, 467 
U.S. 837, 842 (1984)? To find no ambiguity, Congress must have clearly 
manifested its intention with respect to the particular issue. See 
Young v. Community Nutrition Institute, 476 U.S. 974, 980 (1986). If 
Congress has spoken directly and plainly, the Agency must implement 
Congress's unambiguously expressed intent. Chevron, 467 U.S. at 842-
843.
    Second, if the FD&C Act is silent or ambiguous with respect to the 
meaning of ``quality factors'' in section 412(b)(1) of the FD&C Act, is 
the Agency's interpretation based on a permissible construction of the 
statute (``Chevron step two'') Chevron, 467 U.S. at 842-843; FDA v. 
Brown & Williamson Tobacco Corp., 529 U.S. 120, 132 (2000)? When, as is 
the case here, Congress leaves a gap for the Agency to fill by 
regulation, the regulation will pass muster so long as it is not 
``arbitrary, capricious, or manifestly contrary to the statute.'' 
Chevron, 467 U.S. at 844.
    The language in section 412(b)(1) of the FD&C Act provides an 
express delegation of authority to ``by regulation establish 
requirements for quality factors for infant formulas to the extent

[[Page 8004]]

possible consistent with current scientific knowledge.'' This language 
necessarily contemplates broad Agency discretion to define the 
requirements for ``quality factors,'' limited by current scientific 
knowledge.
    Congress also spoke to the precise question of whether ``quality 
factors requirements'' were limited in application to the individual 
nutrients required to be in the formula under section 412(i) of the 
FD&C Act. Congress did not expressly limit quality factors in this way. 
Rather, the statutory language describing what requirements for quality 
factors are to be established states that the Secretary shall by 
regulation establish ``quality factors for infant formulas . . . 
including quality factor requirements for the nutrients required by 
subsection (i).'' The use of the word ``including'' demonstrates that 
Congress did not intend to limit quality factors for infant formulas to 
the nutrients in subsection (i). See Norman J. Singer & J.D. Shambie 
Singer, 2A Sutherland Statutory Construction Sec.  47:7 (7th ed. 2009) 
(explaining that when a statutory definition declares what it 
``includes,'' it ``conveys the conclusion that there are other items 
includable, though not specifically enumerated''); Eric C. Surrette et. 
al., American Jurisprudence Sec.  130 (2nd ed. 2008) (explaining that 
``a statutory definition of a term as 'including' certain things does 
not necessarily put a meaning thereon limited to the inclusion''); Gray 
v. Powell, 314 U.S. 402 (1941) (explaining that ``[t]he definition of 
disposal as including 'consumption or use by a producer, and any 
transfer of title by the producer other than by sale' cannot be said to 
put a meaning on disposal limited to the inclusion.''); Herb's Welding 
v. Gray, 470 U.S. 414, 415, n. 9 (1985) (noting that by use of the term 
``including,'' Congress indicated that the occupations specifically 
mentioned in the law are not exhaustive). In sum, the infant formula 
provisions of the FD&C Act direct the Agency to establish quality 
factor requirements for infant formulas to the extent possible 
consistent with current scientific knowledge, without limitation to 
requirements relating only to the nutrients specified by statute to be 
included in all infant formulas. Congress did not, however, define the 
term ``quality factors,'' nor did it describe what such quality factors 
might be. Instead Congress left a gap for the Agency to fill by 
regulation.
    Because Congress left a gap for the Agency to define the term 
``quality factors'' and determine what quality factor requirements are 
consistent with current scientific knowledge, under Chevron step two, 
FDA may define the term and determine what quality factor requirements 
may be imposed, provided that FDA's interpretation is not arbitrary, 
capricious, or manifestly contrary to the statute. Chevron, 467 U.S. at 
844. Accordingly, when defining quality factors, FDA should consider 
the language itself, the placement of the language in the infant 
formula provisions of the FD&C Act, and other tools of statutory 
construction, including the purpose and the legislative history of the 
Infant Formula Act and the 1986 Amendments, as well as the FD&C Act. 
See Barnhart v. Peabody Coal Co., 537 U.S. 149, 160 (2003) (looking to 
structure, purpose, and legislative history to interpret the Coal Act); 
see also Chevron, 467 U.S. at 843 (noting that if a statute is silent 
with respect to an issue the Agency's answer to the issue should be 
based on a permissible interpretation of the statute).
    The language in the infant formula provisions of the FD&C Act does 
not define ``quality factors,'' but it does define the scope of 
authority that Congress left FDA to establish quality factor 
requirements. As noted previously in this document, according to the 
language in section 412(b)(1) of the FD&C Act, quality factors include 
requirements related to nutrients in section 412(i) of the FD&C Act, 
but are not limited to such nutrients. This statutory language 
indicates that the Secretary must establish quality factors for (1) the 
individual nutrient components required under subsection (i), and, (2) 
the infant formula as a whole to the extent possible consistent with 
current scientific knowledge. If Congress had intended quality factors 
to be limited to individual nutrient components of the formula, such as 
protein and other nutrients that are added to the formula, Congress 
would not have needed to incorporate the ``including'' language 
referencing nutrients required by subsection (i).
    The organization of section 412 of the FD&C Act aids in 
interpreting the intended meaning of quality factors. The statutory 
provisions for quality factor requirements are separate and distinct 
from the provisions for requirements related to CGMP and quality 
control procedures in section 412(b)(2)(A) and (b)(2)(B) of the FD&C 
Act. The placement of quality factor requirements in a separate 
statutory provision means that such requirements pertain to something 
other than the CGMP and quality control provisions that, in part, 
ensure that particular nutrients are present at particular levels in 
each production aggregate of infant formula. The preamble to the 
proposed rule recognized that quality control procedures and quality 
factor requirements are separate and distinct: ``While quality control 
procedures are intended to ensure that the safety and nutritional 
potency of a formula is built into the manufacturing process,'' quality 
factors are ``intended to ensure that an infant formula contains an 
adequate amount of each nutrient in a form that can be digested, 
absorbed, and utilized so that the infant's physiological needs for 
these nutrients will be met'' (61 FR 36154 at 36179). Thus, the quality 
factors pertain not to a measurement of the amount of each nutrient in 
the formula, but to a broader concept of bioavailability; an infant 
formula as a whole and the individual nutrients in the infant formula 
must meet the physiological needs of infants when fed the formula as a 
sole source of nutrition to foster normal growth and development. As 
noted previously in this document, under the language of section 412 of 
the FD&C Act, Congress required the Secretary to establish quality 
factors for the infant formula as a whole as well as for individual 
nutrients to the extent that is consistent with current scientific 
knowledge. Thus, interpreting the infant formula provisions of the FD&C 
Act to mean that quality factor requirements that apply to the infant 
formula as a whole would pertain to the ability of the formula (i.e., 
all the nutrients in combination) to meet an infant's physiological 
needs, is reasonable. The quality factor of ``normal physical growth'' 
is designed to demonstrate the ability of the infant formula as a whole 
to meet such physiological needs.
    Establishing normal physical growth as a quality factor requirement 
is consistent with the overall purpose of the Infant Formula Act. The 
need for an Infant Formula Act was discussed in the wake of the 
marketing of two infant formulas that ``were critically deficient in 
chloride, a life sustaining nutrient.'' S. Rep. No. 96-359, at 3 
(1980). The Infant Formula Act was meant to provide the Secretary with 
the means to ensure that formula ``will promote healthy growth'' in 
infants. H.R. Rep. No. 96-936, at 3 (1980). ``Normal physical growth'' 
is an essential component of ``healthy growth,'' thus a quality factor 
requirement for the demonstration of normal physical growth is 
consistent with the overall purpose of the Infant Formula Act. 
Additionally, a report from the House Committee on Interstate Commerce 
that accompanied the Infant Formula Act supports the view that, as 
originally

[[Page 8005]]

enacted, the Infant Formula Act authorizes the establishment of quality 
factor requirements for normal physical growth. The report states: 
``Quality factors pertain to the bioavailability of the nutrient . . . 
.'' H.R. 96-936, at 6 (1980).
    In the 1986 amendments to the Infant Formula Act Congress clarified 
that quality factor requirements demonstrating the ``bioavailability of 
the nutrient'' referred to all nutrients combined in a formula as well 
as to individual nutrients. See 21 U.S.C. 350a(b)(1). The Infant 
Formula Act stated that the Secretary may by regulation ``establish 
requirements for quality factors for such nutrients [required by 
subsection (g)].'' Infant Formula Act of 1980, Public Law 96-359, Sec.  
2, 94 Stat. 1190 (1980). In 1986, however, the infant formula 
provisions were amended to specify in revised section 412(b)(1) of the 
FD&C Act that the ``Secretary shall by regulation establish 
requirements for quality factors for infant formulas, . . . including 
quality factor requirements for the nutrients required by subsection 
(i).'' (Emphasis added). This amendment clarified that quality factor 
requirements applied to the ``infant formula'' as a whole as well as to 
the individual nutrients required by subsection (i), and also made the 
establishment of requirements for quality factors mandatory.
    Additionally, normal physical growth is an appropriate means to 
assess whether the infant formula as a whole meets the physiological 
needs of infants. Infants frequently consume formula as the sole or 
primary source of nutrition at a time when the requirements for 
nutrients are higher per kilogram body weight than at any other time 
during the life cycle. The net effect for an infant who consumes an 
infant formula that provides required nutrients in a bioavailable form 
is the ability of the infant to achieve normal physical growth. Normal 
physical growth is an indicator that an infant is thriving and is 
inextricably linked to the bioavailability of nutrients in an infant 
formula as a whole. Normal physical growth is an ``integrative 
indicator of the net effect of the overall nutritional quality of the 
formula'' (61 FR 36154 at 36180). Additionally, anthropometric 
measurements of length, weight, and head circumference are easily made, 
familiar to health care professionals, and are the same measurements as 
those done during routine office visits and for which standardized 
growth charts are available for comparison. Also, there is a very large 
amount of data available on what constitutes ``normal physical 
growth.'' Thus, it is reasonable for the Agency to require the conduct 
of a well-controlled growth monitoring study, when necessary, to 
determine whether an infant formula meets the quality factor of normal 
physical growth.
    Further, requiring such a study is reasonable when considering the 
statutory scheme as a whole. See Brown & Williamson, 529 U.S. at 133 
(explaining that the words of a statute must be read in the context of 
the overall statutory scheme). FDA's explicit statutory mission is, in 
part, to protect the public health by ensuring that foods (including 
infant formula) are safe, wholesome, sanitary, and properly labeled 
(section 903(b)(2)(A) of the FD&C Act) (21 U.S.C. 393(b)(2)(A)). 
Further, the FD&C Act touches ``phases of the lives and health of 
people which, in the circumstances of modern industrialism, are largely 
beyond self-protection. Regard for these purposes should infuse 
construction of the legislation if it is to be treated as a working 
instrument of government and not merely as a collection of English 
words.'' United States v. Dotterweich, 320 U.S. 277, 281 (1943); see 
also United States v. Park, 421 U.S. 658, 668 (1975). The Infant 
Formula Act and the 1986 amendments were meant to ensure the ``safety 
and nutrition'' of infant formulas, a purpose achieved, in part, by 
growth monitoring studies. See Infant Formula Act of 1980, Public Law 
96-359, 94 Stat. 1190, 1190 (1980) (prior to 1986 amendment).
    Section 701(a) of the FD&C Act authorizes FDA to issue regulations 
for the efficient enforcement of the FD&C Act in order to ``effectuate 
a congressional objective expressed elsewhere in the Act'' (Association 
of American, Physicians and Surgeons, Inc. v. FDA, 226 F. Supp. 2d 204, 
213 (D.D.C. 2002) (citing Pharm. Mfrs. Ass'n. v. FDA, 484 F. Supp. 
1179, 1183 (D. Del. 1980)). The validity of such regulations issued 
under section 701(a) of the FD&C Act is determined by a consideration 
of the ``statutory purpose'' of the FD&C Act, as well as an 
``understanding of what types of enforcement problems are encountered 
by the FDA [and] the need for various sorts of supervision to 
effectuate the goals of the Act.'' National Confectioners Assoc. v. 
Califano, 569 F.2d 690, 693 (D.C. Cir 1978) (citing Toilet Goods Ass'n 
v. Gardner, 387 U.S. 158, 163-64); see also Association of American 
Physicians and Surgeons, Inc., 226 F. Supp. 2d at 213; NVE Inc. v. HHS, 
436 F.3d 182, 186-190 (3d Cir. 2006) (noting that section 701(a) of the 
FD&C Act grants FDA broad discretion to issue regulations for the 
efficient enforcement of the FD&C Act within the scope of the authority 
granted to it by Congress).
    The interim final rule falls within FDA's discretion to issue 
regulations for the efficient enforcement of the FD&C Act. The interim 
final rule is designed, in part, to help ensure that infant formulas, 
when fed as a sole source of nutrition, will support normal physical 
growth in infants consuming the formula. The requirement to conduct a 
well-controlled growth monitoring study is designed to determine 
whether normal physical growth may be achieved using a particular 
infant formula. Such a study is consistent with the purpose of the 
Infant Formula Act, because it provides a mechanism by which FDA can 
determine whether the formula promotes one of the factors contributing 
to healthy growth (i.e., normal physical growth). See H.R. Rep. No. 96-
936, at 3 (1980). The requirement to conduct such a study is written to 
facilitate efficient and effective action to enforce the FD&C Act's 
terms when necessary. The requirement to conduct a well-controlled 
growth monitoring study is also consistent with FDA's overall mission, 
because the study helps to ensure that the formula is safe and 
wholesome. (See section 903(b)(2)(A) of the FD&C Act (21 U.S.C. 
393(b)(2)(A))).
    FDA acknowledges that a well-controlled growth monitoring study may 
not be necessary to demonstrate normal physical growth for every new 
infant formula, including a change to a marketed formula that results 
in a new infant formula. Thus, FDA has included in the interim final 
rule exemptions from the requirement to conduct a well-controlled 
growth monitoring study for certain changes in processing or methods 
and, in addition, an opportunity for a manufacturer to demonstrate that 
an alternative study design or method would provide assurances that an 
infant formula supports normal physical growth or that a change to a 
formula that has already been shown to meet the quality factor 
requirements does not affect the bioavailability of the new formula, 
including its nutrients. In addition, it is reasonable and necessary 
for efficient enforcement of the FD&C Act for FDA to require that a 
manufacturer make and retain records demonstrating that the formula 
meets the quality factor of normal physical growth, and that certain 
records related to the requirement to conduct a growth monitoring study 
be included in the submission required in section 412(c)(1)(B) of the 
FD&C Act (21 U.S.C. 350a(c)(1)(B)). Under section 412(d)(1)(C) of the 
FD&C Act (21 U.S.C.

[[Page 8006]]

350(d)(1)(C)), assurances that the requirements for quality factors 
have been met must be provided in a submission. FDA is requiring that 
the assurances related to the quality factor requirements in the 
submission be included in the form of a record that FDA can review 
prior to the marketing of the infant formula to determine whether the 
infant formula is adulterated under section 412(a)(2) of the FD&C Act. 
Without records, FDA would not be able to evaluate whether an infant 
formula meets the quality factor requirements, such as normal physical 
growth.
    For example, when a growth monitoring study is required, FDA needs 
certain data and information to evaluate the growth of the study 
participants (infants) who have been fed the infant formula under 
study. As discussed in this document, Sec.  106.96(d) of the interim 
final rule requires manufacturers to make records demonstrating that 
the formula meets the quality factor of normal physical growth. 
Additionally, Sec.  106.121 of the interim final rule requires a 
manufacturer to submit certain data and information that are required 
to be collected during the growth monitoring study and that are 
necessary to assess whether the infant formula supports normal physical 
growth. These data include all measurements for each feeding group at 
the beginning of the study, and at every point where measurements were 
made throughout the study. Without these data, and other data and 
information, FDA would not be able to assess whether the formula 
supports normal physical growth.
    For the reasons stated previously in this document, it is 
reasonable and appropriate under Chevron for the FDA to establish 
normal physical growth as a quality factor requirement for infant 
formula. Further, it is reasonable to include a requirement to conduct 
a well-controlled growth monitoring study to evaluate whether an infant 
formula complies with the quality factor requirement of normal physical 
growth, and to require records related to such requirement.

B. Quality Factors for Infant Formulas

    Section 106.96 of the 1996 proposed rule identified two infant 
formula quality factors: All infant formulas must be capable of 
supporting infants' normal physical growth and all infant formulas must 
be formulated and manufactured to ensure that the protein is of 
sufficient biological quality to satisfy infants' protein requirements. 
The term ``quality factors'' was defined in proposed Sec.  106.3(o) as 
``. . . those factors necessary to demonstrate that the infant formula, 
as prepared for market, provides nutrients in a form that is 
bioavailable and safe as shown by evidence that demonstrates that the 
formula supports healthy growth when fed as a sole source of 
nutrition.'' In the preamble to the 1996 proposed rule (61 FR at 
36179), FDA explained that ``healthy growth'' is a broad concept, 
encompassing all aspects of physical growth and normal maturational 
development, including maturation of organ systems and achievement of 
normal functional development of motor, neurocognitive, and immune 
systems. All of these growth and maturational developmental processes 
are major determinants of an infant's ability to achieve his/her 
biological potential, and all can be affected by the nutritional status 
of an infant.
    To determine whether a formula supports normal physical growth in 
infants when fed as the sole source of nutrition, proposed Sec.  
106.97(a) would have required a formula manufacturer to conduct an 
``adequate and well-controlled clinical study.'' Proposed Sec.  
106.97(b) would also have required a formula manufacturer to collect 
and maintain data to demonstrate that the biological quality of a 
formula's protein is sufficient to meet the needs of infants.
    As discussed in more detail in this document, in both the 2003 and 
2006 reopenings, several issues related to requirements for quality 
factors were identified for additional comment. In response to comments 
and on its own initiative, FDA is reorganizing and consolidating into 
Sec.  106.96 of the interim final rule most of the content of proposed 
Sec. Sec.  106.96 and 106.97 related to requirements for infant formula 
quality factors.

C. Quality Factor: Normal Physical Growth

    In 1996, FDA proposed (Sec.  106.96(b)) ``normal physical growth'' 
as a quality factor for infant formula and stated that such growth is a 
necessary indicator of the overall nutritional quality of a formula. 
The Agency's proposal was consistent with the view of the Committee on 
Nutrition of the American Academy of Pediatrics (CON/AAP) that the 
determination of physical growth is the most valuable component of the 
clinical evaluation of an infant formula (Ref. 67). FDA noted that 
physical measures of growth (e.g., weight gain) are a widely accepted 
measure of an infant's overall ability to utilize a formula's 
nutrients, are familiar to practitioners and parents, are readily made, 
and are not invasive.
    In the 2003 reopening, the Agency expressly requested comment on 
the two quality factors that it had tentatively identified in the 1996 
proposal: Normal physical growth and protein biological quality. In 
particular, FDA requested comment on the appropriateness of these 
quality factors and any information on other quality factors that could 
be implemented consistent with current scientific knowledge, as 
required under section 412(b)(1) of the FD&C Act.
    This interim final rule establishes as part of Sec.  106.96(a) the 
general quality factor of ``normal physical growth.'' (As discussed in 
section IV. C., the proposed definition of ``quality factors'' has been 
slightly revised in Sec.  106.3.) FDA considered comments received from 
the public, as discussed in this document, when including ``normal 
physical growth'' as one quality factor.
    (Comment 196) Several comments supported FDA's proposal to 
designate ``normal physical growth'' as a quality factor for all non-
exempt infant formulas. One comment stated that overall physical growth 
and protein quality are reasonable benchmarks, assuming that the 
formula contains all nutrients required by law.
    (Response) FDA agrees with the comments that support the 
establishment of ``normal physical growth'' and ``protein quality'' as 
infant formula quality factors. In considering the provision for 
``normal physical growth,'' the Agency notes the IOM's conclusion (Ref. 
4, p. 105): ``Growth is well recognized as a sensitive, but 
nonspecific, indicator of the overall health and nutritional status of 
an infant. Monitoring infant growth has always been an integral part of 
pediatric care and is particularly important for young infants.''
    (Comment 197) Another comment agreed that growth is clearly an 
indicator of bioavailability but nonetheless challenged the Agency's 
proposal to define ``normal physical growth'' as a quality factor, 
asserting that few changes in an infant formula raise bioavailability 
questions and objecting to the routine demonstration of growth relative 
to most changes in an infant formula.
    (Response) FDA disagrees with this comment for two reasons. First, 
the comment does not dispute--indeed, agrees--that growth is a clear 
indicator of formula bioavailability. Thus, the comment does not erode 
or otherwise undermine FDA's rationale for defining ``normal physical 
growth'' as a quality factor for infant formula. Second, although the 
comment asserts that few changes in infant formulas create

[[Page 8007]]

bioavailability issues, the comment provided no data or other 
information to support this assertion. The Agency notes that, among 
others, the IOM has recognized that infant formula matrix changes can 
highly influence nutrient bioavailability (Ref. 4, p. 45). In addition, 
the interim final rule provides an exemption for new infant formulas 
from the requirements for a growth monitoring study in Sec.  106.96(b), 
if the formula manufacturer provides assurances that demonstrate that 
the change made to the existing formula does not affect the 
bioavailability of the formula, including the nutrients in such 
formula.
    Accordingly, the interim final rule establishes ``normal physical 
growth'' as a quality factor for infant formula.
1. Appropriateness of a Growth Monitoring Study (GMS)
    In the 1996 proposal, FDA proposed to require (Sec.  106.97(a)(1)) 
that a manufacturer conduct an adequate and well-controlled clinical 
study, in accordance with good clinical practice, to determine whether 
an infant formula supports normal physical growth when fed as the sole 
source of nutrition. Proposed Sec.  106.97(a)(1)(i) would have required 
that the manufacturer conduct a clinical study of at least four months 
with study participants enrolled at no more than one month in age; that 
the manufacturer collect, maintain, and plot on a growth chart certain 
anthropometric measurements; and that these data be collected at 
specified times. In addition, proposed Sec.  106.97(a)(1)(ii) included 
nine proposed recommendations for the protocol of the clinical study.
    FDA addressed the proposed clinical study requirement in the 2003 
reopening. At that time, the Agency requested comment on three specific 
issues related to the clinical study requirement (requirements for 
determining when a clinical study should be required; appropriate 
reference data; and the appropriate infant enrollment age). In 
addition, the Agency announced its intention to remove the proposed 
provision addressing Institutional Review Board (IRB) review and 
approval (proposed Sec.  106.97(a)(1)(ii)(C)) as a result of Agency 
rulemaking since the 1996 proposal and its plan to remove the remaining 
protocol recommendations from the proposed rule and to develop a 
guidance document containing recommendations for the protocol for an 
infant formula clinical growth study (68 FR at 22342-22343).
    Thereafter, in the 2006 reopening, the Agency requested comment on 
several recommendations of the 2004 IOM report, including the need for 
assessments of normal physical growth in addition to a clinical growth 
study, the need for body composition measurements, and the appropriate 
duration of and enrollment age for a clinical growth study.
    This interim final rule includes a growth monitoring study 
requirement in Sec.  106.96(b). This provision requires that a 
manufacturer of infant formula satisfy the quality factor of ``normal 
physical growth'' by conducting an adequate and well-controlled growth 
monitoring study to demonstrate that the formula supports normal 
physical growth in infants when fed as the sole source of nutrition. 
The interim final rule substitutes the descriptor ``growth monitoring 
study'' for ``clinical study,'' the term used in the proposed rule, 
because the new term more accurately describes the nature and purpose 
of the study. Section106.96(b) of the interim final rule establishes 
requirements for the growth monitoring study, which address study 
duration; subject age at enrollment; data collection and maintenance; 
and comparison of data for study subjects and controls. In addition, 
parts 50 and 56 require IRB review and approval and human subject 
protection.
    As discussed in more detail in this document, Sec.  106.96(c) of 
the interim final rule provides certain exemptions from the growth 
monitoring study requirements under Sec.  106.96(b).
    (Comment 198) One comment recommended that a clinical growth study 
be required for any new infant formula, change in the infant formula, 
or change in the packaging of infant formula. To justify this 
recommendation, the comment explained that infant formula is unique in 
that it can be the sole source of nutrition for an infant for an 
extended period and during a most vulnerable time.
    (Response) FDA recognizes that infant formula often serves as the 
sole source of nutrition for a vulnerable population during a 
critically important developmental period, a consideration that broadly 
underlies the interim final rule. To the extent that the comment 
suggests that a growth monitoring study be required for all formulas, 
including formulas that have undergone a ``major change'' in processing 
or in composition, the Agency concludes that the requirements of the 
interim final rule effectively achieve the outcome recommended by this 
comment. Specifically, Sec.  106.96(b) of the interim final rule 
requires a manufacturer to conduct a growth monitoring study of each 
``infant formula,'' and Sec.  106.96(c) of the interim final rule 
includes provisions for specific exemptions from that requirement where 
a manufacturer can establish that the formula is entitled to the 
exemption.
    (Comment 199) One comment stated that while the future introduction 
of novel ingredients in infant formula (such as components of human 
milk not presently in infant formulas) may present new challenges to 
the regulatory process, safety concerns about an ingredient new to 
infant formula are better handled under the regulatory rubrics 
specifically designed for ingredient evaluation, and that FDA's 
Generally Recognized As Safe (GRAS) notification process provides the 
Agency with a context in which to raise any safety concerns, including 
concerns about matrix issues, processing issues, or nutrient 
interactions.
    (Response) As discussed in detail in this document, FDA agrees in 
part with this comment. Ingredient safety is a basic principle of food 
safety, for both food generally and for infant formula specifically. As 
is the case with all foods, a manufacturer has an on-going 
responsibility to ensure the safety of each ingredient in its products 
and each substance produced for addition to food and to ensure that 
such ingredients and substances are otherwise in compliance with all 
applicable legal and regulatory requirements.
    An ingredient newly intended for use in infant formula is 
appropriately evaluated under section 409 of the FD&C Act as a food 
additive or may be an ingredient that the manufacturer has determined 
to be generally recognized as safe (GRAS) under section 201(s) of the 
FD&C Act. For ingredients believed to be GRAS, FDA strongly encourages 
the formula manufacturer or the ingredient supplier to submit the self-
determination of GRAS to FDA under the Agency's GRAS notification 
program (see 62 FR 18937, April 17, 1997) well before the submission of 
a new infant formula notification under section 412(c) of the FD&C Act.
    Importantly, however, the review of a food additive petition under 
section 409 of the FD&C Act or the evaluation of a GRAS notice for an 
ingredient new to infant formula is separate and distinct from the 
provision that a formula meet the quality factor requirements under 
section 412(b)(1) of the FD&C Act. That is, FDA's evaluation and 
determination of an ingredient's safety in response to a food additive 
petition or FDA's response to a GRAS notice does not address the 
scientific issue to be addressed by the quality factors, which is 
whether the formula matrix and

[[Page 8008]]

individual nutrients in the formula support normal physical growth. In 
section IV.C.7. FDA explained in the discussion of the ``quality 
factors'' definition the criticality of ensuring the bioavailability of 
the formula's nutrients in a particular formula matrix, including the 
nutrients in the formula, and ensuring that an infant formula 
containing the new ingredient is capable of supporting normal physical 
growth.
    Similarly, the ingredient safety review does not eliminate the 
responsibility of an infant formula manufacturer to make the submission 
required by section 412(d)(1) of the FD&C Act for each new infant 
formula that the manufacturer wishes to market. Under section 412 of 
the FD&C Act, any new formula ingredient is evaluated as part of a 
complete formulation, and, as noted, under section 412(d)(1)(C) of the 
FD&C Act, the new infant formula manufacturer must provide assurances 
that the formula satisfies the requirements for quality factors for 
specific nutrients and for the formula as a whole.
    For these reasons, FDA is making no changes in response to this 
comment.
    (Comment 200) One comment suggested that the assurances under all 
paragraphs of proposed Sec.  106.97(a) be deleted from the final rule 
citing general legal, scientific, and policy grounds to these 
provisions.
    (Response) As explained previously in this document, proposed Sec.  
106.97(a) has been removed from the interim final rule, and much of its 
content is retained in Sec.  106.96(b) of the interim final rule. 
Despite this revision, FDA responds to the substance of this comment.
    Infant formulas must be able to serve as the sole source of 
nutrition for a period of unparalleled growth and development of 
infants in a form that will meet all of the known nutritional needs of 
infants and to ensure that healthy growth and nutritional well-being 
will be achieved by an infant consuming the infant formula as the sole 
source of nutrition (61 FR 36154 at 36180). The least invasive and most 
practical means to ensure that the formula, as a whole, delivers 
nutrients in a form that is bioavailable and safe is a growth 
monitoring study in which anthropometric measurements of infants fed a 
new infant formula are assessed, and comparison of these data to a 
concurrent control group, in addition to comparison of both test and 
controls groups to a scientifically appropriate reference, is made. 
Anthropometric measurements are easily made, are familiar to parents 
and health care professionals, can be measured during outpatient study 
visits, and are the same measurements as those done during routine 
office visits.
    As discussed in more detail in this document, the requirement for a 
growth monitoring study in Sec.  106.96(b) of the interim final rule 
applies to all infant formulas that are introduced or delivered for 
introduction into interstate commerce. This means that a manufacturer 
of an infant formula for distribution in the U.S. is required to 
conduct a growth monitoring study under Sec.  106.96(b) of the interim 
final rule, unless the manufacturer qualifies for an exemption under 
Sec.  106.96(c) of the interim final rule from the growth monitoring 
study requirements of Sec.  106.96(b) of the interim final rule, as 
explained in section VIII.C and D, respectively. A manufacturer of a 
``new'' infant formula is required to submit such study to FDA in a 90-
day submission, consistent with Sec.  106.120 of the interim final rule 
and section 412(c)(1)(B) and (d)(1)(C) of the FD&C Act. As is discussed 
in further detail in this document, a manufacturer of an ``eligible 
infant formula'' (as defined in Sec.  106.3 of the interim final rule) 
would not be required to make the submission required by Sec.  106.120 
of the interim final rule and sections 412(c)(1)(B) and (d)(1)(C) of 
the FD&C Act, but would be required under Sec.  106.96(d) of the 
interim final rule to make and retain records demonstrating that the 
formula meets the quality factor of normal physical growth. The need 
for a growth monitoring study of an infant formula for export only is 
addressed in section VIII. D.
    FDA recognizes that not every change in an infant formula or change 
in the packaging of infant formula will require a growth monitoring 
study. In recognition of this fact, Sec.  106.96(c) of the interim 
final rule includes several exemptions from the growth monitoring study 
requirement, which are discussed in section VIII.D, ``Exemptions From 
Quality Factor Requirements for Normal Physical Growth.''
    (Comment 201) One comment on proposed Sec.  106.97 stated that FDA 
is correct to insist that new substances themselves added to formula be 
GRAS.
    (Response) FDA believes that it is important to clarify FDA's 
conclusions regarding the GRAS status of substances in formula. As 
discussed previously in this document, all food manufacturers, 
including infant formula manufacturers, have a duty to ensure that the 
ingredients in their products satisfy the applicable statutory 
standard. Under section 409 of the FD&C Act, a substance added to food 
must be either an approved food additive or exempt from the definition 
of food additive because it is GRAS.
    (Comment 202) One comment argued that safety issues, including the 
potential impact on infant growth, need to be raised and resolved, and 
that in order to prevent unnecessary and invasive clinical studies, 
animal studies should be relied upon as much as possible.
    (Response) FDA disagrees with this comment for two reasons. First, 
the study required by Sec.  106.96(b) of the interim final rule is a 
growth monitoring study and is entirely non-invasive. Indeed, the 
anthropometric measurements required of study participants are the same 
measurements that are typically taken by a health care provider at 
``well baby'' visits. Second, FDA is not aware of an animal model that 
is a suitable substitute for the infants in a growth monitoring study, 
and the comment provided no information about such a model.
    (Comment 203) One comment acknowledged that the methodology to 
conduct an adequate and well-controlled clinical study is 
scientifically ideal to answer the question of whether a new substance 
added to an existing formula has an effect on the bioavailability of a 
nutrient required for infant growth. The comment also noted that not 
every change in an infant formula raises questions about infant growth 
that cannot be answered adequately by other supporting scientific data, 
and provided references to sources of information that might be used 
for this purpose.
    (Response) FDA agrees with the comment's assessment of the value of 
clinical study methodology to evaluate the ability of an infant formula 
to support the normal physical growth of infants. FDA also agrees with 
the comment that not every change in an infant formula would require a 
growth monitoring study. This issue is discussed in detail in section 
VIII.D.
    (Comment 204) Another comment stated that routine growth studies 
are not designed and generally not powered to detect rarely occurring 
adverse events and therefore, are not comprehensive safety studies. The 
comment argues that new ingredients are often substances identified in 
human milk as having a nutritional function and that a case-by-case 
review of available evidence can identify when there is a need for 
safety endpoints in clinical studies.
    (Response) Normal physical growth and protein quality are very 
basic benchmarks for evaluating healthy growth of infants when fed an 
infant formula as the sole source of nutrition. FDA agrees that growth 
studies are not

[[Page 8009]]

designed and do not have sufficient statistical power to detect rarely 
occurring adverse events. Importantly, however, the purpose of the 
growth monitoring study is to assess the ability of an infant formula, 
including the nutrients in the formula, to support normal physical 
growth. To the extent that the ingredients may present safety concerns, 
those issues are primarily addressed as part of the review under 
sections 409 and 201(s) of the FD&C Act.
2. Clinical Study Protocols
    In proposed Sec.  106.97(a)(1)(ii), FDA listed provisions that it 
recommended manufacturers include in a clinical study protocol. In the 
notice to reopen the comment period in 2003 (68 FR 22341 at 22343), FDA 
stated its intent to remove the clinical study protocol provisions in 
proposed Sec.  106.97(a)(1)(ii) and develop a guidance document 
detailing the Agency's recommendations for what should be included in 
the protocol for a clinical study that will be submitted to FDA as 
``assurance'' that the formula satisfies the quality factor of normal 
physical growth. Comments received in response to the 2003 reopening 
agreed with FDA's view that detailed directions for the clinical study 
protocols would be better addressed as guidance from the Agency. No 
comments were received that suggested retaining the proposed clinical 
study protocol provisions in the final rule. Therefore, the Agency has 
deleted the specific study protocol recommendations of proposed Sec.  
106.97(a)(1)(ii).
    However, as discussed in section VIII. C., Sec. Sec.  106.96 and 
106.121 of the interim final rule incorporate some of the proposed 
study protocol recommendations as requirements in the interim final 
rule. To the extent that proposed recommendations have become 
requirements, FDA will address the comments received on those specific 
recommendations. Otherwise, the Agency is not individually addressing 
the comments submitted on those recommendations not incorporated into 
the interim final rule. FDA will consider developing guidance in the 
future on the protocol for a growth monitoring study of infant formula 
and will consider relevant comments during the development of such 
guidance.
    As stated previously in this interim final rule, FDA has not 
included all of the clinical study protocol recommendations that were 
included in the 1996 proposal. The Agency has concluded, however, that 
certain basic elements of study design, data collection, and evaluation 
are necessary to ensure that a growth monitoring study provides the 
quality and type of data needed to evaluate whether an infant formula 
supports normal physical growth when fed as the sole source of 
nutrition. Therefore, those elements have been codified in Sec. Sec.  
106.96(b) and 106.121 of the interim final rule. In the responses to 
the comments that follow, FDA explains the reasons for including these 
elements.
3. Design of a Growth Monitoring Study
    a. Appropriate study design. Several comments addressed the design 
of growth monitoring studies of infant formulas.
    (Comment 205) One comment stated that the requirement in proposed 
Sec.  106.97(a)(1) that the study be ``well-controlled'' was too vague 
to be meaningful and suggested that acceptable controls should be 
specified.
    (Response) For several reasons, FDA disagrees with this comment and 
declines to specify acceptable controls for infant formula growth 
monitoring studies. First, the concept of ``well-controlled'' is 
generally well understood in the scientific community. The primary 
purpose of conducting a well-controlled study is to distinguish the 
effect of the treatment (here, feeding of the infant formula being 
evaluated) from other influences, such as chance occurrences, normal 
growth, or biased observation. A well-controlled study methodically 
examines sameness and differences in outcomes across cohorts and 
permits an organized comparison and the delineation of sameness and 
difference.
    Further, it would be unnecessarily restrictive to identify in a 
regulation the specific type or types of controls that, if used in a 
growth monitoring study, would make the study ``well-controlled.'' The 
appropriateness of a particular control group or of other controls is 
determined in part by the nature of the study and of the group being 
studied. Accordingly, it is not possible for FDA to specify a priori 
the controls relevant and appropriate to a particular growth monitoring 
study. Thus, FDA is not revising this provision in the interim final 
rule to elaborate on the controls needed to make an infant formula 
growth monitoring study ``well-controlled.''
    To the extent that the interim final rule addresses the specific 
requirements of a growth monitoring study, FDA has clarified, by adding 
Sec.  106.96(b)(4) and (b)(5) to the interim final rule, that the 
protocol of a well-controlled growth monitoring study would require 
information on infant formula intake for both the test and control 
groups. A study that lacks formula intake data would be difficult to 
interpret and could lead to erroneous conclusions regarding the 
formulas being fed. Clearly, the relationship between formula intake 
and growth is basic to the evaluation of an infant formula's capacity 
to support normal physical growth. Therefore, any study of infants in 
which normal physical growth is being assessed would include the 
collection of formula intake data as part of the design of the study. 
These data are needed to provide fair and meaningful interpretation of 
the study results and to demonstrate whether the new formula is able to 
support normal physical growth. To clarify the specific controls 
expected in a study designed to evaluate whether an infant formula 
supports normal physical growth when fed as the sole source of 
nutrition, FDA is adding Sec.  106.96(b)(2) to the interim final rule 
to require the growth study to include collection and maintenance of 
data on infant formula intake and Sec.  106.96(b)(5) to require 
comparison of the data on formula intake of the test group(s) and 
control group(s), with each other and with a scientifically appropriate 
reference to determine whether both groups had consumed age appropriate 
volumes.
    (Comment 206) Another comment stated that the design of the study 
should address the specific objectives of the study.
    (Response) FDA agrees with this comment. One characteristic of an 
adequate and well-controlled study is that the protocol for the study 
includes a clear statement of the study objective(s). Likewise, a 
report of study results should also contain a clear statement of the 
objective of the investigation. See, e.g., 21 CFR 314.126(b)(1) and 
514.117(b)(1).
    (Comment 207) One comment stated that a randomized clinical study, 
with or without reference to an outside standard, is the best method to 
assess whether infants receiving different feeding regimens differ in 
terms of a primary outcome parameter. The comment also stated that this 
research methodology is recognized as the most definitive method of 
determining whether an intervention has the postulated effect.
    (Response) FDA agrees that a randomized study design is generally 
regarded as the strongest experimental design to determine whether an 
intervention (i.e., feeding a new formulation of an infant formula) has 
the postulated effect because this study design requires a concurrent 
control group. For this reason, the interim final rule requires that 
the growth monitoring study of an infant formula be an

[[Page 8010]]

adequate and well-controlled study, which would include randomizing 
study participants into the treated and control groups.
    Indeed, the purpose of a growth monitoring study is to evaluate 
whether an infant formula supports normal physical growth by comparing 
the growth of infants consuming the test formula with the growth of 
infants consuming a baseline formula. Although weight is the most 
sensitive indicator of infant growth, no single anthropometric 
measurement provides all the information needed to assess growth. 
Measures of length and head circumference provide additional 
information on whether the formula supports normal physical growth. 
Plotting these measures on growth charts for each infant in the test 
and control groups provides information about how the infants in both 
groups are growing compared to a reference population of infants. 
Plotting weight and length on the weight for length charts is an 
additional safety check that the infant is growing proportionally (not 
too thin or too heavy for the measured length) relative to the norms 
represented by the charts.
    FDA received several comments on the proposal to require concurrent 
control groups.
    (Comment 208) One comment disagreed with the Agency on the value of 
a concurrent control group in studies conducted in accordance with 
proposed Sec.  106.97(a)(1). The comment asserted that historical 
control data based on normal infants are available from Fomon and 
Nelson (Ref. 68) and Guo et al. (Ref. 69) and that these data are 
generally more appropriate than concurrent controls because the data 
are based on a large number of normal infants studied under well-
defined conditions.
    (Response) FDA disagrees in part with this comment. The optimal 
comparator for infants consuming a new formulation of an infant formula 
is a concurrent control group of infants fed a base formula. For this 
reason, Sec.  106.96(b)(4) and (b)(5) of the interim final rule require 
that a growth monitoring study of an infant formula use a concurrent 
control group.
    FDA acknowledged in the 1996 proposal that historical controls have 
been used by some investigators to evaluate infant growth while being 
fed a new formulation of a formula. Importantly, however, the Agency 
noted that historical controls have inherent limitations, and the 
differences and similarities in growth between the study infants and 
the population reference standard cannot be meaningfully compared (61 
FR 36154 at 36183). For example, difficulties in interpretation may 
arise when the sample of infants receiving the test formula differs 
significantly from the population in the historical controls; when the 
variability in measures of growth in test subjects is large; when 
attrition rates differ greatly between the population in the historical 
controls and the infants on test; and when events occurring in the 
study cannot be explained in the absence of concurrent controls.
    FDA recognizes that historical control data may be useful in 
certain limited situations in which a manufacturer has access to 
extensive reference data, such as a database on many similarly 
conducted studies in which infants were selected on the basis of nearly 
identical criteria, and the results are available for all important 
measurements, including formula intake and attrition rates. FDA notes 
that the manufacturer is responsible for demonstrating that a new 
formulation of an infant formula satisfies the quality factor of normal 
physical growth. Thus, when designing a study protocol, the 
manufacturer should carefully consider whether historical control data 
permit a meaningful comparison to the infants consuming the new 
formulation.
    Because the use of historical control data may be appropriate in 
certain narrow circumstances, the interim final rule provides 
manufacturers with an opportunity to justify reliance on such data. 
Specifically, a manufacturer may request an exemption under Sec.  
106.96(c)(2)(i) of the interim final rule to conduct a growth 
monitoring study using an alternative study method or design, provided 
that the manufacturer provides assurances that demonstrate that the 
alternative study design is based on sound scientific principles. In 
such a situation, FDA expects that detailed study results from the 
historical control data would be available to FDA for review.
    (Comment 209) One comment stated that because growth may or may not 
be the crucial outcome measured in future formula studies and 
``optimal'' growth and development have yet to be defined, a concurrent 
control group is the optimal comparator.
    (Response) FDA agrees with this comment. As noted, in the 1996 
proposal, the Agency acknowledged that although historical controls 
have been used in some infant formula investigations, these historical 
data have inherent limitations. Accordingly, Sec.  106.96(b)(4) and 
(b)(5) of the interim final rule require that a growth monitoring study 
of an infant formula use a concurrent control group. Importantly, if a 
manufacturer wishes to utilize historical control data in a growth 
monitoring study, the manufacturer may request an exemption under Sec.  
106.96(c)(2)(i) of the interim final rule.
    (Comment 210) One comment recommended a concurrent breastfeeding 
control group, while another comment opined that the universally agreed 
reference population that defines healthy growth as infants breastfed 
by well-nourished mothers cannot be included in a randomized trial.
    (Response) A growth monitoring study need not include a concurrent 
control group of breast-fed infants because comparing the growth of 
infants consuming the new formulation to that of a concurrent control 
group consuming the control formula and to the appropriate reference 
data is sufficient to assess whether the new formula supports normal 
physical growth. Also, infants cannot be randomly assigned to be 
formula-fed or breastfed so there are scientific limitations on the use 
of a concurrent breast-fed control group. In addition, there may be 
significant non-nutritional confounding factors with using breastfed 
infants as a control group, such as the health and nutrition of the 
mothers who choose to breastfeed. The Agency would not object, however, 
if breastfed infants from the same population as the infants consuming 
the infant formula under evaluation were included as a concurrent 
cohort group. In such circumstances, the growth of breast-fed infants 
could also be compared to the group of infants consuming formula as a 
model or reference for growth.
    (Comment 211) Another comment indicated that it may be necessary to 
have a concurrent control from the same population if infants believed 
to have different growth characteristics (e.g., infants from different 
ethnic groups) are used as the study population.
    (Response) FDA agrees in part with this comment. The Agency 
acknowledges that the optimal comparator for a particular growth 
monitoring study is a concurrent control group composed of infants that 
mirror the study infants as closely as possible, including ethnic or 
racial background. Importantly, however, the Agency is aware that the 
pool of infants for study subjects and controls is limited and thus, 
FDA is concerned that to require precise ethnic or racial comparability 
between study and control group members could inhibit the ability to 
recruit subjects and fulfill the growth monitoring study requirement.

[[Page 8011]]

Accordingly, FDA encourages manufacturers to consider factors such as 
ethnic or racial background in developing test and control groups, but 
the Agency declines to specify that such comparability is a necessary 
characteristic of an adequate and well-controlled investigation.
    (Comment 212) One comment stated that infant formulas should be 
clinically tested in randomized trials and conducted in at least two 
centers.
    (Response) FDA agrees with this comment to the extent that it 
asserts that a new formulation of an infant formula should be evaluated 
in a randomized, well-controlled growth monitoring study to demonstrate 
satisfaction of the quality factor of normal physical growth. Like all 
study designs, studies conducted at multiple centers have advantages 
and disadvantages. For example, the use of multiple centers may be 
advantageous because it may make it easier to recruit sufficient 
numbers of infants as study subjects. However, the failure to follow 
the study protocol carefully at all centers may jeopardize the utility 
of the combined data and thus, is a potential disadvantage to a multi-
center study. Such factors as an appropriate study design (including 
suitable control groups and treatments, blinding of all caregivers and 
study evaluators, and selection of appropriate outcome measures), 
strict adherence to protocol requirements, adequately trained and 
experienced study personnel, and appropriate management and analysis of 
study data are critical determinants of the quality and thus, ultimate 
value of a growth monitoring study. Therefore, FDA declines to require 
that a growth monitoring study be conducted in at least two centers.
    (Comment 213) One comment stated that clinical trials of infant 
formula should have a low attrition rate of subjects in each feeding 
group (preferably below 10 percent) as well as effective blinding of 
the study subjects' caregivers and study evaluators to the feeding 
group, whenever feasible.
    (Response) FDA acknowledges that minimizing attrition in a growth 
monitoring study is highly desirable because a high dropout rate may 
introduce bias or otherwise compromise interpretation of the study 
data. However, the comment did not provide a basis for the Agency to 
require an attrition rate below 10 percent in an infant formula growth 
monitoring study, and the Agency declines to do so. It is often 
difficult to ensure a low attrition rate (e.g., below 10 percent) in 
investigations, especially with infant subjects. Importantly, FDA 
expects that study investigators and the manufacturer/sponsor will 
thoroughly investigate and explain all dropouts. FDA intends to monitor 
closely attrition rates in infant formulas growth monitoring studies 
and will consider that higher than anticipated attrition rates may 
signal cause for concern about the use of a particular formulation. 
Thus, FDA is not making changes to the rule in response to this 
comment.
    (Comment 214) One comment asserted that as the changes in formulas 
become more subtle, such as through the addition of long chain 
polyunsaturated fatty acids (LCPUFAs), outcome measures must include 
other relevant effects such as those on visual acuity and intelligence, 
which may only become measurable months to years after formula 
consumption. For this reason, the comment observed that this will 
require manufacturers to conduct post-marketing surveillance as a part 
of every formula study.
    (Response) This comment is not relevant to the issues in this 
rulemaking. The interim final rule requires a single type of study in 
infants: a growth monitoring study. The purpose of a growth monitoring 
study is very narrow and specific: to evaluate the bioavailability of 
the infant formula, including its nutrients, that are required to be in 
infant formula by section 412 of the FD&C Act to ensure that, during 
the period that such formula serves as the sole source of nutrition for 
infants, such infants experience normal physical growth. Contrary to 
suggestion of the comment, a growth monitoring study is not designed to 
evaluate whether there is a benefit of added ingredients such as 
LCPUFAs like arachidonic acid (ARA) and docosahexanoic acid (DHA). 
Accordingly, FDA is not responding to the comment's recommendation for 
post-marketing surveillance for such purpose.
    b. Age of enrollment for a growth monitoring study.
    In 1996, FDA proposed in Sec.  106.97(a)(1)(i)(A) that 
manufacturers shall ``conduct a clinical study that is no less than 4 
months in duration, enrolling infants no more than 1 month old at time 
of entry into the study'' (61 FR 36154 at 36215). In 2002, the Infant 
Formula Subcommittee of the FDA Food Advisory Committee recommended 
that infants be enrolled into clinical growth studies by 14 days of age 
(http://www.fda.gov/ohrms/dockets/ac/cfsan02.htm0), and in 2004, the 
IOM recommended a duration of 6 months (180 days) for growth studies of 
infants (Ref. 4, p. 10). In the 2003 reopening (68 FR 22343) and in the 
2006 reopening (71 FR 43392 at 43397-43398), the Agency expressly 
requested comment on the appropriate age for enrollment of infants into 
growth monitoring studies.
    FDA received several comments regarding the age of subject 
enrollment for growth monitoring studies.
    (Comment 215) One comment stated that there is a rationale for 
including infants not older than 14 days because this early period is 
the time of greatest nutrient requirement and greatest sensitivity to 
nutrient adequacy. Another comment suggested enrollment by 14 days of 
age in order to ensure a 4 month observation period before other foods 
are introduced into the infant's diet.
    (Response) FDA agrees with the recommendations of these two 
comments and thus, Sec.  106.96(b)(1) of the interim final rule 
requires that subjects in a growth monitoring study be no more than 2 
weeks of age at the time of enrollment. FDA included this age 
requirement in the interim final rule for both data quality and 
practical reasons.
    There are three data quality reasons for establishing 14 days as 
the maximum age of enrollment in a growth monitoring study. First, 
early infancy is the period of greatest nutritional risk and the period 
during which infants experience the most rapid growth. Thus, testing a 
new formulation of a formula during this time period means that the 
infant formula will be evaluated under the most demanding conditions of 
use. Second, the earliest days of an infant's life are the most 
sensitive in that this phase includes the most dramatic (and thus most 
readily measurable) growth. Thus, a study including this period would 
be most likely to detect deficiencies in normal physical growth. 
Finally, by enrolling study participants at age 2 weeks or less, it 
will be possible to conduct a growth monitoring study of an appropriate 
length before an infant begins to consume a mixed diet. Health care 
professionals currently recommend adding other foods (such as cereal, 
strained vegetables, pureed fruits) to an infant's diet between the 
ages of 4 to 6 months. (http://www.fns.usda.gov/tn/Resources/feddinginfants-ch2.pdf). When an infant is consuming such a mixed diet, 
study data are likely to be difficult to interpret because dietary 
intake is less controlled.
    There is also a practical reason for establishing 14 days as the 
maximum enrollment age for growth monitoring study participants. Most 
health care professionals recommend that a newborn have his/her first 
well-child visit at 3 to 5 days of age (Ref. 70) and another during the 
second week after birth. Thus, the period of study enrollment coincides 
with infant age

[[Page 8012]]

range for an early well-child visit which will likely enhance 
recruitment of study participants and thereby, support the quality of 
the growth monitoring studies conducted on new formulations of infant 
formulas.
    (Comment 216) One comment stated that for routine growth studies, 
infants would ideally be enrolled by approximately 14 days of age. 
However, the comment further stated that there is no biological reason 
why any enrollment age short of one month should disqualify an infant 
from such a study and noted that in 1993, the European Commission 
Scientific Committee on Food recommended subjects be entered into a 
study within the first month of life.
    (Response) FDA agrees with this comment to the extent that it 
suggests that subjects be enrolled in growth monitoring studies at no 
more than 14 days of age. Importantly, the comment did not provide data 
to support the assertion that there is no biological reason that 
enrollment up to one month of age should disqualify an infant from a 
growth monitoring study. In fact, as discussed previously in this 
document, early infancy is the period of greatest nutritional risk and 
also most rapid growth; both of these biological factors have the 
potential to enhance the quality of the data generated in a growth 
study.
    (Comment 217) Two comments agreed with FDA's 1996 proposal to 
require study subjects to be enrolled during the first month of life.
    (Response) For the reasons outlined previously in this document, 
FDA has revised the required enrollment age for the growth monitoring 
study to 14 days or less, a decision based on the fact that 14 days is 
the optimal age for enrollment because this age will capture the period 
of subjects' greatest nutritional demand and greatest growth.
    (Comment 218) One comment stated that a study to assess the 
nutritional adequacy of a formula to be fed during the first year of 
life by measuring weight gain (Ref. 67) should be initiated within the 
first month of life. However, if the formula is for a different age 
range, the design of the study should reflect this difference.
    (Response) FDA does not agree with this comment. As explained 
previously in this document, in Sec.  106.96(b)(1) of the interim final 
rule, the Agency is establishing 2 weeks as the maximum age at time of 
enrollment for subjects in a growth monitoring study because this age 
will capture the most sensitive period of infant growth and the period 
of greatest nutritional need.
    In addition, the Agency does not agree that the interim final rule 
should establish a different enrollment age for a study of a formula 
intended for a ``different age range.'' First, even if a product is 
marketed for use in older infants, e.g. those older than 6 months of 
age, the product is an ``infant formula'' within the meaning of section 
201(z) of the FD&C Act and 21 CFR 105.3(e). As such, the formula must 
satisfy the nutrient requirements of section 412(i) of the FD&C Act and 
Sec.  107.100 and the quality factor requirements established in Sec.  
106.96 of the interim final rule under section 412(b)(1) of the FD&C 
Act. As noted, the appropriate age of enrollment for a study of an 
``infant formula'' is 14 days or less. Second, even if a particular 
product is marketed for ``older'' infants, there is a possibility that 
it will be fed to neonates. For this reason, it is essential that the 
formula be nutritionally adequate for these younger infants. Testing 
the formula in very young infants will maximize the certainty that such 
formula will be nutritionally sufficient for all infants, including 
neonates. Third, as noted previously in this document, data from 
studies conducted in older babies may be difficult to interpret because 
such infants are likely to be consuming a mixed diet. Finally, if a 
manufacturer believes that the growth monitoring study of a particular 
formula should have an enrollment age other than that established in 
Sec.  106.96(b)(1) of the interim final rule, the manufacturer may 
request an exemption under Sec.  106.96(c)(2)(i) of the interim final 
rule.
    (Comment 219) One comment asserted that the final requirement 
should be more stringent than the proposed, and suggested that infants 
should be enrolled in clinical studies before the end of the first 
postnatal week. Another comment made a similar suggestion, stating that 
the growth monitoring study should enroll infants at 8 days of age.
    (Response) FDA acknowledges that early infancy is the period of 
greatest nutritional risk and the age at which the most rapid growth 
occurs, both of which make this time period the most demanding 
conditions for use of a formula. Although initiating a growth 
monitoring study by the end of the first postnatal week or at 8 days of 
age would capture a greater portion of this period, FDA is concerned 
that this limit on enrollment age could unduly restrict recruitment and 
participation in the required growth monitoring studies. Establishing 
14 days as the maximum age of enrollment strikes a reasonable balance 
between acquiring high quality data and providing flexibility to foster 
recruitment of study subjects.
    c. Duration of a growth monitoring study. As noted, proposed Sec.  
106.97(a)(1)(i)(A) would have required that a manufacturer ``conduct a 
clinical study that is no less than 4 months in duration'' (61 FR 36154 
at 36215). In its 2004 report, the IOM recommended that a growth study 
should cover at least the period when infant formula serves as the sole 
source of nutrients in the infant diet (Ref. 4, p. 108). Accordingly, 
at that time, the Committee recommended a study of 6 months (180 days) 
because such duration would mirror the recommended length of time an 
infant should consume human milk exclusively. However, because current 
infant feeding recommendations are to begin solid foods between the 
ages of 4 and 6 months, the IOM acknowledged that it would be 
difficult, as a practical matter, to convince parents of study subjects 
to postpone such introduction until age 6 months. In the 2003 reopening 
(68 FR 22343) and in the 2006 reopening (71 FR 43392 at 43397-43398), 
the Agency expressly requested comment on the appropriate duration of a 
growth monitoring study.
    In addition to the IOM recommendation, FDA received several 
comments regarding the appropriate duration of growth monitoring 
studies.
    (Comment 220) One comment noted that the IOM report recommended 
that a growth monitoring study of an infant formula containing a new 
ingredient be at least 6 months (180 days) in duration, and that this 
recommendation was based on the use of formula as a substitute for 
human breast milk and the current advice of the AAP that infants be 
exclusively breastfed for at least 4 and, preferably, 6 months. The 
comment expressed concern that the data from a 6-month study would be 
confounded by the introduction and inclusion of complementary foods in 
the diets of study subjects.
    (Response) FDA agrees with this comment for several reasons. First, 
current recommendations are to begin solid food between the ages of 4 
and 6 months. The comment noted, the IOM report acknowledged, and FDA 
agrees that feeding complementary foods to study subjects could 
confound the study results of a 6-month study. The IOM report also 
acknowledged that it would be difficult, as a practical matter, to 
convince parents of study subjects to postpone such introduction until 
age 6 months. Second, the IOM report noted that it would be unlikely 
that adverse effects would appear only between 4 and 6 months if none 
appeared between birth and 4 months, suggesting that no

[[Page 8013]]

significant information on adverse effects would be lost from a shorter 
study. FDA agrees with these observations and concludes that a study of 
4 months duration would provide the data and information necessary for 
a manufacturer to evaluate the ability of an infant formula to support 
normal physical growth. Importantly, however, FDA would not discourage 
an infant formula manufacturer from conducting a growth monitoring 
study of 6 months' duration if the manufacturer is able to address the 
potentially confounding effect of complementary food consumption during 
the study period.
    (Comment 221) One comment recommended that the growth studies of 
infants be conducted from 8 to 112 days of age (a time interval of 15 
weeks). The comment noted that a study period of 8 to 112 days of age 
would permit young infants to participate, and noted that such infants 
may be the most sensitive subjects for demonstrating inadequacies of 
infant formulas. The comment also observed that the period of 8 to 112 
days of age has been used extensively in clinical studies of growth of 
formula-fed infants and that the data from these studies have been used 
to generate historical control data on gains in weight and length 
during infancy (Refs. 68 and 69).
    (Response) Although enrollment at age 8 days may provide an 
additional week to evaluate growth during the most sensitive growth 
period, FDA finds that some flexibility is needed for the enrollment 
timeframe. Section 106.96(b)(1) of the interim final rule permits 
infants to be enrolled in the growth monitoring study up to age 14 
days. FDA has explained its reasons for selecting 14 days as the 
maximum enrollment age in responding to the comments in the immediately 
previous section of this preamble.
    The Agency agrees with this comment to the extent that it 
recommends a growth monitoring study of at least 15-weeks duration. As 
the comment noted, the 15-week duration has been used extensively for 
infant growth studies (Ref. 68), which provides a sound basis for 
choosing this period for the growth monitoring studies required by this 
interim final rule. Also, 15 weeks is a reasonable study duration 
because this period maximizes the time between enrollment (2 weeks of 
age) and the age at which many infants begin to consume a mixed diet 
(17 weeks or 4 months). As explained previously in this document, the 
consumption of a mixed diet by study subjects may complicate 
interpretation of the study results regarding the nutritional 
sufficiency of the test formula because, with a mixed diet, the formula 
is no longer the sole source of nutrition for the infant. Accordingly, 
FDA has revised the interim final rule to require a growth monitoring 
study to be at least 15 weeks in duration.
    (Comment 222) One comment recommended that, as an alternative, a 
growth study be at least four months in duration, enrolling infants at 
no more than one month of age. The comment noted that a 4-month study 
period permits a slightly longer period of observation (as compared to 
a 15-week study) and would provide greater ease of subject recruitment.
    (Response) FDA disagrees with this comment and notes that this 
alternative suggestion is what the Agency proposed in 1996 in proposed 
Sec.  106.97(a)(1)(i)(A). FDA has concluded that the appropriate 
duration for a growth monitoring study is 15 weeks and that study 
subjects should be no more than 14 days old at the time of enrollment. 
The Agency's reasons for these determinations are explained in its 
response to the foregoing comments.
    (Comment 223) One comment stated that growth studies are usually 
conducted for 14 weeks (98 days), with subjects participating from 
approximately age 14 days until age 112 days (i.e., from 2 to 16 weeks 
of age). The comment also noted that in 1993, the European Commission 
Scientific Committee on Food proposed a study period of at least 3 
months to evaluate the nutritional adequacy of infant formula.
    (Response) FDA disagrees with this comment to the extent that it 
recommends a study of 14 weeks. Although the comment asserted that 
growth studies are ``usually'' of 14 weeks duration, the comment 
provided no data or other rationale to support the validity or 
sufficiency of this length of a growth monitoring study. FDA has 
determined that a 15 week study requirement is reasonable for the 
reasons provided in previous comment responses.
    (Comment 224) One comment asserted that selection of 16 weeks or 3 
months, or 4 months as originally proposed by FDA, are based on 
convenience and current well-baby visit schedules and not based on the 
scientific assessments of sensitivity, validity, or the relationship of 
growth over this period to health.
    (Response) FDA disagrees with this comment. As explained in the 
response to Comment 221 the 15-week study duration maximizes the time 
during which study subjects are likely consuming the formula as the 
sole source of nutrition. Once study subjects begin to consume a mixed 
diet, the resulting data are more difficult to interpret because it is 
not possible to distinguish between the nutritional effects of the 
formula and the nutritional effects of the remainder of a subject's 
diet, thereby hampering the accurate assessment of the nutritional 
sufficiency of the formula.
    (Comment 225) One comment recommended that growth studies of infant 
formulas would ordinarily require testing through 8 to 12 months of age 
in order to evaluate the formula throughout the period that it serves 
as the only or main source of calories. Another comment stated that 
because infant formula is given to babies from birth until 12 months of 
age, 12 months is the appropriate duration of time for a study.
    (Response) FDA disagrees with these comments. In order to perform 
an accurate assessment of the nutritional adequacy of an infant 
formula, there must be no competing or supplemental sources of 
nutrition consumed by the study subjects. That is, if the study 
subjects are consuming other foods, any results showing normal physical 
growth may be attributable to the other foods and not to the infant 
formula. For this reason, proposed Sec.  106.97(a)(1) stated that the 
growth monitoring study must determine whether the formula supports 
normal physical growth ``when the formula is fed as the sole source of 
nutrition.'' As explained previously in this document, health care 
professionals generally suggest that infants begin to consume a mixed 
diet sometime after 4 months of age. Thus, it would be difficult if not 
impossible to conduct a growth study with subjects 8 to 12 months of 
age without including infants on a mixed diet and thereby, compromising 
the study results. Also, physical growth rates slow after early 
infancy, thereby resulting in a less sensitive measure to detect 
differences in the ability of an infant formula to support normal 
physical growth.
    (Comment 226) Another comment stated that studies should extend for 
years rather than months to detect the subtle effects of formula 
feedings.
    (Response) FDA has considered whether extending the duration of 
growth monitoring studies to 12 months or longer has merit and has 
concluded that it does not. The rate of physical growth in infants 
slows after early infancy, thereby resulting in a less sensitive 
measure to detect differences in the capability of a new formulation of 
an infant formula to support normal physical growth. Also, consumption 
of foods other than infant formula (typically started at about 4 to 6 
months

[[Page 8014]]

of age) has the potential to confound the growth monitoring study 
results from beyond the period when infant formula is consumed as the 
sole source of nutrition.
    Based on the foregoing, FDA is redesignating proposed Sec.  
106.97(a)(1)(i)(A) as Sec.  106.96(b)(1) in the interim final rule and 
revising the provision to require a growth monitoring study that ``[i]s 
no less than 15 weeks in duration, enrolling infants no more than 2 
weeks old at the time of entry into the study;''.
    d. Review by institutional review board and protection of human 
subjects. In the 1996 proposal, FDA recommended in proposed Sec.  
106.97(a)(1)(ii)(C) that the study conducted under proposed Sec.  
106.97(b) be reviewed by an IRB in accordance with 21 CFR part 56 and 
that the manufacturer establish procedures to obtain informed consent 
from the parent or legal representative of each study participant. 
Thereafter, in the 2003 reopening (68 FR 22341 at 22343), FDA proposed 
to delete the provisions relating to IRB review and informed consent 
due to an independent FDA rulemaking (66 FR 20589, April 24, 2001), one 
effect of which was to make an infant formula growth monitoring study 
subject to the requirements of parts 50 and 56. Specifically, under 
parts 50 and 56, data and information about a clinical study of an 
infant formula, when submitted as part of an infant formula 
notification under section 412(c) of the FD&C Act, constitute an 
``application for research or marketing permit'' and thus, are subject 
to the informed consent and IRB requirements related to such permits in 
parts 50 and 56. Accordingly, as proposed in the 2003 reopening, FDA is 
not including provisions relating to IRB approval and human subject 
protection in the interim final rule because such provisions are 
unnecessary as the requirements are codified in parts 50 and 56.
4. Collection and Evaluation of Anthropometric Data
    In 1996, FDA proposed to require that a growth monitoring study 
include the collection of anthropometric measures of physical growth, 
including body weight, recumbent length, head circumference, and 
average daily weight increment. Under the 1996 proposal, the 
anthropometric measurements would have been required at the beginning 
of the study, at 2 weeks, at 4 weeks, and at least monthly thereafter. 
Subsequently, in the 2003 reopening, FDA requested comment on whether 
certain Iowa data (which were discussed at the November 2002 meeting of 
FDA FAC's Infant Formula Subcommittee) should serve as the comparison 
for the anthropometric data collected during a growth monitoring study 
(68 FR 22341 at 22342-22343).
    In addition, in the 2006 reopening, in response to a recommendation 
in the IOM report, FDA requested comment on whether the Agency should 
require body composition measurement in a growth monitoring study 
conducted under the interim final rule. At that time, FDA stated its 
tentative conclusion that measures of body weight, recumbent length, 
head circumference, and data to calculate average daily weight 
increment would be adequate to assess the quality factor of normal 
physical growth (71 FR 43392 at 43397).
    In 1996, FDA also proposed that the anthropometric data be plotted 
against 1977 reference curves (``growth charts'') from the National 
Center for Health Statistics (NCHS). The 1977 NCHS growth charts were 
substantially revised in 2000 and were referred to as the 2000 CDC 
growth charts (Ref. 72).
    In 2006, WHO released a new international growth standard for 
children ages birth to 59 months that reflects normal physical growth 
for all infants and children. For infants and children less than 24 
months of age, the WHO standard includes charts based on measurements 
of weight for age, length for age, weight for length, and head 
circumference (Ref. 11). Thus, after 2006, two sets of growth charts, 
the 2000 CDC growth charts and the 2006 WHO growth standards, were 
available for assessing early childhood growth. On September 10, 2010, 
CDC formally announced its recommendation that the WHO growth standards 
be used to plot the growth of infants and children from birth to 24 
months of age (published in November 2009).
    The WHO growth standards are based on a high quality comprehensive, 
longitudinal, world-wide study conducted in healthy women and their 
breast-fed infants and included subjects from six countries, including 
the United States, drawn from different ethnic and racial populations. 
Anthropometric measurements of the infants were obtained at birth and 
five additional times between birth and 8 weeks of age. CDC considered 
the WHO study design and results, and conducted expert consultations 
with National Institutes of Health and the AAP, and determined that the 
longitudinal measurements of the WHO study provide the best available 
information on which to base growth curves, rather than the 
mathematical modeling used to develop the 2000 CDC growth charts. CDC 
described these WHO growth standards as providing the standard for how 
infants and children (birth to 24 months) should grow regardless of the 
type of feeding.
    The interim final rule incorporates the new CDC recommendation. 
Specifically, Sec.  106.96(b)(4) of the interim final rule requires 
that the anthropometric measurements obtained in a growth monitoring 
study be plotted on the 2009 growth charts recommended by the CDC based 
on the WHO Child Growth Standards (2009 CDC growth charts), as 
incorporated by reference in Sec.  106.160 of the interim final rule. 
This is a reasonable outcome for the interim final rule for two 
reasons. First, it is appropriate for FDA to defer to CDC's 
recommendation on this issue as CDC is the relevant authoritative 
public health Agency. Second, the basis for the CDC's recommendation is 
sound scientifically and is one with which FDA agrees. In particular, 
the WHO Child Growth Standards, on which the 2009 CDC growth charts are 
based, are derived from a longitudinal study of a number of diverse 
populations with relatively frequent growth measurements. As such, the 
2009 CDC growth charts describe growth of healthy children under 
optimal conditions whereas the 2000 CDC charts describe how certain 
children grew in a particular place and at a particular time (Ref. 11).
    a. Measuring body composition.
    (Comment 227) One comment recognized that there may be occasions in 
which an assessment of body composition might be appropriate but did 
not further elaborate what those occasions might be.
    (Response) FDA notes that this comment did not explain when or why 
body composition measurements are needed to assess normal physical 
growth. Thus, FDA is not revising the rule in response to this comment.
    (Comment 228) One comment disputed the IOM's recommendation to 
measure body composition as part of the assessment of normal physical 
growth. The comment asserted that body composition is not easily 
measured in newborns and young infants and there are few references or 
standards. The comment also claimed that there is potential for a great 
deal of error with such measurements and that some methods of 
measurement would require infants to be exposed to radiation, which 
would be unacceptable. Two other comments stated that sufficient 
reference data for infant body composition do not exist.
    (Response) FDA agrees with these comments. The Agency has 
considered

[[Page 8015]]

whether body composition measurements should be required as a means to 
assess physical growth and has concluded that such measurements should 
not be required because these measurements are not easily made in 
newborns and young infants. In addition, as the comment noted, 
references and standards are lacking, which means that even if the 
measurements could be readily made, it would be difficult to assess 
their significance. Also, as suggested in the comment, some risk is 
associated with any radiation exposure (Ref. 71). Without an 
established need for body composition data and a sound means to assess 
their significance, FDA concludes, that, at this time, any risk from 
the use of radiation in healthy newborns and young infants would not be 
justified.
    (Comment 229) One comment asserted that facilities and equipment 
for body composition measurement are not standardized and are not 
readily available, which would make it more difficult to conduct growth 
monitoring studies, and including such a requirement would add to the 
cost of such studies.
    (Response) The comment did not include any data to support its 
assertions about facilities and equipment availability to measure 
infant body composition and FDA is not independently aware of such 
availability information. The Agency has concluded, in view of the 
challenge of making these measurements, the problems with measurement 
accuracy, and the lack of suitable reference standards, not to require 
body composition to be measured in growth monitoring studies conducted 
under this interim final rule. Therefore, the interim final rule will 
not require the growth monitoring study to include body composition 
measurements.
    b. Collection and maintenance of appropriate anthropometric data.
    Several comments addressed the specific anthropometric measurements 
identified in proposed Sec.  106.97(a)(1)(i)(B) to assess physical 
growth, including a number of comments supporting the Agency's proposed 
use of body weight, recumbent length, and head circumference for such 
purpose.
    (Comment 230) One comment requested that recumbent length 
measurements be excluded from the study requirements because such 
measurements in young infants may involve considerable error. The 
comment recommended that recumbent length continue to be measured as 
part of the standard growth protocol, allowing for calculation of BMI 
and some body composition measures as needed, but that these data not 
be routinely reported to the Agency.
    (Response) FDA disagrees with this comment. As noted in the 1996 
proposal (61 FR 36154 at 36183), ``[g]ains in weight and length of 
young infants reflect the long-term, integrative physiological 
processes that can only be achieved if the infant's nutritional needs 
are met.'' Accordingly, recumbent length, along with head 
circumference, provides a valuable context for interpreting weight 
change data. Changes in length and head circumference data provide 
especially valuable information for interpretation of the weight change 
data in those situations in which weight change with a test formula is 
significantly different than the weight change attained with the 
control formula. Also, careful training of the persons who make the 
recumbent length measurements will help to minimize errors. Therefore, 
FDA is not removing the requirement to make recumbent length 
measurements in response to this comment.
    (Comment 231) Several comments recommended the exclusion of head 
circumference measurements, claiming that head circumference is not 
responsive to small changes in nutritional status citing the conclusion 
of the 1988 CON/AAP consultation (Ref. 67).
    (Response) FDA disagrees with this comment. As noted, recumbent 
length and head circumference provide a valuable context for 
interpreting weight change data. The conclusion of the CON/AAP 
consultation (Ref. 67), cited as support by the comment, applies to a 
situation in which no significant difference is observed in weight 
change. Head circumference measurement may not be as responsive as body 
weight as an indicator of nutritional status. However, because such 
measurements can be routinely made, are not invasive, require no 
specialized equipment, and are not expensive, the value of head 
circumference measurements outweighs any risk or cost of collecting 
these data.
    (Comment 232) One comment asserted that the most sensitive method 
of evaluating infant growth is a comparison of increments in recumbent 
length and body weight over time (e.g., millimeters/day or grams/day) 
rather than comparison of absolute size (e.g., length (centimeters) or 
absolute weight (grams)) at a given age. The comment identified what it 
characterized as suitable reference data (Refs. 68 and 69) for 
evaluation of incremental changes in weight and length.
    (Response) FDA agrees that body weight and rates of change in body 
weight are useful measures of changes in body mass in the newborn and 
the young infant, and that recumbent length and head circumference 
measurements provide information for interpreting these weight change 
data. In the 1996 proposal, the Agency proposed to require in Sec.  
106.97(a)(1)(i)(B) that data on ``average daily weight increment'' be 
collected and maintained as part of the growth monitoring study. At 
that time, however, the Agency did not propose to require the 
collection and maintenance of incremental recumbent length data. FDA 
agrees with this comment that incremental gains for both body weight 
and recumbent length provide sensitive comparisons of anthropometric 
growth measurements in young infants. For this reason, the Agency 
expects that these calculated values will be part of a manufacturer's 
analysis of its growth monitoring study on a new formulation of an 
infant formula. Accordingly, Sec.  106.96(b)(2) of the interim final 
rule requires that a growth monitoring study include the collection and 
maintenance of data on anthropometric measures of physical growth, 
including body weight, recumbent length, head circumference, average 
daily weight increment, and average daily recumbent length increment.
    c. Schedule for and frequency of anthropometric measurements.
    Section 106.97(a)(1)(i)(C) of the 1996 proposed rule would have 
required that the anthropometric measurements in the growth monitoring 
study be collected at the beginning of the study, at 2 weeks, at 4 
weeks, at least monthly thereafter, and at the study's conclusion. The 
Agency received a number of comments on this proposed requirement.
    (Comment 233) One comment requested that proposed Sec.  
106.97(a)(1)(i)(C) be deleted and recommended that the frequency of 
body weight measurements be addressed in guidance and not in the 
regulation.
    (Response) FDA disagrees with this comment. It is important to 
specify the frequency and the schedule for anthropometric measurements 
in the growth monitoring study. This will ensure that the study data 
will be of sufficient quality to evaluate whether the new formulation 
of the infant formula supports normal physical growth. As noted 
earlier, Agency guidance is not binding and thus, even if the frequency 
of the measurements was specified in guidance, a manufacturer would be 
free to establish a schedule and frequency of anthropometric 
measurements that

[[Page 8016]]

deviated from the Agency's best thinking. As a result, the study data 
may not provide an adequate basis for evaluating the formula's ability 
to support normal physical growth.
    (Comment 234) One comment stated that the proposed frequency of 
measurement is unnecessarily burdensome to parents facilitating their 
infants' participation in the growth studies because several of these 
times do not coincide with a regularly scheduled well-baby visit. The 
comment further asserted that clinical studies of new formulas are 
often delayed because it is difficult to recruit sufficient numbers of 
participants. The comment included a study design schematic that 
illustrated the recommended frequency for anthropometric data 
collection as follows:

                                             Study Design Schematic
----------------------------------------------------------------------------------------------------------------
                                            Scheme of data collection
-----------------------------------------------------------------------------------------------------------------
                               Enrollment    14 days of    28 days of    56 days of    84 days of    112 days of
                                visit \1\      age \2\       age \2\       age \2\       age \2\       age \2\
----------------------------------------------------------------------------------------------------------------
Enrollment/Randomization....            X   ............  ............  ............  ............  ............
Demographic Data............            X   ............  ............  ............  ............  ............
Weight, Length..............            X             X             X             X             X             X
Interval History............  ............            X             X             X             X             X
Adverse Events..............            X             X             X             X             X             X
----------------------------------------------------------------------------------------------------------------
\1\ Date of Birth is Day Zero of life (enrollment 0-14 days of age); enrollment may be on day 14 of age visit.
\2\ Visit window  3 days.

    (Response) In the 1996 proposal, FDA addressed the timing and 
interval between measurements (61 FR 36154 at 36184). FDA proposed that 
more frequent anthropometric measurements, especially early in the 
study, would enhance the study's ability to document physical growth 
changes by measuring growth during the most rapid, and thus, the most 
sensitive, phase of an infant's growth; this would increase the ability 
to place individual infants accurately in the correct percentile to 
track their growth patterns over time. In proposing the measurement 
schedule in Sec.  106.97(a)(1)(i)(C), the Agency intended to have 
sufficient serial measurements for comparison between study groups and 
to derive reliable estimates of centile pattern growth and estimates of 
growth rates based on measurements over the entire study period. This 
proposed measurement schedule would accurately capture the curvilinear 
nature of infant growth and would provide sufficient data to interpret 
differences in growth and in growth rates, if differences exist.
    Accordingly, FDA disagrees with the comment recommending fewer 
measurements in the early portion of a growth monitoring study. The 
approach recommended by this comment proposes only five measurements 
for the period between 14 and 112 days of age, with only two 
measurements proposed for the first 4 weeks of the study. Importantly, 
no data were submitted with this comment to support the adequacy of 
fewer measurements for evaluating the curvilinear nature of growth in 
young infants. As noted previously in this document, the most rapid 
phase of infant growth, and thus, the most sensitive period for 
detecting perturbations in growth, is the earliest weeks of an infant's 
life. Thus, it is critical that the anthropometric measurements be 
concentrated in this time period. As noted in this document, the 
interim final rule requires in Sec.  106.96(b)(3) that anthropometric 
measurements be collected at the beginning of the study (maximum age of 
2 weeks), 2 weeks into the study (maximum age of 4 weeks), and 4 weeks 
into the study (maximum age of 6 weeks), which will result in 
relatively more data from the earlier stages of an infant's life.
    (Comment 235) One comment recommended that clinical studies of 
infants be conducted from 8 to 112 days of age with collection of 
anthropometric measurements at ages 8, 14, 28, and 42 days (2 days) and at ages 56, 84, and 112 days (4 days). 
This alternative schedule was recommended because, the comment 
asserted, it would match the measurement schedule of many reference 
(historical) data.
    (Response) The alternative suggested in this comment would result 
in seven measurements over a roughly 15-week study period, with more 
frequent measurements during the early phase of the study, starting at 
8 days of age. However, as discussed previously in this document, the 
Agency is establishing 14 days as the maximum age of enrollment to 
provide flexibility to foster recruitment of infants. Therefore, FDA is 
not persuaded by the information provided in the comment that the 
interim final rule should require enrollment by 8 days of age.
    FDA's concerns with the use of historical data as controls are 
addressed previously in this document in the response to Comment 208. 
FDA agrees that some degree of flexibility in the timing of the serial 
measurements throughout the study is a reasonable design feature for 
the growth monitoring study. Thus, the interim final rule requires 
that, over the minimum 15 week study period needed to assess whether an 
infant formula supports normal physical growth, anthropometric 
measurements shall be made at the beginning and end of the study, with 
three of the six total measurements made within the first 4 weeks of 
the study and three measurements made at approximately 4-week intervals 
over the remaining 11 weeks of the study. Therefore, proposed Sec.  
106.97(a)(1)(i)(C) is renumbered as Sec.  106.96(b)(3) in the interim 
final rule and is revised to require the growth monitoring study of 
normal physical growth include ``anthropometric measurements made at 
the beginning and end of the study, and at least four additional 
measurements made at intermediate time points, with three of the six 
total measurements made during the first 4 weeks of the study and three 
measurements made at approximately four-week intervals over the 
remaining 11 weeks of the study.''
    To ensure the detection of biologically significant differences 
between test and control groups, if they exist, it is important that 
investigators make a diligent effort to take anthropometric 
measurements on infants consuming the test formula at the same ages as 
the measurements for the concurrent or historical control groups. FDA 
recognizes that investigators may not always be able to collect 
clinical data on all infants on the same day of age. FDA plans to 
address this need for flexibility while maintaining the scientific 
integrity of the study in future guidance.
    d. Comparison of anthropometric data.

[[Page 8017]]

    As noted previously in this document, in 1996, FDA proposed to 
require that anthropometric data collected during a growth monitoring 
study be plotted on the 1977 NCHS reference percentile body weight and 
length curves and proposed to incorporate by reference the 1977 NCHS 
growth charts. The Agency subsequently requested comment on whether 
certain Iowa data should serve as the comparison for anthropometric 
data collected during a growth monitoring study.
    FDA received a number of comments on the collection and comparison 
of anthropometric data in a growth monitoring study. The Agency 
responds to those comments in this document.
    (Comment 236) One comment stated that, in general, the use of 
growth curves and historical databases are considered references, not 
standards.
    (Response) FDA agrees in part with this comment, which reflects the 
information available at the time of the two comment period reopenings. 
Until the WHO growth standards, upon which the 2009 CDC growth charts 
are based, became available, growth charts (including the 2000 CDC 
charts) were references that reflect how children in the United States 
have grown, and were not a standard of how children should grow.
    The Agency believes, however, that this comment misunderstood FDA's 
use of the term ``standard'' in the 2003 reopening. In the 2003 
reopening notice, the Agency requested comment on whether the Iowa 
reference data ``should be the standard for clinical growth data rather 
than the NCHS growth charts (68 FR 22341 at 22342-22343).'' In this 
instance, FDA intended the term ``standard'' to refer to a set approach 
of data evaluation and not to describe the growth charts.
    (Comment 237) One comment suggested that new formulations of infant 
formula be tested by comparison to a control group of the same 
population receiving an appropriate control formula, rather than by 
comparison with standard curves, in accordance with proposed Sec.  
106.97(a)(1)(i)(B), because the curves are not considered accurate for 
all ethnic groups.
    (Response) FDA believes that this comment did not fully understand 
the requirements of the proposed rule because the proposed rule would 
have required, and this interim final rule requires, that the growth 
monitoring study be an adequate and well-controlled study, which 
includes concurrent controls. (The issue of concurrent versus 
historical controls is addressed previously in this document in section 
VIII.C.3.a. As noted in that discussion, a manufacturer that wishes to 
use historical controls in a growth monitoring study may request an 
exemption under Sec.  106.96(c)(2)(i) of the interim final rule to do 
so.) FDA notes that the use of historic controls may be problematic 
because the current study population would need to be matched to the 
historic controls, which may not be possible. Thus, the anthropometric 
data collected in a growth monitoring study will be required to be 
compared to a concurrent control group as well as to the standard 
reference data in the 2009 CDC growth charts.
    FDA also notes that although the comment asserts that an 
appropriate concurrent control group needs to be composed of the ``same 
population'' as the infants consuming the test formula, the comment 
neither elaborates on the ``same population'' concept nor provides data 
or other information to support its assertion. Indeed, a clinical 
investigation is ``well-controlled'' only if the control group is 
appropriate to the purpose of the study. Thus, FDA expects that the 
report of a growth monitoring study will address the appropriateness of 
the selected control group. In addition, the interim final rule's 
requirement to use the 2009 CDC growth charts will address the concern 
expressed by this comment because, as discussed previously in this 
document, the WHO growth charts are based on data from six countries 
from different parts of the globe.
    (Comment 238) One comment asserted that plotting anthropometric 
data from a growth monitoring study on CDC ``growth'' charts 
contributes little to the evaluation of the results.
    (Response) FDA disagrees with this comment. Given the timing of the 
submission of this comment, the commenter is likely referencing the 
2000 CDC growth charts. In 1996, FDA proposed that the anthropometric 
data collected during a growth monitoring study be compared to standard 
measurements of infant physical growth as a means of assessing whether 
the pattern of changes in weight and length of each individual infant 
study participant (both on test and control formulas) was similar to 
that observed for healthy infants of the same age, allowing for the 
range of normal individual variation in body weight and length that the 
2000 CDC growth chart percentiles would have provided. Importantly, FDA 
does not intend that comparison with any growth chart be the sole 
analysis of the anthropometric data collected during a growth 
monitoring study. This comparison of the study data with growth charts 
will complement the comparison of data from the two study groups and 
will provide a context for interpreting the primary comparison of 
growth data between test and control groups.
    In addition, by evaluating whether, over time, each infant study 
subject follows the generally expected growth rate for infants, 
deviations in individual growth rate may be identified, thereby 
alerting study investigators and FDA to a possible problem with formula 
sufficiency. The Agency expects that such deviations would be promptly 
scrutinized by study investigators to determine whether the deviations 
are likely to be formula-related. Thus, individual subjects' growth 
during the study may provide an early indication to investigators that 
the new formulation of an infant formula is not nutritionally 
sufficient. Also, monitoring individual infant rate of growth and 
comparing such growth rate to the 2009 CDC growth charts, which 
establish a standard for how infants should grow, may alert the study 
investigator to an individual infant who may be in distress or 
otherwise has potential issues and thereby, ensures the safety and 
well-being of the study subjects. Accordingly, for two separate 
reasons, it is important to compare each individual infant's growth to 
the 2009 CDC growth charts to monitor individual infant growth 
patterns.
    (Comment 239) One comment challenged the use of individual growth 
charts, asserting that such charts are not appropriate to establish 
whether one group of infants differs from another group of infants in 
terms of growth rates. The comment further asserted that the use of 
curves to evaluate growth of infants could lead to inappropriate 
conclusions concerning normal growth, and cited a 2002 paper by 
Grummer-Strawn in support (Ref. 72).
    (Response) FDA regards growth monitoring as the single most useful 
tool in describing health and nutritional status at both the individual 
and group level. Plotting the mean group data on a growth chart permits 
a comparison of how groups of infants grow. In contrast, as described 
previously in this document, plotting the growth of individual infants 
on growth charts provides an early indication of a possible problem 
with formula composition because it allows the investigator to observe 
disturbances in the growth of individual subjects.
    FDA agrees that growth charts based on reference data have 
limitations, many of which have been addressed in the development of 
the 2009 CDC growth charts. As discussed previously in this document, 
the purpose of

[[Page 8018]]

plotting the anthropometric data of study subjects is to monitor 
individual subjects' growth during the study. Under Sec.  106.96(b)(4) 
of the interim final rule, the growth monitoring study must include a 
concurrent control group, and the anthropometric data on the test and 
control groups will be separately compared independent of the growth 
chart activity to determine whether the new formula supports normal 
physical growth. Comparing the anthropometric data to a growth chart is 
intended to complement the use of concurrent controls and evaluation of 
the data from such controls.
    The 2002 paper by Grummer-Strawn does not contradict the interim 
final rule's use of the 2009 CDC growth charts as a complement to the 
use of a concurrent control group (Ref. 72). The Grummer-Strawn paper 
explained why the use of the 2009 CDC growth charts is preferred to the 
use of the 2000 CDC growth charts. Unlike the 2000 CDC growth charts, 
the 2009 CDC growth charts are based on data from a longitudinal study 
of healthy infants growing optimally.
    (Comment 240) One comment asserted that the use of curves to 
evaluate growth of infants could lead to inappropriate conclusions 
concerning normal growth.
    (Response) FDA disagrees with this comment and notes that the 
comment did not explain how the complementary use of growth charts 
could result in inappropriate conclusions about growth. As noted, there 
is a two-fold purpose for plotting study subjects' individual growth 
data on a growth chart. FDA is requiring the plotting of these data as 
a check on the nutrition provided to both the test and control subjects 
and also to monitor the growth of individual study participants as part 
of the controls for human subject protection. The growth monitoring 
study must include a concurrent control group for which anthropometric 
data will be collected, analyzed, and used as a comparison to similar 
data collected from the infants on test formula.
    (Comment 241) One comment stated that because the NCHS growth 
charts had been recently revised and published by the CDC in 2000, and 
because new science is constantly accumulating, which may impact the 
understanding of what constitutes ``expected'' physical growth, it 
would be shortsighted to tie the assessment only to the currently 
existing reference standards.
    (Response) As discussed previously in this document, the CDC now 
recommends the use of the 2009 CDC growth charts that are based on the 
WHO Child Growth Standards for infants and children from birth to 24 
months. To the extent that the CDC growth charts are revised in the 
future, and new growth charts are developed, FDA would consider the 
need to revise the growth charts required by this interim final rule at 
that time.
    (Comment 242) One comment stated that the Iowa reference data, 
while excellent, may be less accessible than the NCHS growth charts, 
and the growth charts do incorporate some mechanism for quantitative 
assessment of growth patterns.
    (Response) Data quality and not data accessibility is the relevant 
issue here. Although the Iowa reference data have some value (Refs. 68 
and 73), the value of these reference data has been superseded by the 
2009 CDC growth charts (Ref. 11). The Iowa data lack the ethnic and 
racial diversity that underlie the 2009 CDC growth charts. Also, the 
2009 CDC growth charts establish a standard for the quantitative 
assessment of infant growth patterns. Given these strengths of the data 
provided in the WHO Child Growth Standards, Sec.  106.96(b)(4) of the 
interim final rule requires that the anthropometric data be plotted on 
the 2009 CDC growth charts that are based on the WHO Child Growth 
Standards. A manufacturer who wishes to compare such data to other 
reference data, such as the Iowa reference data, must request and meet 
the requirements for an exemption under Sec.  106.96(c)(2)(i) of the 
interim final rule.
    (Comment 243) One comment stated that national data that reflect 
the diversity of the U.S. population should be used instead of the Iowa 
data, because Iowa has historically not represented diverse 
populations.
    (Response) As discussed previously in this document, the 2009 CDC 
growth charts reflect appropriate racial and ethnic diversity and thus, 
are appropriate for plotting the growth of infants in the U.S. 
population.
    (Comment 244) One comment recommended that for growth monitoring 
studies conducted outside the United States, the comparisons of 
anthropometric data should be plotted on growth charts that are 
routinely used in the country in which the study is performed.
    (Response) Although the 1996 proposed rule did not specifically 
address the conduct of growth monitoring studies outside the United 
States, the Agency does not disagree that such studies may potentially 
be used as assurances for the quality factor of normal physical growth. 
Importantly, however, any such study would have to meet the 
requirements of the interim final rule, including the human subject 
protections for pediatric studies in 21 CFR part 50, subpart D, and 21 
CFR part 56 to ensure that the infant study subjects are not 
inappropriately exposed to risk. When assessing the adequacy of a 
growth monitoring study conducted in a foreign country, FDA would 
consider whether the study satisfies good clinical practice, whether 
the investigators have recognized competence to conduct the study, 
whether the scientific evidence is valid, and whether the results are 
applicable to the U.S. infant population (Ref. 74). FDA would also 
consider whether the formula studied is the formula to be marketed in 
the United States. If the studied formula is not the formula to be 
marketed in the United States, the manufacturer would be required to 
request and meet the requirements for an exemption under Sec.  
106.96(c)(2)(i) of the interim final rule, and would be expected to 
explain why the formulation studied would be considered an appropriate 
proxy for the formula to be marketed in the United States.
    In terms of the comment's specific concern, FDA notes that, as of 
March 2012, more than 140 countries had adopted the WHO Child Growth 
Standards. Thus, it is very likely that the WHO Child Growth Standards 
would be used in the foreign country in which a growth monitoring study 
is to be conducted, and such data would be consistent with the 2009 CDC 
growth charts.
    (Comment 245) One comment urged that that studies conducted to 
evaluate infant growth test a sufficient number of infants to provide 
precise estimates of mean growth in weight, length, and head 
circumference (with confidence intervals around the mean that exclude 
rates of growth that are outside the bounds of accepted standards.)
    (Response) FDA notes that the comment did not identify ``accepted 
standards'' or describe what would be considered ``outside the bounds'' 
of such standards.
    Nonetheless, FDA agrees that a growth study must include a sample 
size sufficient to permit detection of differences in growth, between 
the control and test formula groups, if such differences exist. 
Confidence intervals are used in statistics to describe a range of 
values in an attempt to quantify the uncertainty of a particular 
statistical estimate. A narrow confidence interval suggests a highly 
precise estimate, and a wide confidence interval implies poor 
precision. The desired confidence interval can be used to estimate 
needed sample size as can a ``power'' calculation, and a wide 
confidence

[[Page 8019]]

interval is often an indication of inadequate sample size. Absent an 
adequate sample size, a study cannot sufficiently test the question 
under study. Although FDA is not codifying statistical requirements for 
a growth monitoring study, the Agency notes that such study must be 
appropriately designed and conducted so as to produce data that can be 
meaningfully interpreted on the question of whether the formula 
supports normal physical growth.
    (Comment 246) One comment noted that because sick infants may grow 
at a slower rate and on lower percentiles due to their underlying 
medical condition rather than any deficiency in the formula being 
consumed, population reference standards are less useful for evaluating 
growth of sick infants than that of healthy infants.
    (Response) FDA is uncertain as to what the comment meant by ``sick 
infants.'' Although the Agency would agree that, generally speaking, 
due to an underlying medical condition, a sick infant will grow at a 
slower rate and on lower percentiles, FDA would not expect a 
manufacturer to plan purposefully to conduct a growth monitoring study 
in a population of ``sick infants.''
    It is possible that the comment had in mind a growth monitoring 
study of a so-called ``exempt infant formula.'' Section 412(h)(1) of 
the FD&C Act exempts certain infant formulas (those for infants with 
inborn errors of metabolism, low birth weight, or other unusual medical 
or dietary problems) from several statutory requirements, including the 
requirement that a manufacturer provide assurances that a formula meets 
the quality factor requirements established by the Secretary. Infants 
for whom ``exempt infant formulas'' are developed could be considered 
``sick.'' Importantly, however, as noted earlier in this preamble, this 
interim final rule applies only to nonexempt infant formulas. Thus, the 
manufacturer of an exempt infant formula is not required to comply with 
the requirement to conduct a growth monitoring study. FDA's current 
thinking on the application of the interim final rule to exempt infant 
formula may be found in a draft FDA guidance document, a notice of 
availability for which is published elsewhere in this issue of the 
Federal Register. Accordingly, the comment about growth rates of ``sick 
infants'' has no bearing on the interim final rule.

D. Exemptions From Quality Factor Requirements for Normal Physical 
Growth

    In the 1996 proposed rule, FDA set forth in proposed Sec.  
106.97(a)(2) exemptions from the growth monitoring study requirements 
of proposed Sec.  106.97(a)(1). Specifically, proposed Sec.  
106.97(a)(2) provided exemptions from the need for a study to evaluate 
physical growth in the following three situations:
     The manufacturer has similar experience using an 
ingredient, an ingredient mixture, or a processing method in the 
production of an infant formula marketed in the United States and can 
demonstrate that infant formula made with that ingredient, ingredient 
mixture, or processing method meets quality factor requirements in 
Sec.  106.96;
     The manufacturer markets a formulation in more than one 
form (e.g., liquid and powdered forms) and can demonstrate that the 
quality factor requirements are met by the form of the formula that is 
processed using the method that has the greatest potential for 
adversely affecting nutrient content and bioavailability; and
     The manufacturer can demonstrate that the requirements (of 
Sec.  106.97(a)(1)) are not appropriate for the evaluation of a 
specific infant formula, and that an alternative method or study design 
for showing that the formula supports healthy growth in infants fed it 
as their sole source of nutrition is available.
    Several comments expressed confusion about the proposed exemptions. 
In response to these comments, FDA has significantly revised the 
proposed exemptions, which are set out in Sec.  106.96(c) of the 
interim final rule. FDA's responses to the comments and the Agency's 
explanation for the revisions of the proposed exemptions are set out in 
this document.
    (Comment 247) One comment recommended that a manufacturer be 
responsible for demonstrating that a growth study is not needed rather 
than exempting the manufacturer from conducting studies in a finite 
number of circumstances.
    (Response) FDA agrees that, in general, a manufacturer should be 
responsible for demonstrating, in appropriate circumstances, that a 
growth study is not needed and that some ``major changes'' may not 
require a growth monitoring study to demonstrate that the formula 
supports normal physical growth. Thus, in the interim final rule, Sec.  
106.96(c)(1) contains a narrowly defined circumstance in which FDA will 
grant a manufacturer an exemption from the growth monitoring study 
requirement upon the manufacturer's request. The interim final rule's 
three additional exemptions from the requirement to meet the specific 
growth monitoring study requirements under Sec.  106.96(b) clearly 
place the responsibility on the manufacturer to demonstrate to the 
Agency's satisfaction that the conditions of the exemption have been 
satisfied.
    (Comment 248) Another comment stated that not every change in an 
infant formula raises questions as to infant growth that cannot be 
answered adequately by other scientific supportive data that may be 
equally convincing and more appropriate.
    (Response) FDA agrees with this comment to the extent that it 
asserts that not every change in an infant formula will require the 
manufacturer to conduct a growth monitoring study of a new formulation 
of an infant formula. As noted in the response to the previous comment, 
the interim final rule provides separate exemptions from the growth 
monitoring study requirement in Sec.  106.96(c)(2) of the interim final 
rule, including an exemption for the situation in which a manufacturer 
establishes that an alternative method or study design that is based on 
sound scientific principles can show that the formula supports normal 
physical growth when fed as the sole source of nutrition (Sec.  
106.96(c)(2)(i) of the interim final rule). Thus, FDA believes that the 
interim final rule responds to this comment.
    (Comment 249) One comment noted that the proposed rule contains a 
broad definition of ``major change'' that would mandate the filing of a 
premarket notification for numerous changes in processing or 
formulation, and that, while the industry recognizes that a growth 
study may be needed to assess some of these major changes (such as the 
use of certain new ingredients with no prior history of use in infant 
formula), there is no scientific basis to mandate a growth study for 
other major changes (such as the manufacture of an infant formula on a 
new processing line).
    (Response) FDA disagrees with this comment to the extent that it 
asserts that the proposed definition of ``major change'' is too broad. 
The definition of ``major change'' in this interim final rule is 
discussed previously in this document in section IV.C.2.
    FDA agrees that a growth monitoring study may be needed to assess 
some major changes (such as the use of certain new ingredients with no 
prior history of use in infant formula). However, in the case of use of 
a new processing line, some changes, such as

[[Page 8020]]

introduction of a new retort system with altered time and temperature 
processing conditions, could potentially have an adverse effect on the 
bioavailability of the formula, including the bioavailability of 
nutrients in the formula. On the other hand, FDA also recognizes that 
not all processing changes have the same potential to affect formula 
bioavailability and bioavailability of nutrients. Thus, Sec.  
106.96(c)(2)(ii) of the interim final rule provides an exemption from 
the quality factor requirements for normal physical growth, Sec.  
106.96(b) of the interim final rule, where the manufacturer provides 
assurances, as required under Sec.  106.121 of the interim final rule, 
that demonstrate that a ``major change'' to an existing formula does 
not affect the bioavailability of the formula, including the 
bioavailability of nutrients in such formula. In addition, the interim 
final rule provides an exemption, upon the manufacturer's request, from 
the requirements of Sec.  106.96(b) of the interim final rule, for a 
change that is a ``major change,'' but is limited to altering the type 
of packaging of an existing infant formula. For these reasons, FDA 
declines to make revisions in response to this comment.
    (Comment 250) One comment requested deletion of proposed Sec.  
106.97(a)(2)(i) because, the comment asserted, providing that an 
exemption ``may be available'' based on a requirement to 
``demonstrate'' that a manufacturer or responsible party has experience 
with an ingredient, ingredient mixture, or a processing method 
constitutes premarket approval, not notification.
    (Response) FDA disagrees with this comment to the extent that it 
asserts that the structure of proposed Sec.  106.97(a)(2)(i) 
constitutes premarket approval. The proposed exemption is part of FDA's 
establishment of requirements for quality factors, an action expressly 
required by section 412(b)(1) of the FD&C Act, and nothing in this 
proposed exemption can or does alter the statutory process of premarket 
notification established by section 412(c) of the FD&C Act. FDA is 
deleting this specific exemption as unnecessary, however, because its 
specific circumstances are covered by the broader exemption in Sec.  
106.96(c)(2)(ii) of the interim final rule.
    (Comment 251) One comment suggested that ``similar experience'' 
with an ingredient, an ingredient mixture, or a processing method 
should be relevant regardless of whether it occurred in the United 
States or elsewhere.
    (Response) As noted, FDA is deleting the specific exemption in 
proposed Sec.  106.97(a)(2)(i) because its circumstances will be 
covered by the broader exemption in Sec.  106.96(c)(2)(ii) of the 
interim final rule. As part of the showing required by Sec.  
106.96(c)(2)(ii) of the interim final rule, a manufacturer may submit 
data from marketing outside the United States. FDA expects that, in 
such circumstances, the manufacturer will explain why such data are 
both relevant to a change in an infant formula marketed in the United 
States and why FDA should consider such data. Thus, under the interim 
final rule, the information relating to a manufacturer's experience 
outside the United States with an ingredient, ingredient mixture, or 
processing method will not be categorically classified as irrelevant to 
a change in a formula distributed in the United States.
    (Comment 252) One comment requested deletion of Sec.  
106.97(a)(2)(ii) from the final rule but did not state why. Another 
comment agreed with the concept of choosing the most stringent case for 
conducting quality factor testing, whenever possible, but also stated 
that the choice of the representative formula should not be based 
solely on greatest adverse nutrient effect and provided the following 
example: If a product has two forms, one a liquid, ready-to-feed 
formula for hospital use only, and the other a powder formula for 
retail use, it may be more appropriate to study the form that is 
intended for long term use (i.e., the powder) as opposed to the very 
short term formula (i.e., the liquid), where processing actually may 
have the greatest adverse nutrient effect.
    (Response) FDA disagrees with this comment. All forms of infant 
formula (ready-to-feed, concentrate, and powder) are marketed for 
extended use and thus, all must be capable of supporting normal 
physical growth of healthy term infants when used as the sole source of 
nutrition. For this reason, FDA disputes the comment's suggestion that 
powdered infant formula is the infant formula form intended for long-
term use and thus, is the form that should be used in a growth 
monitoring study. The comment did not directly dispute FDA's view that 
the infant formula form processed under the most severe conditions is 
the form with the greatest likelihood of having adverse effects on its 
nutrient content and, thus, on the formula's bioavailability to the 
infant. In most cases, the most highly processed form of formula is the 
liquid product that undergoes pasteurization plus a heat treatment 
(typically, retorting to temperatures of 244[emsp14][deg]F) to ensure 
commercial sterility. Such retorting is more severe than the heat 
treatment applied during the production of powdered products, which 
typically involves only pasteurization plus a relatively milder heat 
treatment during spray drying (powder temperature reaching 110-175 
[deg]F at the dryer outlet) (Ref. 75).
    For this reason, FDA concludes that, in all likelihood, it would be 
appropriate to test in a growth monitoring study the liquid form of an 
infant formula processed under the most severe conditions, which 
results would be applicable to the less highly processed powdered form 
of the formula. For companies producing only powdered infant formula, 
the appropriate formula to test would, of course, be the powdered form. 
Given the disparities in processing and the effects of processing, 
however, the results of a growth monitoring study of powdered product 
generally would not be evidence that more highly processed liquid forms 
of the formulation satisfy the quality factor of normal physical growth 
in healthy term infants.
    (Comment 253) One comment asserted that in applying the exemption 
of proposed Sec.  106.97(a)(2)(ii), the manufacturer must be given 
responsibility for determining the most representative form to test.
    (Response) FDA notes that the exemption in proposed Sec.  
106.97(a)(2)(ii) has been recodified at Sec.  106.96(c)(2)(iii) of the 
interim final rule.
    FDA disagrees in part with this comment to the extent that the 
comment asserts that the manufacturer should be able to determine 
unilaterally which form of a formulation to test in a growth monitoring 
study. The provision in question is part of the assurances that a 
formula satisfies the requirements for quality factors, which 
requirements and assurances the statute authorizes FDA to establish. 
Although the statutory scheme does not require the Agency to establish 
exemptions from the assurances that such requirements are satisfied, 
FDA has determined, in its discretion, to do so. Accordingly, it is 
also within the Agency's discretion to establish the terms of such 
exemptions, including the requirement that a manufacturer must satisfy 
FDA that the conditions of an exemption exist.
    Moreover, in this case, it is reasonable that a manufacturer 
establish, to the Agency's satisfaction, that the form of the formula 
tested in a growth monitoring study is the form processed using the 
method with the greatest potential for adverse effects on the nutrient 
content and bioavailability. This standard will provide the greatest

[[Page 8021]]

certainty that all forms of a formula will be nutritionally sufficient 
regardless of the means of processing. FDA does agree, however, that 
under this exemption, the manufacturer may initially choose which form 
of a formulation to test for such purposes, but when submitting its 
assurances to the Agency, the manufacturer must demonstrate that the 
form tested meets the standard in Sec.  106.96(c)(2)(iii) of the 
interim final rule.
    (Comment 254) One comment argued that when studies have already 
been carried out on a form of the product that meets neither criterion 
(i.e., a formula with greatest potential for an adverse effect on 
nutrients or a formula intended for long term use), but the new 
formulation cannot reasonably be expected to differ significantly from 
the formula in question in terms of nutrient levels or bioavailability, 
those studies should also be able to provide the basis for exemption 
from additional studies. The comment stated that to require duplicative 
studies on different forms of a product that do not differ 
significantly would be difficult to justify on an ethical basis.
    (Response) As noted previously in this document, FDA has added an 
exemption to the interim final rule allowing manufacturers to request 
an exemption and provide assurances that demonstrate that an 
alternative method or study design that is based on sound scientific 
principles is available to show that the formula supports normal 
physical growth in infants when the formula is fed as the sole source 
of nutrition. This would permit a manufacturer to submit data relating 
to a particular formulation and to demonstrate that, even if the 
formulation tested is not the most heavily processed, sound science 
principles support reliance on such data to demonstrate that all forms 
of the formulation satisfy the quality factor of normal physical 
growth. Thus, there is an option in the interim final rule for the 
manufacturer to request an exemption from the need for a growth 
monitoring study under the circumstances identified in the comment.
    (Comment 255) One comment requested deletion of proposed Sec.  
106.97(a)(2)(iii), but did not state why. Another comment noted FDA's 
recognition of the flexibility necessary to accommodate evolution in 
clinical study design and suggested that consideration should be given 
to situations where formula is not intended as the sole source of 
nutrition.
    (Response) The request to allow infant formulas to be tested other 
than as the sole source of nutrition was addressed previously in this 
document in section VIII.C.4.c. Consistent with this discussion, the 
Agency does not agree that ``sole source of nutrition'' should be 
removed from the language in the exemption.
    FDA acknowledged in proposed Sec.  106.97(a)(2)(iii) that it is 
possible to assure the Agency that an alternative method or study 
design may be appropriate for the evaluation of the ability of some 
infant formulas to support normal physical growth. Therefore, FDA is 
providing a mechanism whereby manufacturers may request an exemption 
from the growth monitoring study requirement and use an alternate 
method or study design to provide assurances of normal physical growth. 
Because questions about the adequacy of a study design or method may be 
varied and may raise unique questions about the ability of such method 
or design to generate data to demonstrate normal physical growth, FDA 
is requiring that the assurances, required under Sec.  106.121 of the 
interim final rule for such an exemption, demonstrate that the 
alternative method or study design be based on sound scientific 
principles and show that the formula supports normal physical growth 
when the formula is the sole source of nutrition (see section X for 
further discussion on the assurances required by Sec.  106.121 of the 
interim final rule). This exemption, as revised, is now Sec.  
106.96(c)(2)(i) of the interim final rule.
    (Comment 256) One comment suggested that proposed Sec.  
106.97(a)(2) be revised to allow a manufacturer to request an exemption 
from the individual testing requirements of proposed Sec.  106.97(a)(1) 
if the manufacturer has determined that a change in formulation or 
processing does not cause the formula to be adulterated under section 
412(a) of the FD&C Act and provides to FDA the basis for this 
determination. The comment argued that without the suggested change, 
the proposed rule provides no exemptions for changes such as minor 
changes in ingredient levels, replacing one nutrient form with another, 
or insignificant changes in processing conditions. The comment argued 
that such changes would require a submission under proposed Sec.  
106.140, which includes assurances under proposed Sec.  106.121. The 
comment asserted that it was not the Agency's intent or a correct 
interpretation of section 412(d)(3) of the FD&C Act to require clinical 
testing and protein efficiency ratio (PER) data for such minor changes.
    (Response) FDA disagrees with this comment. The fact that the 
proposed rule would have required a quality factors submission 
complying with proposed Sec.  106.121 is clear evidence of FDA's 
intent. This intent is consistent with the statute, which requires that 
a manufacturer of a new infant formula provide assurance that the 
formula meets quality factor requirements in a ``before first 
processing'' (BFP) submission made under section 412(d)(3) of the FD&C 
Act. In lieu of a growth monitoring study, the manufacturer may request 
an exemption under Sec.  106.96(c)(2)(ii) of the interim final rule and 
provide the scientific basis to explain why the changes in the formula 
would not affect the bioavailability of the formula and its nutrients 
and submit the results of the nutrient testing on finished product 
required under Sec.  106.91(a) of the interim final rule.
    The comment misunderstood the intent of the requirements for growth 
monitoring studies. FDA does not intend to require a growth monitoring 
study for all changes to a formula. A BFP notification under section 
412(d)(3) of the FD&C Act must be submitted when the manufacturer 
determines that a change in the formulation of the formula or a change 
in the processing of the formula ``may affect whether the formula is 
adulterated'' under section 412(a) of the FD&C Act, e.g., when there 
are questions about whether a formula provides nutrients required by 
section 412(i) of the FD&C Act, meets quality factor requirements, or 
is in compliance with CGMP and quality control procedures. The 1986 
Guidelines Concerning Notification and Testing of Infant Formulas 
listed several examples of types of changes for BFPs, such as replacing 
certain nutrient forms with another form or adjustments in the quantity 
of a nutrient in a premix or individually added nutrient that results 
in a specification change for that nutrient in the finished product, or 
changes in time-temperature conditions of preheating during handling of 
bulk product that cannot reasonably be expected to cause an adverse 
impact on nutrient levels or nutrient availability.

E. Quality Factor: Protein Quality

    In 1996, FDA proposed (Sec.  106.96(c)) protein of sufficient 
biological quality as a second quality factor for infant formula and 
stated that a formula must not only contain adequate amounts of protein 
but also protein in a form that can be utilized by infants. At that 
time, the Agency noted that protein quality depends on a number of 
factors and complex interactions, including

[[Page 8022]]

differences in the digestibility of proteins from different sources and 
on the processing method for the formula. FDA also observed that the 
nutritive value of protein depends upon the presence of all essential 
amino acids at levels and relative proportions that will support 
healthy growth and stated that this quality factor would require an 
evaluation of whether the formula contains the essential amino acids 
and total nitrogen in the amount and proportion to permit normal tissue 
and organ growth and development (61 FR 36154 at 36181). In proposed 
Sec.  106.97(b)(1), FDA proposed to require that biological protein 
quality be established using the Protein Efficiency Ratio (PER) rat 
bioassay described in the Official Methods of AOAC International, which 
the Agency proposed to incorporate by reference (61 FR at 36215). In 
proposed Sec.  106.97(b)(2), the proposed rule identified two 
situations in which the manufacturer could request an exemption from 
the PER assay requirement.
    FDA received no general comments on the Agency's proposal to 
establish protein of sufficient biological quality as a quality factor 
for infant formula. As noted previously in this document, FDA is 
reorganizing and consolidating into Sec.  106.96 of the interim final 
rule most of the content of proposed Sec.  106.96 and proposed Sec.  
106.97 related to requirements for infant formula quality factors. 
Thus, in the absence of comments, Sec.  106.96(e) of the interim final 
rule establishes a second infant formula quality factor, biological 
quality of protein sufficient to meet the protein requirements of 
infants. Accordingly, Sec.  106.96(e) states the following: ``An infant 
formula manufacturer shall meet the quality factor of sufficient 
biological quality of protein.''
1. Methods for Determining Biological Quality of Protein in Infant 
Formulas
    (Comment 257) One comment objected that the proposal specified a 
particular AOAC method for evaluating protein quality and stated that 
the biological quality of the protein in infant formula could be 
established with any AOAC approved method including the PER.
    (Response) FDA disagrees with this comment. As noted, protein will 
be of sufficient quality only if it contains sufficient amounts of all 
amino acids essential for infants, is present in adequate amounts, and 
is present in a form that infants can utilize. In the 1996 proposed 
rule, the Agency explained that ``A protein source may contain the 
necessary amino acids, but they may be in a form that the infant cannot 
digest and absorb. Furthermore, processing methods may alter the 
chemical nature of the protein source, possibly making the protein more 
resistant to digestion by the infant'' (61 FR 36154 at 36187). FDA 
proposed the PER method because, unlike chemical measures of protein 
composition, PER provides an estimate of the bioavailability of the 
protein. The Agency notes that the comment did not offer specific 
objections to the PER method. Nor did the comment identify other 
official AOAC methods that could successfully evaluate the presence and 
bioavailability of protein in an infant formula. Accordingly, FDA is 
not modifying this provision in response to this comment.
    (Comment 258) Several comments questioned whether the PER is the 
best method of determining the protein quality of an infant formula and 
whether measurements of protein status in the infant would be more 
appropriate.
    (Response) FDA disagrees with these comments to the extent that 
they challenge the use of the PER method. The PER method uses an animal 
model and thus, will allow a manufacturer to assess an infant formula's 
protein quality before the formula is fed to infants in a growth 
monitoring study or otherwise. High quality proteins are easily 
digestible and contain all of the essential amino acids in amounts that 
humans require. As stated in the previous response, evaluating protein 
quality requires both measuring the amount present and the amount that 
is bioavailable. The PER permits a comparison of different protein 
sources (i.e., is the test protein better or worse than the control 
protein?). FDA is aware that the PER, although sensitive, is not 
specific. The PER method has limitations (as discussed in this 
document); however, FDA is not aware of any other available method to 
assess protein bioavailability, and no comment, including this one, 
identified any such method.
    FDA notes that the Agency consulted with an expert panel 
established by the Life Sciences Research Office (LSRO) of the 
Federation of American Societies for Experimental Biology (FASEB). The 
LSRO panel was asked about minimum and maximum levels of protein in 
infant formula and considered methods that measured protein quality but 
not protein bioavailability (Ref. 76). Although total protein 
(measurement of nitrogen) as well as amino acid patterns can now be 
measured and such measures may be appropriate for certain aspects of 
protein quality, chemical measures of this type do not address the 
protein's bioavailability. The ability to estimate protein 
bioavailability is the advantage of a biological test system such as 
the PER assay.
    FDA is well aware of the limitations of the PER as these 
limitations have been known for many years (Refs. 77 and 78). A 
principal criticism of the PER is that it is highly correlated to 
weight gain but does not characterize the protein, rather it reflects 
the rate of weight gain of the rat consuming the test substance with 
the weight gain of a control group. The Agency acknowledges that body 
weight gain does not necessarily correspond to gain in muscle related 
to protein intake nor does body weight gain detect changes in body 
composition (Refs. 77 and 78). The PER assay has also been criticized 
because, even under standardized conditions, laboratories may obtain 
variable results in terms of the ratio percentage. However, PER is a 
simple test with an AOAC standardized method that has improved the 
assay (Ref. 79). Appropriate modifications of the PER are described in 
this document.
    For the foregoing reasons, FDA declines to delete the requirement 
that infant formula protein be assayed using the PER method.
    (Comment 259) One comment stated that when a manufacturer proposes 
to alter the protein source or composition of an infant formula, the 
manufacturer should be required to demonstrate that the serum amino 
acid levels of infants consuming the altered formula are comparable to 
those of breast-fed infants or infants fed other standard infant 
formulas.
    Another comment countered that universally requiring amino acid 
determinations in infants consuming the altered infant formula would 
add nothing to the assessment of new combinations of protein sources 
and the potential for the use of additional invasive procedures to 
collect these data would be considered unethical unless specifically 
justified. The comment further stated that the need for such analyses 
can only be determined on a case-by-case basis.
    (Response) Determining serum free amino acid levels in infants 
consuming the test formula would not be an adequate means of assessing 
protein quality. Importantly, the comment did not provide evidence to 
support this recommendation, and there are at least two reasons that 
such tests would have limited value, if any. First, serum free amino 
acids reflect circulating amino acids, which may be present in an 
infant's blood either from the diet (i.e., the infant formula being 
consumed) or from endogenous sources, such as the breakdown of the 
infant's muscles. In

[[Page 8023]]

addition, determining serum levels of free amino acids would require 
blood draws, an invasive procedure. Given the limited usefulness of 
serum free amino acid analyses, requiring such analyses and thus, an 
invasive procedure, is not reasonable. Accordingly, FDA declines to 
revise the interim final rule to require formula manufacturers to 
demonstrate routinely that serum amino acid levels of study infants are 
comparable to those of breast-fed infants or of infants fed other 
appropriate infant formulas.
    (Comment 260) One comment disputed that PER measurements in young 
rats would add anything to the data collected in human infants. The 
comment asserted that anthropometric measures, nitrogen balance 
studies, and biochemical markers required by FDA in the growth 
monitoring study would provide an indication of the sufficiency of 
protein quality and quantity and that these measures in human infants 
would be sufficient to confirm that such quality and quantity are 
adequate.
    (Response) FDA disagrees with this comment. Contrary to what some 
comments have suggested, FDA did not propose to require nitrogen 
balance studies or biochemical markers as requirements for infant 
formula quality factors. (A balance study is a study that measures each 
individual study subject's intake and excretion of one or more 
particular substances, such as required nutrients.)
    Moreover, the PER analysis would contribute valuable information to 
the assessment of an infant formula's nutritional adequacy, value not 
provided by a growth monitoring study, for two reasons. First, as 
noted, the PER analysis is conducted in an animal model and thus, will 
permit determination of a formula's protein quality before infants are 
exposed to the formula. This ensures that infants will not be fed a 
formula with inadequate or biologically unavailable protein, which is 
critical because when an infant formula is the sole source of 
nutrition, any inadequacy in protein quality cannot be compensated for 
by other dietary components, and such inadequacy may result in serious, 
and in some cases, permanent, adverse effects on an infant's growth and 
development (Ref. 80).
    Second, as discussed previously in this document, a growth 
monitoring study that includes anthropometric measurements assesses 
whether the complete infant formula matrix supports normal physical 
growth and contributes to an assessment of healthy growth. However, it 
is imperative that protein quality be established prior to its use in 
an infant formula, particularly where there is an accepted means (the 
PER) to do so. It is critical that the composition of the protein, 
e.g., type and amounts of essential amino acids, in a formula be 
adequate to support the needs of a developing infant, and that the 
formula containing the protein support normal physical growth. 
Importantly, the failure of a formula to support normal physical growth 
could be the result of a number of shortcomings in the formula. Thus, 
the growth monitoring study will not provide information specific to 
protein quality and bioavailability.
2. Method for Assessing Protein Efficiency Ratio (PER)
    (Comment 261) One comment pointed out that the citation to the PER 
method in proposed Sec.  106.97(b)(1) should be changed to Protein 
Efficiency Ratio (PER) rat bioassay described in the ``Official Methods 
of Analysis of AOAC INTERNATIONAL,'' 16th ed., AOAC[supreg] Official 
Methods 960.48, Protein Efficiency Ratio Rat Bioassay and 982.30, 
Protein Efficiency Ratio, Calculation Method.
    (Response) In Sec.  106.96(f) of the interim final rule, FDA has 
updated the references to AOAC International and to the AOAC methods, 
and has used the current name and address for AOAC International in 
Sec.  106.160, ``Incorporation by reference.''
    (Comment 262) Another comment stated that proposed Sec.  
106.97(b)(1) should be revised to recognize other AOAC methods as they 
become available.
    (Response) FDA will evaluate any AOAC method that becomes available 
that might serve as a substitute for, or alternative to, the PER assay 
and, if appropriate, will consider amending Sec.  106.96(f) to include 
such method or methods.
    Although FDA is not revising the requirement to use the PER assay 
in response to comments, the Agency is making, in addition to several 
minor editorial changes, three revisions to proposed Sec.  106.97(b)(1) 
on its own initiative.
    First, at the time of the 1996 proposal, certain language was 
inadvertently omitted from proposed Sec.  106.97(b). In particular, the 
phrase by ``an appropriate modification of'' should have been included 
so that the sentence, as proposed, would read ``The manufacturer shall 
establish the biological quality of the protein in its infant formula 
by demonstrating that the protein source supports adequate growth using 
an appropriate modification of the Protein Efficiency Ratio (PER) rat 
bioassay described in the ''Official Methods of Analysis of the 
Association of Official Analytical Chemists . . . .'' The basis for 
this change is explained in this document.
    The requirement to assess the quality of the protein component of 
an infant formula was originally established in FDA's quality control 
regulations for infant formula, 21 CFR 106.30(c)(2), which were issued 
in 1982 (47 FR 17016 at 17026 (April 26, 1982)). Comments on the 
proposed rule asserted that, without certain modifications, the 
official AOAC assay for PER would not give valid test results for 
infant formulas due to the type of fat and concentrations of lactose 
and fat required in infant formula (47 FR 17016 at 17023). The Agency 
agreed with this view and thus, Sec.  106.30(c)(2) of the final rule 
provided that ``The biological quality of the protein shall be 
determined by an appropriate modification of the AOAC bioassay method 
of analysis.''
    The purpose of the PER rat bioassay is to compare the quality of 
protein in a finished infant formula product to a protein of known high 
biological quality (casein) to demonstrate that the protein in a 
proposed formula is bioavailable (supports comparable growth of the 
rats), as a decrease in the protein's biological value would not be 
detected by chemical analysis. As noted previously in this document, 
the PER rat bioassay is currently the only method that accounts for 
protein digestibility and absorption in a living animal system. 
Digestibility and absorption are critical elements to ensuring, prior 
to marketing, that an infant formula has sufficient protein quality.
    The official AOAC method is based on weight gain in test animals 
where one group of rats is fed a casein control diet and another group 
is fed a diet containing the test product (infant formula) (Ref. 81), 
and the animals' food intake and body weight are measured. The mean 
protein efficiency ratio (PER) is calculated based on the protein 
consumed by and weight gain of each animal group. Prior to study 
initiation, the test product (finished infant formula) and the casein 
control are subjected to a compositional assessment (proximate 
analysis). The diets are then formulated to contain matching amounts of 
protein, fat, minerals, fiber, and moisture. These diets are analyzed 
for protein to confirm that they were formulated correctly, which 
information is used to calculate the PER at completion of the trial.
    Although the method has limitations with respect to assessment of 
the quality of protein sources for infant formulas, the limitations are 
greatly reduced by modification of the test and control diets. Three 
dietary adjustments

[[Page 8024]]

commonly required for evaluation of the protein quality of infant 
formulas are:
     Adjustment of the fat content: In most cases, when the 
infant formula is incorporated into the protein evaluation diet based 
on the nitrogen content, the fat content will be above the limit (8 
percent) specified by the AOAC Official Method. The fat content of the 
reference control (casein) diet must be adjusted to match the fat 
content of the infant formula test diet.
     Carbohydrate composition adjustments: Lactose is the 
carbohydrate component of most milk-based infant formulas. Rats do not 
tolerate lactose well and often develop diarrhea, which may lead to an 
underestimation of protein quality of the formula. The casein reference 
control diet(s) must contain levels of lactose comparable to the amount 
in the infant formula test diet to adjust for possible confounding of 
the estimation of protein quality. If an infant formula contains a 
carbohydrate source other than lactose (e.g., sucrose, corn syrup 
solids), the source of carbohydrate in the formula should be used in 
the control diet as well.
     Removal of water from liquid infant formula: Infant 
formula is incorporated into the protein evaluation diet based on its 
nitrogen content. Because of the high water content of infant formulas 
in liquid form, these products usually are below the lower limit of 
total nitrogen (1.8 percent by weight) required for the PER bioassay. 
Liquid infant formulas must be freeze-dried so that the test sample 
contains more than 1.8 percent nitrogen before the infant formula test 
diet is formulated.
    Second, in order to ensure that determination of the biological 
quality of the protein of a new formulation precedes the initiation of 
the growth monitoring study required by Sec.  106.96(b) of the interim 
final rule, the Agency is adding the following sentence in Sec.  
106.96(f) of the interim final rule: ``The PER rat bioassay shall be 
conducted on a formula and the results evaluated prior to the 
initiation of a growth monitoring study of the formula that is required 
under paragraph (b).'' This will prevent the exposure of growth 
monitoring study subjects to a protein of undetermined biological 
quality and any unnecessary attendant risk of such exposure.
    Finally, proposed Sec.  106.97(b)(1) provided that ``[i]f the 
manufacturer is unable to conduct a PER rat bioassay because of the 
composition of the protein in the formula, then it shall demonstrate 
that the amino acid composition of the protein meets the known amino 
acid requirements of infants for whom the formula is intended.'' As an 
example of a formula for which this proposed flexibility might be 
necessary, the preamble cited the instance of an ``exempt infant 
formula'' that contains an incomplete protein (61 FR 36154 at 36187). 
As discussed previously in this document, this interim final rule only 
applies to non-exempt infant formulas; the composition of the protein 
of such non-exempt formulas would not preclude the use of the PER to 
determine protein quality. Therefore, FDA is excluding as unnecessary 
from Sec.  106.96(f) of the interim final rule the following 
sentence:''If the manufacturer is unable to conduct a PER rat bioassay 
because of the composition of the protein in the formula, then it shall 
demonstrate that the amino acid composition of the protein meets the 
known amino acid requirements of infants for whom the formula is 
intended.''

F. Exemption From the Quality Factor of Protein Quality Sufficiency

    As noted, the 1996 proposed rule identified two situations in which 
the manufacturer could request an exemption from the PER assay 
requirement in proposed Sec.  106.97(b)(2). Specifically, an exemption 
from the PER requirement would have been available where the 
manufacturer was already using the same protein source produced by the 
same processing method in another infant formula marketed in the United 
States, and the manufacturer could demonstrate that current formula met 
the quality factor requirements of the proposed rule, and where the 
protein source, including any processing method used to produce the 
protein, would not have been a major change from its predecessor 
formula and the manufacturer could demonstrate that the predecessor 
formula met the quality factor requirements of the proposed rule.
    As discussed previously in this document in section VIII.D. in this 
interim final rule, FDA is revising the exemptions from conducting a 
growth monitoring study under Sec.  106.96(b). Section 106.96(c)(1) of 
the interim final rule provides that, in response to a manufacturer's 
request, the Agency will exempt the manufacturer from the obligation to 
conduct a growth monitoring study when the manufacturer requests an 
exemption and provides assurances under Sec.  106.121 of the interim 
final rule that the changes to the existing formula are limited to 
changing the type of packaging for an existing infant formula.
    An assay of protein quality would also not be required in the 
foregoing circumstance because the change would not be expected to have 
an effect on protein quality or on any of the other nutrients in the 
formula that could affect the bioavailability of the protein. 
Accordingly, Sec.  106.96(g)(1) of the interim final rule provides that 
FDA will exempt a manufacturer from the requirement to conduct a PER 
assay where the manufacturer requests an exemption and provides 
assurances that the change to an existing infant formula is limited to 
changing the type of packaging for an existing formula.
    FDA also recognizes that not all changes to an infant formula have 
the potential to affect the biological quality of the protein in the 
formula. Accordingly, to provide flexibility in the interim final rule 
for these types of circumstances, Sec.  106.96(g)(2) of the interim 
final rule includes an additional exemption. FDA emphasizes that it is 
the obligation of the manufacturer to establish that all the conditions 
of the exemption are satisfied. Specifically, Sec.  106.96(g)(2) of the 
interim final rule provides that a manufacturer may request an 
exemption from the requirement to perform the PER assay if the 
manufacturer demonstrates that a change made by the manufacturer to an 
existing formula does not affect the quality or the bioavailability of 
the protein.

G. Miscellaneous Comments on the Quality Factor for Sufficient 
Biological Quality of Protein

    (Comment 263) In response to the 2003 reopening notice, one comment 
stated that protein quality for infant formula is based on estimates, 
extrapolations, and safety margins that have caused some products to 
provide protein intakes to formula-fed babies at twice the rate of 
breastfed infants. The comment stated that ``Heat-treated proteins have 
lower digestibility with high amounts contributing to metabolic and 
excretory stress in the infant.''
    (Response) This comment appears to raise issues related to the 
quantity of protein in infant formulas rather than protein quality and 
did not suggest changes to the proposed quality factor of protein 
quality. The issue raised in this comment would be more appropriately 
considered in any future revision of Sec.  107.100 and the maximum 
protein levels for infant formulas, an issue that is outside the scope 
of this interim final rule. Accordingly, no response to this comment is 
required.

H. Application of Quality Factors to Currently Marketed and Previously 
Marketed Formulas

    As noted in section VIII.C.1, in 1996, FDA proposed ``normal 
physical

[[Page 8025]]

growth'' as a quality factor (proposed Sec.  106.96(b)) and proposed 
requirements for the assurances for such quality factor (proposed Sec.  
106.97(a)). At the same time, FDA proposed ``sufficient biological 
quality'' of the formula's protein component as a second quality factor 
(proposed Sec.  106.96(c)) and proposed requirements for the assurances 
for this quality factor (proposed Sec.  106.97(b)). As proposed, the 
quality factors described in proposed Sec.  106.96 and the assurance 
provisions of proposed Sec.  106.97 would have applied to all infant 
formulas distributed in U.S. commerce and not simply ``new infant 
formulas.'' Subsequently, in the 2003 reopening, the Agency expressly 
requested comment on the appropriateness of the two quality factors 
proposed in 1996 (68 FR 22341 at 22342-22343).
    This interim final rule establishes two quality factors, the 
quality factor of ``normal physical growth'' (Sec.  106.96(a) of the 
interim final rule) and the quality factor of ``sufficient biological 
quality of protein'' (Sec.  106.96(e)), and sets minimum requirements 
for both quality factors (Sec.  106.96(b) and (f) of the interim final 
rule, respectively). Under the interim final rule, for each quality 
factor, the results of a single study, when conducted consistent with 
the requirements of the interim final rule, are sufficient to establish 
that the formula meets the quality factor. Thus, under the interim 
final rule, a single study--a growth monitoring study conducted as 
specified in Sec.  106.96(b) of the interim final rule--is sufficient 
to demonstrate that an infant formula supports normal physical growth. 
Similarly, a single study--a protein efficiency ratio (PER) study 
conducted as specified in Sec.  106.96(f) of the interim final rule--is 
sufficient to establish that a formula's protein component is of 
sufficient biological quality.
    Like the proposed rule, the quality factors set forth in the 
provisions of Sec.  106.96(a) and (e) of the interim final rule apply 
to all infant formulas distributed in interstate commerce. This means 
that a ``not new'' infant formula (i.e., an infant formula that 
previously was the subject of a new infant formula submission made 
under section 412(c)(1) of the FD&C Act) must satisfy the two quality 
factors established by this interim final rule. These ``not new'' 
infant formulas may be formulas that are not currently distributed as 
well as formulas that are currently distributed in the United States. 
Any formula, including a ``not new'' formula, that does not satisfy the 
quality factor requirements established under section 412(b)(1) of the 
FD&C Act is deemed adulterated under section 412(a)(2) of the FD&C Act.
    As discussed in the introduction of this document, the 1986 
amendments mandated that FDA establish by regulation requirements for 
quality factors for infant formula. Section 412(b)(1) of the FD&C Act, 
the quality factor requirements provision, is not self-executing and 
thus, there have been no enforceable quality factor requirements 
pending the issuance of this interim final rule. Prior to and since the 
1986 amendments, a variety of infant formula products have been 
distributed in the United States. Consistent with section 412(c) and 
(d) of the FD&C Act, manufacturers of these products have been required 
to notify FDA of their intent to market these infant formulas and to 
make a new infant formula submission, and they have done so. In the 
absence of implementing regulations, however, these notifications were 
not required to provide assurances that the formula meets any quality 
factor requirements.
    Nevertheless, many notifications made after publication of the 1996 
proposed rule have included information about the ability of the infant 
formula that is the subject of the notification to support normal 
physical growth and about the protein quality. Several submissions have 
included growth information on the formula, some of which was derived 
from growth studies that conform, more or less, to the provisions in 
proposed Sec.  106.97(a). Some submissions have also included evidence 
on the biological quality of the formula's protein component. Over this 
same period, as manufacturers have brought to market new products 
containing new ingredients, they have often stopped distributing 
previous versions of the newer products. Thus, there is an existing 
body of data and information, both published and unpublished, on many 
currently marketed and previously marketed formulas that may be 
relevant to whether such formulas support normal physical growth and 
whether the protein component of each such formula is of sufficient 
biological quality.
    FDA evaluated the data and information available to the Agency that 
is relevant to whether currently marketed infant formulas meet the two 
quality factors established by the interim final rule. This information 
includes material submitted to FDA and also published studies. The 
Agency recognizes, however, that formula manufacturers may have 
information on their products in addition to that available to FDA. 
Importantly, none of the available evidence suggests that any currently 
marketed infant formula fails to support normal physical growth or uses 
a protein component that lacks sufficient biological quality. By the 
same token, however, the available scientific record evaluated by FDA 
did not include sufficient information to document that all currently 
marketed infant formulas meet the quality factors of normal physical 
growth and are composed of a protein of sufficient biological quality.
    Although the data and information available to FDA may not be 
sufficient to demonstrate that every currently marketed formula meets 
the two quality factors, the Agency acknowledges that removal of infant 
formula from the market, based on limitations in the data and 
information that is available to FDA to date, would likely be very 
disruptive. Therefore, the Agency has developed separate provisions and 
an orderly process for these formulas to transition to the newly 
established requirements. There are two reasons that an orderly process 
that minimizes disruption in the marketplace is essential for a product 
like infant formula.
    First, as noted previously in this document, for many infants, 
infant formula is the sole source or the primary source of nutrition in 
the critical early months of growth and development, and formula often 
continues to be an integral part of the diet of many infants through 12 
months of age. Indeed, based on the CDC's study of breastfeeding rates 
in the U.S., in 2010, one quarter of U.S. infants were formula-fed from 
birth (approximately 1,027,000 infants) and by three months of age, 
two-thirds of U.S. infants (approximately 2,700,000 infants) relied on 
formula for some portion of their nutrition (http://www.cdc.gov/breastfeeding/data/reportcard.htm) (Ref. 82). Thus, it is essential 
that an adequate supply of formula be maintained as infant formula 
products transition to compliance with the requirements established by 
the interim final rule.
    Disruption in the infant formula supply in the United States could 
be especially problematic for the USDA's Special Supplemental Nutrition 
Program for Woman, Infants, and Children (WIC). More than half of the 
infant formula fed to U.S. infants is purchased through the WIC 
program. This program provides Federal grants to states for 
supplemental foods, health care referrals, and nutrition education to 
low-income pregnant, breastfeeding, and non-breastfeeding postpartum 
women, and to infants and children up to age five who are at 
nutritional risk. Under the current WIC program, each state contracts 
with a single formula

[[Page 8026]]

manufacturer to provide formula to the WIC participants in the state. 
Although it is possible for a state to change its contractual 
arrangements, it is nevertheless important to avoid market disruptions 
that could have an impact on the availability of formulas distributed 
through the WIC program.
    Second, maintaining sufficient availability of a variety of infant 
formulas in the marketplace during this transition period is important. 
Although all infant formula products must satisfy the nutrient 
requirements of FDA's regulations in Sec.  107.100, these products 
differ in their overall composition; such differences are not only in a 
formula's protein source (cow milk protein or soy protein isolate) but 
extend to other ingredients and components. The variations in formula 
products may not be equally tolerated by every infant and, thus, 
different infant formulas may not be interchangeable. For this reason, 
pediatricians generally recommend that parents of a formula-fed infant 
identify a single formula that their infant can tolerate and feed that 
formula to their child. Thus, it is also important to maintain a 
consistent supply of a variety of formula products.
    As noted, there is a considerable body of evidence relevant to 
whether currently marketed and previously marketed infant formulas are 
likely to satisfy the quality factors established by the interim final 
rule. These data and information consist of a variety of different 
studies and sources of information. The studies may not, strictly 
speaking, fulfill the detailed requirements of the interim final rule 
in that, for example, there is not likely to be a single growth 
monitoring study that satisfies all of the requirements of Sec.  
106.96(b) of the interim final rule. Importantly, however, this 
existing body of evidence, when viewed collectively, may show that a 
particular infant formula supports normal physical growth. FDA further 
recognizes that if these existing data and this existing information 
were not considered in assessing currently marketed and previously 
marketed formulas, it would likely be necessary for formula 
manufacturers to conduct new growth monitoring studies on such 
formulas, which would require infant study subjects to be exposed to 
the risks, however small, of the study protocol. In contrast, 
considering the existing clinical evidence to assess whether a 
currently marketed or previously marketed formula supports normal 
physical growth may avoid exposing infants to these additional risks.
    Going forward, infant formula manufacturers will be aware of the 
interim final rule's requirement for a growth monitoring study and the 
design characteristics required for such a study. Thus, the Agency 
fully expects that, in the future, the data and information used by a 
manufacturer to demonstrate that a new infant formula supports normal 
physical growth will conform to the specific requirements of Sec.  
106.96(b) of the interim final rule unless the formula qualifies for an 
exemption under Sec.  106.96(c) of the interim final rule.
    To minimize market disruption and its potential public health 
impact, and to limit the exposure of infants to the risks of additional 
clinical studies while ensuring that a formula meets the quality 
factors established in this interim final rule, the interim final rule 
includes specific provisions that apply to certain currently marketed 
and previously marketed formulas. The interim final rule designates 
these formulas as ``eligible'' infant formulas.
    The following discussion explains Sec.  106.96(i) of the interim 
final rule and specifically addresses: (1) Which formulas are covered 
by these provisions (2) the applicable standard for each quality factor 
and its basis, (3) the voluntary petition process and the outcome of a 
manufacturer's participation in the petition process, (4) records 
maintenance requirements, (5) the consequences of engaging or not 
engaging in the voluntary petition process, and (6) compliance dates.
    The provisions of Sec.  106.96(i) of the interim final rule apply 
to any infant formula that satisfies the definition of ``eligible 
infant formula.'' An ``eligible infant formula'' is defined in Sec.  
106.3 of the interim final rule as an infant formula that ``could have 
been or was lawfully distributed in the United States on May 12, 2014. 
Thus, any formula that has been the subject of a properly submitted 
infant formula notification under section 412(c) of the FD&C Act at 
least 1 day before the publication date of the interim final rule is 
eligible to utilize the provisions in Sec.  106.96(i) of the interim 
final rule.
    All infant formulas, including eligible infant formulas, must 
satisfy the two quality factors established by the interim final rule, 
normal physical growth and sufficient biological quality of the protein 
component of the formula. Section 106.96(i) of the interim final rule 
establishes quality factor requirements for eligible infant formulas. 
Although the requirements of Sec.  106.96(i) of the interim final rule 
are somewhat more flexible than the interim final rule's quality factor 
requirements for infant formulas that are not ``eligible'' infant 
formulas, these requirements are substantial. In particular, each of 
the three alternative means of demonstrating quality factor 
satisfaction mandates that scientific evidence be used to demonstrate 
that the formula meets the quality factors. Moreover, under Sec.  
106.96(i)(4) of the interim final rule, the manufacturer of each 
eligible infant formula is required to make and retain records to 
substantiate the view that the formula meets the quality factors, and 
such records must contain all relevant scientific data and information 
relied upon by the manufacturer for such substantiation as well as a 
narrative explanation of the manufacturer's conclusion.
    It is reasonable to extend the provisions in Sec.  106.96(i) and 
its more flexible standards to formulas that are lawfully marketed by 
the 89th day after the publication date of this interim final rule 
because these are the formulas currently fulfilling the needs of 
formula-fed infants. Establishing a mechanism to facilitate their 
continued availability and thus, to minimize disruptions in the 
availability of this essential source of infant nutrition, is 
imperative. It is also sound to extend these provisions only to those 
formulas that may be lawfully marketed by the 89th day after the 
publication of this interim final rule. With the publication of this 
interim final rule, infant formula manufacturers are now fully aware of 
the standards that its products must satisfy and thereby, are 
positioned to develop the required data and information for any new 
infant formula that is the subject of a submission under section 412(c) 
of the FD&C Act, including information that satisfies Sec.  106.96(b) 
and (f) of the interim final rule. By comparison, a manufacturer of an 
eligible infant formula could not reasonably have been expected to 
develop the data and information to fulfill the specific requirements 
of Sec.  106.96(b) and (f) of the interim final rule.
    Section 106.96(i)(1) of the interim final rule addresses the 
quality factor of normal physical growth. Under this provision, an 
``eligible infant formula'' that fulfills one or more of three criteria 
meets the quality factor of normal physical growth. FDA recognizes that 
there may be one or more eligible infant formulas for which no growth 
monitoring studies may have been conducted. In such circumstances, FDA 
recommends that the manufacturer conduct a growth monitoring study and 
may choose to design and conduct the study in conformity with the 
primary quality factor requirements of the interim final rule in Sec.  
106.96(b). Thus, Sec.  106.96(i)(1)(i) of the interim final rule

[[Page 8027]]

provides that an eligible infant formula meets the quality factor of 
normal physical growth if the scientific evidence on such formula 
fulfills the requirements of Sec.  106.96(b) of the interim final rule. 
Similarly, a manufacturer who previously chose to develop evidence of a 
formula's ability to support normal physical growth may have, quite 
reasonably, chosen to conduct a growth monitoring study, the design of 
which conformed to the provisions proposed in 1996 as those proposed 
provisions represented FDA's then-best judgment about the design and 
conduct of a growth monitoring study. To provide for these 
circumstances, the Agency has set forth in Sec.  106.96(i)(1)(ii) of 
the interim final rule the requirements for a growth monitoring study 
that were proposed in 1996, and Sec.  106.96(i)(1)(ii) of the interim 
final rule states that an eligible infant formula meets the quality 
factor of normal physical growth if the scientific evidence on such 
formula meets the provisions of that paragraph. The growth charts that 
the 1996 proposed rule stated should be used for plotting growth data 
are incorporated by reference under Sec.  106.160 of the interim final 
rule. Finally, there may be some eligible infant formulas for which 
there is no single growth study satisfying Sec.  106.96(i)(1)(i) or 
(i)(1)(ii) of the interim final rule but for which there is a body of 
scientific evidence drawn from multiple sources that, taken as a whole, 
demonstrates that the formula supports normal physical growth. Thus, 
Sec.  106.96(i)(1)(iii) of the interim final rule provides that an 
eligible infant formula meets the quality factor of normal physical 
growth if the scientific evidence on such formula otherwise 
demonstrates that the formula supports normal physical growth. This 
third option will require FDA to exercise its scientific judgment about 
the data and other information and whether that evidence demonstrates 
that the formula supports normal physical growth.
    Section 106.96(i)(2) of the interim final rule addresses the 
quality factor of sufficient biological quality of a formula's protein 
component. Under this provision, an ``eligible infant formula'' that 
fulfills one or more of three criteria meets the quality factor of 
sufficient biological quality of the protein component. FDA recognizes 
that there may be eligible infant formulas for which a protein 
efficiency ratio (PER) study was not conducted. The manufacturer may 
choose to conduct a PER study as specified in Sec.  106.96(f) of the 
interim final rule. Thus, Sec.  106.96(i)(2)(i) of the interim final 
rule provides that an eligible infant formula satisfies the quality 
factor of sufficient biological quality of the protein component if the 
scientific evidence on such formula fulfills the requirements of Sec.  
106.96(f) of the interim final rule. Similarly, a manufacturer who 
previously chose to develop evidence of the sufficient biological 
quality of a formula's protein component may have, quite reasonably, 
chosen to conduct a PER study according to the proposed rule's 
provisions. To provide for these circumstances, the Agency has set 
forth in Sec.  106.96(i)(2)(ii) of the interim final rule the 
requirements for establishing sufficient biological quality of a 
formula's protein component that were proposed in 1996, and Sec.  
106.96(i)(2)(ii) of the interim final rule states that an eligible 
infant formula meets the quality factor of sufficient biological 
quality of the protein component if the scientific evidence on such 
formula meets the provisions of that paragraph. The official method of 
analysis of AOAC to conduct a PER study that was proposed in the 1996 
proposed rule is incorporated by reference in Sec.  106.160 of the 
interim final rule. Finally, there are some eligible infant formulas 
for which there may be a body of scientific evidence drawn from 
multiple sources that, taken collectively, demonstrates that the 
formula's protein component is of sufficient biological quality. Thus, 
Sec.  106.96(i)(2)(iii) of the interim final rule provides that an 
eligible infant formula satisfies the quality factor of sufficient 
biological quality of the protein component if the scientific evidence 
on such formula otherwise demonstrates that the protein component of 
the formula has sufficient biological quality. Like Sec.  
106.96(i)(1)(iii) of the interim final rule, this third option will 
require FDA to exercise its scientific judgment about the data and 
other information and whether that evidence demonstrates that the 
protein component of the formula is of sufficient biological quality.
    An infant formula, including a ``not new'' infant formula, that 
does not comply with established quality factor requirements is deemed 
adulterated under section 412(a)(2) of the FD&C Act. As an adulterated 
food, this formula is subject to seizure, condemnation, and forfeiture 
under section 304 of the FD&C Act. Similarly, those who ship the 
formula in interstate commerce, cause its interstate shipment, or 
commit another prohibited act related to an adulterated food may be 
enjoined under sections 301 and 302 of the FD&C Act.
    FDA recognizes that to facilitate marketing and distribution plans, 
a manufacturer of an eligible infant formula may wish to understand the 
Agency's assessment of the quality factor evidence for that formula. To 
permit the manufacturer of an eligible infant formula to be aware of 
FDA's view of the manufacturer's determination that their formula meets 
the quality factor requirements of Sec.  106.96 of the interim final 
rule prior to the compliance date for meeting the requirements under 
106.96(i), Sec.  106.96(i)(3) of the interim final rule includes a 
time-limited petition process that allows a manufacturer to submit a 
citizen petition to FDA that contains scientific data and information 
to demonstrate that an eligible formula supports normal physical 
growth, that the formula's protein component is of sufficient 
biological quality, or both. FDA emphasizes that although participation 
in the petition process established by Sec.  106.96(i)(3) of the 
interim final rule is voluntary, satisfying the two quality factor 
requirements of the interim final rule is required of all infant 
formulas distributed in interstate commerce. The Agency encourages any 
manufacturer planning to file a petition under Sec.  106.96(i)(3) of 
the interim final rule to contact FDA to discuss any questions.
    The procedure in Sec.  106.96(i)(3) of the interim final rule uses 
the FDA citizen petition process in 21 CFR 10.30, and allows such a 
petition for an eligible formula to be submitted untilNovember 12, 
2015. Although there is likely to be some existing scientific evidence 
relating to quality factor status of many eligible formulas, some 
manufacturers may need to design, conduct, and analyze the results of a 
growth monitoring study before they can make a submission to FDA 
through the voluntary petition process. Because the Agency recognizes 
that one or more manufacturers of eligible infant formulas may need to 
design, conduct, and analyze the results of a growth monitoring study 
to develop evidence of the formula's ability to support normal physical 
growth, the interim final rule establishes a separate compliance date 
for certain quality factor provisions that apply to eligible infant 
formulas. Specifically, Sec. Sec.  106.96(a), 106.96(e), 106.96(i)(5), 
106.100(p)(2) and 106.100(q)(2) of the interim final rule are binding 
as of November 12, 2015. This means that eligible infant formulas must 
meet the quality factors, and keep records demonstrating that they meet 
the quality factors, as of November 12, 2015. Postponing the compliance 
date for these provisions for eligible infant formulas, combined with 
the same nearly 2-year period to submit a

[[Page 8028]]

voluntary petition will provide manufacturers of eligible infant 
formulas with sufficient time to develop the required data and 
information to demonstrate that their products meet the quality 
factors, and to submit such data and information to FDA through the 
voluntary petition process.
    FDA notes that under current Agency regulations and practice, a 
response to a citizen petition is publicly available and is routinely 
posted on the Agency's Web site. The Agency intends to follow this 
practice for infant formula quality factor citizen petitions and FDA's 
responses to such petitions by establishing a Web page dedicated to 
such petitions and responses. This practice will allow the public, 
including competitors, purchasers for retailer stores, and individual 
consumers, to know whether the manufacturer of an eligible infant 
formula product has availed itself of the opportunity to demonstrate 
that the formula meets the quality factors of normal physical growth 
and sufficient quality of the protein and to be informed of FDA's 
response to such submission.
    The petition process in Sec.  106.96(i)(3) of the interim final 
rule is a voluntary process, one that will provide FDA with access to 
important information relating to eligible infant formulas. For infant 
formula manufacturers and other interested parties, this process has 
the advantage of clarity and certainty in terms of whether FDA views a 
formula to be in compliance with the relevant quality factor 
requirements. Likewise, infant formula purchasers at all levels of the 
supply chain will indirectly benefit from this process because they 
will have access to scientific evidence and other information on the 
quality factor status of eligible infant formulas as well as FDA's view 
of that evidence.
    Accordingly, under Sec.  106.96(i)(3) of the interim final rule, 
the manufacturer of an eligible infant formula may, not later than 
November 12, 2015, submit a citizen petition to FDA under 21 CFR 10.30 
that such formula fulfills one or more of the criteria in Sec.  
106.96(i)(1) of the interim final rule relating to the quality factor 
of normal physical growth, one or more of the criteria in Sec.  
106.96(i)(2) of the interim final rule relating to the quality factor 
of sufficient biological quality of the protein component, or both. 
Consistent with the citizen petition regulation, Sec.  10.30(a), a 
petition filed under Sec.  106.96(i)(3) of the interim final rule must 
contain all data and information relied upon by the manufacturer to 
demonstrate that the formula fulfills one or more of the quality factor 
requirements in Sec.  106.96(i)(1) or (i)(2) of the interim final rule. 
Also, to help enhance the clarity and focus of these quality factor 
petitions, Sec.  106.96(i)(4) of the interim final rule provides that 
each such petition shall address only a single infant formula 
formulation. Importantly, however, a single petition may address both 
Sec.  106.96(i)(3)(i) and (i)(3)(ii) of the interim final rule for the 
same formulation.
    Additionally, as noted previously in this document, the 
manufacturer of an infant formula, including an eligible infant 
formula, is responsible for ensuring that the formula meets the two 
quality factors established by the interim final rule. Regardless of 
whether the formula is a new infant formula or a ``not new'' formula, 
it is reasonable to expect the manufacturer to have scientific data and 
information demonstrating that the quality factors are met because only 
with such data and information can a manufacturer make an informed 
decision to market and lawfully distribute a particular formula. Given 
this responsibility and the means reasonably required to fulfill that 
responsibility, an infant formula manufacturer must necessarily 
establish and maintain records documenting that each eligible formula 
meets the two quality factors. As noted, the provisions of the interim 
final rule in Sec.  106.96(i) recognize this need for records of the 
quality factor evidence for eligible infant formulas. Specifically, 
Sec.  106.96(i)(5) of the interim final rule requires the manufacturer 
of each eligible infant formula to make and retain records to 
demonstrate that such formula supports normal physical growth in 
infants when fed as the sole source of nutrition and to demonstrate 
that the protein in such infant formula is of sufficient biological 
quality. The records established under Sec.  106.96(i)(5) of the 
interim final rule must contain all relevant scientific data and 
information as well as a narrative explanation of why the data and 
information demonstrate that the formula meets the two quality factors 
established by the interim final rule. The requirement for a narrative 
explanation is a logical extension of the responsibility for ensuring 
that a formula meets the quality factors because without analyzing and 
summarizing the relevant data and information, a manufacturer has 
little or no basis to conclude that a particular formula supports 
normal physical growth or that it contains protein of sufficient 
biological quality. Additionally, this record requirement is 
reasonable, because without records, FDA has no way of determining 
whether a formula meets the quality factor requirements established 
under section 412(b)(1) of the FD&C Act. As noted in sections III and 
VIII.A, section 701(a) of the FD&C Act authorizes FDA to issue 
regulations for the efficient enforcement of the FD&C Act in order to 
effectuate an objective stated elsewhere in the FD&C Act. Thus, under 
sections 701(a) and 412(b)(1) of the FD&C Act, FDA has the authority to 
require a manufacturer of an eligible formula to maintain records 
demonstrating that their formula meets the quality factor requirements 
that apply to such formula. FDA emphasizes that this record-keeping 
provision for quality factor data and information required by Sec.  
106.96(i)(5) of the interim final rule applies to all eligible infant 
formulas that a manufacturer distributes or intends to distribute in 
interstate commerce and not simply to eligible formulas that are the 
subject of a petition under Sec.  106.96(i)(3) of the interim final 
rule.
    Although there are several distinct advantages to a manufacturer of 
an eligible infant formula that submits a petition to FDA under Sec.  
106.96(i)(3) of the interim final rule, the Agency recognizes that some 
manufacturers of eligible formulas may choose not to submit such a 
petition. Where no petition is submitted for an eligible infant 
formula, FDA intends to conduct an inspection of the formula's 
manufacturer and to review and evaluate the records for the formula 
that are required under Sec.  106.96(i)(5) of the interim final rule. 
If the data and information or the narrative explanation in the records 
made and retained under Sec.  106.96(i)(5) of the interim final rule do 
not demonstrate that the formula supports normal physical growth and 
that the protein in such infant formula is of sufficient biological 
quality, FDA will consider the formula to be adulterated under section 
412(a)(2) of the FD&C Act and will pursue the Agency's customary 
regulatory process, which may include official communication with the 
firm such as a Warning Letter followed by appropriate legal remedies.
    FDA received several comments related to the issue of currently 
marketed and previously marketed formulas. The Agency responds to these 
comments in this document.
    (Comment 264) One comment stated that it did not believe that it is 
FDA's intent to require all infant formulas currently on the market in 
the United States to undergo the study required by proposed Sec.  
106.97(a) and if this is the Agency's intent, the comment strongly 
objects to this requirement as unnecessarily burdensome and without 
cause.

[[Page 8029]]

    (Response) The commenter's statement of FDA's intent is not 
correct. As discussed previously in this document, all currently 
marketed formulas must be shown to meet the two quality factors 
established by the interim final rule. The Agency's intent was clear in 
that the 1996 proposed rule established quality factors for ``infant 
formulas'' and did not describe any subset that would not be covered by 
the requirements set forth in this interim final rule. Section 
412(a)(2) of the FD&C Act states that infant formulas that do not meet 
the quality factor requirements are deemed adulterated. Significantly, 
this adulteration provision applies to all infant formulas (not just 
``new infant formulas''). Thus, all infant formulas must meet the 
quality factors established in this interim final rule. However, as 
discussed in detail previously in this document, the interim final rule 
includes in Sec.  106.96(i) specific quality factor requirements for a 
formula that meets the definition of ``eligible infant formula.''
    (Comment 265) One comment noted that not all infant formula 
products currently marketed in the United States have undergone a 
clinical study as described in proposed Sec.  106.97(a). The comment 
asserted that there is no reason to believe these currently marketed 
products do not support normal physical growth and suggested that 
proposed Sec.  106.97(a)(2)(i) be revised to reduce unnecessary 
clinical studies, particularly where currently marketed formulas that 
have not been the subject of a growth monitoring study have undergone 
small changes in formulation or processing. The comment stated that if 
proposed Sec.  106.97(a)(2)(i) is not changed, it may pose an 
``unresolvable'' dilemma in the case of future modifications of some 
currently marketed infant formulas.
    (Response) The comment did not provide data or other information to 
explain the basis for its assertion that ``there is no reason to 
believe these currently marketed products do not support ``normal 
physical growth.'' FDA is a science-based Agency, and as such, must 
rely on valid data and other sound scientific information to draw 
conclusions about product safety, including the safety and nutritional 
sufficiency of infant formula.
    FDA disagrees that the expectation that all currently marketed 
formulas be demonstrated with valid scientific evidence to satisfy the 
quality factor of normal physical growth will result in an 
``unresolvable'' dilemma. The interim final rule provides specific 
provisions for manufacturers of eligible infant formulas to demonstrate 
that their products meet the quality factors of normal physical growth 
and sufficiency biological quality of the protein component, and Sec.  
106.96(i) of the interim final rule clearly contemplates that 
previously conducted growth studies, as well as other scientific data 
and information, may be used to demonstrate satisfaction of these 
quality factors. FDA believes that the opportunity to utilize existing 
data is certain to reduce the likelihood of requiring unnecessary 
growth monitoring studies.
    Requirements to assure that quality factors have been met in the 
case of small changes to formulations is discussed under Comment 256 
regarding submissions made under section 412(d)(3) of the FD&C Act.
    (Comment 266) Another comment stated that the Agency has no way of 
being assured that an infant formula that may have been marketed at 
some time in the past, but which is not currently on the market, would 
meet quality factor requirements. Therefore, the comment asserts, if a 
manufacturer wanted to reintroduce such a formula into the market, the 
manufacturer would need to submit a new infant formula notification.
    (Response) If a formula manufacturer wishes to reintroduce a 
formula into the market place, the reintroduced formula would need to 
meet the quality factors of normal physical growth and sufficient 
biological quality of the protein component. The mechanism in Sec.  
106.96(i) of the interim final rule contemplates this situation and 
establishes quality factor requirements for eligible infant formulas, 
which include certain previously marketed formulas. In addition, under 
Sec.  106.96(i)(5) of the interim final rule, the manufacturer of an 
eligible infant formula, including a previously marketed formula that 
is reintroduced, is required to make and retain records that 
demonstrate that such formula meets the two quality factors. FDA 
disagrees, however, that a reintroduced formula must necessarily be the 
subject of a new infant formula submission because the requirement to 
make such a submission applies only to a formula that is a ``new infant 
formula'' as defined by section 412(c) of the FD&C Act and Sec.  106.3 
of the interim final rule. If a previously marketed formula is altered 
such that the formula would be classified as a ``new infant formula,'' 
such formula would need to be the subject of a new infant formula 
submission, and would not be eligible to meet the quality factors under 
Sec.  106.96(i) of the interim final rule.
    (Comment 267) One comment requested that FDA confirm that the 
protein quality factor pertains only to new situations that arise after 
the effective date of the quality factor requirements. The comment 
argued that this is reasonable because the assurance of quality factors 
of all currently marketed formulas has been provided by the good health 
of infants that have been raised on those formulas over the years.
    (Response) Under section 412(b)(1) of the FD&C Act, quality factor 
requirements apply to all infant formulas; not only new infant 
formulas. As such, currently marketed formulas must meet the quality 
factors under this interim final rule, including the quality factor of 
sufficient biological quality of protein. However, as is explained 
previously in this document, currently marketed formulas that are 
``eligible formulas'' under Sec.  106.96(i) of the interim final rule 
have some flexibility in terms of how satisfaction of the two quality 
factors may be demonstrated.

I. Records Demonstrating Compliance With the Quality Factor 
Requirements for Infant Formulas That Are Not Eligible Infant Formulas

    For consistency with other records requirements, FDA is adding a 
provision in the interim final rule (Sec.  106.96(d)) that requires a 
manufacturer of a new infant formula that is not an eligible infant 
formula to make and retain certain records demonstrating that such 
formula meets the quality factor of normal physical growth. Likewise, 
FDA is adding a provision in the interim final rule (Sec.  106.96(h)) 
that requires a manufacturer of a new infant formula that is not an 
eligible infant formula to make and retain certain records 
demonstrating that the formula meets the quality factor of sufficient 
biological quality of protein. As noted previously in this document in 
section VIII.A, it is reasonable and necessary for the efficient 
enforcement of the FD&C Act for FDA to require a manufacturer of infant 
formula to make and retain records demonstrating that the formula 
satisfies the quality factors requirements. These records may assist 
FDA in determining whether an infant formula meets the quality factor 
requirements.
    As is discussed further in section IX.F, in order to comply with 
this records requirement, a manufacturer of a new formula that is not 
an eligible infant formula will be required to make and retain records 
demonstrating compliance with the growth monitoring study requirements 
under Sec.  106.96(b) of the interim final rule, or make and

[[Page 8030]]

retain records demonstrating satisfaction of an applicable exemption 
under section Sec.  106.96(c) of the interim final rule.
    In the proposed rule, proposed Sec.  106.97(a)(i)(B) would have 
required a manufacturer to collect and maintain, in the growth study, 
anthropometric measures of physical growth. This interim final rule 
expands and clarifies this collection and maintenance requirement, to 
require that a manufacturer make and retain records demonstrating 
compliance with the growth monitoring study requirements under Sec.  
106.96(b) of the interim final rule, or in the alternative, records 
demonstrating satisfaction of an applicable exemption under section 
Sec.  106.96(c) of the interim final rule.
    Likewise, the interim final rule includes a provision (Sec.  
106.96(h)) that requires a manufacturer of a new infant formula to make 
and retain certain records demonstrating that the formula meets the 
quality factor of sufficient biological quality of protein. With 
respect to the quality factor of sufficient biological quality of 
protein, the proposed rule would have required a manufacturer of an 
infant formula to collect and maintain data establishing that the 
biological quality of protein in the infant formulas is sufficient to 
meet the protein requirements of infants proposed Sec.  106.97(b)(1) . 
As is discussed in further detail in section IX.F, this interim final 
rule clarifies that the requirement to make and retain records 
demonstrating that the formula has sufficient biological quality of 
protein includes, when applicable, records demonstrating satisfaction 
of an applicable exemption under Sec.  106.96(g) of the interim final 
rule. If the formula manufacturer is not seeking an exemption from the 
requirements of Sec.  106.96(f) of the interim final rule, the formula 
manufacturer would need to make and retain records demonstrating 
compliance with the requirements under Sec.  106.96(f) of the interim 
final rule.

J. Establishment of Other Quality Factors

1. General Comments
    Several comments agreed with FDA's tentative conclusion in the 2003 
reopening notice that the quality factors of normal physical growth and 
protein biological quality are sufficient at this time for assessing 
the bioavailability of nutrients in an infant formula and that the 
physical growth and protein quality would be considered reasonable 
benchmarks, presuming the infant formula contains all nutrients 
required by section 412 of the FD&C Act. Other comments recommended 
that the Agency identify additional quality factors and establish 
requirements for such factors.
    (Comment 268) One comment expressed concern about the Agency's 
suggestion in the 1996 proposal (61 FR 36154 at 36181) that additional 
quality factors may be identified on a case-by-case basis for specific 
formula products, stating that this would create difficulties for 
manufacturers without more explicit guidance as to what is required.
    (Response) FDA is not including in the interim final rule 
requirements for quality factors other than those for normal physical 
growth and biological quality of the protein. The Agency notes that, in 
the future, it may propose requirements for additional quality factors 
for infant formula, or nutrients in such formula, in general or for 
specific types of formula or for specific nutrients. However, any 
additional quality factors requirements will be established in a future 
rulemaking or FDA will make recommendations in a future guidance 
established under FDA's GGPs (21 CFR 10.115). Both of these processes 
would include prior notice and the opportunity for public 
participation.
    (Comment 269) One comment stated that, due to the increasing 
complexity of infant formula ingredients, benchmarks such as growth and 
protein quality do not evaluate the effect of new ingredients, such as 
long-chain polyunsaturated fatty acids and probiotic microorganisms or 
other complex ingredients. The comment suggested that instead, FDA 
evaluate overall nutrient quality and availability, targeted vitamins, 
minerals, and macronutrients.
    (Response) The quality factors of normal physical growth and 
sufficient biological protein quality are necessary to demonstrate that 
the required nutritional components of infant formula are bioavailable, 
in order to help ensure that the formula supports healthy growth. 
Evaluation of normal physical growth by a well-controlled growth 
monitoring study and evaluation of the biological quality of the 
protein by PER rat bioassay are not intended to, and do not, evaluate 
other purported effects of new ingredients (e.g., effects of long-chain 
polyunsaturated fatty acids on visual development or effects of 
probiotic microorganisms on gut flora). Thus, the suggestion of this 
comment is beyond the scope of this interim final rule.
2. Quality Factors for Fat, Calcium, and Phosphorus
    In the 1996 proposal (61 FR 36154 at 36182), FDA stated ``because 
of the potential seriousness of the public health impact of not meeting 
quality factors, FDA also believes that it is desirable to establish 
additional quality factors, as soon as they are warranted by evolving 
scientific knowledge, to ensure adequate nutrient bioavailability.'' 
The Agency notes that the CON/AAP Task Force (Ref. 67) recommended 
metabolic balance studies to determine whether a formula meets quality 
factors for fat, calcium, and phosphorus. FDA specifically requested 
comment on whether the scientific evidence and usefulness of results 
are sufficient to support establishing quality factor requirements for 
nutrients other than protein, such as fat, calcium, and phosphorus, and 
if so, what assurances should be established for such factors (61 FR 
36154 at 36181). The Agency also requested comment on balance studies 
or other methods that could be used to assess potential quality factor 
requirements for these three nutrients. This opportunity was renewed 
with the 2003 reopening of the comment period.
    Several comments responded to FDA's request for comment on whether 
quality factor requirements should be established for fat, calcium, and 
phosphorus.
    (Comment 270) One comment supported including quality factor 
requirements for fat, calcium, and phosphorus in assessments of the 
nutritional adequacy of formulas, and stated that manufacturers are 
currently expected to include these measures in the clinical evaluation 
of their formulas and the measurement of these quality factors should 
not present difficulties to manufacturers or those involved in the 
clinical study of infant formulas.
    (Response) FDA disagrees with this comment to the extent that it 
asserts that manufacturers currently measure the bioavailability of 
fat, calcium, and phosphorus in their clinical evaluations of infant 
formulas. To date, FDA has not recommended that manufacturers include 
metabolic balance studies to evaluate the adequacy of fat, calcium, and 
phosphorus in new infant formulas. In fact, in the 1996 proposal, FDA 
tentatively concluded that the clinical and nutritional sciences had 
not reached a level of development such that specific tests were 
available to establish that infant formulas could be demonstrated to 
satisfy quality factors for each of the essential nutrients listed in 
Sec.  107.100, except for protein. In particular, the Agency expressed

[[Page 8031]]

concern about the absence of meaningful measures for the assessment of 
the bioavailability of calcium and phosphorus. At the same time, FDA 
noted that studies of infant excretion of fat indicate that the fats in 
formula are highly digestible, thus mitigating questions about fat 
bioavailability. The comment did not provide any information to 
contradict the Agency's tentative conclusion that quality factor 
requirements should not be established for nutrients other than 
protein. Accordingly, FDA declines to establish quality factor 
requirements for fat, calcium, and phosphorus in this interim final 
rule.
    (Comment 271) Some comments disagreed with FDA's statement in the 
1996 proposal (61 FR 36154 at 36187) about the degree of technical 
difficulty in performing fat balance studies, saying that metabolic 
studies are difficult to perform well and are conducted at few research 
centers (Ref. 67).
    (Response) FDA agrees in part with this comment. In the 1996 
proposed rule, FDA stated that the current method for measuring fat 
excretion is noninvasive, by which FDA meant that these studies 
consisted of collecting feces and urine which are naturally excreted 
from the body of infants. However, as noted in the comment, the 
accurate collection of such specimens is technically very difficult 
and, in some or all cases, would require hospitalization to ensure 
accurate sampling and measurement. The limitations on such studies are 
a second separate reason not to require metabolic balance studies of 
infant formula.
    (Comment 272) With respect to fat balance studies, one comment 
stated that the level of fat malabsorption that leads to clinical or 
body composition effects is not well defined and may not be 15 percent 
as stated in the 1996 proposal (61 FR 36154 at 36181). The comment 
concluded that this factor adds to the limitations of fat balance 
studies.
    (Response) FDA agrees with this comment that the level of fat 
malabsorption that leads to clinical or body composition effects is not 
well defined and that this fact would be a further limitation to fat 
balance studies. The mean amount of fat not absorbed is approximately 
15%, but the degree of malabsorption depends on the type of fat at 
issue. One source shows that the range of fat excreted (Ref. 83, 
pp.164-165) is between 0.66 to 9.3 percent of intake when vegetable 
oils are the fat source in a milk-based infant formula, and that 
infants excrete a higher proportion of fat when homogenized cow milk is 
consumed; the latter level is related to the type of fat in cow milk 
(butterfat), which young infants cannot readily digest because they 
lack the necessary bile salts and enzyme. Thus, this comment supports 
the Agency's decision not to establish quality factor requirements for 
fat.
    (Comment 273) One comment opposed the establishment of quality 
factor requirements for fat, calcium, and phosphorus because, the 
comment asserted, the collection of formula intake and stool data by 
untrained parents (which would be part of a metabolic balance study) 
would result in extremely inaccurate data if studies were conducted on 
term infants in the home.
    (Response) FDA agrees that the use of untrained parents to collect 
study data is one very practical limitation of a balance study and 
thus, is an additional reason to not identify, and establish 
requirements for, quality factors for fat, calcium, and phosphorus at 
this time.
    (Comment 274) Other comments noted that financial and, perhaps, 
ethical difficulties may be associated with balance studies because 
such studies may require hospitalization and restraint of infants. The 
comment characterized hospitalization as ``invasive.''
    (Response) FDA does not agree with the comment that hospitalization 
is conventionally considered ``invasive.'' However, the Agency agrees 
that to ensure maximum accuracy in the collection of infant input and 
output information in a balance study, it could be necessary to confine 
the infant study subjects to a hospital and, in some cases, to restrain 
the subjects. FDA agrees that these two possibilities are significant 
negatives of establishing a quality factor for fat and requiring a 
balance study of a new formulation of an infant formula to demonstrate 
that the quality factor is satisfied.
    (Comment 275) Several comments suggested that fat, calcium, and 
phosphorus balance studies should be performed on a voluntary basis 
when the manufacturer believes they are necessary to assess specific 
effects of a formula or ingredient.
    (Response) FDA does not disagree with this comment. To the extent 
that a formula manufacturer believes that fat, calcium, or phosphorus 
studies would be meaningful for evaluating a particular infant formula, 
FDA would generally not object to the conduct of such a study. 
Importantly, however, prior to conducting any such study, the 
manufacturer should be certain that data from such study are necessary 
and will be meaningful so as to avoid subjecting the infants study 
subjects to unnecessary testing.
    (Comment 276) One comment stated that balance studies are more 
useful for comparing formulas than for assessing adequacy of a 
particular formula and suggested that the decision to include balance 
studies should be made during development of a study protocol.
    (Response) FDA agrees with this comment to the extent that it 
asserts that a balance study must be designed to answer the research 
question at issue. However, the comment did not explain how adequacy of 
a particular formula could be determined without comparing the test 
formula to a control formula that has already been evaluated for 
nutritional adequacy.
    Generally speaking, a balance study would be used to compare one 
factor under investigation (e.g., the fat blend of a formula) while all 
other factors are kept constant. Thus, in a study comparing the fat 
blend of one formula to another, the study design would require that 
the test and control formulas contain all the same nutrients except the 
fat source, which would be different in the test and control formulas 
(Refs. 83 and 84). As noted, however, FDA is affirming the Agency's 
tentative 1996 decision that no metabolic balance studies will be 
required of new formulations of infant formulas.
    Several comments addressed specific aspects of balance study design 
and methodology.
    (Comment 277) One comment pointed out the desirability of using 
comparable levels of minerals in both the test and control formulas 
since mineral retention in balance studies tends to become more 
positive with higher intakes.
    (Response) FDA agrees that mineral retention in balance studies 
tends to become more positive with higher intakes and that, when 
conducting a balance study, it is desirable to use comparable levels of 
minerals in test and control formulas to reduce the potential for 
confounding, which could result in misinterpretation of study results. 
As noted, however, FDA is affirming the Agency's tentative 1996 
decision that no balance studies will be required of new formulations 
of infant formulas.
    (Comment 278) One comment asserted that serum alkaline phosphatase 
determination would be of no value in calcium and phosphorus balance 
studies as the time course of its response is slower than the brief 
period of a balance study and there are age specific, gestational, and 
nutrient effects that complicate its interpretation.
    (Response) FDA agrees with this comment that alkaline phosphatase

[[Page 8032]]

analysis in balance studies would be of limited value for the reasons 
given. As noted, however, FDA is affirming the Agency's tentative 1996 
decision that no balance studies will be required of new formulations 
of infant formulas. Therefore, this comment has no bearing on the 
interim final rule.
    (Comment 279) Another comment pointed out that preterm infants, who 
have sometimes been used as subjects for balance studies, would not be 
appropriate subjects for the studies of formulas for term infants.
    (Response) FDA agrees with this comment. Preterm infants would not 
be appropriate participants for balance studies evaluating the 
bioavailability of infant formulas intended for term infants because 
each group has specific nutrient needs that are not identical. In 
particular, preterm infants are at great risk for malnutrition and 
require relatively greater amounts of energy, protein, calcium, 
phosphorus, vitamin D, and vitamin A levels compared to the needs of 
healthy term infants. Thus, extrapolation of data from preterm infants 
to healthy term infants could result in erroneous conclusions about 
necessary nutrients for healthy term infants. For a study of a formula 
intended for use in term infants, the study population must be composed 
of such infants. Because the Agency has confirmed its 1996 tentative 
decision not to require balance studies of infant formula, however, no 
change in the interim final rule is required in response to this 
comment.
    (Comment 280) One comment indicated that sensitivity of balance 
studies is greater with a crossover design (Ref. 67). Another comment 
pointed out that crossover design would subject an infant to a longer 
period of confinement and restraint and considered this unwarranted for 
routine testing of all products.
    (Response) FDA agrees that a crossover design could be used in a 
balance study to increase the power of a study using a small study 
population because each participant would serve as his or her own 
control. Importantly, however, balance studies require that the infant 
be confined to a hospital for 72 hours for each study period, 
immobilized in a ``papoose-like'' devise that permits all urine and 
feces to be continuously collected. Given these necessary conditions of 
a balance study, this type of study should only be performed when 
absolutely necessary because of its extremely restrictive nature (Ref. 
85). Given the lack of sound methods for measuring essential nutrients 
and the lack of predictive outcomes from many of these of studies, FDA 
has determined that balance studies should not be required by this 
interim final rule for any nutrient in infant formula.
    Several comments addressed the use of methods other than balance 
studies to evaluate bioavailability of total fat, calcium, and 
phosphorus.
    (Comment 281) One comment concurred with FDA's tentative conclusion 
in the 1996 proposal that there is no current practical and generally 
accepted alternative to balance studies for assessing bioavailability 
of these nutrients (61 FR 36154 at 36188). However, the comment noted 
that newer measures of assessing bone mineralization directly hold 
considerable promise for evaluating these nutrients in infant formulas, 
suggesting that these methods could be useful when they become more 
standardized and more normative data become available for infants.
    (Response) FDA agrees with this comment that, at the time of the 
1996 proposal, new means of assessing bone mineralization directly, 
such as dual-energy x-ray absorptiometry (DEXA) scans, appeared 
promising. However, DEXA has not achieved sufficient reliability to be 
considered a ``gold standard'' for body composition of infants and is 
currently confined largely to use as a research tool. The Agency has 
considered the data presented at the 2002 meeting of the FAC, as well 
as recent studies (Refs. 86 and 87), and finds no basis to require DEXA 
scans in growth monitoring studies. Accordingly, the Agency is not 
persuaded at this time to add tests using these methods as a 
requirement to demonstrate the bioavailability of an infant formula or 
of calcium and phosphorus in infant formulas.
    (Comment 282) One comment stated that, when alterations in fat 
source or composition are proposed, the manufacturer should be required 
to demonstrate that study subjects' serum fatty acid levels are 
comparable to those of breast-fed infants or infants fed other standard 
infant formulas.
    (Response) FDA does not agree with this comment. The comment 
provided no evidence or reasoning to support the recommendation that 
the evaluation of serum fatty acid levels of infants consuming a new 
infant formula formulation should be required to be measured and 
determined to be equivalent to infants that are breast-fed or are 
consuming a standard infant formula. Moreover, FDA is aware of no 
scientific evidence that suggests that measurement of serum fatty acids 
would be a means to assessing the ability of an infant formula to 
ensure healthy growth. Although measuring serum fatty acids reflects, 
to some extent, an infant's diet, serum fatty acids are also influenced 
by other factors such as timing of the blood draw in relation to 
formula consumption and hormonal responses. Finally, the fatty acids in 
circulation do not predict growth. The levels of some fatty acids can 
be used to determine whether there are adequate levels of essential 
fatty acids (linoleic and linolenic) but these circulating levels are 
not directly related to normal physical growth.
    For the reasons discussed previously in this document, the Agency 
is not establishing in this interim final rule requirements for quality 
factors related to fat, calcium, or phosphorus.
3. Quality Factor for Iron
    In the 1996 proposal (61 FR 36154 at 36182 and 36189), FDA 
requested comment on whether a quality factor for iron should be 
established and what data would be needed to establish that the iron in 
an infant formula is sufficiently bioavailable and maintains the iron 
status of infants that consume the formula. The Agency observed that 
the data on iron bioavailability would need to demonstrate that an 
infant formula provides enough iron to prevent iron deficiency and 
anemia. The Agency expressed concern, however, that a growth monitoring 
study of full-term infants aged zero to four to five months might not 
be sensitive enough to detect significant differences in iron 
bioavailability of a formula product because healthy, full-term infants 
are usually born with adequate iron stores to maintain normal iron 
status for the first three to four months of life--the time when the 
growth monitoring study would be conducted. Without assurance that the 
test results would be meaningful, the Agency tentatively decided not to 
establish quality factor requirements for iron.
    A number of comments supported the inclusion of a quality factor 
for iron for infant formulas and supported establishing requirements 
for such quality factor. Other comments objected to a general quality 
factor for iron.
    (Comment 283) One comment stated that manufacturers are currently 
expected to include these measures in the clinical evaluation of their 
formulas and thus, it is not anticipated that measurements of this 
quality factor should present difficulties to manufacturers or those 
involved in the clinical study of infant formulas.
    (Response) FDA disagrees with this comment to the extent that it 
asserts that manufacturers currently measure the bioavailability of 
iron in their clinical

[[Page 8033]]

evaluations of infant formulas. To date, FDA has not recommended that 
manufacturers include metabolic balance studies to evaluate the 
adequacy of iron in new infant formulas. In fact, in the 1996 proposal, 
FDA tentatively concluded that the clinical and nutritional sciences 
had not reached a level of development such that specific tests were 
available to establish that infant formulas could be demonstrated to 
satisfy quality factors for each of the essential nutrients listed in 
Sec.  107.100, except for protein (61 FR 36154 at 36182). This comment 
did not provide any information to contradict the Agency's tentative 
conclusion that quality factor requirements should not be established 
for nutrients other than protein. Accordingly, FDA declines to 
establish a quality factor for iron in this interim final rule.
    (Comment 284) Another comment regarded the failure to include a 
quality standard for iron as a problem, noting that iron deficiency 
would not be detected by anthropometric (weight) measurements used to 
evaluate the normal physical growth quality factor.
    (Response) FDA disagrees in part with this comment. The Agency 
agrees that iron insufficiency will not be readily detected in a growth 
study evaluating normal physical growth. Importantly, however, as noted 
in the preamble to the proposed rule, infants are born with iron stores 
sufficient until age three to four months. For this reason, the growth 
monitoring study required by Sec.  106.96(b) of the interim final rule 
to assess normal physical growth will be neither sensitive enough nor 
long enough to show iron deficiency. Thus, FDA is not adding a 
requirement to measure iron to the requirements for the growth 
monitoring study.
    (Comment 285) Another comment strongly supported establishing a 
quality factor for iron, concluding that implementation of the iron 
status quality factor would go a long way toward providing the 
scientific data to resolve the issue of what level of iron is correct 
for infant formula.
    (Response) FDA agrees that iron status is important to infants' 
nutritional well-being. Although there are some available methods for 
evaluating iron status, the most sensitive of these methods require 
invasive procedures. Balance studies also offer a means to assess 
bioavailability of iron but the balance method is less sensitive and, 
as noted previously in this document, requires hospitalization and 
prolonged restraint of the infants.
    As noted in the 1996 proposed rule, term infants are generally born 
with adequate iron stores to meet their needs for the first few months 
of life. Even if suitably sensitive and noninvasive methods were 
available to measure iron status in infants, it is questionable whether 
such measurements made during early infancy would provide meaningful 
information on the bioavailability of iron in infant formulas. For 
these reasons, FDA does not agree that the Agency should establish a 
quality factor for iron at this time.
    The purpose of establishing a quality factor for a nutrient is to 
require a determination of whether the nutrient is bioavailable in the 
infant formula, i.e., that the nutrient is digested and absorbed by the 
infant as the product is formulated for market. The question of what 
level of a nutrient is ``correct'' for infant formula is better 
addressed by studies with outcome measures designed to answer that 
question specifically.
    (Comment 286) One comment stated that a poorly available source of 
iron would be a problem for an infant between the ages 4 and 12 months 
fed only formula and noted that, while feeding only formula to healthy 
infants from 4 to 12 months of age is not consistent with CON/AAP 
recommendations, there are instances where a formula-only diet has been 
fed for extended periods of time to infants 4 to 12 months of age.
    (Response) FDA agrees that there may be rare cases in which formula 
is the exclusive nourishment provided to infants after age 4 months and 
that it could be problematic if that formula is deficient in iron. 
Importantly, however, the comment included no evidence to establish the 
concern that currently marketed formulas are poor sources of iron. 
Infants are usually seen by their pediatricians every 1 to 2 months 
during the first year of life, and, consistent with AAP 
recommendations, most but not all infants are starting complementary 
foods by 4 months of age (Refs. 70 and 88). Thus, these rare instances 
of formula-only diets in older infants do not require the Agency to 
establish a quality factor for iron, particularly given the factors 
weighing against such establishment.
    (Comment 287) One comment recommended that studies of iron status 
in infants be performed only when the manufacturer believes that such 
studies may help assess effects of a specific formula or ingredient.
    (Response) FDA does not disagree with this comment. To the extent 
that a formula manufacturer believes that an iron status study would be 
meaningful for evaluating a particular infant formula with a specific 
ingredient, FDA would not object to the conduct of such a study. 
Importantly, however, before conducting any such study, the 
manufacturer should be certain that data from such study are necessary 
and will be meaningful so as to avoid subjecting the infant study 
subjects to unnecessary testing.
    (Comment 288) Several comments noted that the quality factor for 
iron would be of little value in the first four months of life, when 
the standard growth study would be conducted.
    (Response) FDA agrees with this comment. As noted in the 1996 
proposed rule, full-term infants are generally born with adequate iron 
stores to meet their iron needs for the first few months of life, a 
fact that restricts the ability to conduct an accurate assessment of 
iron bioavailability during the period of the growth monitoring study. 
The Agency did not receive data or other information challenging FDA's 
statement about newborn iron stores nor did any comment dispute that 
these stores would interfere with the ability to measure iron 
bioavailability during the growth monitoring study.
    (Comment 289) Other comments objected to establishment of a quality 
factor for iron status because it would require an invasive procedure 
of drawing blood. The comments further stated that when blood draws are 
required in infants, physicians are more reluctant to conduct studies 
on well babies and parents are much more likely to refuse enrollment or 
drop out of the study.
    (Response) FDA agrees that establishing a quality factor for iron 
and a requirement to show that this quality factor is satisfied by an 
infant formula would likely require blood draws of study subjects, 
which would be an invasive procedure not otherwise required in the 
growth monitoring study. However, as noted previously in this document, 
FDA is not establishing a quality factor for iron because it is not 
possible to perform an accurate assessment of iron's bioavailability in 
the early months of infancy, the period during which formula is 
consumed as the sole source of nutrition. FDA concludes that the risk, 
however small, of the invasive procedure of a blood draw is not 
justified given that any resulting iron bioavailability data would be 
of very limited, if any, value.
    (Comment 290) One comment noted that the creation of a quality 
factor for iron is complicated by the presence in the U.S. market of 
formulas with varying levels of iron fortification, some of which are 
nutritionally adequate from the standpoint of iron and others which may 
not be adequate, but still meet the

[[Page 8034]]

standards of the FD&C Act. The comment contended that it makes little 
sense to develop a quality factor for a nutrient that is not required 
by law in formulas for healthy infants in nutritionally adequate 
amounts and that no quality factor recommendation would be appropriate 
until and unless the FD&C Act is modified to establish a required level 
of bioavailable iron.
    (Response) FDA disagrees with this comment. Although the comment is 
correct that Sec.  107.100 permits a wide range of iron content in 
infant formula (0.15 to 3 mg/100 kcal), the comment appears to confuse 
the range of permitted iron levels in infant formulas with the need for 
the iron in formulas to be bioavailable. The iron in infant formula 
must be bioavailable, regardless of the amount present. As noted, FDA 
is not establishing a quality factor for iron in this interim final 
rule, but not for the reason given in this comment.
    (Comment 291) One comment recommended that FDA establish a quality 
factor for iron and require animal assays to assess the iron's 
bioavailability, rather than require additional assessment measures in 
a standard growth study.
    (Response) As explained previously in this document, FDA is not 
establishing a quality factor for iron because of constraints on the 
use of available methods for measuring the iron status of healthy term 
human infants. The comment did not identify any animal assay that could 
potentially be used to demonstrate that a particular infant formula 
satisfies an established quality factor for iron. The Agency is aware 
that nonhuman primate and rodent models have been used in studies of 
iron status and infant neurocognitive and neurobehavioral development 
(Ref. 89), and newborn piglets have also been used in studies of 
nutrient absorption from infant formulas, but the comment provided no 
animal data on iron bioavailability that could readily be applied to 
infants. Without such information, FDA is not persuaded to establish a 
quality factor for iron and to require an animal test to demonstrate 
the bioavailability of iron in infant formula.
    (Comment 292) Several comments that supported inclusion of a 
quality factor for iron concluded that serum ferritin (i.e., a stage 1 
measurement of iron status) would be the appropriate quality factor 
measurement because if ferritin is sufficient in the infant, there is 
no risk that stage 2 or 3 iron status will be reached. The comment 
further suggested that a measurement of ferritin alone would make 
studies more efficient, cost effective, and less invasive.
    (Response) FDA agrees that serum ferritin is a very useful tool for 
assessing iron nutritional status. However, as FDA noted in the 
proposed rule (61 FR 36154 at 36182), healthy, full-term infants are 
usually born with adequate iron stores to maintain normal iron status 
for the first 3 to 4 months of life--the period of time that a growth 
monitoring study will be conducted. Moreover, the serum ferritin 
assessment requires an invasive procedure (blood draw). For these 
reasons, FDA declines to establish the measurement of ferritin as a 
quality factor requirement for new infant formulas.
    For the foregoing reasons, FDA is not revising Sec.  106.96 in this 
interim final rule to establish a quality factor for iron.
4. Standard Laboratory Measures
    In the 1996 proposal, FDA requested, and received, comment on 
whether the collection of standard laboratory measures, such as 
complete blood count (white blood cell count and red blood cell count), 
hemoglobin concentration or hematocrit percentage, and serum or plasma 
concentrations of albumin, urea, nitrogen, electrolytes (sodium, 
potassium, and chloride), alkaline phosphatase, and creatinine, would 
be useful and necessary information for determining whether a formula 
causes adverse consequences that may not be reflected in the quality 
factor requirements for normal physical growth (61 FR 36154 at 36184).
    (Comment 293) One comment pointed out that FDA did not propose to 
make serum chemistries into quality factors and that there are 
situations where the relevant clinical endpoints would be biochemical 
indicators of nutritional status.
    (Response) FDA notes that the comment did not submit any data or 
other information identifying the particular situations that would 
require serum chemistries to evaluate the nutritional adequacy of an 
infant formula or why serum chemistry evaluations should be a standard 
requirement for growth monitoring studies. The growth monitoring study, 
which is often conducted on an outpatient basis, evaluates the adequacy 
of the formula to support normal physical growth and an infant's 
tolerance of the formula. Although the AAP report (Ref. 67) recommended 
that some blood tests might be useful at the conclusion of the study 
period, the decision lies with those responsible for designing and 
conducting the study. FDA concludes, as discussed in the 1996 proposed 
rule, that it is not appropriate to require invasive procedures, such 
as blood draws, as part of this interim final rule. As discussed in 
this document, the Agency encourages manufacturers to evaluate each new 
formulation to determine whether the nature of the particular new 
formulation suggests that serum blood chemistries should be required. 
Accordingly, FDA is making no change in the interim final rule in 
response to this comment.
    (Comment 294) One comment stated that doing such blood work is not 
a standard practice of investigators and that drawing blood would 
violate the principles that the FDA cites for protecting the infant 
from unnecessary testing. The comment further asserted that 
establishing a requirement for drawing blood would cause many parents 
to refuse to have their infants participate in a study. Thus, the 
comment argued, collecting this information routinely would not be 
useful and could be detrimental for the timely completion of clinical 
studies.
    (Response) FDA agrees with this comment. No comments submitted in 
response to the Agency's request included data or other information to 
demonstrate that standard blood chemistry measures are necessary to 
evaluate whether an infant formula supports normal physical growth of 
infants, and without question, collecting such data would require blood 
draws, which is an invasive procedure. Accordingly, FDA is not 
persuaded to require these standard laboratory measures as a part of 
all growth studies.
    FDA notes, however, that some or all of these measures may be 
appropriate for the testing of certain formulas or for certain changes 
in a particular formula. For example, if a formula is developed with an 
unusual renal solute load, measures of albumin, urea, electrolytes, and 
creatinine in serum may be appropriate. The Agency encourages 
manufacturers to evaluate each new formulation to determine whether 
testing a particular formulation requires some or all of these blood 
chemistries.
    For these reasons, FDA is making no change in the interim final 
rule in response to these comments.

K. Miscellaneous Comments on Quality Factors

    (Comment 295) One comment challenged the statement in the 1996 
proposal (61 FR 36154 at 36179) that referred to selenium as a 
``nonrequired nutrient.'' The comment asserted that selenium is an 
essential nutrient for infants, i.e., a required nutrient for infants.

[[Page 8035]]

    (Response) FDA is aware that selenium is an essential nutrient for 
infants. In the preamble to the 1996 proposal (61 FR 36154 at 36155), 
FDA stated ``For the purpose of this document, the nutrients that are 
required to be in infant formula under Sec.  107.100 will be referred 
to as ``required nutrients.'' Thus, the term ``nonrequired'' referred 
to the status of selenium on the Congressionally-mandated list of 
ingredients set out in section 412(i) of the FD&C Act and established 
by regulation at 21 CFR 107.100. The list of minimum and maximum 
specifications for nutrients in infant formulas was most recently 
revised in 1986, 3 years before establishment of a recommended dietary 
allowance for selenium for infants (Ref. 60).
    Additionally, in the Federal Register of April 16, 2013 (78 FR 
22442), FDA published a proposed rule to amend the regulations on 
nutrient specifications and labeling for infant formula to add selenium 
to the list of required nutrients and to establish minimum and maximum 
levels of selenium in infant formula.
    (Comment 296) One comment agreed with FDA's proposal (61 FR 36154 
at 36178) to revoke the requirement in current Sec.  106.30(c)(2) for 
determination of vitamin D by a rat bioassay method.
    (Response) In this interim final rule, FDA is revoking the 
requirements in current Sec.  106.30(c)(2) for the determination of 
vitamin D by a rat bioassay method. As explained in the proposed rule, 
this rat bioassay for vitamin D is no longer a reasonable requirement 
because appropriate animals for conducting this test are difficult to 
acquire (Ref. 90), and an alternate analytical method for the 
determination of vitamin D in infant formulas has been approved by AOAC 
(Ref. 91).

IX. Subpart F--Records and Reports

    As noted in the introductory section of this preamble, in 1991, FDA 
revised subpart C in part 106, and established records and reports 
requirements for infant formula (56 FR 66566, December 24, 1991). These 
regulations were authorized by section 412 of the FD&C Act, as amended 
by the 1986 amendments, and replaced the original records regulations 
established in 1982 (47 FR 17016, April 20, 1982).
    Thereafter, in 1996, the Agency proposed additional revisions to 
the infant formula records and reports regulations and proposed to 
redesignate these requirements as subpart F in part 106. The proposed 
requirements related to batch (production aggregate) records (proposed 
Sec.  106.100(e)), records to document compliance with CGMP (proposed 
Sec.  106.100(f)), infant formula distribution records (proposed Sec.  
106.100(g)), and records of regularly scheduled audits (proposed Sec.  
106.100(j)). As noted in the proposed rule, FDA is retaining 21 CFR 
106.100(l) of the current infant formula regulations. Thus, all of the 
records that are required to be maintained under this interim final 
rule shall be made readily available for FDA inspection.
    FDA received a number of comments on the proposed revisions to the 
records and reports requirements. These comments are summarized in this 
document along with the Agency's responses.

A. General Comments on Records (Proposed Sec.  106.100)

    (Comment 297) One comment objected to the phrase that relevant 
records shall ``include but are not limited to'' in proposed Sec.  
106.100(e), (e)(1), (e)(3), (f), (f)(6), and (g). The comment asserted 
that the required records should be limited to focus on and incorporate 
the statutory reference to ``necessary'' documents, rather than the 
broader language that was proposed.
    (Response) FDA is removing the phrase ``but are not limited to'' 
language from the proposed sections identified in the comment, but not 
for the reason stated in the comment. The language is unnecessary 
because the words ``include,'' ``includes,'' and ``including'' have the 
connotation that the itemized list that follows is not exclusive.
    Importantly, however, the Agency did not intend to identify in the 
proposed codified each and every record that may be required where 
these terms appear. Section 412(b)(4)(A)(i) of the FD&C Act requires 
the Secretary to establish requirements that provide for the retention 
of all records ``necessary to demonstrate compliance with the good 
manufacturing practices and quality control procedures. . . .'' 
Proposed Sec.  106.100(e), for example, would require a manufacturer to 
prepare and maintain records that include ``complete information 
relating to the production and control of the batch.'' Although 
proposed Sec.  106.100(e) specifies certain records that must be 
established and maintained under this section, this provision does not 
list every record related to ``complete information relating to the 
production and control of the batch.'' Thus, if a manufacturer includes 
in its master manufacturing order certain documents that are related to 
the production and control of a production aggregate of infant formula, 
such information would be required to be maintained under this 
regulation even if the documents are not expressly identified in 
proposed Sec.  106.100(e)(1).
    (Comment 298) One comment asserted that the proposed documentation 
requirements are very burdensome and would necessitate additional 
staffing to implement. However, the comment claimed that it was 
difficult to quantify the additional cost without further clarification 
and that it was not possible to comment further on the estimated annual 
recordkeeping burden until the regulations are finalized.
    (Response) This comment simply asserts that records requirements 
are burdensome without any attempt to quantify recordkeeping costs or 
to estimate the recordkeeping burden. Also, the comment included no 
supporting data or information for FDA to consider and to which the 
Agency could respond. Therefore, FDA is not revising the interim final 
rule in response to this comment.
    (Comment 299) Another comment observed that in the proposed rule, 
FDA proposes large increases in recordkeeping, which will involve 
recording results for each batch (production aggregate) of ingredients, 
including the source of production, the batch (production aggregate) 
number, the lot (production unit) number, and analysis records of raw 
materials.
    (Response) The records required by this interim final rule are 
necessary to achieve the public health goals of the FD&C Act, including 
the CGMP regulations, which are designed to prevent the adulteration of 
infant formula caused by equipment or utensils, automatic equipment, 
ingredients, containers, and closures, as well as to prevent 
adulteration of formula during manufacturing, packaging, and labeling. 
The comment does not challenge these goals or contradict the need for 
these records. Accordingly, FDA is not revising the interim final rule 
in response to this comment.
    (Comment 300) One comment claimed that under the proposed rule, 
production records such as pH, temperature, solids, fat, protein, and 
lactose would also have to be retained for 2 years after the expiration 
date of the product and that this will be very expensive and contribute 
little to the overall quality of the product. The comment also 
questioned the need to retain results for 2 years following a product's 
withdrawal from marketing.
    (Response) It is unclear which provision of the proposal is the 
subject of this comment. The proposed rule did not contain, and the 
interim final rule

[[Page 8036]]

does not contain, a 2-year record retention requirement.
    The comment may be referring to current 21 CFR 106.100(n), which 
requires retention of production records for 1 year after the 
expiration of the shelf-life of a infant formula or 3 years from the 
date of its manufacture, whichever is greater. FDA did not propose any 
changes to this requirement, and is making no changes to this 
requirement in this interim final rule. Although the comment asserted 
that required records retention would be ``very expensive,'' the 
comment did not offer any data or information to quantify any added 
expense. Similarly, although the comment asserts that records retention 
will contribute little to the overall quality of infant formula, the 
comment provided no data, information, or explanation to support its 
assertion about the alleged lack of effect on product quality. 
Accordingly, FDA is making no revisions to the interim final rule in 
response to this comment.

B. Production Aggregate Production and Control Records (Proposed Sec.  
106.100(e))

    As discussed in section IV.C, to improve the clarity of the interim 
final rule and eliminate certain ambiguity and confusion, FDA is 
establishing in this interim final rule new terminology to refer to the 
basic volumes of formula produced by a manufacturer. The two new terms, 
which are identified in Sec.  106.3 of the interim final rule, are 
``production aggregate'' and ``production unit.'' In the discussion 
that follows, FDA is adding the parenthetical ``(production 
aggregate)'' or ``(production unit),'' as appropriate, after the word 
``batch'' or ``lot'' when used in a comment summary and is substituting 
the new term ``production aggregate'' or ``production unit'' for 
``batch'' or ``lot,'' as appropriate, in responses to comments and 
where ``batch'' or ``lot'' was used in the proposed rule.
    (Comment 301) One comment acknowledged that complete documentation 
of the manufacture and release of each batch (production aggregate) of 
infant formula (which proposed Sec.  106.100(e) would require) is 
essential, and such documentation must be readily available for review. 
However, the comment argued that compilation of such documentation into 
one record for each batch (production aggregate) would be redundant and 
overly burdensome to manufacturers having established documentation 
review systems designed to provide retrieval of all critical 
information upon request. The comment requested that the Agency clarify 
whether current practices could be continued under this regulation.
    (Response) FDA is not able to respond directly to the request for 
clarification concerning the continuation of current practices because 
there are multiple infant formula manufacturers in the U.S. and the 
practices of those manufacturers are both likely to be different and 
are likely to have changed since the submission of the comment.
    Importantly, however, the Agency agrees with the comment that 
establishing and maintaining complete documentation of a production 
aggregate of infant formula is essential because the manufacturer, FDA, 
or both may need to access and consult the records rapidly in order to 
identify and resolve a problem related to the production of a 
particular production aggregate before the infant formula product is 
released for distribution. In establishing Sec.  106.100(e) of the 
interim final rule, FDA's goal is to ensure that the complete 
production aggregate documentation is immediately available and 
accessible to both FDA and the manufacturer. In the case of records 
maintained as hard copies, immediate availability and accessibility is 
accomplished by co-locating all required records relating to a 
particular production aggregate (i.e., by establishing a single, 
consolidated record in one physical location). For records that are 
maintained electronically, immediate availability and accessibility is 
accomplished by linking electronically all required records that 
pertain to the same production aggregate in a way that will permit 
their instantaneous retrieval.
    The Agency disagrees that maintaining a single record for each 
production aggregate would be overly burdensome to manufacturers who 
have established documentation review systems that can retrieve all 
critical information immediately upon the Agency's request. If such 
documentation in written form is kept in a location other than the 
production and control record for the particular production aggregate, 
there is no way to review the entire production process during 
manufacture without retrieving all of the critical information from 
other records and storage locations. Similarly, if electronic records 
are not properly linked, neither the producer nor FDA will have prompt 
access to such records. Accordingly, FDA is clarifying the proposed 
requirement in Sec.  106.100(e) of the interim final rule in response 
to this comment, by amending Sec.  106.100(m) of the interim final rule 
to explain that all records, no matter what their form, must be 
maintained in a way that allows for immediate access.
1. Master Manufacturing Order Records
    (Comment 302) One comment objected to the requirement in proposed 
Sec.  106.100(e)(1)(ii) that where a manufacturing facility has more 
than one set of equipment or more than one processing line, the master 
manufacturing order identify the equipment and processing lines used in 
making a particular batch (production aggregate). The comment suggested 
that this provision be revised to require that, in such circumstances, 
the master manufacturing order include the identity of only the major 
equipment systems used in producing the batch (production aggregate). 
The comment argued that it is reasonable to require the identity of 
major equipment systems, such as processing systems and filling lines, 
if more than one is available; however, it is not reasonable to expect 
every piece of processing equipment, such as every transfer line, hook-
up station, jumper, and valve, to be identified in the production 
records. The comment noted that infant formula manufacturing involves 
multitudes of equipment pieces and lines, so the itemization of these 
for every batch (production aggregate) would require significant 
resources with no practical benefits.
    (Response) FDA is not persuaded to revise Sec.  106.100(e)(1)(ii) 
to limit the subject equipment to ``major equipment systems'' because 
doing so may exclude equipment that, while not ``major,'' may, in the 
event of a malfunction or contamination, be implicated nonetheless in 
the adulteration of an infant formula. The purpose of this requirement 
is in part to facilitate the identification of all production 
aggregates of formula that may be affected by a particular instance of 
equipment malfunction or that were produced on the same equipment as a 
production aggregate that is discovered to be microbiologically 
contaminated (61 FR 36154 at 36190). To achieve this purpose, a 
manufacturer must identify such equipment and processing lines to 
ensure, for example, that any equipment malfunctions that adulterate or 
may lead to adulteration of the infant formula can be linked to any 
implicated production aggregates of infant formula, which will 
facilitate a material review and disposition decision and appropriate 
corrective action. Similarly, it would be important to identify in the 
production aggregate record any equipment components that could be a 
source of adulteration but would not be readily

[[Page 8037]]

identified from the piece of equipment used.
    Although FDA is not making the revision requested by this comment, 
the Agency is adding a phrase to Sec.  106.100(e)(1)(ii) in the interim 
final rule to clarify that records of the identity of the equipment and 
processing lines only need to be kept for the equipment and processing 
lines for which the manufacturer has identified points, steps, or 
stages in the production process where control is necessary to prevent 
adulteration. Thus, Sec.  106.100(e)(1)(ii) of the interim final rule 
states: ``For a manufacturing facility that has more than one set of 
equipment or more than one processing line, the identity of equipment 
and processing lines for which the manufacturer has identified points, 
steps, or stages in the production process where control is necessary 
to prevent adulteration.''
    (Comment 303) One comment requested that proposed Sec.  
106.100(e)(1)(v) be revised to delete the requirement that the master 
manufacturing order include copies of all labeling and substitute a 
requirement that the master manufacturing order include copies of all 
primary container labels used and the results of examinations during 
finishing operations to provide assurance that containers and packages 
have the correct label. The comment agreed with the requirement to 
include a sample of the primary container label in each batch 
(production aggregate) record, but asserted that including trays, 
cartons, and shippers that are also considered labeling would 
substantially increase the size of the batch (production aggregate) 
record because the trays, cartons, and shippers are relatively bulky.
    (Response) FDA agrees that it is adequate to include in the master 
manufacturing order record only a copy of the labeling used on the 
immediate container of the finished production aggregate of infant 
formula. Such labels are usually distinctive in appearance and, unlike 
trays, cartons, and shippers, generally are the labeling on which 
consumers rely when purchasing and using a formula. FDA notes that, by 
definition, the word ``label'' is written, printed, or graphic matter 
affixed to the immediate container of a product. 21 U.S.C. 321(k). 
Accordingly, FDA is modifying Sec.  106.100(e)(1)(v) in the interim 
final rule to require that the master manufacturing order include a 
copy of each label used on a finished production aggregate of infant 
formula and the results of examinations conducted during the finishing 
operations to provide assurance that all containers have the correct 
label.
    (Comment 304) One comment objected to the use of the phrase 
``corrective actions'' in proposed Sec.  106.100(e)(2), (e)(3)(ii), and 
(e)(4)(i) and requested that the phrase be replaced with ``specific 
actions'' in each of these sections. The comment argued that, due to 
timing, it is not always practical to include corrective actions in the 
same batch (production aggregate) record as the documentation of 
deviations. The comment explained that if the corrective action is 
immediate, it would be reasonable to include documentation of the 
corrective action in the batch (production aggregate) record. However, 
the comment contended, it is impractical to include the corrective 
action when the deviation requires investigation and research over an 
extended period of time or involves the evaluation of multiple batches 
(production aggregates) before the appropriate corrective action is 
identified. In these cases, the comment maintained, it would be 
impractical to place a copy of the corrective action taken into the 
record of each affected batch (production aggregate) after the fact but 
it would be sufficient to require documentation of the manufacturer's 
response to each deviation in its respective batch (production 
aggregate) record. The comment argued that this action would include 
responses to the deviations, if immediately known, or a statement of 
the need for further evaluation, or some other appropriate indication 
of the status of the investigations or corrective action.
    (Response) FDA is not persuaded by this comment because it ignores 
the role of production records, including records of corrective 
actions, in ensuring the safety of infant formula.
    In the preamble to the 1996 proposal, FDA discussed why these 
records must appear in the production aggregate production and control 
record (61 FR 36154 at 36190-36191). These records have a critical role 
helping the manufacturer to ensure that the infant formula is in 
compliance with the CGMP requirements for infant formula and to ensure 
that any deviation that has occurred during the production of the 
infant formula will not adulterate or lead to adulteration of the 
product. A manufacturer must not release a finished production 
aggregate of infant formula until it determines that the production 
aggregate meets all of its specifications, or until the documented 
review of the failure to meet any of the manufacturer's specifications 
finds that the failure does not result in, or could not lead to, 
adulteration of the product (see Sec.  106.70(a) of the interim final 
rule). A manufacturer would need to determine what, if any, 
specifications are or may not be met and otherwise address a deviation 
from the master manufacturing order before the production aggregate of 
infant formula is released for distribution. Thus, any determination of 
how to handle a deviation will occur during the time period when the 
production and control record is being prepared. Once a manufacturer 
has determined how to handle a deviation from specifications, any 
corrective action shall be recorded and that record made part of the 
production aggregate record at that time.
    Furthermore, if a deviation is noted in the production and control 
record for the production aggregate, documentation of any corrective 
action taken must appear in the production aggregate record to make it 
complete and to ensure that the deviation was appropriately 
investigated and addressed. Therefore, documentation of any corrective 
action(s) taken is appropriately part of the production and control 
record for the production aggregate to provide a basis for the ultimate 
decision to release (or not release) the production aggregate for 
distribution. Because the record of a corrective action is part of the 
history of a particular production aggregate, this documentation should 
not be maintained in another record or location that is not linked 
directly and closely to the production of the particular production 
aggregate of infant formula. In addition, the comment provided no 
rationale for why FDA should use the term ``specific actions'' instead 
of ``corrective actions.'' For these reasons, FDA is not revising 
proposed Sec.  106.100(e)(2), proposed Sec.  106.100(e)(3)(ii), and 
proposed Sec.  106.100(e)(4)(i) in response to this comment, and these 
provisions are included in this interim final rule as proposed.
2. Records of the Production and In-process Control System
    (Comment 305) One comment suggested revising proposed Sec.  
106.100(e)(3) by changing the term ``necessary'' to ``critical'' and 
thus requiring that documentation be included where control is deemed 
critical to prevent adulteration.
    (Response) FDA is not persuaded by this comment. As discussed 
previously in this document in section IV.C.8, FDA is not persuaded 
that the word ``critical'' enhances the clarity of the phrase 
``necessary to prevent adulteration.'' Therefore, FDA is not revising 
proposed Sec.  106.100(e)(3) in response to this

[[Page 8038]]

comment, and this provision is included in this interim final rule as 
proposed.
    (Comment 306) One comment suggested that proposed Sec.  
106.100(e)(4)(i) be revised to state ``any deviation from the 
manufacturing order and any specific action taken to adjust or correct 
a batch [production aggregate] in response to a deviation,'' and that, 
as a result, proposed Sec.  106.100(e)(4)(iii) could be deleted as 
redundant. (Proposed Sec.  106.100(e)(4)(iii) would require that the 
batch (production aggregate) production and control record contain the 
conclusions and followup, along with the identity, of the individual 
qualified by training or experience who investigated a failure to meet 
any standard or specification at any point, step, or stage in the 
production process where control is necessary to prevent adulteration.)
    (Response) FDA declines to make the suggested revisions to Sec.  
106.100(e)(4) in the interim final rule. The comment did not provide a 
reasoned basis for substituting the term ``specific action'' for 
``corrective action'' or for inserting the phrase ``to adjust or 
correct a batch in response to a deviation'' to describe the corrective 
actions taken. Further, FDA disagrees that Sec.  106.100(e)(4)(iii) 
would be redundant with proposed Sec.  106.100(e)(4)(i) even if the 
latter provision were revised as suggested. The scope of proposed Sec.  
106.100(e)(4)(i) and proposed Sec.  106.100(e)(4)(iii) are very 
different. Proposed Sec.  106.100(e)(4)(i) covers only deviations from 
the master manufacturing order. (A master manufacturing order provides 
the plan for manufacture of the infant formula.) In contrast, proposed 
Sec.  106.100(e)(4)(iii) relates to the investigation of a failure to 
meet any specification in the production process where control is 
deemed necessary to prevent adulteration, a provision that extends to 
the entire production process, including a deviation from the master 
manufacturing order and a deviation from any part of the manufacturing 
process, such as a deviation from the provisions of proposed Sec. Sec.  
106.10, 106.20, 106.30 106.35 or 106.40. Accordingly, FDA is not 
revising Sec.  106.100(e)(4) as requested in this comment.
3. Records on Production Aggregate (Batch) Testing
    (Comment 307) One comment objected to the stability testing record 
requirements in proposed Sec.  106.100(e)(5), which would require that 
the batch (production aggregate) production and control record include 
records of the results of all testing performed on the batch 
(production aggregate) of infant formula, including testing on the in-
process product, at the final product stage, and on finished product 
throughout the shelf life of the product. The comment argued that the 
requirement to include all stability test results in the individual 
batch (production aggregate) records is an additional administrative 
burden and can easily be avoided by requiring that shelf life testing 
results be made available to the Agency upon request, either by outside 
communication or through inspection. The comment stated that if a 
requirement were made to store the data with the manufacturing work 
order, an additional system would need to be developed to link the data 
at an additional cost with no commensurate benefit to public health.
    (Response) FDA is not persuaded that requiring all stability 
testing results to be included in the production aggregate production 
and control record would be an unwarranted administrative burden to 
formula manufacturers. FDA notes that the comment's concern was limited 
to the administrative burden of maintaining stability records in the 
production and control record and did not explain why stability testing 
records are different from all other testing records in terms of such 
burden.
    The principle underlying proposed Sec.  106.100(e)(5) is that all 
testing records that relate to a specific production aggregate (batch) 
must be co-located (or linked electronically) so that, should there be 
an adulteration concern about a particular production aggregate, both 
the manufacturer and FDA can have immediate access to all relevant 
testing records for the formula in question. Also, maintaining 
stability testing records in the production and control record will 
help avoid duplication. This is because the final product testing that 
would be required by proposed Sec.  106.91(a)(4) may also serve as the 
initial (baseline) stability testing.
    The Agency acknowledges that, with the exception of initial 
stability testing, all stability testing is likely to occur after the 
finished infant formula has been released for distribution, and the 
production and control record for a production aggregate is likely to 
be established at or near the time the formula is manufactured. 
However, it is not unreasonable to require stability testing records to 
be co-located (for hard copy records) or electronically linked (for 
electronic records) with the production aggregate production and 
control record and that any records created post-distribution may 
simply be added to or linked with the production and control record. As 
noted, the comment did not distinguish stability testing records from 
other production records that this interim final rule requires to be 
maintained in the production aggregate production and control record. 
Absent such distinction, it is entirely reasonable that stability 
testing records be maintained with other records relating to a 
particular production aggregate.
    Moreover, as discussed in section VI. Quality Control Procedures, 
stability testing of finished infant formula is critical because it 
evaluates whether all nutrients (both those required by Sec.  107.100 
and those otherwise added by the manufacturer) are present in the 
formula at the desired level throughout the formula's shelf life. A 
formula that lacks one or more of these nutrients at the appropriate 
level may be unable to support normal growth of the infants consuming 
it as their sole source (or virtually sole source) of nutrition. 
Similarly, the records of stability testing of a particular production 
aggregate are an integral part of the history of the particular 
production aggregate of formula and, like other production records that 
supply the history of a production aggregate, these stability testing 
records need to be immediately accessible to both the manufacturer and 
FDA. For these reasons, FDA declines to revise Sec.  106.100(e)(5) in 
response to this comment.
    (Comment 308) Another comment suggested that because the results of 
stability testing should be required as a part of the good 
manufacturing practice records instead of as a part of the batch 
(production aggregate) production and control records, the summary of 
results from the stability testing program required by proposed Sec.  
106.100(e)(5)(i)(B) should be incorporated into the good manufacturing 
practice records.
    (Response) FDA disagrees with this comment. As outlined in the 
preceding response, records of stability testing are part of the 
manufacturing history of the particular production aggregate and, as 
such, are reasonably required to be maintained in the production 
aggregate production and control record. The summary of such testing 
required by Sec.  106.100(e)(5)(i)(B) of the interim final rule is 
appropriately maintained as part of the same production and control 
record. Thus, FDA is not making any revisions in response to this 
comment.
    (Comment 309) One comment suggested that FDA revise both proposed 
Sec.  106.100(e)(5)(i)(A), which would require a summary table 
identifying the stages of the manufacturing process at which the 
manufacturer conducts the nutrient analysis required under proposed

[[Page 8039]]

Sec.  106.91(a) for each required nutrient, and proposed Sec.  
106.100(e)(5)(i)(B), which would require a summary table of the 
stability testing program that would be required under proposed Sec.  
106.91(b), including the nutrients tested and the testing frequency for 
nutrients throughout the shelf life of the product. The comment 
suggested that ``table'' should be changed to ``document'' because 
``document'' implies a reference best suited to the manufacturer's 
system, as opposed to a specific type of a reference, such as table.
    (Response) FDA agrees with this comment. It is reasonable to 
provide formula manufacturers with flexibility to create a summary 
document so long as the chosen format accurately and succinctly conveys 
the data identified as appropriate in proposed Sec.  106.91(a) and 
proposed Sec.  106.91(b). The summary document may, but is not required 
to, be in the form of a table, if the manufacturer determines that such 
format is a convenient and accurate summary document. Thus, in response 
to this comment FDA is modifying both Sec.  106.100(e)(5)(i)(A) and 
(e)(5)(i)(B) by changing the word ``table'' to ``document.''

C. Records of CGMP (Proposed Sec.  106.100(f))

    FDA did not receive any comments requesting modification of 
proposed Sec.  106.100(f)(1) and proposed Sec.  106.100(f)(3). Thus, 
these provisions are included in this interim final rule as proposed. 
FDA received a comment on proposed Sec.  106.100(f)(2), which suggested 
that the words ``standards'' be omitted from that provision. As 
discussed previously in this document, the Agency agrees generally with 
this comment and has revised several provisions in this interim final 
rule, including proposed Sec.  106.100(f)(2), by deleting ``standard 
or.''
1. Records on Equipment and Utensils
    (Comment 310) One comment objected to the inclusion of the ``lot 
number'' in proposed Sec.  106.100(f)(4), which would require that 
records be maintained, in accordance with proposed Sec.  106.30(f), on 
equipment cleaning, sanitizing, and maintenance that show, among other 
things, the lot number of each batch (production aggregate) of infant 
formula processed between equipment startup and shutdown for cleaning, 
sanitizing, and maintenance. Proposed Sec.  106.100(f)(4) also would 
require the person performing and checking the cleaning, sanitizing, 
and maintenance to date and sign or initial the record indicating that 
the work was performed. The comment contended that the requirement to 
document all lot numbers of batches (production aggregates) produced 
between all equipment cleaning, sanitizing, and maintenance is an 
overwhelming administrative requirement that is unnecessary on a daily 
basis. The comment asserted that the records should have sufficient 
detail and reference points (e.g., time, location) to allow 
reconstruction of this type of information if needed, but to require it 
routinely serves no purpose.
    (Response) FDA disagrees. Accurate recordkeeping on equipment 
cleaning, sanitizing, and maintenance showing the date and time of such 
activities will provide a means by which the manufacturer can ensure 
that equipment is being cleaned and maintained regularly and that the 
frequency of such cleaning is appropriate in light of the actual use of 
the equipment. Moreover, records that identify the production unit 
number or production aggregate number (see Sec.  106.3 of the interim 
final rule) of each production unit or production aggregate of infant 
formula processed between equipment startup and shutdown for cleaning, 
sanitizing, and maintenance are essential in situations of equipment 
contamination because such records will permit a manufacturer to 
determine which production units or production aggregates of infant 
formula are or may be adulterated. Thus, the requirements of Sec.  
106.100(f)(4) are both reasonable and critical to the production of 
safe infant formulas.
    FDA is not persuaded that Sec.  106.100(f)(4) should be modified 
because other records could be used to reconstruct this information, if 
needed. The most reliable and accurate way to develop this type of 
information is to create an appropriate record in real time for this 
specific purpose. Maintaining this type of information would be 
particularly important when equipment maintenance, planned or 
unplanned, might have an impact on infant formula production aggregates 
produced between the previous maintenance and the time the equipment 
was repaired. In such a case, it may be necessary for a firm to 
investigate and identify which production aggregates were manufactured 
between those time periods. These records will complement the 
production aggregate production and control records and will facilitate 
a manufacturer's trace back to all potentially affected production 
units or production aggregates when there is an instance of an 
equipment failure that might result in an adulterated product (e.g., 
microbiological contamination). Therefore, FDA is not revising proposed 
Sec.  106.100(f)(4) in response to this comment, and this provision is 
included in this interim final rule, with minor editorial changes, as 
proposed.
2. Records on Automatic Equipment
    (Comment 311) One comment suggested, consistent with the comment's 
recommendation that proposed Sec.  106.35 be deleted, the deletion of 
proposed Sec.  106.100(f)(5), which relates to records on automatic 
(mechanical or electronic) equipment required in accordance with 
proposed Sec.  106.35(c).
    (Response) As discussed previously in this document in section V.G, 
FDA does not agree that proposed Sec.  106.35 should be eliminated. As 
noted in that discussion, the Agency has clarified the application of 
validation to the manufacture of infant formula. Because the comment 
provides no independent basis for deleting proposed Sec.  
106.100(f)(5), FDA declines to eliminate the recordkeeping requirements 
of proposed Sec.  106.100(f)(5) in response to this comment.
    (Comment 312) One comment suggested that proposed Sec.  
106.100(f)(5)(i), which requires a list of all systems used with a 
description of computer files and the inherent limitations of each 
system, be revised to require a list of all systems used with a 
description of computer files and the defined capabilities of each 
system. The comment asserted that the range in capability of a system 
is a better description than the inherent limitations of a system and 
would include at least the same information.
    (Response) FDA disagrees that providing the defined capabilities of 
each system would provide a better description of the system rather 
than a description of the system's inherent limitations. The purpose of 
proposed Sec.  106.100(f)(5)(i) is to require that the records for 
automatic equipment include a sufficiently detailed description of the 
system to enable the manufacturer to operate and troubleshoot the 
system. The Agency disagrees that a description of the defined 
capabilities of a system would include the same information as a 
description of the inherent limitations of a system. A description of 
the defined capabilities of a system identifies what the system is 
designed to do while a description of the system's inherent limitations 
identifies what the system is incapable of doing. Upon further 
consideration, FDA has determined that in order for a manufacturer to 
operate and troubleshoot a system, it is essential that a 
manufacturer's records include a description of both the defined 
capabilities and inherent limitations of

[[Page 8040]]

the system. Accordingly, FDA is revising Sec.  106.100(f)(5)(i) to 
require ``A list of all systems used with a description of the computer 
files and the defined capabilities and inherent limitations of each 
system.''
    (Comment 313) One comment on proposed Sec.  106.100(f)(5)(vii) 
asserted that hard copy recording should be reduced to a minimum and 
attempts made to ensure that all key process results are obtained 
electronically because the latest instruments automatically record to a 
computer with data processing, graphing, and alarm signals produced 
instantaneously. The comment claimed that back-up methods can eliminate 
fears of data loss so there is now no need for burdensome recording 
better suited to the last century.
    (Response) FDA agrees that technology has changed since publication 
of the proposal and has made modifications to the interim final rule to 
permit the use of back-up systems that may become available in the 
future as well as those systems currently in use. Specifically, FDA is 
revising Sec.  106.100(f)(5)(vii) to delete the reference to specific 
older storage systems (e.g., diskettes) and to substitute the term 
``electronic records.'' This will provide a manufacturer with the 
option to use newly developed technologies, if the manufacturer chooses 
to do so. Thus, Sec.  106.100(f)(5)(vii) of the interim final rule 
requires ``A backup file of data entered into a computer or related 
system. The backup file shall consist of a hard copy or alternative 
system, such as duplicate electronic records, tapes, or microfilm, 
designed to ensure that backup data are exact and complete, and that 
they are secure from alteration, inadvertent erasures, or loss.''

D. Records on Infant Formula for Export Only (Proposed Sec.  
106.100(g))

    (Comment 314) One comment requested clarification of proposed Sec.  
106.100(g), which requires that the manufacturer maintain all records 
pertaining to distribution of an infant formula, including records 
showing that products produced for export only are exported. The 
comment stated that it is reasonable to expect a manufacturer to 
maintain distribution records regarding shipment of infant formula 
under the manufacturer's control. However, the comment contended that 
once the infant formula is in the hands of the retailer, customer, 
consumer, or exporter, the manufacturer can no longer be responsible 
for obtaining or keeping these records and should not retain that 
responsibility after the infant formula has left its control. The 
comment also stated that sometimes manufacturers ship infant formula to 
a customer who, in turn, intends it only for export. Because the 
manufacturer is not responsible for the actual export, the manufacturer 
would have no records regarding distribution of such infant formula 
after it is turned over to the exporter.
    (Response) FDA agrees that an infant formula manufacturer must 
maintain distribution records regarding shipment of infant formula 
under the manufacturer's control, including records of shipments to a 
manufacturer's consignees. Such distribution records are routinely 
maintained by manufacturers. Thus, if a consignee is a foreign 
purchaser, the manufacturer would have records of shipment to such 
consignee. A sale of infant formula for export only directly to a 
foreign purchaser would be consistent with the requirement in section 
801(e)(1)(D) of the FD&C Act (21 U.S.C. 381(e)(1)(D)) that a product 
not be ``sold or offered for sale in domestic commerce,'' provided that 
the product is, in fact, exported. In contrast, if a manufacturer sells 
an infant formula to a distributor in the U.S., the manufacturer would 
not be in compliance with section 801(e)(1)(D) of the FD&C Act because 
this transaction would involve the sale (or the offer for sale) of the 
infant formula in domestic commerce. FDA recognizes that, in some 
cases, however, a manufacturer may transfer an infant formula to a 
domestic third-party (e.g., contractor or other agent of the 
manufacturer) who, on behalf of the manufacturer, exports the product 
to a foreign consignee. This latter transaction would not be considered 
a ``sale'' of the infant formula in domestic commerce for the purposes 
of section 801(e)(1)(D) of the FD&C Act because there is no transfer of 
ownership to the third-party acting on behalf of the manufacturer. In 
such situation, FDA expects that the manufacturer would have access to 
the records of export of such third-party. Therefore, where the 
manufacturer ships its product to a foreign consignee, either directly 
or through a third-party who ships such product to a foreign consignee, 
the manufacturer would have the necessary access to distribution 
records (e.g., bill of lading) showing that the infant formula produced 
for export only is actually exported. The distribution records are 
required under section 412(g) of the FD&C Act and are required by 
current Sec.  106.100(l) to be available for inspection. FDA notes that 
these and other records may also be required under 21 CFR 1.101(b)(4) 
for foods, in general, that are for export only.
    For the foregoing reasons, FDA is only making minor editorial 
changes to Sec.  106.100(g).
    In the proposed rule, FDA expressed concerns about infant formulas 
produced for export only that are diverted and sold in the United 
States (61 FR 36154 at 36194). Proposed Sec.  106.100(g) was intended, 
in part, to be a means to verify that the infant formula was not in 
fact sold or offered for sale in domestic commerce. Id. A manufacturer 
of an infant formula for export only has a responsibility under section 
801(e)(1)(D) of the FD&C Act and section 412(b)(2) of the FD&C Act to 
ensure that it or any third-party acting on its behalf exports the 
infant formula for export only and does not divert it for sale in 
domestic commerce. As noted previously in this document, under section 
801(e) of the FD&C Act, an infant formula for export only is deemed not 
to be adulterated or misbranded if the formula satisfies the criteria 
in section 801(e) of the FD&C Act, including that it is not sold or 
offered for sale in domestic commerce. In order to move such a product 
lawfully in interstate commerce, the manufacturer must take the 
necessary steps to ensure that the product complies with section 801(e) 
of the FD&C Act. See United States v. Parfait Powder Puff Co., 163 F.2d 
1008, 1010 (7th Cir. 1947) (explaining that ``one who owes a certain 
duty to the public and entrusts its performance to another, whether it 
be an independent contractor or agent, becomes responsible criminally 
for the failure of the person to whom he has delegated the obligation 
to comply with the law, if the nonperformance of such duty is a 
crime''). Further, a manufacturer of infant formula for export only, 
which formula is otherwise adulterated or misbranded under U.S. law, 
has an obligation under section 412 of the FD&C Act to establish 
adequate controls under CGMP respecting the distribution of such 
product to ensure that adulterated product is not sold or offered for 
sale in domestic commerce.
    Section 412(d) of the FD&C Act requires a formula manufacturer to 
make certain submissions that provide assurances that the firm's 
formula is not adulterated. FDA is not requiring, under the 
requirements in Sec.  106.120 of the interim final rule for new infant 
formula submissions, that a manufacturer of infant formula for export 
only submit the same information that would be required for a formula 
intended or offered for sale in domestic commerce. Instead, to meet the 
requirements in

[[Page 8041]]

sections 412(d)(1)(C) and (D) of the FD&C Act and Sec.  106.120 of the 
interim final rule, such a manufacturer may provide assurances that 
include, among other commitments, that the infant formula will not be 
sold or offered for sale in domestic commerce, consistent with section 
801(e) of the FD&C Act. In addition, to ensure that a manufacturer 
takes the necessary precautions to prevent an infant formula it 
distributes for export only from being diverted for sale in domestic 
commerce, FDA is requiring in this interim final rule, as part of the 
submission requirements in Sec.  106.120(c) of the interim final rule, 
that a manufacturer of infant formula for export only certify that it 
has adequate controls in place to ensure its formula for export only is 
actually exported (see discussion in section X.C.3 for Sec.  106.120(c) 
of the interim final rule). In making this certification, the 
manufacturer is assuring that the product will not be sold or offered 
for sale in domestic commerce and thereby meets the requirements of the 
FD&C Act under sections 412(d)(1)(C) and (D) that, if not met, would 
result in the formula being deemed adulterated under sections 412(a)(2) 
and (3) of the FD&C Act.

E. Means of Recordkeeping (Sec.  106.100(m))

    (Comment 315) One comment recommended that the final regulation 
reflect the acceptability of electronic recordkeeping.
    (Response) FDA agrees that it may be appropriate to use electronic 
recordkeeping to meet the requirements of Sec.  106.100, provided that 
the records are maintained in accordance with part 11 (21 CFR part 11). 
Part 11 applies to any electronic records that are maintained to comply 
with the requirements of this interim final rule. The Agency advises 
that the use of electronic records is voluntary and thus, a paper 
record system may be used to comply with these recordkeeping 
requirements. In response to this comment, FDA is revising Sec.  
106.100(m) to state that records required under part 106 may be 
retained as original records, as true copies of the original records in 
a form such as photocopies, microfilm, microfiche, or other accurate 
reproductions of the original records, or as electronic records. In 
addition, FDA is modifying Sec.  106.100(m) to require all electronic 
records maintain under part 106 to comply with part 11.
    The requirements for electronic records extend to electronic 
signatures. FDA has issued final guidance for industry on this topic. 
The guidance entitled ``Part 11, Electronic Records; Electronic 
Signatures Scope and Application'' sets out the Agency's enforcement 
policies with respect to certain aspects of part 11. The guidance is 
available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm125067.htm. This guidance applies to any electronic record, 
including electronic signatures, established or maintained to meet a 
requirement in this interim final rule.

F. Records of Quality Factors (Sec.  106.100(p) and (q))

    For consistency with other records requirements, FDA is adding two 
new provisions to Sec.  106.100 of the interim final rule to clarify 
the requirements for making and retaining records that demonstrate that 
an infant formula meets the quality factor requirements. All of the 
records requirements for part 106 are located in subpart F. Therefore, 
for comprehensiveness and clarity, FDA is adding language to Sec.  
106.100 in the interim final rule to include the recordkeeping 
requirements for quality factors.
    As is discussed in section VIII.I, the interim final rule contains 
the requirement that an infant formula manufacturer make and retain 
records demonstrating that such formula meets the quality factors 
requirements. Section VIII.I also explains that, although both 
``eligible'' and non-eligible formulas will be required to meet the 
quality factors of normal physical growth and sufficient biological 
quality of protein, ``eligible infant formulas'' will be able to use 
separate established criteria to demonstrate compliance with those 
quality factors. As such, these new provisions in subpart F describe 
the separate quality factor records requirements for eligible formulas 
and non-eligible formulas. For a formula that is not an eligible 
formula, the manufacturer of the formula must make and retain records 
that demonstrate compliance with the requirements in Sec.  106.96(b) 
and (f) of the interim final rule, or, as applicable, an exemption to 
either provision. An eligible formula manufacturer must make and retain 
records that demonstrate compliance with the requirements in Sec.  
106.96(i)(1) and (i)(2) of the interim final rule.

G. Adulteration as a Consequence of the Failure To Keep Records (Sec.  
106.100(r))

    For clarity, FDA is also adding a paragraph to Sec.  106.100 in the 
interim final rule that discusses when an infant formula will be 
considered adulterated for the failure to make or retain a record.
    As noted, the records requirements in part 106 are located in 
subpart F. However, despite the fact that these records provisions are 
located in subpart F, many of these records are considered to be a 
current good manufacturing practice, quality control procedure, or 
quality factor requirement. For example, Sec.  106.100(e)(3) of the 
interim final rule requires records documenting the monitoring at any 
point, step, or stage in the manufacturer's production process where 
control is deemed necessary to prevent adulteration. Such monitoring is 
a part of good manufacturing practices. Thus, although the substance of 
the recordkeeping requirement to make and retain records of this 
practice is located in subpart F, Sec.  106.100(e)(3) of the interim 
final rule is also a part of current good manufacturing practices.
    Because some of the requirements in subpart F are a part of the 
current good manufacturing practices, quality control procedures, and 
quality factor requirements, the failure to follow some of the 
requirements in subpart F will necessarily adulterate the infant 
formula. The failure to follow any CGMP or quality control requirement 
will adulterate the formula under section 412(a)(3) of the FD&C Act. 
Likewise, the failure to follow any quality factor requirement will 
adulterate the formula under section 412(a)(2) of the FD&C Act.

X. Subpart G--Registration, Submission, and Notification Requirements

    In the 1996 proposed rule, FDA proposed a new subpart G to 
establish requirements for registration by an infant formula 
manufacturer (implementing section 412(c)(1)(A) of the FD&C Act), 
submission of information relating to a new infant formula 
(implementing section 412(d) of the FD&C Act), and notification 
relating to any adulterated or misbranded infant formula that has left 
the control of a manufacturer (implementing section 412(e) of the FD&C 
Act.) The 2003 reopening requested comments on all aspects of the 1996 
proposal, including proposed Subpart G.
    FDA received comments on a number of the provisions in proposed 
subpart G. The Agency's responses are set out in this document.

A. General Comments

    Several comments stated that the premarket notification 
requirements of section 412(c) and (d) of the FD&C Act do not 
constitute a premarket approval process for infant formula and cited 
legislative history in support of their assertion.

[[Page 8042]]

    (Comment 316) One comment stated that FDA's role in the premarket 
notification process was perceived by Congress as comprising the task 
of confirming that the required [nutrient] specifications are met for 
each new or significantly modified formula.
    (Response) FDA disagrees with the comment to the extent that it 
suggests that FDA's role in the premarket notification process is 
limited to confirming that the FD&C Act's nutrient specifications are 
met. In fact, through the premarket notification process in section 412 
of the FD&C Act, Congress assigned FDA a comprehensive role in 
evaluating new infant formulas. As noted in the 1996 proposal, the FD&C 
Act requires that the manufacturer of a new infant formula submit a 
variety of information on the new infant formula, including information 
on its quantitative composition, on any reformulation, on any changes 
in processing, assurances that quality factor requirements have been 
met, assurances that the nutrient requirements have been met, and 
assurances that the manufacturing adhere to CGMP and quality control 
procedures. All of this information is reviewed by the Agency to ensure 
that the infant formula will be a safe product that adheres to all 
applicable laws and regulations.
    (Comment 317) Another comment asserted that, over the years, the 
practices and procedures FDA has followed in reviewing notifications 
under section 412 of the FD&C Act have consistently taken on more and 
more of the trappings of premarket approval systems quite different 
from the limited, precise review function contemplated in the statutory 
scheme.
    (Response) As explained in the previous response, FDA disagrees 
that the Agency's review role under section 412 of the FD&C Act is a 
narrow one. In addition, the comment did not provide any underlying 
details to explain its assertion that FDA's review procedures have 
``taken on the trappings of premarket approval systems.''
    Accordingly, the Agency is making no changes to the rule in 
response to Comments 316 and 317.
    (Comment 318) One comment requested that the Agency establish and 
make public a well-defined, transparent, and practical process for the 
receipt, review, and disposition of various infant formula submissions 
from industry. The comment suggested that the process include review 
time lines, the definition of the review process, the identification of 
reviewers, and a response and dialogue process, and asserted that such 
process definition is necessary for industry planning and 
implementation of infant formula advancements in a mutually cooperative 
manner.
    (Response) FDA disagrees in part with this comment. The interim 
final rule provides a well-defined, transparent, and practical process 
for the receipt and review of the infant formula submissions required 
by section 412 of the FD&C Act. The interim final rule clearly 
identifies the information that must be provided to FDA in the various 
submissions, the form in which it is to be submitted, and where the 
information is to be submitted. Under the FD&C Act, a manufacturer must 
make a submission to FDA at least 90 days before marketing a new infant 
formula.
    FDA does not agree that certain matters should be made available to 
the public, as suggested by the comment. In particular, review time 
lines, a description of the review process, and the identification of 
Agency reviewers are all internal administrative management items and 
are not relevant to a manufacturer's obligations or responsibilities 
under the FD&C Act. Indeed, the comment itself did not explain why 
formula manufacturers need such information. Accordingly, the interim 
final rule does not commit FDA to disclosing these types of details.

B. New Infant Formula Registration (Proposed Sec.  106.110)

    In 1996, FDA proposed to establish requirements to implement 
section 412(c)(1)(A) of the FD&C Act. Specifically, FDA proposed in 
Sec.  106.110 that, before a new infant formula may be introduced or 
delivered for introduction into interstate commerce, the manufacturer 
of such formula must register with FDA and provide the name of such 
formula, the name of the manufacturer, the manufacturer's place of 
business, and all establishments at which the manufacturer intends to 
manufacture such formula.
    The Agency responds in this document to the comments received on 
proposed Sec.  106.110.
    (Comment 319) One comment suggested that FDA revise proposed Sec.  
106.110 on new infant formula registration to require that 
manufacturers of infant formula for export register with FDA. The 
comment suggested revising Sec.  106.110 to include the requirement 
that infant formula products for export only comply with section 801(e) 
of the FD&C Act and deleting the requirement in Sec.  106.120(c), a 
revision that would, the comment asserted, reduce the time and expense 
for preparing and reviewing submissions for infant formula intended for 
export.
    (Response) FDA agrees that the interim final rule should require a 
manufacturer of an infant formula product intended for export only to 
register with FDA. Section 412(c)(1)(A) of the FD&C Act requires that 
no person shall introduce or deliver for introduction into interstate 
commerce any new infant formula unless such person has registered with 
the Secretary (and by delegation, FDA). The act of exporting infant 
formula necessarily requires the introduction or delivery for 
introduction into interstate commerce of the formula. Infant formula 
manufactured for export only may nonetheless be a ``new infant 
formula'' as defined in Sec.  106.3 of the interim final rule. 
Therefore, FDA is revising Sec.  106.110(a) in the interim final rule 
to clarify that a manufacturer who produces formula for export only is 
required to register with FDA. The Agency is also revising Sec.  
106.110(a) to update the contact information for FDA's Center for Food 
Safety and Applied Nutrition. Thus, Sec.  106.110(a) of the interim 
final rule states ``Before a new infant formula may be introduced or 
delivered for introduction into interstate commerce, including a new 
infant formula for export only, the manufacturer of the formula shall 
register with the Food and Drug Administration, Center for Food Safety 
and Applied Nutrition, Office of Nutrition, Labeling, and Dietary 
Supplements, Infant Formula and Medical Foods Staff (HSF-850), 5100 
Paint Branch Pkwy., College Park, MD 20740-3835.''
    The Agency disagrees that proposed Sec.  106.110 should be revised 
to require that infant formula products intended for export comply with 
section 801(e) of the FD&C Act and that proposed Sec.  106.120(c) be 
deleted for the reasons the comment provided. A manufacturer of an 
infant formula for export only must still provide a submission under 
sections 412(c)(1)(B) and (d)(1) of the FD&C Act. Section 412(c)(1)(B) 
of the FD&C Act requires that no person shall introduce or deliver for 
introduction into interstate commerce any new infant formula unless 
such person has at least 90 days before marketing such new infant 
formula made the submission required under the FD&C Act. The failure to 
provide notice under section 412(c) of the FD&C Act, including the 
submission in section 412(d)(1) of the FD&C Act, is a prohibited act 
under section 301(s) of the FD&C Act (21 U.S.C. 331(s)). However, as is 
explained in response to Comment 328, FDA is revising Sec.  106.120(c) 
in the interim final

[[Page 8043]]

rule to clarify the assurances that must be provided for infant formula 
for export only.
    (Comment 320) One comment suggested that proposed Sec.  
106.110(b)(4), which would require that the new infant formula 
registration include all establishments at which the manufacturer 
intends to manufacture such new infant formula, be revised to require 
the name and addresses of all establishments at which the manufacturer 
intends to manufacture such new infant formula.
    (Response) FDA agrees with this comment. The name and address of 
the establishments is a necessary component of the registration and 
will allow the Agency to identify and locate each establishment; only 
if FDA can locate an establishment can the Agency inspect such firms 
and otherwise carry out its regulatory responsibilities. Therefore, 
Sec.  106.110(b)(4) of the interim final rule requires that the new 
infant formula registration include the name and street address of each 
establishment at which the manufacturer intends to manufacture a new 
infant formula.

C. New Infant Formula Notifications (Proposed Sec.  106.120)

    In 1996, FDA proposed to establish requirements to implement 
section 412(c)(1)(B) and 412(d)(1) of the FD&C Act. Specifically, FDA 
proposed in Sec.  106.120 that at least 90 days before the interstate 
distribution of a new infant formula, a manufacturer submit certain 
information to FDA pertaining to the new infant formula.
    FDA received a number of comments on proposed Sec.  106.120 and 
responds in this document to those comments.
1. Form of Submission (Proposed Sec.  106.120(a))
    The proposed rule, Sec.  106.120(a), would have required that an 
original and two copies of a new infant formula submission be provided 
to FDA. As discussed previously in this document, in response to a 
comment, Sec.  106.100(m) of the interim final rule permits a 
manufacturer to maintain records as original paper records, as true 
copies of the originals (e.g., microfilm), or as electronic records. 
Such electronic records are required to conform to 21 CFR Part 11. 
Consistent with this revision, FDA is, on its own initiative, revising 
Sec.  106.120(a) in the interim final rule to permit new infant formula 
submissions to be submitted electronically and, in such case, to 
require only a single copy of such electronic submission. Thus, Sec.  
106.120(a) of the interim final rule states, ``At least 90 days before 
a new infant formula is introduced or delivered for introduction into 
interstate commerce, a manufacturer shall submit notice of its intent 
to do so to the Food and Drug Administration at the address given in 
Sec.  106.110(a). An original and two paper copies of the notice of its 
intent to do so shall be submitted, unless the notice is submitted in 
conformance with part 11 of this chapter, in which case, a single copy 
shall be sufficient.''
2. Contents of a New Infant Formula Submission (Proposed Sec.  
106.120(b))
    Proposed Sec.  106.120(b) would have established the required 
contents of a new infant formula submission. FDA received comments on a 
number of the provisions of proposed Sec.  106.120(b), and responds in 
this section.
    a. Quantitative formulation (Proposed Sec.  106.120(b)(3)).
    (Comment 321) One comment questioned the requirement in proposed 
Sec.  106.120(b)(3) that the quantitative formulation of the new infant 
formula be submitted in units per volume for liquid formulas. The 
comment asserted that formulations are routinely listed and have 
traditionally been submitted to the Agency in units per weight of 
liquid. The comment also requested clarification of the volume units to 
use in the quantitative formulation and whether the information should 
be provided on an ``as sold'' or ``as fed'' basis in the submission.
    (Response) The Agency has examined previously received infant 
formula submissions and determined that the formulations of liquid 
formulas have been provided to the Agency in either units per weight 
(e.g., milligrams/kilogram) or in units per volume (e.g., milligrams/
liter). Accordingly, the interim final rule, at Sec.  106.120(b)(3), 
permits a manufacturer to provide the quantitative formulation of a new 
infant formula either in units per weight or units per volume, and on 
an ``as sold'' or ``as fed'' basis, provided that the manufacturer 
specifies whether the quantitative formulation is on an ``as sold'' or 
``as fed'' basis. For a powdered infant formula, the submission must 
also specify the weight of powder to be reconstituted in a specific 
volume of water (e.g., grams (g) of powder per fluid (fl) ounce (oz) of 
water).
    (Comment 322) One comment requested clarification on whether FDA 
requires a table of nutrients as well as a table of ingredients as part 
of the quantitative formulation.
    (Response) The interim final rule does not require a manufacturer 
to submit a table reflecting the amount of various nutrients in an 
infant formula formulation as part of the requirement to provide the 
quantitative formulation. FDA is taking this opportunity to clarify 
that the ``quantitative formulation'' required by section 412(d)(1)(A) 
and (d)(3) of the FD&C Act is a list of all ingredients (including 
individual ingredients and premixes of two or more ingredients) in a 
product and the amount by weight of each ingredient in a set volume or 
weight of the formula. For example, several ingredients in an infant 
formula formulation may contain calcium. Thus, the quantitative 
formulation would identify each individual ingredient (e.g., calcium 
phosphate, calcium carbonate, calcium hydroxide) and the amount (by 
weight or volume) of each ingredient. For mineral salts, the state of 
hydration must be provided because the amount of water contained in the 
salt affects the amount of mineral (e.g. calcium) provided. For 
vitamins, the source of the vitamin (e.g., vitamin A palmitate or 
vitamin A acetate) must be provided because the proportion of vitamin 
differs with each source.
    If a nutrient is added to the formulation as a part of a premix, 
the form of the nutrient and the amount the nutrient must be provided 
(listed) as part of the premix information.
    Not all sources of nutrients may be readily apparent in 
quantitative formulations, as some nutrients may be endogenous to 
certain ingredients (e.g., calcium and phosphorous in condensed skim 
milk). In such a case, the identity and amount of the ingredient (e.g., 
the condensed skim milk) is required to be listed in the quantitative 
formulation--the amounts of endogenous nutrients (e.g., the calcium and 
phosphorus contained in the condensed skim milk) would also need to be 
provided, and their listing is analogous to the listing requirement for 
premixes.
    Although not required by the interim final rule, including a 
separate table of nutrients per 100 kcal in the submission will help to 
expedite FDA's review of the new infant formula submission.
    FDA notes that under Sec.  106.130 of the interim final rule, a 
manufacturer is required to provide in the verification submission for 
a new infant formula the level of all nutrients contained in the 
formula product that reflect the analysis of the product at the 
finished product stage.
    b. Description of a change in processing (Proposed Sec.  
106.120(b)(4)).
    (Comment 323) One comment objected to the requirement of proposed 
Sec.  106.120(b)(4) that the description of any change in processing of 
the infant formula identify the specific change and include side-by-
side, detailed schematic

[[Page 8044]]

diagrams comparing the new processing to the previous processing 
(including processing times and temperatures). The comment asserted 
that, to date, a narrative description of the change has been 
acceptable and that preparing side-by-side, detailed schematic diagrams 
of current and new systems would require substantial amounts of 
additional administrative support, and no deficiencies in the narrative 
description have been identified.
    (Response) FDA disagrees with this comment. The Agency regards the 
two elements in proposed Sec.  106.120(b)(4) (narrative description of 
change and side-by-side diagrams) as complementary parts that will 
ensure that the Agency receives a complete picture of the proposed 
processing change(s). A narrative can provide a succinct means of 
describing the specific parameters of the change; however, it is not 
always apparent where the change fits into the overall processing 
operation, and detailed side-by-side diagrams of the current and new 
processing systems provide an efficient way to present the entire 
picture of the infant formula production and draw attention to the 
specific change or changes. These diagrams assist the Agency in 
understanding the manufacturer's processing methods, the 
interrelationship of various parts of the manufacturing process, and 
the sequence of production events for an infant formula. At least some 
infant formula manufacturers understand the value of these comparative 
diagrams because they are routinely included in their infant formula 
submissions to complement the narrative description of a processing 
change. Because manufacturers must update their schematic processing 
diagrams as part of their CGMP procedures, it seems unlikely that 
requiring comparative diagrams in new infant formula submissions will 
be an undue burden. For these reasons, FDA is not persuaded to revise 
proposed Sec.  106.120(b)(4) in response to these comments. Section 
106.120(b)(4) is included in this interim final rule as proposed, with 
the exception of minor editorial changes.
    c. Assurance for quality factors (Proposed Sec.  106.120(b)(5)).
    In 1996, FDA proposed to implement section 412(d)(1)(C) of the FD&C 
Act through proposed Sec.  106.120(b)(5). Proposed Sec.  106.120(b)(5) 
would have required a new infant formula submission to include 
assurances that the infant formula would not be marketed unless the 
formula met the quality factor requirements of section 412(b)(1) of the 
FD&C Act and the nutrient content requirements of section 412(i) of the 
FD&C Act. Proposed Sec.  106.120(b)(5)(i) provided that the assurances 
relating to quality factor requirements would be satisfied by a 
submission complying with proposed Sec.  106.121, and proposed Sec.  
106.120(b)(5)(ii) provided that assurances relating to nutrient content 
would be satisfied by a statement that the formula would not be 
marketed unless it met the nutrient requirements of Sec.  107.100, as 
demonstrated by required quality control testing.
    FDA received no comments on proposed Sec.  106.120(b)(5) that are 
not addressed elsewhere in the interim final rule.
    d. Assurance for processing infant formulas (Proposed Sec.  
106.120(b)(6)).
    The 1996 proposal (proposed Sec.  106.120(b)(6)) would have 
required that the new infant formula submission include assurance that 
the processing of the infant formula complies with section 412(b)(2) of 
the FD&C Act. Proposed Sec.  106.120(b)(6)(ii) would have required that 
the submission include the basis on which each ingredient meets the 
requirements of Sec.  106.40(a) and that any claim that an ingredient 
is GRAS be supported by citation to the Agency's regulations or by an 
explanation of the basis for the general recognition of safety of the 
ingredient in infant formula. The proposed rule would have required 
that such explanation include a list of published studies and a copy of 
those publications that provide the basis for the general recognition 
of safety for the use of the ingredient in infant formula.
    FDA received several comments on proposed Sec.  106.120(b)(6)(ii) 
and responds to those comments directly below.
    (Comment 324) One comment requested that FDA delete proposed Sec.  
106.120(b)(6)(ii), challenging FDA's legal interpretation that this 
information could be required as a part of the new infant formula 
submission. The comment asserted that in promulgating the Infant 
Formula Act, Congress intended that the law be used to ensure that the 
manufacturer produce formulas that meet the Infant Formula Act nutrient 
composition requirements and that are not contaminated with substances 
or organisms that might adulterate the product.
    (Response) FDA disagrees with this comment. The authority for the 
requirement in proposed Sec.  106.120(b)(6)(ii) is derived from section 
412(d)(1)(D) of the FD&C Act. The submission requirement under section 
412(d)(1)(D) of the FD&C Act requires infant formula manufacturers to 
provide assurances that the formula complies with section 412(b)(2) of 
the FD&C Act. The FD&C Act is silent as to the specific assurances that 
must be made to demonstrate that the formula is processed in accordance 
with section 412(b)(2) of the FD&C Act. Because the FD&C Act is silent, 
the Agency may issue a regulation to fill any gaps in the statutory 
requirement to provide assurances that an infant formula is processed 
in accordance with section 412(b)(2) of the FD&C Act so long as the 
regulation is not ``arbitrary, capricious, or manifestly contrary to 
statute.'' See Chevron, 467 U.S. at 844.
    Section 412(b)(2) of the FD&C Act requires FDA to issue regulations 
to establish good manufacturing practices and quality control 
procedures that the Secretary (and by delegation, FDA) determines are 
necessary to assure that the formula provides nutrients in accordance 
with section 412(i) of the FD&C Act and is manufactured in a manner 
designed to prevent adulteration of the formula.
    Compliance with proposed Sec.  106.120(b)(6)(ii) will provide 
assurance that an infant formula is manufactured in a manner designed 
to prevent adulteration. As noted previously in this document, under 
the CGMP requirement in Sec.  106.40(a) of the interim final rule, the 
only substances that may be used in infant formula are those that are 
GRAS for such use, are used in accordance with a food additive 
regulation, or are authorized by a prior sanction. The failure to use a 
lawful ingredient in the manufacture of an infant formula would 
adulterate such formula. To provide adequate assurance that this CGMP 
requirement has been met, FDA is including a requirement that a new 
infant formula submission include the basis on which each ingredient 
satisfies the requirements of Sec.  106.40(a) of the interim final 
rule.
    Infant formula manufacturers may add ingredients to infant formula 
that are not ``nutrients'' as defined in this interim final rule. In 
fact, many infant formulas on the market today contain ingredients that 
are not required by section 412(i) of the FD&C Act, such as DHA, ARA, 
and microorganisms referred to as ``probiotics.'' In circumstances in 
which the manufacturer has determined that an ingredient is GRAS for 
use in infant formula, there is no requirement under the FD&C Act that 
FDA review such ingredient prior to its use in infant formula and 
before the formula is marketed for use by infants. For certain 
ingredients (e.g., oligosaccharides, oils containing long chain 
polyunsaturated fatty acids, or intentionally added microorganisms), 
identification of the

[[Page 8045]]

ingredient and the supplier is necessary in order for FDA to determine 
whether the manufacturer is using the ingredient that has gone through 
the food additive petition or GRAS notification process.
    FDA considers the provision in proposed Sec.  106.120(b)(6)(ii) to 
be important in ensuring public health protection to this particularly 
vulnerable population. The submission of the information required under 
Sec.  106.120(b)(6)(ii) of the interim final rule will provide FDA with 
the information it needs to ensure that a manufacturer has considered 
the basis for why each ingredient used in its infant formula is lawful 
prior to using an ingredient in the manufacture of infant formula. By 
identifying the basis on which each ingredient is believed to lawful, 
assurances are provided under section 412(d)(1)(D) of the FD&C Act that 
the use of each ingredient is safe and suitable under the applicable 
food safety provisions of the FD&C Act, as required by Sec.  106.40(a) 
of the interim final rule. Therefore, FDA is not removing Sec.  
106.120(b)(6)(ii) in response to this comment, and Sec.  
106.120(b)(6)(ii) is included in this interim final rule as proposed.
    (Comment 325) One comment objected to this provision arguing that 
Congress did not intend to give FDA premarket approval authority over 
infant formula or, in this case, over food ingredients employed in 
formula. The comment further asserted that 21 CFR 170.30 does not 
mandate that the information the manufacturer is relying upon be 
submitted to the Agency or be formally acknowledged or listed as GRAS.
    (Response) As is explained previously in this document, Congress 
gave FDA the authority to establish regulations to assure that formula 
is manufactured in a manner designed to prevent its adulteration, and 
also gave FDA the authority to require that manufacturers provide 
assurance that the formula is manufactured in such a manner. To the 
extent that the comment asserts that proposed Sec.  106.120(b)(6)(ii) 
establishes premarket approval authority for infant formula or its 
ingredients, FDA disagrees. Proposed Sec.  106.120(b)(6)(ii) would 
simply require that the manufacturer provide the basis for why each 
ingredient it uses in its infant formula is safe under the FD&C Act. 
The review of ingredient safety under section 409 of the FD&C Act is 
separate and distinct from the responsibility for a manufacturer, as 
part of CGMP, to ensure that the formula satisfies the requirements 
designed to prevent the use of an unlawful ingredient in infant 
formula. Therefore, FDA is making no changes to Sec.  106.120(b)(6)(ii) 
in the interim final rule in response to this comment.
    (Comment 326) One comment stated that in many or most cases, 
manufacturers will, in the interest of reducing regulatory 
uncertainties, find it in their own self-interest to submit such 
information required under proposed Sec.  106.120(b)(6)(ii); however, 
such submissions should remain voluntary. Therefore, the comment 
concluded, the manufacturer should be able to market the infant formula 
without submitting this information, because it is the manufacturer's 
responsibility to ensure the safety and suitability of its individual 
infant formula products.
    (Response) As discussed previously in this document, FDA disagrees 
that proposed Sec.  106.120(b)(6)(ii) should be removed from the 
interim final rule, and thus, does not believe that the provisions in 
proposed Sec.  106.120(b)(6)(ii) should be voluntary. Additionally, FDA 
notes that ensuring that the ingredients used to produce an infant 
formula are lawful under the separate applicable statutory and 
regulatory requirements of the FD&C Act is still the responsibility of 
the infant formula manufacturer. Nothing in this interim final rule 
relieves a manufacturer of its obligations to evaluate the safety of 
the ingredients in its infant formula products and to comply with other 
substantive provisions of the FD&C Act relating to the safety of 
ingredients in infant formula.
    (Comment 327) Several comments requested that proposed Sec.  
106.120(b)(6)(ii) be revised to apply only to ``newly added'' 
ingredients and not to ingredients already found in infant formula. The 
comments asserted that absent this change, information in infant 
formula submissions would be redundant and that this information is 
unnecessary for ingredients previously used and submitted by a 
manufacturer.
    (Response) FDA disagrees with this comment. Only substances that 
are GRAS for use in infant formula, used in accordance with a food 
additive regulation, or authorized by a prior sanction may be used in 
infant formula. FDA notes that it may be appropriate in certain 
situations for a formula manufacturer to reference a previous 
submission in order to provide the basis that an ingredient in the 
formula satisfies Sec.  106.40(a) of the interim final rule.
3. Products for Export Only (Proposed Sec.  106.120(c))
    Proposed Sec.  106.120(c) would have required that for products 
intended for export only, a new infant formula submission include, in 
lieu of the information required under proposed Sec.  106.120(b), a 
statement that the infant formula complies with section 801(e) of the 
FD&C Act (i.e., that the formula meets the specifications of the 
foreign purchaser, does not conflict with the laws of the country to 
which it is intended for export, is labeled on the outside of the 
shipping package to indicate that it is intended for export only, and 
will not be sold or offered for sale in domestic commerce).
    (Comment 328) One comment objected to proposed Sec.  106.120(c) 
asserting that is it redundant with section 801(e) of the FD&C Act.
    (Response) FDA disagrees that proposed Sec.  106.120(c) is 
redundant with section 801(e) of the FD&C Act. Proposed Sec.  
106.120(c) would permit a manufacturer of new infant formula for export 
only to submit, in lieu of the information required under Sec.  
106.120(b), a statement that the infant formula meets the 
specifications of the foreign purchaser, does not conflict with the 
laws of the country to which it is intended for export, is labeled on 
the outside of the shipping package to indicate that it is intended for 
export only, and will not be sold or offered for sale in domestic 
commerce. A manufacturer of a new infant formula, including a new 
infant formula for export only, is required by section 412(c)(1)(B) of 
the FD&C Act to make a submission to FDA 90 days prior to going to 
market. The failure to provide the notice required by section 412(c) of 
the FD&C Act (which includes a submission to FDA required by section 
412(d) of the FD&C Act) is a prohibited act under section 301(s) of the 
FD&C Act (21 U.S.C. 321(s)). Section 412(d)(1) of the FD&C Act requires 
all persons who introduce a new infant formula, or deliver such formula 
for introduction into interstate commerce, to make a submission. Such 
persons include those who manufacture a new infant formula for export 
only; although such formula is exported, the formula is still 
introduced or delivered for introduction into ``interstate commerce,'' 
as such term is defined in section 201(b) of the FD&C Act (21 U.S.C. 
321(b)). There is no exception for an infant formula for export only in 
either section 412 or section 801 of the FD&C Act to the submission 
requirements of section 412 of the FD&C Act. Thus, a manufacturer that 
produces an infant formula for export only is required to make a 
submission under section 412(c) of the FD&C Act. Consequently, FDA is 
not removing from the interim final rule the

[[Page 8046]]

submission requirement for these formulas.
    However, FDA is revising Sec.  106.120(c) in the interim final rule 
to clarify the assurances that must be provided under section 412(d) of 
the FD&C Act for a new infant formula for export only.
    Proposed Sec.  106.120(c) would allow a manufacturer of a new 
infant formula for export only to make a submission to FDA that 
includes a statement that the formula meets the specifications of the 
foreign purchaser, does not conflict with the laws of the foreign 
country to which it is intended for export, is labeled on the outside 
of the package that it is intended for export only, and that it will 
not be sold in domestic commerce.
    A product intended for export shall not be deemed to be adulterated 
or misbranded under the provisions of the FD&C Act if such product 
satisfies the criteria in section 801(e) of the FD&C Act. Thus, an 
infant formula for export only would not need to show that its formula 
meets those requirements of section 412 of the FD&C Act that, if not 
met, would cause the product to be adulterated, provided that the 
manufacturer shows that the formula meets the requirements in section 
801(e) of the FD&C Act. This fact means that the submission of a 
manufacturer of a new infant formula intended for export could differ 
from the submission of a manufacturer of a new infant formula that is 
to be sold in domestic commerce, specifically with respect to the 
requirements of section 412(d)(1)(C) of the FD&C Act (quality factor 
and nutrient requirements) and section 412(d)(1)(D) of the FD&C Act 
(CGMP and quality control requirements), both of which establish 
conditions under which a formula would be adulterated under section 
412(a) of the FD&C Act. In lieu of providing assurances that the 
processing of the formula complies with applicable quality factor, 
nutrient, and CGMP requirements under section 412(d)(1)(C) and 
(d)(1)(D) of the FD&C Act, a manufacturer of an infant formula for 
export only would notify FDA in its submission that its formula 
satisfies the criteria in section 801(e) of the FD&C Act.
    Importantly, however, the submission requirements in sections 
412(d)(1)(A) and (d)(1)(B) of the FD&C Act do not relate to 
adulteration: Section 412(d)(1)(A) of the FD&C Act requires a 
submission that includes the quantitative formulation of the formula 
and section 412(d)(1)(B) of the FD&C Act requires a description of any 
reformulation or change in the processing of the formula. The proposed 
rule would not have required a manufacturer of a new infant formula for 
export only to submit the quantitative formulation of the new infant 
formula or a description of any reformulation or change in the 
processing of the formula.
    Because proposed Sec.  106.120(c) would allow a manufacturer of a 
new infant formula for export only to make an alternate submission to 
fulfill all of the submission requirements, including the requirements 
not specifically related to adulteration of the infant formula, FDA is 
revising Sec.  106.120(c) to permit a manufacturer of a new infant 
formula for export only to make an alternative submission to satisfy 
only those requirements of section 412(d)(1) of the FD&C Act that are 
related to adulteration. Thus, under the interim final rule, a 
manufacturer of a new infant formula for export only is required, as it 
would be for an infant formula for domestic commerce, to submit the 
quantitative formulation of the formula and a description of any 
reformulation or change in the processing of such formula. By providing 
such information, the manufacturer of a new infant formula for export 
only will be complying with the submission requirement in section 
412(d)(1) of the FD&C Act in a way that is consistent with the 
requirements in section 801(e) of the FD&C Act. Additionally, as 
explained previously in this document, FDA is revising proposed Sec.  
106.120(c) to require that, as a condition of making the alternate 
submission under Sec.  106.120(c), a manufacturer of a new infant 
formula for export only certify that the manufacturer has adequate 
controls in place to ensure that such formula is actually exported.
    (Comment 329) Several comments claimed that manufacturers of infant 
formulas for export only should not be required to make the submission 
under proposed Sec.  106.120(c) 90 days before marketing, asserting 
that there may be situations in which 90 days advance notice could 
cause hardship to a manufacturer. One comment proposed that a 
manufacturer could notify FDA of its intent to export infant formula 
prior to commercial distribution, arguing that this process should not 
cause FDA hardship because the relative simplicity of the export 
notification and the brevity of the review typically required.
    (Response) As explained in response to the previous comment, every 
manufacturer of a new infant formula, including a new infant formula 
for export only, is required by section 412(c)(1)(B) of the FD&C Act to 
make a submission to FDA 90 days prior to going to market. Thus, FDA is 
making no changes to Sec.  106.120(c) in response to this comment.
    (Comment 330) One comment suggested that proposed Sec.  106.120(c) 
should be revised to state ``For products for export only and in 
compliance with Section 801(e) of the FD&C Act, the information under 
paragraph (b) of this section is not required and need not be 
submitted.'' The comment asserted that FDA's proposed requirements 
under proposed Sec.  106.120(c) are adequately covered under the FDA 
Export Reform Enhancement Act and its implementing regulations (21 CFR 
part 1).
    (Response) FDA disagrees with this comment. The requirements in 
this interim final rule are separate and distinct from those issued 
under other authorities related to requirements in 21 CFR part 1. 
Section 106.120(c) of the interim final rule specifies what must be 
included in a submission required under section 412(d)(1) of the FD&C 
Act for a new infant formula intended for export only. As explained 
previously in this document, this submission is required for all new 
infant formulas, including a new infant formula for export only. The 
requirements in 21 CFR Part 1, Subpart E, do not implement section 412 
of the FD&C Act. Therefore, FDA is not making the changes requested in 
this comment.
4. Administrative Procedures for Handling Notifications (Proposed Sec.  
106.120(d), (e), and (f))
    Proposed Sec.  106.120 includes several subparts that address the 
administrative aspects of new infant formula submissions. Specifically, 
proposed Sec.  106.120(d) would have provided that a submission would 
not constitute notice under section 412 of the FD&C Act unless the 
submission complied fully with proposed Sec.  106.120(b) and was 
readily understandable, and that FDA would notify the submitter of the 
inadequacy of a submission. Proposed Sec.  106.120(e) would have 
provided that FDA would acknowledge receipt of an adequate submission 
and the date of receipt (``the filing date''), and restated the 
prohibition against marketing the new infant formula until 90 days 
after the filing date. Finally, proposed Sec.  106.120(f) would have 
stipulated that if a manufacturer supplemented a new infant formula 
submission, FDA would determine whether it was a substantive amendment, 
and if so, the Agency would assign a new filing date and notify the 
submitter of the new date.
    (Comment 331) One comment suggested that proposed Sec.  106.120(d) 
be revised to require FDA to notify the submitter within 10 working 
days if the submission is not complete because it

[[Page 8047]]

does not meet the requirements of sections 412(c) and (d) of the FD&C 
Act. The comment asserted that manufacturers filing a new infant 
formula submission need certainty for planning purposes, that an Agency 
notice of inadequacy received well into the 90-day review period can be 
seriously disruptive, and that a submission should receive immediate 
review for completeness.
    (Response) FDA agrees that a new infant formula submission should 
be checked immediately for completeness to ensure that it contains all 
elements required under proposed Sec.  106.120(b). A submission lacking 
any element required under proposed Sec.  106.120(b) will not be filed, 
and the Agency will notify the submitter in a timely manner that the 
submission is not complete. FDA would anticipate that this completeness 
determination could generally be made within 10 business days. However, 
given the constraints and conflicting demands on Agency resources at 
various times, the Agency declines to add this time restriction to 
Sec.  106.120(d).
    (Comment 332) One comment suggested that FDA delete the last 
sentence of proposed Sec.  106.120(e), which would have stipulated that 
a manufacturer not market a new infant formula until 90 days after the 
filing date, because this language is not found in the FD&C Act and is 
unnecessarily restrictive. The comment noted that the 1996 proposal 
stated (61 FR 36154 at 36198) that the purpose of the 90 day notice is 
to provide the Agency sufficient time to examine the submission and 
decide whether there is any basis for concern about the marketing of 
the formula, and, the comment contended, a manufacturer should not be 
prohibited from marketing a formula if, prior to the 90th day, the 
Agency has made its determination that there is no concern.
    (Response) FDA disagrees with this comment. Section 412(c)(1)(B) of 
the FD&C Act states that no ``person shall introduce or deliver for 
introduction into interstate commerce any new infant formula unless . . 
. such person has at least 90 days before marketing such new infant 
formula, made the submission to the Secretary required by subsection 
(c)(1).'' \8\ The clear import of this provision is that a new infant 
formula shall not be marketed until the passage of the 90 day period. 
The statute does not require FDA to communicate with the submitter, and 
the Agency, in its discretion, has chosen not to impose such an 
obligation on itself because the requirement is unnecessary and would 
be burdensome. In these circumstances, a manufacturer will know that 
marketing of its new infant formula is lawful only with the passing of 
the 90th day. FDA notes that, if the Agency's review of a new infant 
formula submission uncovers deficiencies such that the new infant 
formula in question would not be in compliance with the FD&C Act, the 
Agency intends to notify the manufacturer of such deficiencies prior to 
the 90th day. Accordingly, FDA declines to revise proposed Sec.  
106.120(e) in response to this comment.
---------------------------------------------------------------------------

    \8\ FDA has previously stated the view that this reference to 
subsection (c)(1) is a drafting error and is understood to refer to 
subsection (d)(1)). (61 FR 36154 at 36195, footnote 6).
---------------------------------------------------------------------------

    (Comment 333) One comment suggested that proposed Sec.  106.120(e) 
be revised to state that if a new infant formula submission is complete 
and includes all information required by Sec.  106.120(b), FDA will 
acknowledge its receipt and notify the submitter of the date of the 
receipt. The comment expresses concern that the Agency might wish to 
delay the starting date of the 90 day period when the notification is 
complete but questions or disagreement remain with respect to the 
content. The comment contended that the marketing of an infant formula 
should not be deferred while the Agency takes issue with minor elements 
of the notification and that when FDA receives a notification that 
supplies information in accordance with Sec.  106.120, the 90-day clock 
must begin to run.
    (Response) FDA stated in the response to Comment 331 that, in the 
Agency's view, there is a distinction between verifying a submission's 
completeness versus determining that the information satisfies the 
requirements of the law and the relevant regulations by providing the 
necessary assurances and demonstrating that the new infant formula will 
not be adulterated under the FD&C Act. The latter determination 
requires complete and careful examination of the submitted material by 
Agency personnel with the necessary expertise, such as manufacturing 
specialists, statisticians, microbiologists, nutritionists, food 
technologists, and medical officers. In contrast, once the Agency 
determines that a new infant formula submission is complete in that it 
purports to address all the requirements of Sec.  106.120(b) of the 
interim final rule, FDA intends to provide the submitter with a prompt 
acknowledgement letter, and the 90 day period will begin as of the date 
that the Agency receives a complete submission.
    In response to the foregoing comments, FDA is revising proposed 
Sec.  106.120(e) to clarify the distinction between an FDA notification 
that a submission is complete and a notification that the submission 
does not provide the assurances required by section 412(d)(1) of the 
FD&C Act and the regulations implementing those assurances.
    (Comment 334) One comment suggested that, in proposed Sec.  
106.120(f), instead of referring to the ``manufacturer'' providing 
additional information in support of a new infant formula submission 
and FDA notifying the manufacturer of the new filing date, it would be 
more appropriate to refer to the ``submitter'' providing additional 
information and FDA notifying the ``submitter'' of the new filing date.
    (Response) FDA disagrees with the suggestion of this comment and, 
for the reasons discussed below, is retaining the term ``manufacturer'' 
in Sec.  106.120(f) of the interim final rule. For purposes of 
uniformity, the Agency is also revising Sec. Sec.  106.120(d), 
106.130(c), and 106.140(c) by replacing the term ``submitter'' with 
``manufacturer.''
    The manufacturer of an infant formula is ultimately responsible for 
ensuring that that its formula products are lawful. In the case of a 
new infant formula, FDA must be provided with all the information 
required in a new infant formula submission at least 90 days before the 
new formula is distributed in commerce. Thus, the formula manufacturer 
must ensure that such information is provided in a timely fashion to 
FDA. Also, section 412(c) of the FD&C Act refers to ``person'' and 
requires such person to notify FDA of all establishments at which such 
person intends to manufacture the new infant formula. Thus, ``person,'' 
as used in section 412(c) of the FD&C Act, refers to the manufacturer 
of the infant formula.
    FDA recognizes that a manufacturer may contract with other entities 
to execute certain aspects of formula production. However, the 
manufacturer will be held responsible for the information submitted to 
FDA, whether submitted by the manufacturer or another person who 
submits it on behalf of the manufacturer, and FDA will notify the 
manufacturer, under Sec.  106.120(f) of the interim final rule, whether 
the Agency considers additional information submitted by any person on 
behalf of the manufacturer in support of the submission to constitute a 
substantive amendment resulting in a new filing date.
    For these reasons, FDA is retaining the term ``manufacturer'' in 
Sec.  106.120(f) of the interim final rule, and, for consistency 
reasons, is amending Sec. Sec.  106.120(d), 106.130(c), and

[[Page 8048]]

106.140(c) in the interim final rule by replacing the term 
``submitter'' with the term ``manufacturer.''
    (Comment 335) One comment requested that FDA revise proposed Sec.  
106.120(f) by adding a time period (5 working days) within which FDA 
would acknowledge receipt of additional information provided to support 
a new infant formula submission that is a substantive amendment to the 
submission, asserting that FDA must be bound by some reasonable time 
requirements so that manufacturers can plan appropriately.
    (Response) FDA agrees that the Agency should promptly notify a 
manufacturer of receipt of a supplement to a new infant formula 
submission, but the Agency declines to add a 5-day time limit to 
proposed Sec.  106.120(f) within which to acknowledge such receipt. FDA 
would anticipate that this acknowledgement could generally be made 
within 5 business days. However, given the constraints and conflicting 
demands on Agency resources at various times, the Agency declines to 
add this time restriction or any other specific time restriction to 
Sec.  106.120(f) in the interim final rule. There is no assurance that 
FDA can meet this 5-day time limit given constraints that may be placed 
on Agency resources at various times.
5. Submissions for Exempt Infant Formulas (Proposed Sec.  106.120(g))
    On its own initiative, FDA is adding Sec.  106.120(g) to the 
interim final rule to clarify that the submission requirements for 
exempt infant formulas are codified in 21 CFR 107.50. Section 
106.120(g) of the interim final rule states: ``Submissions relating to 
exempt infant formulas are subject to the provisions of Sec.  107.50 of 
this chapter.'' The regulations in 21 CFR 107.50 pertaining to exempt 
infant formula were finalized in 1985 (50 FR 48183) prior to the 1986 
amendments. As explained in the 1996 proposal, the Agency will address 
in a separate rulemaking the effect of the 1986 amendments on the 
exempt infant formula regulations and exempt infant formulas (61 FR 
36154 at 36201-36202). Until FDA publishes such rulemaking, exempt 
infant formula submissions are subject to Sec.  107.50.

D. Quality Factor Submissions for Infant Formulas (Proposed Sec.  
106.121)

    To provide assurance that an infant formula meets the quality 
factor requirements set forth in subpart E, the proposed rule described 
in detail the requirements for a quality factor submission in proposed 
Sec.  106.121. The Agency received comments on these proposed 
requirements, and responds below. Although much of the substance of 
proposed Sec.  106.121 has been retained in the interim final rule, FDA 
notes that the numbering of the section has been revised.
1. General Comments
    (Comment 336) One comment suggested that proposed Sec.  106.121 be 
revised to clarify that the quality factor submission requirements of 
proposed Sec.  106.121 only apply to ``new infant formulas'' as defined 
by these regulations.
    (Response) FDA agrees with this comment. Under section 412(d)(1) of 
the FD&C Act, any infant formula subject to section 412(c) must make a 
submission to FDA. Each ``new infant formula'' is subject to section 
412(c) of the FD&C Act. As such, FDA is making revisions to Sec.  
106.121 in the interim final rule to clarify that the submission 
requirements only apply to a ``new infant formula.'' The Agency notes, 
however, that all infant formulas, whether new or ``not new,'' are 
required to satisfy the applicable quality factor requirements of Sec.  
106.96 of the interim final rule.
    (Comment 337) One comment recommended that Sec.  106.121(a) be 
retained as proposed and that the remaining paragraphs in Sec.  106.121 
applying to the quality factor of normal physical growth (proposed 
Sec.  106.121(b), (c), (d), and (f)) be deleted for the reasons 
identified in the comments objecting to establishment of ``normal 
growth'' as a quality factor. The comment's support for retention of 
proposed Sec.  106.121(a), as well as its support for deletion of Sec.  
106.121(d), was contingent on FDA's acceptance of the comment's 
suggested changes to proposed Sec.  106.120(b)(6)(i), (ii), and (iii). 
Another comment on proposed Sec.  106.121 identified various changes to 
infant formula and suggested a decision-tree approach to determining 
the documentation that would be required for each such change to 
support nutritional adequacy. The comment concluded that FDA should 
provide information about presentation of clinical growth study data in 
an Agency guidance and not the final rule.
    (Response) FDA disagrees with the comment that all information on 
the presentation of growth monitoring study data should be incorporated 
into an FDA guidance and not codified in Sec.  106.121. The data and 
information required in a quality factor submission to assure normal 
physical growth (proposed Sec.  106.121(b), (c), (d), and (f)) provide 
the basic factual information that is needed for the Agency's review of 
the growth monitoring study. Because these items are necessary to an 
adequate review of the study, they should not, and cannot, be described 
as optional elements of a submission. Therefore, FDA declines to delete 
proposed Sec.  106.121(b), (c), (d), and (f), and these requirements 
are, with minor editorial changes, incorporated into the interim final 
rule recodified as Sec.  106.121(a)(2), (a)(3), (a)(4), and (h) 
respectively. Proposed Sec.  106.121(a) is recodified as Sec.  
106.121(a)(1) in the interim final rule, with minor editorial changes.
    Additional comments were submitted for proposed Sec.  106.121(b), 
(c), and (f) and are addressed below.
2. Submission of Growth Data (Proposed Sec.  106.121(b))
    Proposed Sec.  106.121(b) would have required that a quality factor 
submission include certain data from the growth monitoring study. FDA 
received several comments that addressed the types of data that should 
be submitted to comply with proposed Sec.  106.121(b).
    (Comment 338) One comment objected to submitting data for 
individual subjects or a subgroup of individuals from a formula feeding 
group. This comment expressed concern that, because few infants will be 
at the lower or upper end of a particular growth parameter in a normal 
distribution, the characteristics of these individuals could 
erroneously be considered representative of a significant subgroup of 
the sample. The comment requested that FDA clarify that group 
statistics will provide the primary basis for the manufacturer's 
finding that normal physical growth has been attained and that the 
growth data for individual study infants will be considered as 
supportive data and only to demonstrate that there was no significant 
subgroup of the study group that experienced adverse effects.
    (Response) FDA declines to implement the suggestion of this 
comment. Although the Agency intends to rely primarily on the group 
data of a growth monitoring study to demonstrate the safety, including 
the nutritional adequacy, of an infant formula, it has been the 
Agency's experience that the review of summary data may raise issues 
the resolution of which requires the consideration of individual or 
subgroup data. For example, by examining detailed data, FDA has been 
able to determine that there were no subgroups of the test population 
for whom the formula had adverse effects. Thus, providing individual 
subject data will facilitate FDA's review of the submission because the 
Agency will be able to review individual data promptly and resolve 
particular questions without

[[Page 8049]]

an intervening request to the manufacturer for additional data and 
information. This efficiency is especially important given the limited 
time (90 days) provided by the statute for the Agency's review of a new 
infant formula submission. Accordingly, FDA is not persuaded to revise 
the requirement of proposed Sec.  106.121(b), and this provision is 
codified with minor editorial changes in the interim final rule as 
Sec.  106.121(a)(2).
    (Comment 339) One comment suggested that growth data be presented 
as plotted growth curves of the group means and that the Agency not 
require individual case report forms and data. The comment pointed out 
that including data on individual infants would add to the length of 
the submission and to the length of the FDA's review without providing 
a meaningful benefit to the public.
    (Response) FDA disagrees with this comment. As noted previously in 
this document, the prompt availability of individual study results will 
support the efficiency of FDA's review of the growth study and the 
prompt resolution of issues identified by the Agency's review of the 
group study results. Growth curves reflecting group means only may be 
submitted but their submission is not an acceptable alternative for 
submission of individual data. Importantly, FDA notes that in terms of 
the form of individual study results, original records are not required 
but may be submitted. In addition to the requirement to submit data 
plotted on the 2009 CDC growth charts, manufacturers may submit such 
information in any easily understandable format, which includes 
spreadsheets, data tables, copies of investigators' original clinical 
study records, or case report forms with original data (for example, 
individual anthropometric data sheets). A submission form that contains 
the individual subject data in an accessible format will satisfy FDA's 
need for comprehensive information.
    (Comment 340) One comment requested that the preamble acknowledge 
that the ``records'' contemplated by proposed Sec.  106.121(b) need not 
be the investigator's original records, but could be records that 
contain the necessary information drawn from the investigator's 
original records.
    (Response) As noted in the response to the preceding comment, to 
comply with Sec.  106.121(a)(2) of the interim final rule, a 
manufacturer may submit the required information in any easily 
interpretable format. Original records are not required to, but may, be 
submitted to comply with Sec.  106.121(a)(2) of the interim final rule.
    (Comment 341) One comment on proposed Sec.  106.121(b) disagreed 
with the requirement to submit the records that contain the information 
required by proposed Sec.  106.97(a)(1)(ii).
    (Response) As discussed previously in this document in section 
VIII.C, FDA is not finalizing the Agency's proposed recommendations for 
a clinical study protocol in the interim final rule. However, not 
issuing proposed Sec.  106.97(a)(1)(ii) in the interim final rule does 
not change FDA's need to review the data and information that were 
covered by proposed Sec.  106.121(b) to provide assurance that a new 
infant formula meets the quality factor requirement of normal physical 
growth. Thus, Sec.  106.96(b) of the interim final rule identifies the 
data and other information that must be collected during a growth 
monitoring study. FDA's reasons for retaining these substantive 
requirements are discussed previously in this document in section 
VIII.C. Accordingly, the Agency is not revising proposed Sec.  
106.121(b) in response to this comment; the provision is recodified as 
Sec.  106.121(a)(2) in the interim final rule with minor editorial 
changes.
3. Statistical Power Calculations (Proposed Sec.  106.121(c)(2))
    Proposed Sec.  106.121(c)(2) would have required the quality factor 
submission to include the calculation of the statistical power of a 
study at its completion. FDA received several comments on this proposed 
requirement.
    (Comment 342) One comment noted that a calculation of a study's 
statistical power is needed before a study is initiated and it is 
reasonable to expect from a study report that there was an a priori 
calculation of the study's power, the number of subjects to be 
recruited, and the number of subjects who actually completed the study. 
The comment asserted that a calculation of a study's power at its 
completion, as would have been required by proposed Sec.  
106.121(c)(2), is unnecessary and of unproven value and could be a 
confounding and burdensome calculation. Accordingly, the comment 
recommended that FDA not require inclusion of such a calculation in a 
quality factor submission.
    (Response) FDA agrees with this comment to the extent that it 
asserts that the statistical power of a study should be calculated 
prior to study initiation to determine the number of subjects needed to 
answer the clinical question. It is both reasonable and reflects a 
sound scientific approach for a manufacturer to perform a prospective 
power calculation and include that calculation in a quality factor 
submission relating to the growth monitoring study. A prospective power 
calculation may be used to determine whether the study, as designed, 
will have sufficient statistical power to answer the question of 
whether a formula has the ability to satisfy the quality factor of 
normal physical growth. Thus, the interim final rule requires a 
manufacturer to calculate the statistical power of a growth monitoring 
study prior to its initiation and to submit that calculation to FDA in 
a new infant formula submission.
    The proposed rule would have required the calculation of the 
statistical power of the growth monitoring study at its completion and 
the inclusion of the calculation in the quality factor submission. A 
prospective calculation of study power and sample size is based on 
predicted variance and expected dropout rates whereas a power 
calculation conducted at the end of a study uses actual values for the 
study size and drop-out rates. As explained in the 1996 proposal (61 FR 
36154 at 36199), a study may not achieve the power predicted by the 
prospective power calculation if dropout rates or measurement errors 
are greater than anticipated. Thus, an end-of-study calculation can 
help determine whether the failure to detect a difference between 
formulas occurred because the clinical study lacked the statistical 
power to detect differences if such differences existed. Failure to 
detect real differences could result in an erroneous conclusion that a 
formula supports normal physical growth, when in fact, it does not. 
Although post hoc analyses are generally discouraged, a planned, post-
study statistical power calculation is, in FDA's view, necessary to 
ensure that the study, as actually conducted, achieved the statistical 
power projected by the prospective statistical power analysis.
    FDA disagrees that a post-study power calculation is confounding 
and burdensome. The data needed for these calculations are required to 
be collected during the growth monitoring study, and the calculations 
are straightforward and performed using standard statistical software 
packages. For these reasons, the Agency is not deleting proposed Sec.  
106.121(c)(2) in response to this comment.
    Based on the foregoing comments, the interim final rule requires 
that the quality factor portion of a new infant formula submission 
include both a prospective and a retrospective power calculation. Thus, 
proposed

[[Page 8050]]

Sec.  106.121(c)(2) is included in this interim final rule as Sec.  
106.121(a)(3)(ii) and states ``Calculations of the statistical power of 
the study before study initiation and at study completion.''
4. Protein Quality (Proposed Sec.  106.121(e))
    Proposed Sec.  106.121(e) would have required that the quality 
factor submission include the results of the PER study, consistent with 
proposed Sec.  106.97(b). FDA received comments on this proposed 
requirement.
    (Comment 343) One comment suggested that proposed Sec.  106.121(e) 
be deleted and that the results of the PER be submitted to the Agency 
after the first production, and before the introduction into interstate 
commerce, of the new infant formula, as part of the verification 
submission required by proposed Sec.  106.130. The comment further 
suggested that proposed Sec.  106.130(b) be revised to require that the 
verification submission include an assurance that the bioassay for 
protein biological quality has commenced, and that the PER results will 
be provided to FDA within 10 working days of their receipt by the 
manufacturers or responsible party as a supplement to the verification 
submission.
    The comment also asserted that if the use of new production 
equipment triggers the 90-day premarket notification requirement, a 
requirement to submit the PER testing in the 90-day premarket 
submission would accelerate the need to start testing by 5 months (2 
months to conduct the PER test plus three months to be able to give the 
notification 90 days before marketing). This would delay the start-up 
with the new equipment by 5 months or require the manufacturer to 
convince FDA that the research production system was ``close enough'' 
to the full scale system so that the product of the former would be 
viewed as representative of the latter.
    (Response) FDA is not persuaded by this comment to require the 
submission of PER bioassay results as part of the verification 
submission under Sec.  106.130. Nor is the Agency persuaded to require 
that the verification submission only require an assurance that the 
bioassay for protein biological quality was commenced, and that the 
results will be forwarded to FDA within 10 working days of their 
receipt by the manufacturer.
    Requiring the results of the PER bioassay to be submitted in a new 
infant formula submission is consistent with both the relevant law and 
sound science. As discussed previously in this document in section 
VIII.E, FDA has established biological quality of the protein as a 
quality factor for infant formula and has identified the PER bioassay 
(appropriately modified) as the requirement that must be met to provide 
assurance that this quality factor is satisfied. Section 412(d)(1) of 
the FD&C Act requires that a new infant formula submission contain 
assurances that the formula will not be marketed unless it satisfies 
the quality factors established under section 412(b)(1) of the FD&C 
Act. Indeed, in the 1996 proposal (61 FR 36154 at 36196), FDA 
tentatively concluded that it would be appropriate to require the 
assurance that the quality factors will be met by the submission of 
data under proposed Sec.  106.120(b)(5)(i) and not as part of the 
verification submission so that the Agency has all the information 
relevant to the nutritional adequacy of the formula for a period of 
time sufficient to conduct a meaningful review. Further, as discussed 
previously in this document, it is appropriate that the biological 
quality of a formula's protein component be established by the 
manufacturer prior to initiation of a growth monitoring study to avoid 
exposing infants to a test formula for which the protein quality has 
not been confirmed. For these reasons, FDA concludes that it is 
appropriate to require that the results of the PER assay be submitted 
to the Agency as a part of the new infant formula submission made under 
Sec.  106.120 of the interim final rule.
5. Certification Statement (Proposed Sec.  106.121(f))
    Proposed Sec.  106.121(f) would have required that a new infant 
formula submission include a statement that certifies that the 
manufacturer has collected and considered all information on the 
ability of an infant formula to satisfy the quality factor requirements 
and that the manufacturer is unaware of other information or data that 
would show that the formula did not satisfy the quality factors 
requirements. FDA received one comment on this provision.
    (Comment 344) One comment suggested a change to proposed Sec.  
106.121(f). The comment requested that FDA change ``certifying'' to 
``of assurance'' to reflect the language of section 412(d)(1)(C) and 
(d)(1)(D) of the FD&C Act, which language refers to ``assurances'' and 
not ``certifications.''
    (Response) FDA is not persuaded by this comment. The requirement 
that a manufacturer include this certification in a quality factor 
submission is a means of assuring FDA that the manufacturer has 
considered the totality of available information and is not aware of 
any information or data that would show that the formula does not meet 
quality factor requirements. Therefore, FDA declines to revise proposed 
Sec.  106.121(f) in response to this comment. Accordingly, proposed 
Sec.  106.121(f) is recodified as Sec.  106.121(i) and is included in 
this interim final rule as proposed.
6. Satisfaction of an Exemption From Certain Quality Factor 
Requirements
    As discussed in section VIII.D, FDA is including exemptions from 
the quality factor requirements in Sec.  106.96(b) and (f) as part of 
this interim final rule (see Sec.  106.96(c) and (g) of the interim 
final rule). A manufacturer may rely on an exemption, as applicable, in 
a new infant formula submission to provide assurances that the formula 
meets a quality factor requirement. Therefore, FDA is adding conforming 
changes to Sec.  106.121 of the interim final rule to clarify the 
requirements pertaining to each of these exemptions. To the extent a 
manufacturer relies on an exemption in a new infant formula submission, 
the applicable requirement in Sec.  106.121 of the interim final rule 
would provide the Agency with the data and information in such 
submission that the manufacturer relies on to demonstrate that the 
formula satisfies such exemption from the quality factor requirements.

E. Verification Submissions (Proposed Sec.  106.130)

    In 1996, FDA proposed to implement section 412(d)(2) of the FD&C 
Act by requiring that, after the first production, but before the 
introduction into interstate commerce, of a new infant formula, a 
manufacturer verify in a written submission to FDA that the formula 
complies with the FD&C Act and is not adulterated. The proposal would 
have required that the verification submission summarize test results 
and records demonstrating that the formula satisfies the requirements 
of section 412(b)(1), (b)(2)(A), (b)(2)(B)(i), (b)(2)(B)(iii), 
(b)(3)(A), (b)(3)(C), and (i) of the FD&C Act.
    FDA received several comments on the proposed verification 
requirement.
1. Scope of Verification Submission Requirement
    (Comment 345) One comment requested that FDA clarify that infant 
formulas for export only are not required to submit a verification 
submission under proposed Sec.  106.130.
    (Response) FDA agrees that clarification about how a manufacturer 
of a new infant formula for export only can comply with Sec.  106.130 
is needed.

[[Page 8051]]

The verification that must be submitted to FDA under section 412(d)(2) 
of the FD&C Act relates to whether the formula is adulterated under 
section 412(a) of the FD&C Act. As discussed previously in this 
document, a manufacturer of a new infant formula for export only may 
choose to comply with Sec.  106.120(c) of the interim final rule 
instead of Sec.  106.120(b) of the interim final rule. If a 
manufacturer complies with Sec.  106.120(c) of the interim final rule, 
there would not be a need for the manufacturer of a product that is for 
export only to submit a verification concerning compliance with 
requirements that relate to the adulteration provisions. FDA would 
consider the submission under Sec.  106.120(c) of the interim final 
rule to satisfy the verification submission requirement in Sec.  
106.130 of the interim final rule for such formula. Therefore, FDA has 
revised Sec.  106.130(a) in the interim final rule as follows: ``A 
manufacturer shall, after the first production and before the 
introduction into interstate commerce of a new infant formula (except 
for a new infant formula that is for export only for which a submission 
is received in compliance with Sec.  106.120(c)), verify in a written 
submission to FDA at the address given in Sec.  106.110(a) that the 
infant formula complies with the requirements of the Federal Food, 
Drug, and Cosmetic Act and is not adulterated.''
2. Identification Number (Proposed Sec.  106.130(b)(1))
    (Comment 346) One comment suggested that proposed Sec.  
106.130(b)(1), which would have required that the verification 
submission include the identification number assigned by the Agency to 
the new infant formula submission, should be qualified to state that 
the verification submission must include this identification number, if 
available. The comment asserted that oftentimes, the identification 
number might not have been assigned or be available.
    (Response) FDA does not agree with this comment. Including the FDA-
assigned identification number in the verification submission is a 
simple and reasonable means to permit FDA to link a verification 
submission with the corresponding new infant formula submission. As 
part of its standard procedures, FDA assigns an identification number 
to each new infant formula submission received and includes this number 
in a letter to the manufacturer acknowledging the new infant formula 
submission. An infant formula manufacturer that does not receive, in a 
timely way, an Agency acknowledgement letter in response to an infant 
formula submission should contact FDA during the 90-day review period. 
Accordingly, FDA is not revising proposed Sec.  106.130(b)(1), and this 
provision is included in this interim final rule as proposed.
3. Verified Formula Matches Notified Formula (Proposed Sec.  
106.130(b)(2))
    (Comment 347) One comment requested that proposed Sec.  
106.130(b)(2), which would have required that the verification 
submission include a statement that the infant formula to be introduced 
into interstate commerce is the same as the infant formula that was the 
subject of the new infant formula submission and for which the 
manufacturer provided assurances in accordance with the requirements of 
Sec.  106.120, should be modified to allow that if the infant formula 
is not the same, the verification submission must include an 
explanation of how the infant formula is different and why this 
difference does not affect the quality factor requirements. In support 
of this change, the comment stated that occasionally, a minor change 
may be made to an infant formula between the time a 90-day submission 
is made and the first production occurs and that, although these 
changes are not expected to have an adverse impact on nutrient levels 
or nutrient availability, the two formulations would not be ``the 
same.'' Thus, the comment asserted that the verification submission 
should provide a mechanism to record and explain these situations.
    (Response) FDA disagrees with this comment. Section 412(d)(2) of 
the FD&C Act requires that an infant formula manufacturer submit a 
written verification to FDA after the first production of an infant 
formula (the ``first-produced'' formula) subject to section 412(c) of 
the FD&C Act and before such formula is introduced into interstate 
commerce. Therefore, the FD&C Act requires that the infant formula 
addressed by the verification submission be the same formula that is 
the subject of the new infant formula submission (the ``notified 
formula'') previously submitted under section 412(c) of the FD&C Act. 
In the proposed rule (61 FR 36154 at 36200), FDA tentatively concluded 
that if a manufacturer can make the statement that would have been 
required by proposed Sec.  106.130(b)(2), it means that the quality 
factor assurances that the manufacturer provided in the new infant 
formula submission continue to be relevant and applicable to the 
product and thus, no additional information would need to be included 
in the verification submission to demonstrate compliance with sections 
412(b)(1) and 412(b)(2)(A) of the FD&C Act. FDA concludes that the 
statement in proposed Sec.  106.130(b)(2) is necessary and is in lieu 
of additional test results or records demonstrating compliance of the 
``first-produced'' formula with these sections of the FD&C Act. If the 
``first-produced'' formula differs from the ``notified formula'' in 
ways that would constitute a major change or if the ``first-produced'' 
formula has otherwise been changed such that previous submission on 
quality factor requirements and ingredient safety is no longer 
relevant, the manufacturer could not truthfully make the statement in 
proposed Sec.  106.130(b)(2). Thus, a manufacturer must evaluate 
whether it can make the statement in Sec.  106.130(b)(2) in light of 
any changes to the formula.
    For these reasons, FDA is not revising proposed Sec.  106.130(b)(2) 
in response to this comment, and this provision is included in this 
interim final rule as proposed.
4. Certification Statement (Proposed Sec.  106.130(b)(4))
    (Comment 348) One comment suggested that proposed Sec.  
106.130(b)(4) be revised to delete the proposed requirement that a 
verification submission contain a certification that the manufacturer 
has established current good manufacturing practices, including quality 
control procedures and in-process controls such as testing, designed to 
prevent adulteration of this formula in accordance with subparts B and 
C of part 106, and instead, to require that the verification submission 
contain assurance that the manufacturer has done so. The comment states 
that the suggested use of ``assurance'' was based on the provisions of 
the Infant Formula Act relating to verification that refer specifically 
to ``assurance'' as opposed to certification.
    (Response) FDA is not persuaded by this comment. First, although 
FDA agrees that the word ``assurance'' is used in section 412 of the 
FD&C Act, the comment does not describe the difference, material or 
otherwise, between a suggested requirement that a manufacturer provide 
``assurance'' and the proposed requirement that a manufacturer provide 
a ``certification'' as to compliance with CGMP requirements. Absent 
such a distinction, FDA sees no reason to change the language proposed. 
The certification is the means by which a manufacturer provides the 
assurance required under section 412(d) of the FD&C Act.
    Second, the proposed certification requirement is reasonable. FDA 
is

[[Page 8052]]

responsible for reviewing the manufacturer's submission to ensure the 
infant formula complies with the FD&C Act, and the Agency must be 
satisfied that a manufacturer has, in accordance with subparts B and C 
of part 106, established current good manufacturing practices, 
including quality control procedures, in-process controls, and testing 
required by CGMP that is designed to prevent adulteration of the 
formula. Section 412(d)(2) of the FD&C Act requires that after the 
first production of a new infant formula and before its introduction 
into interstate commerce, the formula manufacturer submit written 
verification summarizing test results and records demonstrating that 
the formula complies with the requirements of section 412(b)(1), 
(b)(2)(A), (b)(2)(B)(i), (b)(2)(B)(iii), (b)(3)(A), (b)(3)(C), and (i) 
of the FD&C Act. As the Agency tentatively concluded in the proposed 
rule, and concludes in this interim final rule, additional test results 
or records demonstrating compliance with section 412(b)(2)(B)(i), 
(b)(3)(A), and (b)(3)(C) of the FD&C Act are unnecessary because such 
testing is subsumed under Sec.  106.130(b)(3) of the interim final rule 
in the summary of test results for the level of each nutrient required 
by Sec.  107.100. Section 106.130(b)(3) of the interim final rule 
includes the test results for the level of nutrients required by 412(i) 
of the FD&C Act. Further, the Agency concludes that it would be 
unnecessary to require submission of the records demonstrating 
compliance with section 412(b)(1) of the FD&C Act because the records 
demonstrating compliance with quality factors would have been submitted 
as part of the submission under section 412(c) and (d)(1)(C) of the 
FD&C Act. The certification requirement in proposed Sec.  106.130(b)(4) 
is a means to satisfy the statutory provision that a manufacturer 
summarize test results and records to demonstrate compliance with 
sections 412(b)(2)(A) and (b)(2)(B)(iii) of the FD&C Act. Such records 
would be available for inspection by FDA. This requirement will be a 
strong incentive to a manufacturer to confirm that the test results and 
records that demonstrate compliance with section 412(b)(2)(A) and 
(b)(2)(B)(iii) of the FD&C Act are complete based on the manufacturer's 
established procedures. For these reasons, FDA is not revising proposed 
Sec.  106.130(b)(4) in response to this comment, and the provision is 
included in this interim final rule as proposed.
5. Administrative Procedures for Handling Verification Submissions 
(Proposed Sec.  106.130(c))
    (Comment 349) One comment suggested modifying proposed Sec.  
106.130(c), which states that a submission will not constitute written 
verification under section 412(d)(2) of the FD&C Act when any data 
prescribed by proposed Sec.  106.130(b) are lacking or are not set 
forth so as to be readily understood and that, in such circumstances, 
the Agency will notify the submitter that the verification is not 
adequate. The comment suggested that this proposed provision be revised 
to state that the Agency will notify the submitter within 5 working 
days that the notice is not complete and asserted that without such 
rapid notice, a manufacturer will not be able to market its product 
with assurance that FDA found the submission acceptable. The comment 
also recommended that the FDA develop a form for verifications that 
will help in FDA's review of the sufficiency of these submissions.
    (Response) FDA disagrees with this comment. Although the Agency 
fully intends to notify a manufacturer of the inadequacy of a 
verification submission as promptly as possible, it is not reasonable 
for FDA to commit to a specific time frame for such notice where it is 
not compelled by statute and where, in some cases, competing priorities 
or diminished resources may affect the Agency's ability to respond.
    Similarly, it is not necessary for the Agency to develop a form for 
verification notifications because proposed Sec.  106.130 specifies the 
information required in such a notification, and the Agency's review 
will focus on those requirements. Development and clearance of such a 
form would require Agency resources, and the comment did not 
specifically identify the efficiencies or other benefits from the use 
of the suggested form that would be expected to offset these 
development and clearance costs. Accordingly, FDA is not revising 
proposed Sec.  106.130(c) in response to this comment, and, with minor 
editorial changes, the provision is included in this interim final rule 
as proposed.

F. Submission Concerning a Change in Infant Formula That May Adulterate 
the Product (Proposed Sec.  106.140)

    In 1996, the Agency proposed submission requirements to implement 
section 412(d)(3) of the FD&C Act by issuing proposed Sec.  106.140. 
Proposed Sec.  106.140 would have required that when a manufacturer 
makes a change in the formulation or processing of an infant formula 
that may affect whether the formula is adulterated under section 412(a) 
of the FD&C Act, the manufacturer shall, before the first processing of 
such formula, make a submission to FDA at the address given in proposed 
Sec.  106.110(a).
    The Agency received several comments on proposed Sec.  106.140, and 
responds below.
    (Comment 350) One comment expressed concern that infant formula 
manufacturers may be reluctant to make minor changes in packaging 
materials because they may think that these changes would require 
additional stability testing of their formulas and additional 
notifications to FDA under proposed Sec.  106.140. The comment 
requested that FDA clarify that an infant formula manufacturer does not 
need to conduct special stability testing or make a filing with FDA, in 
accordance with proposed Sec.  106.140, when a packaging change is made 
that clearly will not affect potential migration of packaging 
components to the formula or the integrity of the packaging.
    (Response) FDA is not persuaded to make changes to the codified 
based on this comment. Section 412(d)(3) of the FD&C Act provides that 
a manufacturer is to make the determination as to whether a change in 
the processing may affect whether the formula is adulterated. FDA 
considers that a change in packaging constitutes a change in processing 
for purposes of section 412(d)(3) of the FD&C Act. Therefore, if a 
manufacturer determines that a packaging change may affect whether a 
formula may be adulterated, a notification to FDA, in accordance with 
Sec.  106.140 of the interim final rule, is required.
    Stability testing is governed by Sec.  106.91(b)(2) of the interim 
final rule. Under that provision, a manufacturer is responsible for 
ensuring that an infant formula satisfies the nutrient requirements of 
the FD&C Act throughout the shelf life of the product. When a 
manufacturer makes a packaging change for a specific formula, the 
manufacturer must determine whether that change requires the 
manufacturer to conduct additional stability testing to ensure that the 
infant formula will contain the required nutrients throughout the shelf 
life of the product. Moreover, the definition of ``major change'' 
includes a situation where there is a fundamental change in the type of 
packaging used and such a change would make the formula a ``new'' 
infant formula for which a submission would be required under section 
412(c) of the FD&C Act.

[[Page 8053]]

    Accordingly, FDA is not revising proposed Sec.  106.140 in response 
to this comment, and the provision is included in this interim final 
rule as proposed.
1. ``Before First Processing'' (BFP) Submissions (Proposed Sec.  
106.140(a))
    (Comment 351) One comment suggested that proposed Sec.  106.140(a) 
be revised to state that when a manufacturer makes a change in the 
formulation or processing of a formula that the manufacturer or 
responsible party determines may affect whether the formula is 
adulterated under section 412(a) of the FD&C Act, the manufacturer 
shall, before the first processing of such formula, make a submission 
to the FDA. The comment asserted that this revision would clarify what 
constitutes a ``minor change'' versus a ``major change.''
    (Response) Elsewhere in this preamble, FDA has declined to define 
``minor change'' and reaffirms that decision now in response to this 
comment. FDA notes that this comment suggests changes to proposed Sec.  
106.140 that the comment believes would clarify what constitutes a 
``major'' or ``minor'' change. However, the definition of ``major 
change'' is addressed in section 412(c) of the FD&C Act and is defined 
in Sec.  106.3 of the interim final rule. The comment does not explain 
the utility or necessity of defining ``minor change,'' and such a 
definition is not necessary. Also, unlike ``major change,'' for which 
there are regulatory consequences (for example, filing a submission 
under Sec.  106.120), there are no regulatory consequence identified in 
the law or by the comment for a change that would be a ``minor 
change.'' For this reason, FDA declines to define ``minor change'' in 
response to this comment.
    (Comment 352) Another comment stated that under current practice, 
infant formula manufacturers currently evaluate all changes to 
formulation or processing of their infant formulas and if the 
manufacturer determines the change may affect the nutrient content of 
the formulation, the manufacturer notifies FDA. The comment asserted 
that this requirement will increase the number of these submissions and 
require additional personnel if a manufacturer is required to notify 
FDA when any of the changes listed as examples of ``notifiable 
changes'' in the preamble to the proposed rule occurs.
    (Response) Proposed Sec.  106.140 was designed to implement section 
412(d)(3) of the FD&C Act, which requires that a manufacturer make a 
submission to FDA before the first processing of a formula when the 
manufacturer determines that a change in formulation or in the 
processing of an infant formula may affect whether a formula is 
adulterated under section 412(a) of the FD&C Act; the submission is 
required by section 412(d)(3) of the FD&C Act to conform to the 
requirements in section 412(d)(1) of the FD&C Act. A change that 
constitutes a ``major change'' within the meaning of Sec.  106.3 of the 
interim final rule is not the type of change that requires notification 
under Sec.  106.140 because a ``major change'' makes a formula a ``new 
infant formula'' and under section 412(c)(1) of the FD&C Act, the 
manufacturer of a ``new infant formula'' must notify FDA of the change 
in accordance with section 412(c)(1) of the FD&C Act and Sec.  106.120 
of the interim final rule. The comment cited examples of changes that 
FDA identified in the preamble to the proposed rule that could affect 
whether a formula is adulterated and stated that increased submissions 
and a need for additional personnel would be required, but the comment 
did not explain why such examples are inconsistent with section 
412(d)(3) of the FD&C Act. The examples FDA provided are of the type 
that the Agency considers appropriate for submission under section 
412(d)(3) of the FD&C Act and proposed Sec.  106.140(a).
    Based on the foregoing, FDA is not revising proposed Sec.  
106.140(a) in response to these comments, and proposed Sec.  106.140(a) 
is included in this interim final rule, with minor editorial changes, 
as proposed.
    No comments were received requesting modification of proposed Sec.  
106.140(b)(1). Thus, proposed Sec.  106.140(b)(1) is included in this 
interim final rule as proposed.
2. Steps To Ensure That Formula Will Not Be Adulterated (Proposed Sec.  
106.140(b)(2))
    (Comment 353) One comment suggested that proposed Sec.  
106.140(b)(2), which requires that the submission explain why the 
change in formulation or processing may affect whether the formula is 
adulterated, also would require that the submission explain the steps 
that will be taken to ensure that the formula will not be introduced 
into interstate commerce unless it is not adulterated. The comment 
asserted that this suggested requirement will enable FDA to receive a 
more complete explanation of the change.
    (Response) FDA agrees with this comment. The Agency believes that 
requiring a manufacturer to consider how it will resolve a question of 
whether the formula is actually adulterated and to provide that 
explanation to FDA will help to ensure that no adulterated formula will 
enter distribution. Accordingly, FDA is revising Sec.  106.140(b)(2) in 
response to this comment to require that the submission explain the 
steps that will be taken to ensure that, before the formula is 
introduced into interstate commerce, the formula will not be 
adulterated.
3. Administrative Procedures (Proposed Sec.  106.140(c))
    (Comment 354) One comment suggested that proposed Sec.  106.140(c), 
which provides that the Agency will notify the submitter if a notice is 
not adequate because it does not meet the requirements of section 
412(d)(3) of the FD&C Act, be revised to state that FDA will promptly 
acknowledge receipt and notify the submitter if the notice is not 
adequate because it does not meet the requirements of section 412(d)(3) 
of the FD&C Act. The comment asserted that FDA should be required to 
notify manufacturers within 1 week, or some other reasonable period of 
time, if a submission is not adequate and that otherwise, a 
manufacturer will not be able to market its product with assurance that 
FDA found the submission to be adequate.
    (Response) FDA disagrees with this comment. The Agency's current 
practice is to acknowledge the receipt of a new infant formula 
submission. However, FDA declines to revise the interim final rule to 
require such acknowledgment because future changes in Agency resources 
and program priorities may make the current practice of acknowledgement 
not feasible. Also, a manufacturer may make independent arrangements to 
confirm FDA's receipt of its submission, such as by sending the 
submission via U.S. mail with return receipt service.
    Similarly, although the Agency intends to notify a manufacturer of 
the inadequacy of a submission made under Sec.  106.140 of the interim 
final rule as promptly as possible, it is not reasonable for FDA to 
commit to a specific time frame for such notice where such timing is 
not compelled by statute and where, in some cases, competing priorities 
or diminished resources may affect the Agency's ability to respond. 
Thus, FDA is not persuaded to revise proposed Sec.  106.140(c) in 
response to this comment, and this provision is included in this 
interim final rule, with minor editorial changes, as proposed.
4. Infant Formulas Intended for Export Only
    (Comment 355) One comment requested clarification as to whether

[[Page 8054]]

infant formulas intended only for export must make the submission 
concerning a change in infant formula that may adulterate the product. 
The comment suggested that Sec.  106.140 include a paragraph (d) that 
would state that the requirements of Sec.  106.140 do not apply to any 
infant formula product legally exported under section 801(e) of the 
FD&C Act.
    (Response) The Agency is not revising Sec.  106.140 in response to 
this comment. Notification under Sec.  106.140 is only necessary when 
the manufacturer makes a change to the formula that affects whether the 
formula may be adulterated under section 412(a) of the FD&C Act. As 
explained previously in this document, an infant formula intended for 
export is not deemed to be adulterated under the FD&C Act, including 
under section 412(a) of the FD&C Act, if it is in compliance with 
section 801(e) of the FD&C Act. FDA would not consider an infant 
formula intended for export that is in compliance with Sec.  106.120(c) 
of the interim final rule and section 801(e) of the FD&C Act to be 
adulterated under section 412(a) of the FD&C Act. Therefore, an infant 
formula for export only that is in compliance with Sec.  106.120(c) of 
the interim final rule and section 801(e) of the FD&C Act would not be 
required to make any notification under Sec.  106.140 of the interim 
final rule.
    However, the Agency advises that if a manufacturer makes a change 
to its infant formula for export only that constitutes a ``major 
change'' within the meaning of Sec.  106.3 of the interim final rule, 
the manufacturer would be required to make a 90-day new infant formula 
submission under Sec.  106.120 of the interim final rule. As stated in 
earlier in this preamble, a new infant formula that is for export only 
shall comply with Sec. Sec.  106.110 and 106.120 of the interim final 
rule. Importantly, a manufacturer of a new infant formula for export 
only may make an alternative submission under Sec.  106.120(c) of the 
interim final rule for the submission requirements that relate to 
whether the new infant formula is adulterated under section 412(a) of 
the FD&C Act. However, if a manufacturer of a new infant formula for 
export only elects to make a new infant formula submission under Sec.  
106.120(b) of the interim final rule, the manufacturer would be 
required to submit a verification submission under Sec.  106.130 of the 
interim final rule and the submission concerning a change in infant 
formula that may adulterate the product, if the formula was changed 
under Sec.  106.140 of the interim final rule. When a manufacturer 
makes a new infant formula submission under Sec.  106.120(b) of the 
interim final rule, the Agency reviews the application using the 
requirements in the FD&C Act and FDA's implementing regulations to 
determine whether the formula meets these requirements and thus, is 
eligible to be marketed in the United States. If a manufacturer elects 
to have its formula reviewed as a formula to be marketed in the United 
States, it must make all of the relevant submissions required by the 
FD&C Act for such formulas.

G. Notification of an Adulterated or Misbranded Infant Formula 
(Proposed Sec.  106.150)

    In the 1996 proposal, FDA proposed to recodify Sec.  106.120(b) in 
subpart G and to designate the recodified provision as Sec.  106.150. 
The proposed recodification included several minor editorial changes to 
the text of current Sec.  106.120(b).
    The Agency received several comments on this proposed 
recodification, and responds below.
    (Comment 356) One comment suggested a modification of proposed 
Sec.  106.150(a)(2), which would have required that a manufacturer 
promptly notify FDA if an infant formula that the manufacturer has 
processed and that has left the manufacturer's control may be 
adulterated or misbranded. The comment suggested adding the following: 
``In the case of 'adulteration' based on a failure to follow CGMP, the 
failure must be of such a nature as to reasonably call into question 
the suitability of the formula. Notification shall not be required for 
minor or technical misbranding.'' In support of this suggestion, the 
comment asserted that a violation of the infant formula CGMP, no matter 
how minor or inconsequential, will constitute a ``technical 
adulteration or misbranding'' of the product, that formula 
manufacturers are of the only members of the food industry compelled to 
notify FDA when a distributed product is or may be ``adulterated'' or 
``misbranded,'' and thus, it is critical to weigh each proposed 
regulation for the consequences of a finding of ``adulteration'' or 
``misbranding'' to ensure that such regulations are appropriate. The 
comment concluded that only adulteration of public health significance 
and only significant or actionable misbranding should trigger 
notification.
    (Response) FDA disagrees that with this comment. Proposed Sec.  
106.150, and its predecessor, current Sec.  106.120(b), implement 
section 412(e)(1)(B) of the FD&C Act. This statutory provision requires 
a formula manufacturer to notify the Secretary (and by delegation, FDA) 
when the manufacturer has knowledge which reasonably supports the 
conclusion that an infant formula which has been processed by the 
manufacturer and which has left an establishment subject to the control 
of the manufacturer may not provide the nutrients required by section 
412(i) of the FD&C Act or ``may be otherwise adulterated or 
misbranded.'' Section 412(e)(1) of the FD&C Act provides that the 
Secretary (and by delegation, FDA), and not the manufacturer, shall 
determine whether the released infant formula presents a risk to human 
health. Thus, it is incumbent upon the FDA to evaluate the public 
health risk that may be associated with an adulterated or misbranded 
infant formula, and the modification requested in this comment would be 
inconsistent with the governing statutory provision.
    In addition, FDA disagrees that Sec.  106.150(a) should be modified 
so that notification of adulteration based on a failure to follow CGMP 
need only be made if the failure to follow CGMP reasonably calls into 
question the suitability of the formula. A failure to follow CGMP 
indicates that a manufacturer's process is not under appropriate 
control, and thus, a manufacturer should promptly and fully address 
such failure following discovery. Only if FDA is aware of the finding 
of a breach of infant formula CGMP can the Agency appropriately monitor 
the manufacturer and ensure that further problems do not develop. 
Moreover, as noted elsewhere in this preamble, safety considerations 
are of unique importance with infant formula because such formula is 
intended to be the sole source of nutrition for infants during the 
early period of significant development and growth. Therefore, it is 
incumbent upon the Agency to evaluate the public health risks that may 
be associated with an adulterated or misbranded infant formula.
    FDA recognizes that some infant formula CGMP failures may not have 
public health consequences. However, the Agency must be made aware of 
all formulas that have left the control of the manufacturer that may be 
adulterated or misbranded so that FDA can discharge its obligation 
under section 412(e)(1) of the FD&C Act. Accordingly, FDA declines to 
modify proposed Sec.  106.150 in response to this comment.
    The Agency is, however, modifying Sec.  106.150(b) to update the 
contact information for submission of a notification of an adulterated 
or misbranded infant formula. Thus, Sec.  106.150(b) of the interim 
final rule

[[Page 8055]]

requires, in part, that the manufacturer ``shall promptly send written 
confirmation of the notification to the Food and Drug Administration, 
Center for Food Safety and Applied Nutrition, Office of Compliance, 
Division of Enforcement (HFS-605), Recall Coordinator, 5100 Paint 
Branch Parkway, College Park, MD 20740, and to the appropriate FDA 
district office.''

H. Incorporation by Reference

    Certain material is incorporated by reference in the interim final 
rule with the approval of the Director of the Federal Register. For 
purposes of clarity and ease of reference, FDA has gathered in a single 
place in the interim final rule (Sec.  106.160) a list of the material 
that is incorporated by reference and information about how these 
materials may be obtained from their source.

XI. Conforming Amendments to Part 107

    In 1996, FDA proposed revisions to the regulations in part 107 to 
reflect the changes made by the 1986 amendments and the regulations 
that FDA was proposing to adopt in part 106. The Agency also proposed 
certain editorial changes. FDA received no comments on the proposed 
revisions to part 107.
    As explained elsewhere in this preamble, the interim final rule 
revises certain proposed provisions in part 106, which revisions were 
made in response to comments or for other reasons. Also, due to the 
passage of time, additional technical changes to part 107 are necessary 
to update Agency addresses and telephone numbers. Accordingly, as 
included in this interim final rule, part 107 reflects the revisions 
proposed in 1996 modified by additional technical changes and changes 
required for consistency with the provisions of part 106.

XII. Environmental Impact

    The Agency has determined under 21 CFR 25.30(j) and 25.32(n) that 
this action is of a type that does not individually or cumulatively 
have a significant effect on the human environment. Therefore, neither 
an environmental assessment nor an environmental impact statement is 
required.

XIII. Federalism

    FDA has analyzed this interim final rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the rule does not contain policies that have substantial direct effects 
on the States, on the relationship between the National Government and 
the States, or on the distribution of power and responsibilities among 
the various levels of government. Accordingly, the Agency concludes 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

XIV. Regulatory Impact Analysis for Interim Final Rule

    FDA has examined the impacts of this interim final rule under 
Executive Order 12866, Executive Order 13563, the Regulatory 
Flexibility Act (5 U.S.C. 601-612), and the Unfunded Mandates Reform 
Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and 13563 direct 
Agencies to assess all costs and benefits of available regulatory 
alternatives and, when regulation is necessary, to select regulatory 
approaches that maximize net benefits (including potential economic, 
environmental, public health and safety, and other advantages; 
distributive impacts; and equity). We have developed a detailed 
Regulatory Impact Analysis (RIA) that presents the benefits and costs 
of this interim final rule (Ref. 92) which is available at http://www.regulations.gov (enter Docket No. FDA-1995-N-0036). The full 
economic impact analyses of FDA regulations are no longer (as of April 
2012) published in the Federal Register but are submitted to the docket 
and are available at http://www.regulations.gov. We believe that the 
interim final rule is not a significant regulatory action as defined by 
Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. According to our analysis, we believe that the 
interim final rule will not have a significant economic impact on a 
substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $141 million, using the most current (2012) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
interim final rule to result in any 1-year expenditure that would meet 
or exceed this amount.
    The analyses that we have performed to examine the impacts of this 
interim final rule under Executive Order 12866, Executive Order 13563, 
the Regulatory Flexibility Act, and the Unfunded Mandates Reform Act of 
1995 are included in the RIA (Ref. 92).
    We included a Summary of the Economic Analysis of the Proposed Rule 
in the RIA (Ref. 92. We received comments on our analysis of the 
impacts presented in those sections, and the RIA (Ref. 92) contains our 
responses to those comments.

XV. Paperwork Reduction Act of 1995

    This interim final rule contains information collection 
requirements that are subject to review by the Office of Management and 
Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520) (the PRA). A description of these provisions with estimates of 
the annual reporting, recordkeeping, and third-party disclosure burden 
are included in the RIA in section IV, entitled ``Paperwork Reduction 
Act of 1995'' (Ref. 92). An agency may not conduct or sponsor, and a 
person is not required to respond to, a collection of information 
unless it displays a currently valid OMB control number.
    In the July 9, 1996, proposed rule, FDA included an analysis of the 
information collection provisions of the proposal under the PRA and 
requested comments on four questions relevant to that analysis (61 FR 
at 36205-36206). Subsequently, in 2003, the Agency reopened the comment 
period to update comments and to receive any new information on all 
issues, including on the PRA analysis (68 FR 22341). In response to 
these requests, FDA received no comments specifically referring to the 
Agency's 1996 PRA analysis or otherwise referring to the PRA. FDA did 
receive comments on the substantive provisions of the proposed rule, 
including comments on the proposed recordkeeping and other provisions 
of the proposal that would result in information collections. FDA has 
summarized and responded to these comments in the RIA (Ref. 92).
    As noted, the 1996 proposal included a PRA analysis. FDA is re-
estimating the burden of this interim final rule using current burden 
analysis methodology. The Agency invites comments on new issues 
relating to the following topics: (1) Whether the proposed collection 
of information is necessary for the proper performance of FDA's 
functions, including whether the information will have practical 
utility; (2) the accuracy of

[[Page 8056]]

FDA's estimate of the burden of the proposed collection of information, 
including the validity of the methodology and assumptions used; (3) 
ways to enhance the quality, utility, and clarity of the information to 
be collected; and (4) ways to minimize the burden of the collection of 
information on respondents, including through the use of automated 
collection techniques, when appropriate, and other forms of information 
technology.
    In compliance with the PRA, FDA has submitted the information 
collection provisions of this interim final rule to OMB for review. 
Prior to the effective date of this interim final rule, FDA will 
publish a notice in the Federal Register announcing OMB's decision to 
approve, modify, or disapprove the information collection provisions in 
this interim final rule. An Agency may not conduct or sponsor, and a 
person is not required to respond to, a collection of information 
unless it displays a currently valid OMB control number.

XVI. Comments

    The requirements in this interim final rule will be in effect on 
July 10, 2014. FDA invites the public to comment on this interim final 
rule. Comments submitted in response to this interim final rule should 
be limited to those that present new issues or new information. 
Comments previously submitted to the Division of Dockets Management 
have been considered and addressed in this interim final rule and 
should not be resubmitted.
    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
interim final rule. It is only necessary to send one set of comments. 
Identify comments with the docket number found in brackets in the 
heading of this document. Received comments may be seen in the Division 
of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

XVII. References

    The following references have been placed on display in the 
Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, 
MD 20852, and may be seen by interested persons between 9 a.m. and 4 
p.m., Monday through Friday. We have verified all the Web site 
addresses in the References section, but we are not responsible for any 
subsequent changes to the Web sites after this document publishes in 
the Federal Register.

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2013).
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Group. A White Paper: ``The Use of NCHS and CDC Growth Charts in 
Nutritional Assessment of Young Infants,'' Prepared for the Food 
Advisory Committee on Infant Formula, Food and Drug Administration. 
November 18, 2002.
73. Nelson S.E., R.R. Rogers, E.E. Ziegler, S.J. Fomon, ``Gain in 
weight and length during early infancy.'' Early Human Development 
Jul;19(4):223-39, 1989.
74. Food and Drug Administration. ``Guidance for Industry Acceptance 
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(accessed April 5, 2013).
75. L[ouml]nnerdal, B. and L. Hernell. ``Effects of feeding 
ultrahigh-temperature (UHT)-treated infant formula with different 
protein concentrations or powdered formula, as compared with breast-
feeding, on plasma amino acids, hematology, and trace element 
status.'' American Journal of Clinical Nutrition 68:350-356, 1998.
76. Raiten, D.J., J.M. Talbot, and J.H. Waters (Eds). ``Assessment 
of nutrient requirements for infant formulas.'' Journal of Nutrition 
128(11S):2064S-2066S, 1998.
77. Hegsted, D.M. and Y-O. Chang. ``Protein utilization in growing 
rats. I. Relative growth index as a bioassay procedure.'' Journal of 
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121-146, 1993.
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by normal full-term infants fed various milks and formulas.'' 
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Fomon (Ed.), Mosby-Year Book, Inc., St. Louis, MO. pp. 459-464, 
1993.
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used as a criterion reference for body fat measurements in 
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Regarding Iron Status and Infant Development.'' Journal of Nutrition 
137(2): 524S-530, 2007.
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Vitamin D Rat Bioassay, May 12, 1994.
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based Infant Formula, Phase IV. Iodine, Linoleic Acid, and Vitamins 
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Collaborative Study.'' Journal of the Association of Official 
Analytical Chemists International 76: 1042-1056, 1993.
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List of Subjects

21 CFR Part 106

    Food grades and standards, Infants and children, Incorporation by 
reference, Nutrition, Reporting and recordkeeping requirements.

21 CFR Part 107

    Food labeling, Infants and children, Nutrition, Reporting and 
recordkeeping, Signs and symbols.


[[Page 8059]]


    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
106 and 107 are amended as follows:

0
1. Revise part 106 to read as follows:

PART 106--INFANT FORMULA REQUIREMENTS PERTAINING TO CURRENT GOOD 
MANUFACTURING PRACTICE, QUALITY CONTROL PROCEDURES, QUALITY 
FACTORS, RECORDS AND REPORTS, AND NOTIFICATIONS

Subpart A--General Provisions
Sec.
106.1 Status and applicability of the regulations in part 106.
106.3 Definitions.
Subpart B--Current Good Manufacturing Practice
106.5 Current good manufacturing practice.
106.6 Production and in-process control system.
106.10 Controls to prevent adulteration by workers.
106.20 Controls to prevent adulteration caused by facilities.
106.30 Controls to prevent adulteration caused by equipment or 
utensils.
106.35 Controls to prevent adulteration due to automatic (mechanical 
or electronic) equipment.
106.40 Controls to prevent adulteration caused by ingredients, 
containers, and closures.
106.50 Controls to prevent adulteration during manufacturing.
106.55 Controls to prevent adulteration from microorganisms.
106.60 Controls to prevent adulteration during packaging and 
labeling of infant formula.
106.70 Controls on the release of finished infant formula.
106.80 Traceability.
106.90 Audits of current good manufacturing practice.
Subpart C--Quality Control Procedures
106.91 General quality control.
106.92 Audits of quality control procedures.
Subpart D--Conduct of Audits
106.94 Audit plans and procedures.
Subpart E--Quality Factors for Infant Formulas
106.96 Requirements for quality factors for infant formulas.
Subpart F--Records and Reports
106.100 Records.
Subpart G--Registration, Submission, and Notification Requirements
106.110 New infant formula registration.
106.120 New infant formula submission.
106.121 Quality factor assurances for infant formulas.
106.130 Verification submission.
106.140 Submission concerning a change in infant formula that may 
adulterate the product.
106.150 Notification of an adulterated or misbranded infant formula.
106.160 Incorporation by reference.

    Authority:  21 U.S.C. 321, 342, 350a, 371.

Subpart A--General Provisions


Sec.  106.1  Status and applicability of the regulations in part 106.

    (a) The criteria set forth in subparts B, C, and D of this part 
prescribe the steps that manufacturers shall take under section 
412(b)(2) and (b)(3) of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 350a(b)(2) and (b)(3)) in processing infant formula. If the 
processing of the formula does not comply with any regulation in 
subparts B, C, or D of this part, the formula will be deemed to be 
adulterated under section 412(a)(3) of the Federal Food, Drug, and 
Cosmetic Act.
    (b) The criteria set forth in subpart E of this part prescribe the 
requirements for quality factors that infant formula shall meet under 
section 412(b)(1) of the Federal Food, Drug, and Cosmetic Act. If the 
formula fails to comply with any regulation in subpart E of this part, 
it will be deemed to be adulterated under section 412(a)(2) of the 
Federal Food, Drug, and Cosmetic Act.
    (c) The criteria set forth in subpart F of this part prescribe 
records requirements for quality factors under section 412(b)(1) of the 
Federal Food, Drug, and Cosmetic Act and for good manufacturing 
practices and quality control procedures, including distribution and 
audit records, under section 412(b)(2). If an infant formula 
manufacturer fails to comply with the quality factor record 
requirements in subpart F of this part with respect to an infant 
formula, the formula will be deemed to be adulterated under section 
412(a)(2) of the Federal Food, Drug, and Cosmetic Act. If an infant 
formula manufacturer fails to comply with the good manufacturing 
practices or quality control procedures record requirements in subpart 
F of this part with respect to an infant formula, the infant formula 
will be deemed to be adulterated under section 412(a)(3) of the Federal 
Food, Drug, and Cosmetic Act. The criteria set forth in subpart F of 
this part also implement record retention requirements under section 
412(b)(4) of the Federal Food, Drug, and Cosmetic Act. Failure to 
comply with any regulation in subpart F of this part is a violation of 
section 301(e) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
331(e)).
    (d) The criteria set forth in subpart G of this part describe, in 
part, certain good manufacturing practices, quality control procedures, 
and quality factor records requirements under section 412(b)(1) and 
(b)(2) of the Federal Food, Drug and Cosmetic Act. If an infant formula 
manufacturer fails to comply with such records requirements with 
respect to an infant formula, the infant formula will be deemed to be 
adulterated under section 412(a)(2) or (a)(3) of the Federal Food, 
Drug, and Cosmetic Act, as applicable. The criteria set forth in 
subpart G of this part also describe the circumstances in which an 
infant formula manufacturer is required to register with, submit to, or 
notify the Food and Drug Administration, and the content of a 
registration, submission, or notification, under section 412(c), (d), 
and (e) of the Federal Food, Drug, and Cosmetic Act. Failure to comply 
with any regulation in subpart G of this part is a violation of section 
301(s) of the Federal Food, Drug, and Cosmetic Act.


Sec.  106.3  Definitions.

    The definitions in this section and the definitions contained in 
section 201 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321) 
shall apply to infant formula requirements in 21 CFR parts 106 and 107 
of this chapter.
    Eligible infant formula means an infant formula that could have 
been or was lawfully distributed in the United States on May 12, 2014.
    Final product stage means the point in the manufacturing process, 
before distribution of an infant formula, at which the infant formula 
is homogeneous and is not subject to further degradation due to 
processing.
    Indicator nutrient means a nutrient whose concentration is measured 
during the manufacture of an infant formula to confirm complete 
addition and uniform distribution of a premix or other substance of 
which the indicator nutrient is a part.
    Infant means a person not more than 12 months of age.
    Infant formula means a food which purports to be or is represented 
for special dietary use solely as a food for infants by reason of its 
simulation of human milk or its suitability as a complete or partial 
substitute for human milk.
    In-process production aggregate means a combination of ingredients 
at any point in the manufacturing process before packaging.
    Major change in an infant formula means any new formulation, or any 
change of ingredients or processes where experience or theory would 
predict a possible significant adverse impact on levels of nutrients or 
bioavailability of nutrients, or any

[[Page 8060]]

change that causes an infant formula to differ fundamentally in 
processing or in composition from any previous formulation produced by 
the manufacturer. Examples of infant formulas deemed to differ 
fundamentally in processing or in composition include:
    (1) Any infant formula produced by a manufacturer who is entering 
the U.S. market;
    (2) Any infant formula powder processed and distributed by a 
manufacturer who previously only produced liquids (or vice versa);
    (3) Any infant formula having a significant revision, addition, or 
substitution of a macronutrient (i.e., protein, fat, or carbohydrate), 
with which the manufacturer has not had previous experience;
    (4) Any infant formula manufactured on a new processing line or in 
a new plant;
    (5) Any infant formula manufactured containing a new constituent 
not listed in section 412(i) of the Federal Food, Drug, and Cosmetic 
Act (21 U.S.C. 350a(i)), such as taurine or L-carnitine;
    (6) Any infant formula processed by a manufacturer on new equipment 
that utilizes a new technology or principle (e.g., from terminal 
sterilization to aseptic processing); or
    (7) An infant formula for which there has been a fundamental change 
in the type of packaging used (e.g., changing from metal cans to 
plastic pouches).
    Manufacturer means a person who prepares, reconstitutes, or 
otherwise changes the physical or chemical characteristics of an infant 
formula or packages or labels the product in a container for 
distribution. The term ``manufacturer'' does not include a person who 
prepares, reconstitutes, or mixes infant formula exclusively for an 
infant under his/her direct care or the direct care of the institution 
employing such person.
    Microorganisms means yeasts, molds, bacteria, and viruses and 
includes, but is not limited to, species having public health 
significance.
    New infant formula means:
    (1) An infant formula manufactured by a person that has not 
previously manufactured an infant formula, and
    (2) An infant formula manufactured by a person that has previously 
manufactured infant formula and in which there is a major change in 
processing or formulation from a current or any previous formulation 
produced by such manufacturer, or which has not previously been the 
subject of a submission under section 412(c) of the Federal Food, Drug, 
and Cosmetic Act for the U.S. market.
    Nutrient means any vitamin, mineral, or other substance or 
ingredient that is required in accordance with the ``Nutrients'' table 
set out in section 412(i)(1) of the Federal Food, Drug, and Cosmetic 
Act or by regulations issued under section 412(i)(2) or that is 
identified as essential for infants by the Food and Nutrition Board of 
the Institute of Medicine through its development of a Dietary 
Reference Intake, or that has been identified as essential for infants 
by the Food and Drug Administration through a Federal Register 
publication.
    Nutrient premix means a combination of ingredients containing two 
or more nutrients received from a supplier or prepared by an infant 
formula manufacturer.
    Production aggregate means a quantity of product, or, in the case 
of an infant formula produced by continuous process, a specific 
identified amount produced in a unit of time, that is intended to have 
uniform composition, character, and quality, within specified limits, 
and is produced according to a master manufacturing order.
    Production unit means a specific quantity of an infant formula 
produced during a single cycle of manufacture that has uniform 
composition, character, and quality, within specified limits.
    Production unit number or production aggregate number means any 
distinctive combination of letters, numbers, symbols, or any 
combination of them, from which the complete history of the 
manufacture, processing, packing, holding, and distribution of a 
production aggregate or a production unit of infant formula can be 
determined.
    Quality factors means those factors necessary to demonstrate the 
bioavailability and safety of the infant formula, as prepared for 
market and when fed as the sole source of nutrition, including the 
bioavailability of individual nutrients in the formula, to ensure the 
healthy growth of infants.
    Representative sample means a sample that consists of a number of 
units that are drawn based on rational criteria, such as random 
sampling, and intended to ensure that the sample accurately portrays 
the material being sampled.
    Shall is used to state mandatory requirements.

Subpart B--Current Good Manufacturing Practice


Sec.  106.5  Current good manufacturing practice.

    (a) The regulations set forth in this subpart define the minimum 
current good manufacturing practices that are to be used in, and the 
facilities or controls that are to be used for, the manufacture, 
processing, packing, or holding of an infant formula. Compliance with 
these provisions is necessary to ensure that such infant formula 
provides the nutrients required under Sec.  107.100 of this chapter and 
is manufactured in a manner designed to prevent its adulteration. A 
liquid infant formula that is a thermally processed low-acid food 
packaged in a hermetically sealed container is also subject to the 
regulations in part 113 of this chapter, and an infant formula that is 
an acidified food, as defined in Sec.  114.3(b) of this chapter, is 
also subject to the regulations in part 114 of this chapter.
    (b) The failure to comply with any regulation in this subpart in 
the manufacture, processing, packing, or holding of an infant formula 
shall render such infant formula adulterated under section 412(a)(3) of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 350a(a)(3)); the 
failure to comply with any regulation in part 113 of this chapter in 
the manufacture, processing, packing, or holding of a liquid infant 
formula shall render such infant formula adulterated under section 
412(a)(3); and the failure to comply with any regulation in part 114 of 
this chapter in the manufacture, processing, packing, or holding of an 
infant formula that is an acidified food shall render such infant 
formula adulterated under section 412(a)(3).


Sec.  106.6  Production and in-process control system.

    (a) A manufacturer shall conform to the requirements of this 
subpart by implementing a system of production and in-process controls. 
This production and in-process control system shall cover all stages of 
processing, from the receipt and acceptance of the raw materials, 
ingredients, and components through the storage and distribution of the 
finished product and shall be designed to ensure that all the 
requirements of this subpart are met.
    (b) The production and in-process control system shall be set out 
in a written plan or set of procedures that is designed to ensure that 
an infant formula is manufactured in a manner that will prevent 
adulteration of the infant formula.
    (c) At any point, step, or stage in the production process where 
control is necessary to prevent adulteration, a manufacturer shall:
    (1) Establish specifications to be met;
    (2) Monitor the production and in-process control point, step, or 
stage;

[[Page 8061]]

    (3) Establish a corrective action plan for use when a specification 
established in accordance with paragraph (c)(1) of this section is not 
met;
    (4) Review the results of the monitoring required by paragraph 
(c)(2) of this section, and review and evaluate the public health 
significance of any deviation from specifications that have been 
established in accordance with paragraph (c)(1) of this section. For 
any specification established in accordance with paragraph (c)(1) of 
this section that a manufacturer fails to meet, an individual qualified 
by education, training, or experience shall conduct a documented review 
and shall make a material disposition decision to reject the affected 
article, to reprocess or otherwise recondition the affected article, or 
to approve and release the article for use or distribution; and
    (5) Establish recordkeeping procedures, in accordance with Sec.  
106.100(e)(3), that ensure that compliance with the requirements of 
this section is documented.
    (d) Any article that fails to meet a specification established in 
accordance with paragraph (c)(1) of this section shall be controlled 
under a quarantine system designed to prevent its use pending the 
completion of a documented review and material disposition decision.


Sec.  106.10  Controls to prevent adulteration by workers.

    (a) A manufacturer shall employ sufficient personnel, qualified by 
education, training, or experience, to perform all operations, 
including all required recordkeeping, in the manufacture, processing, 
packing, and holding of each infant formula and to supervise such 
operations to ensure that the operations are correctly and fully 
performed.
    (b) Personnel working directly with infant formula, infant formula 
raw materials, infant formula packaging, or infant formula equipment or 
utensil contact surfaces shall practice good personal hygiene to 
protect the infant formula against contamination. Good personal hygiene 
includes:
    (1) Wearing clean outer garments and, as necessary, protective 
apparel such as head, face, hand, and arm coverings; and
    (2) Washing hands thoroughly in a hand washing facility with soap 
and running water at a suitable temperature before starting work, after 
each absence from the work station, and at any other time when the 
hands may become soiled or contaminated.
    (c) Any person who reports that he or she has, or appears by 
medical examination or supervisory observation to have, an illness, 
open lesion (including boils, sores, or infected wounds), or any other 
source of microbial contamination that creates a reasonable possibility 
that the safety of an infant formula may be adversely affected, shall 
be excluded from direct contact with ingredients, containers, closures, 
in-process materials, equipment, utensils, and infant formula product 
until the condition is corrected or determined by competent medical 
personnel not to jeopardize the safety of the infant formula.


Sec.  106.20  Controls to prevent adulteration caused by facilities.

    (a) Buildings used in the manufacture, processing, packing, or 
holding of infant formula shall be maintained in a clean and sanitary 
condition and shall have space for the separation of incompatible 
operations, such as the handling of raw materials, the manufacture of 
the product, and packaging and labeling operations.
    (b) Separate areas or another system of separation, such as a 
computerized inventory control, a written card system, or an automated 
system of segregation, shall be used for holding raw materials, in-
process materials, and final infant formula product at the following 
times:
    (1) Pending release for use in infant formula production or pending 
release of the final product;
    (2) After rejection for use in, or as, infant formula; and
    (3) After release for use in infant formula production or after 
release of the final product.
    (c) Lighting shall allow easy identification of raw materials, 
packaging, labeling, in-process materials, and finished products that 
have been released for use in infant formula production and shall 
permit the easy reading of instruments and controls necessary in 
processing, packaging, and laboratory analysis. Any lighting fixtures 
directly over or adjacent to exposed raw materials, in-process 
materials, or bulk (unpackaged) finished product shall be protected to 
prevent glass from contaminating the product in the event of breakage.
    (d) A manufacturer shall provide adequate ventilation or control 
equipment to minimize odors and vapors (including steam and noxious 
fumes) in areas where they may contaminate the infant formula; and 
shall minimize the potential for contamination of raw materials, in-
process materials, final product infant formula, packing materials, and 
infant formula-contact surfaces, through the use of appropriate 
measures, which may include the use of air filtration.
    (e) All rodenticides, insecticides, fungicides, fumigating agents, 
and cleaning and sanitizing agents shall be stored and used in a manner 
that protects against contamination of infant formula.
    (f) Potable water used in the manufacture of infant formula shall 
meet the standards prescribed in the Environmental Protection Agency's 
(EPA's) Primary Drinking Water regulations in 40 CFR part 141, except 
that the water used in infant formula manufacturing shall not be 
fluoridated or shall be defluoridated to a level as low as possible 
prior to use.
    (1) The water shall be supplied under continuous positive pressure 
in a plumbing system that is free of defects that could contaminate an 
infant formula.
    (2) A manufacturer shall test representative samples of the potable 
water drawn at a point in the system at which the water is in the same 
condition that it will be when it is used in infant formula 
manufacturing.
    (3) A manufacturer shall conduct the tests required by paragraph 
(f)(2) of this section with sufficient frequency to ensure that the 
water meets the EPA's Primary Drinking Water Regulations but shall not 
conduct these tests less frequently than annually for chemical 
contaminants, every 4 years for radiological contaminants, and weekly 
for bacteriological contaminants.
    (4) A manufacturer shall make and retain records, in accordance 
with Sec.  106.100(f)(1), of the frequency and results of testing of 
the water used in the production of infant formula.
    (g) There shall be no backflow from, or cross-connection between, 
piping systems that discharge waste water or sewage and piping systems 
that carry water for infant formula manufacturing.
    (h) Only culinary steam shall be used at all direct infant formula 
product contact points. Culinary steam shall be in compliance with the 
3-A Sanitary Standards, No. 60903, which is incorporated by reference 
at Sec.  106.160. Boiler water additives in the steam shall be used in 
accordance with Sec.  173.310 of this chapter.
    (i) Each infant formula manufacturing site shall provide its 
employees with readily accessible toilet facilities and hand washing 
facilities that include hot and cold water, soap or detergent, single-
service towels or air dryers in toilet facilities. These facilities 
shall be maintained in good repair and in a sanitary condition at all 
times. These facilities shall provide for proper disposal of the 
sewage. Doors to the

[[Page 8062]]

toilet facility shall not open into areas where infant formula 
ingredients, containers, or closures are stored, or where infant 
formula is processed or stored.


Sec.  106.30  Controls to prevent adulteration caused by equipment or 
utensils.

    (a) A manufacturer shall ensure that equipment and utensils used in 
the manufacture, processing, packing, or holding of an infant formula 
are of appropriate design and are installed to facilitate their 
intended function and their cleaning and maintenance.
    (b) A manufacturer shall ensure that equipment and utensils used in 
the manufacture, processing, packing, or holding of an infant formula 
are constructed so that surfaces that contact ingredients, in-process 
materials, or infant formula are made of nontoxic materials and are not 
reactive or absorptive. A manufacturer shall ensure that such equipment 
and utensils are designed to be easily cleanable and to withstand the 
environment of their intended use and that all surfaces that contact 
ingredients, in-process materials, or infant formula are cleaned and 
sanitized, as necessary, and are maintained to protect infant formula 
from being contaminated by any source. All sanitizing agents used on 
such equipment and utensils that are regulated as pesticide chemicals 
under 21 U.S.C. 346a(a) shall comply with the Environmental Protection 
Agency's regulations established under such section, and all other such 
sanitizers shall comply with all applicable Food and Drug 
Administration laws and regulations.
    (c) A manufacturer shall ensure that any substance, such as a 
lubricant or a coolant, that is required for operation of infant 
formula manufacturing equipment and which would render the infant 
formula adulterated if such substance were to come in contact with the 
formula, does not come in contact with formula ingredients, containers, 
closures, in-process materials, or with infant formula product during 
the manufacture of an infant formula.
    (d) A manufacturer shall ensure that each instrument used for 
measuring, regulating, or controlling mixing time and speed, 
temperature, pressure, moisture, water activity, or other parameter at 
any point, step, or stage where control is necessary to prevent 
adulteration of an infant formula during processing is accurate, easily 
read, properly maintained, and present in sufficient number for its 
intended use.
    (1) The instruments and controls shall be calibrated against a 
known reference standard at the time of or before first use and 
thereafter at routine intervals, as specified in writing by the 
manufacturer of the instrument or control, or as otherwise deemed 
necessary to ensure the accuracy of the instrument or control. The 
known reference standard shall be certified for accuracy at the 
intervals specified in writing by the manufacturer of the instrument or 
control, or at routine intervals otherwise deemed necessary to ensure 
the accuracy of the instrument or control. A manufacturer shall make 
and retain records of the calibration activities in accordance with 
Sec.  106.100(f)(2).
    (2) Instruments and controls that cannot be adjusted to agree with 
the reference standard shall be repaired or replaced.
    (3) If calibration of an instrument shows a failure to meet a 
specification for a point where control is deemed necessary to prevent 
adulteration of infant formula product, a written evaluation of all 
affected product, and of any actions that need to be taken with respect 
to that product, shall be made, in accordance with Sec.  106.100(f)(2).
    (e) The following provisions apply to thermal processing and cold 
storage of infant formulas:
    (1) Equipment and procedures for thermal processing of infant 
formula packaged in hermetically sealed containers shall conform to the 
requirements in 21 CFR parts 108 and 113.
    (2)(i) Except as provided in paragraph (e)(2)(ii) of this section, 
a manufacturer shall maintain all areas of cold storage at a 
temperature of 40 [deg]F (4.4 [deg]C) or below.
    (ii) A manufacturer may maintain a cold storage area for an in-
process infant formula or for a final infant formula at a temperature 
not to exceed 45 [deg]F (7.2 [deg]C) for a defined period of time 
provided that the manufacturer has scientific data and other 
information to demonstrate that:
    (A) Compliance with paragraph (e)(2)(i) of this section would have 
an adverse effect on the quality of the in-process or the final infant 
formula through, e.g., destabilization or loss of homogeneity; and
    (B) The time and temperature conditions of such storage are 
sufficient to ensure that there is no significant growth of 
microorganisms of public health significance during the period of 
storage of the in-process or final infant formula product.
    (3)(i) Cold storage compartments and thermal processing equipment 
shall be equipped with easily readable, accurate temperature-indicating 
devices.
    (ii) A manufacturer shall ensure that the temperature of each cold 
storage compartment is maintained by:
    (A) Monitoring the temperature of the cold storage compartment on a 
temperature-indicating device and recording this temperature in a 
record with such frequency as is necessary to ensure that temperature 
control is maintained;
    (B) Equipping the cold storage compartment with one or more 
temperature-recording devices that will reflect, on a continuing basis, 
the true temperature, within the compartment;
    (C) Equipping the cold storage compartment with a high temperature 
alarm that has been validated to function properly and recording the 
temperature in a record with such frequency as is necessary to ensure 
that temperature control is maintained; or
    (D) Equipping the cold storage compartment with a maximum-
indicating thermometer that has been validated to function properly and 
recording this temperature in a record with such frequency as is 
necessary to ensure that temperature control is maintained.
    (iii) A manufacturer shall, in accordance with Sec.  106.100(f)(3), 
make and retain records of the temperatures recorded in compliance with 
Sec.  106.30(e)(3)(ii).
    (4) When a manufacturer uses a temperature-recording device for a 
cold storage compartment, such device shall not read lower than the 
reference temperature-indicating device.
    (5) A manufacturer shall monitor the temperature in thermal 
processing equipment at points where temperature control is necessary 
to prevent adulteration. Such monitoring shall be at such frequency as 
is required by regulation or is necessary to ensure that temperature 
control is maintained.
    (f) A manufacturer shall ensure that equipment and utensils used in 
the manufacture of infant formula are cleaned, sanitized, and 
maintained at regular intervals to prevent adulteration of the infant 
formula.
    (1) An individual qualified by education, training, or experience 
to conduct such a review shall review all cleaning, sanitizing, and 
maintenance to ensure that it has been satisfactorily completed.
    (2) A manufacturer shall make and retain records on equipment 
cleaning, sanitizing, and maintenance, in accordance with Sec.  
106.100(f)(4).
    (g) A manufacturer shall ensure that compressed air or other gases 
that are mechanically introduced into infant formula, that are used to 
clean any equipment, or that come into contact

[[Page 8063]]

with any other surface that contacts ingredients, in-process materials, 
or infant formula product are treated in such a way that their use will 
not contaminate the infant formula with unlawful or other chemical, 
physical, or microbiological contaminants. When compressed gases are 
used at product filling machines to replace air removed from the 
headspace of containers, a manufacturer shall install, as close as 
practical to the end of the gas line that feeds gas into the space, a 
filter capable of retaining particles 0.5 micrometer or smaller.


Sec.  106.35  Controls to prevent adulteration due to automatic 
(mechanical or electronic) equipment.

    (a) For the purposes of this section:
    (1) ``Hardware'' means all automatic equipment, including 
mechanical and electronic equipment (such as computers), that is used 
in production or quality control of infant formula.
    (2) ``Software'' means any programs, procedures, rules, and 
associated documentation used in the operation of a system.
    (3) ``System'' means a collection of components (including software 
and hardware) organized to accomplish a specific function or set of 
functions in a specified environment.
    (4) ``Validation'' means establishing documented evidence that 
provides a high degree of assurance that a system will consistently 
produce a product meeting its predetermined specifications and quality 
characteristics.
    (b) All systems shall be designed, installed, tested, and 
maintained in a manner that will ensure that they are capable of 
performing their intended function and of producing or analyzing infant 
formula in accordance with this subpart and subpart C of this part.
    (1) A manufacturer shall ensure that hardware that is capable of 
being calibrated is routinely calibrated according to written 
procedures, and that all hardware is routinely inspected and checked 
according to written procedures.
    (2) A manufacturer shall check and document the accuracy of input 
into, and output generated by, any system used in the production or 
quality control of an infant formula to ensure that the infant formula 
is not adulterated. The degree and frequency of input/output 
verification shall be based on the complexity and reliability of the 
system and the level of risk associated with the safe operation of the 
system.
    (3) A manufacturer shall ensure that each system is validated prior 
to the release for distribution of any infant formula manufactured 
using the system.
    (4) A manufacturer shall ensure that any system that is modified is 
revalidated following the modification and prior to the release for 
distribution of any infant formula manufactured using the modified 
system. All modifications to software shall be made by a designated 
individual and shall be checked by the infant formula manufacturer to 
ensure that infant formula that is produced or analyzed using the 
modified software complies with this subpart and with subpart C of this 
part.
    (c) A manufacturer shall make and retain records, in accordance 
with Sec.  106.100(f)(5), concerning mechanical or electronic 
equipment.


Sec.  106.40  Controls to prevent adulteration caused by ingredients, 
containers, and closures.

    (a) The only substances that may be used in an infant formula are 
substances that are safe and suitable for use in infant formula under 
the applicable food safety provisions of the Federal Food, Drug, and 
Cosmetic Act; that is, a substance is used in accordance with the 
Agency's food additive regulations, is generally recognized as safe 
(GRAS) for such use, or is authorized by a prior sanction.
    (b) Infant formula containers and closures shall not be reactive or 
absorptive so as to affect the safety of the infant formula. The 
following substances may be used as packaging material that comes in 
contact with an infant formula:
    (1) A food additive that is the subject of a regulation issued 
under section 409(c) of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 348(c)) and is used consistent with the conditions of use of 
that regulation;
    (2) A food contact substance that is the subject of an effective 
notification under section 409(h) of the Federal Food, Drug, and 
Cosmetic Act and is used consistent with the conditions of use in that 
notification;
    (3) A substance that is exempt from regulation as a food additive 
under Sec.  170.39 of this chapter and its use conforms to the use 
identified in the exemption letter;
    (4) A substance that is generally recognized as safe for use in or 
on infant formula or for use in infant formula packaging;
    (5) A substance the use of which is authorized by a prior sanction 
from the Food and Drug Administration or from the U.S. Department of 
Agriculture; and
    (6) A substance that is not a food additive within the meaning of 
section 201(s) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
321(s)) because the substance is not reasonably expected to become a 
component of food or otherwise affect the characteristics of food.
    (c) Ingredients, containers, and closures used in the manufacture 
of infant formula shall be identified with a lot number to be used in 
recording their disposition.
    (d) A manufacturer shall develop written specifications for 
ingredients, containers, and closures used in manufacturing infant 
formula and shall develop and follow written procedures to determine 
whether all ingredients, containers, and closures meet these 
specifications. When any specification is not met, an individual 
qualified by education, training, or experience shall conduct a 
documented review, shall determine whether a failure to meet such a 
specification could result in an adulterated infant formula, and shall 
make and document a material disposition decision to reject the 
ingredient, container, or closure or the affected infant formula; to 
reprocess or otherwise recondition the ingredient, container, or 
closure or the affected infant formula; or to approve and release the 
ingredient, container, or closure or the affected infant formula for 
use.
    (e) Ingredients, containers, and closures shall be stored in 
separate areas or separated by a system of segregation, such as a 
computerized inventory control, a written card system, or an automated 
system of segregation, clearly designated for materials pending release 
for use; materials released for use; or materials rejected for use in 
infant formula production.
    (1) Any lot of an ingredient, a container, or a closure that does 
not meet the manufacturer's specifications shall be quarantined under a 
system designed to prevent its use in the manufacture of infant formula 
until an individual qualified by education, training, or experience has 
conducted a documented review, has determined whether such failure 
could result in an adulterated infant formula, and has made and 
documented a material disposition decision to reject the ingredient, 
container, closure, or the affected infant formula; to reprocess or 
otherwise recondition the ingredient, container, closure, or the 
affected infant formula; or to approve and release the ingredient, 
container, closure, or the affected infant formula for use.
    (2) Any ingredient, container, or closure that has been reprocessed 
or otherwise reconditioned shall be the subject of a documented review 
and

[[Page 8064]]

material disposition decision by an individual qualified by education, 
training, or experience to determine whether it may be released for 
use.
    (3) A manufacturer shall not reprocess or otherwise recondition an 
ingredient, container, or closure rejected because it is contaminated 
with microorganisms of public health significance or other 
contaminants, such as heavy metals.
    (f) If an ingredient, container, or closure that complies with a 
manufacturer's specifications, or that has been released for use 
following a material review and disposition decision, is subsequently 
exposed to air, heat, or other conditions that may adversely affect it, 
or if a manufacturer reasonably believes that an ingredient, container, 
or closure that complies with a manufacturer's specifications, or that 
has been released for use following a material review and disposition 
decision, has been exposed to air, heat, or other conditions that may 
adversely affect it, the ingredient, container, or closure shall be 
quarantined under a system designed to prevent its use in the 
manufacture of infant formula until an individual qualified by 
education, training, or experience has conducted a documented review 
and has made and documented a material disposition decision to reject 
the ingredient, container, or closure; to reprocess or otherwise 
recondition the ingredient, container, or closure; or to approve and 
release the ingredient, container, or closure for use.
    (1) Any ingredient, container, or closure that is reprocessed or 
otherwise reconditioned shall be retested or reexamined and be the 
subject of a documented review and material disposition decision by an 
individual qualified by education, training, or experience to determine 
whether the ingredient, container, or closure should be rejected, 
further reprocessed or otherwise further reconditioned, or approved and 
released for use.
    (2) Any rejected ingredient, container, or closure shall be clearly 
identified as having been rejected for use in infant formula 
manufacturing or processing operations and shall be controlled under a 
quarantine system designed to prevent its use in infant formula 
manufacturing or processing operations.
    (3) Any ingredient, container, or closure that has not been 
manufactured, packaged, labeled, or held under conditions to prevent 
adulteration under section 402(a)(1) through (a)(4) of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 342(a)(1) through (a)(4)) shall 
not be approved and released for use.
    (g) A manufacturer shall make and retain records, in accordance 
with Sec.  106.100(f)(6), on the ingredients, containers, and closures 
used in the manufacture of infant formula.


Sec.  106.50  Controls to prevent adulteration during manufacturing.

    (a) A manufacturer shall prepare and follow a written master 
manufacturing order that establishes controls and procedures for the 
production of an infant formula.
    (1) The manufacturer shall make and retain records, in accordance 
with Sec.  106.100(e), that include complete information relating to 
the production and control of the production aggregate. An individual 
qualified by education, training, or experience shall conduct an 
investigation of any deviations from the master manufacturing order and 
document any corrective action taken.
    (2) Changes made to the master manufacturing order shall be 
drafted, reviewed, and approved by a responsible official and include 
an evaluation of the effect of the change on the nutrient content and 
the suitability of the formula for infants.
    (b) A manufacturer shall establish controls to ensure that each raw 
or in-process ingredient required by the master manufacturing order is 
examined by one person and checked by a second person or system. This 
checking shall ensure that the correct ingredient is added during the 
manufacturing process, that the ingredient has been released for use in 
infant formula, and that the correct weight or measure of the 
ingredient is added to the production unit.
    (c) A manufacturer shall establish a system of identification for 
the contents of all compounding and storage containers, processing 
lines, and major equipment used during the manufacture of a production 
aggregate of an infant formula. The system shall permit the 
identification of the processing stage and the unique identification 
number for the particular production unit or production aggregate of 
infant formula.
    (d) A manufacturer shall establish controls to ensure that the 
nutrient levels required by Sec.  107.100 of this chapter are 
maintained in the formula, and that the formula is not contaminated 
with microorganisms or other contaminants. Such controls shall include:
    (1) The mixing time; the speed, temperature, and flow rate of 
product; and other critical parameters necessary to ensure the addition 
of required ingredients to, and the homogeneity of, the formula;
    (2) The spray-drying process for powdered infant formula, including 
the filtering of the intake air before heating, to prevent microbial 
and other contamination;
    (3) The removal of air from the finished product to ensure that 
nutrient deterioration does not occur;
    (4) Ensuring that each container of finished product is properly 
sealed. Such controls shall involve use of established procedures, 
specifications, and intervals of examination that are designed by 
qualified individuals and are sufficient to:
    (i) Detect visible closure or seal defects, and
    (ii) Determine closure strength through destructive testing. A 
manufacturer of a liquid infant formula that is a thermally processed 
low-acid food packaged in a hermetically sealed container shall perform 
such closure integrity testing in accordance with Sec.  113.60(a) of 
this chapter.
    (e) A manufacturer shall establish controls that ensure that the 
equipment used at points where control is deemed necessary to prevent 
adulteration is monitored, so that personnel will be alerted to 
malfunctions.
    (f) A manufacturer shall establish controls for in-process material 
as follows:
    (1) For any specification established in accordance with Sec.  
106.6(c)(1) that a manufacturer fails to meet for in-process material, 
an individual qualified by education, training, or experience shall 
conduct a documented review and shall make a material disposition 
decision to reject the affected in-process material, to reprocess or 
otherwise recondition the affected in-process material, or to approve 
and release the affected in-process material for use or distribution;
    (2) Pending a documented review and material disposition decision, 
any in-process material that fails to meet any specification 
established in accordance with Sec.  106.6(c)(1) shall be clearly 
identified as such and shall be controlled under a quarantine system 
designed to prevent its use in manufacturing or processing operations 
until completion of the documented review and material disposition 
decision;
    (3) Any in-process material that has been reprocessed or otherwise 
reconditioned shall be the subject of a documented review and material 
disposition decision by an individual qualified by education, training, 
or experience to determine whether it may be released for use; and
    (4) Any rejected in-process material shall be clearly identified as 
having been rejected for use in infant formula

[[Page 8065]]

and shall be controlled under a quarantine system designed to prevent 
its use in infant formula manufacturing or processing operations.


Sec.  106.55  Controls to prevent adulteration from microorganisms.

    (a) A manufacturer of infant formula shall establish a system of 
process controls covering all stages of processing that is designed to 
ensure that infant formula does not become adulterated due to the 
presence of microorganisms in the formula or in the processing 
environment.
    (b) A manufacturer of liquid infant formula shall comply, as 
appropriate, with the procedures specified in part 113 of this chapter 
for thermally processed low-acid foods packaged in hermetically sealed 
containers and part 114 of this chapter for acidified foods.
    (c) A manufacturer of powdered infant formula shall test 
representative samples of each production aggregate of powdered infant 
formula at the final product stage, before distribution, to ensure that 
each production aggregate meets the microbiological quality standards 
in the table in paragraph (e) of this section.
    (d) A manufacturer shall make and retain records, in accordance 
with Sec.  106.100(e)(5)(ii) and (f)(7), on the testing of infant 
formulas for microorganisms.
    (e) A powdered infant formula that contains any microorganism that 
exceeds the M value listed for that microorganism in the table in 
paragraph (e) of this section shall be deemed adulterated under 
sections 402(a)(1), 402(a)(4), and 412(a)(3) of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 350a(a)(3)). The Food and Drug 
Administration will determine compliance with the M values listed below 
using the latest edition of the Bacteriological Analytical Manual (BAM) 
(http://www.fda.gov/Food/FoodScienceResearch/LaboratoryMethods/BacteriologicalAnalyticalManualBAM/default.htm) (accessed April 8, 
2013).

----------------------------------------------------------------------------------------------------------------
                 Microorganism                       n \1\                 Sample size                M value
----------------------------------------------------------------------------------------------------------------
Cronobacter spp...............................              30  10 g (grams)....................          \2\ 0.
Salmonella spp................................              60  25 g............................          \2\ 0.
----------------------------------------------------------------------------------------------------------------
\1\ Number of samples.
\2\ None detected.

Sec.  106.60  Controls to prevent adulteration during packaging and 
labeling of infant formula.

    (a) A manufacturer shall examine packaged and labeled infant 
formula during finishing operations to ensure that all containers and 
packages in the production aggregate have the correct label, the 
correct use-by date, and the correct code established under Sec.  
106.80.
    (b) Labels shall be designed, printed, and applied so that the 
labels remain legible and attached during the conditions of processing, 
storage, handling, distribution, and use.
    (c) Packaging used to hold multiple containers of an infant formula 
product shall be labeled as follows:
    (1) Where all containers are the same infant formula product and 
all bear the same code established under Sec.  106.80, the packaging 
label shall include the product name, the name of the manufacturer, 
distributor, or shipper, and the code established under Sec.  106.80.
    (2) Where the containers are not the same infant formula product or 
do not all bear the same code established under Sec.  106.80, the 
packaging label shall:
    (i) Include the product name of each product, the name of the 
manufacturer, distributor, or shipper of each product, the code 
established under Sec.  106.80 for each product, and a ``use by'' date 
that is no later than the ``use by'' date of the container exhibiting 
the closest ``use by'' date applied to satisfy the requirement of Sec.  
107.20(c) of this chapter; or
    (ii) Include a unique identification number assigned by the 
packager, provided that the distributor of the package maintains a 
record linked to such unique number that identifies the product name of 
each product, the name of the manufacturer, distributor, or shipper of 
each product, the code established under Sec.  106.80 for each product, 
and the ``use by'' date for each product applied to satisfy the 
requirement of Sec.  107.20(c) of this chapter.


Sec.  106.70  Controls on the release of finished infant formula.

    (a) A manufacturer shall control under a quarantine system designed 
to prevent use or distribution of each production aggregate of infant 
formula until it determines that the production aggregate meets all of 
the manufacturer's specifications, including those adopted to meet the 
standards of Sec.  106.55 on microbiological contamination and of Sec.  
106.91(a) on quality control procedures, or until the documented review 
of the failure to meet any of the manufacturer's specifications finds 
that the failure does not result in, or could not lead to, adulteration 
of the product.
    (b) Any production aggregate of infant formula that fails to meet 
any of the manufacturer's specifications shall be quarantined under a 
system designed to prevent its use in the manufacture of infant formula 
or its distribution until an individual qualified by education, 
training, or experience has conducted a documented review and has made 
and documented a material disposition decision to reject the infant 
formula; to reprocess or otherwise recondition the infant formula; or 
to approve and release the infant formula. Any production aggregate of 
infant formula that is reprocessed or otherwise reconditioned shall be 
the subject of a documented review and material disposition decision by 
an individual qualified by education, training, or experience to 
determine whether it may be released for use or distribution.
    (c) Any rejected infant formula shall be clearly identified as 
having been rejected for use and shall be controlled under a quarantine 
system designed to prevent its release or distribution.
    (d) A production aggregate of infant formula, including a 
reprocessed or reconditioned production aggregate, that does not meet 
the nutrient requirements of section 412(i) of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 350a(i)) or that has not been manufactured, 
packaged, labeled, and held under conditions to prevent adulteration 
under sections 402(a)(1) through (a)(4) of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 342(a)(1) through (a)(4)) shall not be approved 
and released for distribution.


Sec.  106.80  Traceability.

    Each production aggregate of infant formula shall be coded with a 
sequential number that identifies the product and the establishment 
where the product was packed and that permits tracing of all stages of 
manufacture of that production aggregate, including the year, the days 
of the year, and the period during those days that the product was 
packed, and the receipt and handling of raw materials used.

[[Page 8066]]

Sec.  106.90  Audits of current good manufacturing practice.

    (a) A manufacturer of an infant formula, or an agent of such 
manufacturer, shall conduct regularly scheduled audits to determine 
whether the manufacturer has complied with the current good 
manufacturing practice regulations in this subpart. Such audits shall 
be conducted at a frequency that is required to ensure compliance with 
such regulations.
    (b) The audits required by paragraph (a) of this section shall be 
performed by an individual or a team of individuals who, as a result of 
education, training, or experience, is knowledgeable in all aspects of 
infant formula production and of the Agency's regulations concerning 
current good manufacturing practice that such individual or team is 
responsible for auditing. This individual or team of individuals shall 
have no direct responsibility for the matters that such individual or 
team is auditing and shall have no direct interest in the outcome of 
the audit.

Subpart C--Quality Control Procedures


Sec.  106.91  General quality control.

    (a) During manufacture, a manufacturer shall test each production 
aggregate for nutrients as follows:
    (1) Each nutrient premix used in the manufacture of an infant 
formula shall be tested for each nutrient (required under Sec.  107.100 
of this chapter or otherwise added by the manufacturer) that the 
manufacturer is relying on the premix to provide, to ensure that the 
premix is in compliance with the manufacturer's specifications;
    (2) During the manufacturing process, after the addition of the 
premix, or at the final product stage but before distribution, each 
production aggregate of infant formula shall be tested for at least one 
indicator nutrient for each of the nutrient premixes used in the infant 
formula to confirm that the nutrients supplied by each of the premixes 
are present, in the proper concentration, in the production aggregate 
of infant formula.
    (3) At the final product stage, before distribution of an infant 
formula, each production aggregate shall be tested for vitamins A, C, 
E, and thiamin.
    (4) During the manufacturing process or at the final product stage, 
before distribution, each production aggregate shall be tested for all 
nutrients required to be included in such formula under Sec.  107.100 
of this chapter for which testing is not conducted for compliance with 
paragraphs (a)(1) or (a)(3) of this section and for any nutrient added 
by the manufacturer for which testing is not conducted for compliance 
with paragraph (a)(1) of this section.
    (b) A manufacturer shall test each production aggregate of finished 
product for nutrients as follows:
    (1) For an infant formula that is a new infant formula, Sec.  
106.3, the manufacturer shall collect, from each manufacturing site and 
at the final product stage, a representative sample of the first 
production aggregate of packaged, finished formula in each physical 
form (powder, ready-to-feed, or concentrate) and evaluate the levels of 
all nutrients required under Sec.  107.100 of this chapter and all 
other nutrients added by the manufacturer. The manufacturer shall 
repeat such testing every 3 months thereafter throughout the shelf-life 
of the product.
    (2) The manufacturer shall collect, from each manufacturing site 
and at the final product stage, a representative sample of each 
subsequent production aggregate of packaged, finished formula in each 
physical form (powder, ready-to-feed, or concentrate) and evaluate the 
levels of all nutrients required under Sec.  107.100 and all other 
nutrients added by the manufacturer. The manufacturer shall repeat such 
testing at the midpoint and at the end of the shelf-life of the 
product.
    (3) If the results of the testing required by paragraph (b)(1) of 
this section do not substantiate the shelf life of the infant formula, 
the manufacturer shall either repeat the testing required by such 
paragraph on a subsequently produced production aggregate to 
substantiate the shelf life of the infant formula or revise the shelf 
life label statement for such product so that such statement is 
substantiated by the stability testing results.
    (4) If results of the testing required by paragraph (b)(2) of this 
section show that any required nutrient is not present in the 
production aggregate of infant formula at the level required by Sec.  
107.100 of this chapter or that any nutrient added by the manufacturer 
is not present at the level declared on the label of the production 
aggregate of infant formula, the manufacturer shall:
    (i) Investigate the cause of such variance in the level of any 
required or added nutrient;
    (ii) Evaluate the significance, if any, of the results for other 
production aggregates of the same formula that have been released for 
distribution;
    (iii) Address, as appropriate, all production aggregates of formula 
released for distribution that are implicated by the testing results; 
and
    (iv) Determine whether it is necessary to repeat the testing 
required by paragraph (b)(1) of this section.
    (5) The testing required by paragraphs (b)(1) and (b)(2) of this 
section is not required to evaluate the level of minerals present in 
the infant formula.
    (c) All quality control testing shall be conducted using 
appropriate, scientifically valid test methods.
    (d) A manufacturer shall make and retain quality control records in 
accordance with Sec.  106.100(e)(5)(i).


Sec.  106.92  Audits of quality control procedures.

    (a) A manufacturer of an infant formula, or an agent of such a 
manufacturer, shall conduct regularly scheduled audits to determine 
whether the manufacturer has complied with the requirements for quality 
control procedures that are necessary to ensure that an infant formula 
provides nutrients in accordance with section 412(b) and (i) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 350a(b) and (i)) and is 
manufactured in a manner designed to prevent adulteration of the infant 
formula under section 412(a)(1) and (a)(3) of the Federal Food, Drug, 
and Cosmetic Act. Such audits shall be conducted at a frequency that is 
required to ensure compliance with the requirements for quality control 
procedures.
    (b) The audits required by paragraph (a) of this section shall be 
performed by an individual or a team of individuals who, as a result of 
education, training, or experience, is knowledgeable in all aspects of 
infant formula production and of the regulations concerning quality 
control procedures that such individual or team is responsible for 
auditing. This individual or team of individuals shall have no direct 
responsibility for the matters that such individual or team is auditing 
and shall have no direct interest in the outcome of the audit.

Subpart D--Conduct of Audits


Sec.  106.94  Audit plans and procedures.

    (a) A manufacturer shall develop and follow a written audit plan 
that is available at the manufacturing facility for Food and Drug 
Administration inspection.
    (b) The audit plan shall include audit procedures that set out the 
methods the manufacturer uses to determine whether the facility is 
operating in accordance with current good manufacturing practice, with 
the quality control procedures that are necessary to ensure that an 
infant formula provides nutrients in accordance with sections

[[Page 8067]]

412(b) and (i) of the Federal Food, Drug, and Cosmetic Act, and in a 
manner designed to prevent adulteration of the infant formula.
    (c) The audit procedures shall include:
    (1) An evaluation of the production and in-process control system 
established under Sec.  106.6(b) by:
    (i) Observing the production of infant formula and comparing the 
observed process to the written production and in-process control plan 
required under Sec.  106.6(b);
    (ii) Reviewing records of the monitoring of points, steps, or 
stages where control is deemed necessary to prevent adulteration; and
    (iii) Reviewing records of how deviations from any specification at 
points, steps, or stages where control is deemed necessary to prevent 
adulteration were handled; and
    (2) A review of a representative sample of all records maintained 
in accordance with Sec.  106.100(e) and (f).

Subpart E--Quality Factors for Infant Formulas


Sec.  106.96  Requirements for quality factors for infant formulas.

    The regulations set forth in this subpart define the minimum 
requirements for quality factors for infant formulas:
    (a) An infant formula shall meet the quality factor of normal 
physical growth.
    (b) A manufacturer of an infant formula that is not an eligible 
infant formula shall demonstrate that a formula supports normal 
physical growth in infants when fed as a sole source of nutrition by 
conducting, in accordance with good clinical practice, an adequate and 
well-controlled growth monitoring study of the infant formula that:
    (1) Is no less than 15 weeks in duration, enrolling infants no more 
than 2 weeks old at time of entry into the study;
    (2) Includes the collection and maintenance of data on formula 
intake and anthropometric measures of physical growth, including body 
weight, recumbent length, head circumference, average daily weight 
increment, and average daily recumbent length increment;
    (3) Includes anthropometric measurements made at the beginning and 
end of the study, and at least four additional measurements made at 
intermediate time points with three of the six total measurements made 
within the first 4 weeks of the study and three measurements made at 
approximately 4-week intervals over the remaining 11 weeks of the 
study;
    (4) Compares the anthropometric data for the test group to a 
concurrent control group or groups at each time point and compares the 
anthropometric data for each infant (body weight for age, body length 
for age, head circumference for age, and weight for length) in the test 
group and the control group to the 2009 CDC growth charts, which are 
incorporated by reference at Sec.  106.160; and
    (5) Compares the data on formula intake of the test group with a 
concurrent control group or groups and a scientifically appropriate 
reference.
    (c) The Food and Drug Administration will exempt a manufacturer 
from the requirements of paragraph (b) of this section, if:
    (1) The manufacturer requests an exemption and provides assurances, 
as required under Sec.  106.121, that the changes made by the 
manufacturer to an existing infant formula are limited to changing the 
type of packaging of an existing infant formula (e.g., changing from 
metal cans to plastic pouches); or
    (2) The manufacturer requests an exemption and provides assurances, 
as required under Sec.  106.121, which demonstrate that:
    (i) An alternative method or study design that is based on sound 
scientific principles is available to show that the formula supports 
normal physical growth in infants when the formula is fed as the sole 
source of nutrition;
    (ii) The change made by the manufacturer to an existing formula 
does not affect the bioavailability of the formula, including the 
bioavailability of nutrients in such formula; or
    (iii) The manufacturer markets a formulation in more than one form 
(e.g., liquid and powdered forms) and the quality factor requirements 
are met by the form of the formula that is processed using the method 
that has the greatest potential for adversely affecting nutrient 
content and bioavailability.
    (d) A manufacturer of a new infant formula that is not an eligible 
infant formula shall, in accordance with Sec.  106.100(p)(1), make and 
retain records demonstrating that the formula meets the quality factor 
of normal physical growth.
    (e) An infant formula shall meet the quality factor of sufficient 
biological quality of protein.
    (f) A manufacturer of an infant formula that is not an eligible 
infant formula shall demonstrate that a formula meets the quality 
factor of sufficient biological quality of protein by establishing the 
biological quality of the protein in the infant formula when fed as the 
sole source of nutrition using an appropriate modification of the 
Protein Efficiency Ratio (PER) rat bioassay described in the ``Official 
Methods of Analysis of AOAC International,'' 18th ed., sections 45.3.04 
and 45.3.05, ``AOAC Official Method 960.48 Protein Efficiency Ratio Rat 
Bioassay,'' which is incorporated by reference at Sec.  106.160. The 
PER rat bioassay shall be conducted on a formula and the results 
evaluated prior to the initiation of a growth monitoring study of the 
formula that is required under paragraph (b) of this section.
    (g) The Food and Drug Administration will exempt a manufacturer 
from the requirements of paragraph (f) of this section, if:
    (1) The manufacturer requests an exemption and provides assurances 
as required under Sec.  106.121 that the changes made by the 
manufacturer to an existing infant formula are limited to changing the 
type of packaging of an existing infant formula (e.g., changing from 
metal cans to plastic pouches); or
    (2) The manufacturer requests an exemption and provides assurances, 
as required under Sec.  106.121, that demonstrate that the change made 
by the manufacturer to an existing formula does not affect the 
bioavailability of the protein.
    (h) A manufacturer of a new infant formula that is not an eligible 
infant formula shall, in accordance with Sec.  106.100(q), make and 
retain records demonstrating that the formula meets the quality factor 
of sufficient biological quality of protein.
    (i) The following provisions for requirements for quality factors 
apply only to an ``eligible infant formula'' as defined in Sec.  106.3:
    (1) An eligible infant formula that fulfills one or more of the 
following criteria meets the quality factor of normal physical growth:
    (i) The scientific evidence on such infant formula meets the 
requirements of paragraph (b) of this section that apply to infant 
formula that is not an eligible infant formula;
    (ii) The scientific evidence on such infant formula meets the 
following provisions:
    (A) The evidence is an adequate and well-controlled growth study, 
conducted in accordance with good clinical practice, to determine 
whether an infant formula supports normal physical growth in infants 
when the formula is fed as the sole source of nutrition;
    (B) The growth study is no less than 4 months in duration, 
enrolling infants no more than 1 month old at time of entry into the 
study;

[[Page 8068]]

    (C) The growth study collects from the study subjects data on 
anthropometric measures of physical growth, including body weight, 
recumbent length, head circumference, and average daily weight 
increment, and plots the data on the following charts from ``Physical 
Growth: National Center for Health Statistics Percentiles'' for body 
weight, body length, and head circumference, which are incorporated by 
reference at Sec.  106.160:
    (1) Figure 1. Length by age percentiles for girls aged birth-36 
months (p. 609);
    (2) Figure 2. Length by age percentiles for boys aged birth-36 
months (p. 610);
    (3) Figure 3. Weight by age percentiles for girls aged birth-36 
months (p. 611);
    (4) Figure 4. Weight by age percentiles for boys aged birth-36 
months (p. 612);
    (5) Figure 5. Head circumference by age percentiles for girls aged 
birth-36 months (p. 613);
    (6) Figure 6. Weight by length percentiles for girls aged birth-36 
months (p. 613);
    (7) Figure 7. Head circumference by age percentiles for boys aged 
birth-36 months (p. 614); and
    (8) Figure 8. Weight by length percentiles for boys aged birth-36 
months (p. 614); and
    (D) The growth study collects anthropometric measurements at the 
beginning of the growth study, at 2 weeks, at 4 weeks, at least monthly 
thereafter, and at the conclusion of the study; or
    (iii) The scientific evidence on such infant formula otherwise 
demonstrates that such formula supports normal physical growth.
    (2) An eligible infant formula that fulfills one or more of the 
following criteria meets the quality factor of sufficient biological 
quality of the protein:
    (i) The scientific evidence on such infant formula meets the 
requirements of paragraph (f) of this section that apply to infant 
formula that is not an eligible infant formula;
    (ii) The scientific evidence on such infant formula is a study that 
establishes the biological quality of the protein in an infant formula 
by demonstrating that the protein source supports adequate growth using 
the Protein Efficiency Ratio (PER) rat bioassay described in sections 
45.3.04 and 45.3.05 of the ``Official Methods of Analysis of the 
Association of Official Analytical Chemists,'' 16th ed., which are 
incorporated by reference at Sec.  106.160; or
    (iii) The scientific evidence on such infant formula otherwise 
demonstrates that the protein in such infant formula is of sufficient 
biological quality.
    (3) The manufacturer of an eligible infant formula may, not later 
than November 12, 2015, submit a petition to the Food and Drug 
Administration under Sec.  10.30 of this chapter that:
    (i) Demonstrates that such formula fulfills one or more of the 
criteria in paragraph (i)(1) of this section; or
    (ii) Demonstrates that such formula fulfills one or more of the 
criteria in paragraph (i)(2) of this section.
    (4) A petition filed under paragraph (i)(3) of this section shall 
address only one infant formula formulation and shall contain all data 
and information relied upon by the manufacturer to demonstrate that 
such formulation fulfills one or more of the criteria in paragraph 
(i)(1) or in paragraph (i)(2) of this section. A manufacturer may 
combine petitions submitted under paragraphs (i)(3)(i) and (i)(3)(ii) 
of this section that relate to the same formulation.
    (5) The manufacturer of each eligible infant formula shall make and 
retain, in accordance with Sec.  106.100(p)(2), records to demonstrate 
that such formula supports normal physical growth in infants when fed 
as the sole source of nutrition and shall make and retain, in 
accordance with Sec.  106.100(q)(2), records to demonstrate that that 
the protein in such infant formula is of sufficient biological quality. 
The records required by this paragraph shall include all relevant 
scientific data and information and a narrative explanation of why the 
data and information demonstrate that the formula supports normal 
physical growth and a narrative explanation of why the data and 
information demonstrate that the protein in such infant formula is of 
sufficient biological quality.

Subpart F--Records and Reports


Sec.  106.100  Records.

    (a) Every manufacturer of infant formula shall maintain the records 
specified in this regulation in order to permit the Food and Drug 
Administration to determine whether each manufacturer is in compliance 
with section 412 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
350a)).
    (b) The manufacturer shall maintain all records that pertain to 
food-packaging materials subject to Sec.  174.5 of this chapter and 
that bear on whether such materials would cause an infant formula to be 
adulterated within the meaning of section 402(a)(2)(C) of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 342(a)(2)(C)).
    (c) The manufacturer shall maintain all records that pertain to 
nutrient premix testing that it generates or receives. Such records 
shall include, but are not limited to:
    (1) Any results of testing conducted to ensure that each nutrient 
premix is in compliance with the premix certificate and guarantee and 
specifications that have been provided to the manufacturer by the 
premix supplier, including tests conducted when nutrients exceed their 
expiration date or shelf life (retest date).
    (2) All certificates and guarantees given by premix suppliers 
concerning the nutrients required by section 412(i) of the Federal 
Food, Drug, and Cosmetic Act and Sec.  107.100 of this chapter.
    (d) The premix supplier shall maintain the results of all testing 
conducted to provide all certificates and guarantees concerning 
nutrient premixes for infant formulas. Such records shall include but 
are not limited to:
    (1) The results of tests conducted to determine the purity of each 
nutrient required by section 412(i) of the Federal Food, Drug, and 
Cosmetic Act or Sec.  107.100 of this chapter and any other nutrient 
listed in the certificate and guarantee;
    (2) The weight of each nutrient added;
    (3) The results of any quantitative tests conducted to determine 
the amount of each nutrient certified or guaranteed; and
    (4) The results of any quantitative tests conducted to identify the 
nutrient levels present when nutrient premixes exceed their expiration 
date or shelf life (retest date).
    (e) For each production aggregate of infant formula, a manufacturer 
shall prepare and maintain records that include complete information 
relating to the production and control of the production aggregate. 
These records shall include:
    (1) The master manufacturing order. The master manufacturing order 
shall include:
    (i) The significant steps in the production of the production 
aggregate and the date on which each significant step occurred;
    (ii) For a manufacturing facility that has more than one set of 
equipment or more than one processing line, the identity of equipment 
and processing lines for which the manufacturer has identified points, 
steps, or stages in the production process where control is necessary 
to prevent adulteration;
    (iii) The identity of each lot of ingredients, containers, and 
closures used in producing the production aggregate of formula;
    (iv) The amount of each ingredient to be added to the production 
aggregate of

[[Page 8069]]

infant formula and a check (verification) that the correct amount was 
added; and
    (v) A copy of each infant formula label used on a finished 
production aggregate of infant formula and the results of examinations 
conducted during the finishing operations to provide assurance that the 
containers and packages have the correct label.
    (2) Any deviations from the master manufacturing order and any 
corrective actions taken because of the deviations.
    (3) Documentation, in accordance with Sec.  106.6(c), of the 
monitoring at any point, step, or stage in the manufacturer 's 
production process where control is deemed necessary to prevent 
adulteration. These records shall include:
    (i) A list of the specifications established at each point, step, 
or stage in the production process where control is deemed necessary to 
prevent adulteration, in accordance with Sec.  106.6(c)(1), including 
documentation of the scientific basis for each specification;
    (ii) The actual values obtained during the monitoring operation, 
any deviations from established specifications, and any corrective 
actions taken; and
    (iii) Identification of the person monitoring each point, step, or 
stage in the production process where control is deemed necessary to 
prevent adulteration.
    (4) The conclusions and followup, along with the identity of the 
individual qualified by education, training, or experience who 
investigated:
    (i) Any deviation from the master manufacturing order and any 
corrective actions taken;
    (ii) A finding that a production aggregate or any of its 
ingredients failed to meet the infant formula manufacturer's 
specifications; and
    (iii) A failure to meet any specification at any point, step, or 
stage in the production process where control is deemed necessary to 
prevent adulteration.
    (5) The results of all testing performed on the production 
aggregate of infant formula, including testing on the in-process 
production aggregate, at the final product stage, and on finished 
product throughout the shelf life of the product. The results recorded 
shall include:
    (i) The results of all quality control testing conducted in 
accordance with Sec.  106.91(a) and (b) to verify that each nutrient 
required by Sec.  107.100 of this chapter is present in each production 
aggregate of infant formula at the level required by Sec.  107.100 of 
this chapter, and that all other nutrients added by the manufacturer 
are present at the appropriate level. The record of the results of the 
quality control testing shall include:
    (A) A summary document identifying the stages of the manufacturing 
process at which the nutrient analysis for each required nutrient is 
conducted as required under Sec.  106.91(a); and
    (B) A summary document on the stability testing program conducted 
under Sec.  106.91(b), including the nutrients tested and the frequency 
of nutrient testing throughout the shelf life of the product.
    (ii) For powdered infant formula, the results of any testing 
conducted in accordance with Sec.  106.55(c) to verify compliance with 
the microbiological quality standards in Sec.  106.55(e).
    (f) A manufacturer shall make and retain all records described in 
subparts B and C of this part, including:
    (1) Records, in accordance with Sec.  106.20(f)(4), of the 
frequency and results of testing of the water used in the production of 
infant formula;
    (2) Records, in accordance with Sec.  106.30(d), of accuracy checks 
of instruments and controls. A certification of accuracy of any known 
reference standard used and a history of recertification shall be 
maintained. At a minimum, such records shall specify the instrument or 
control being checked, the date of the accuracy check, the standard 
used, the calibration method used, the results found, any actions taken 
if the instrument is found to be out of calibration, and the initials 
or name of the individual performing the test. If calibration of an 
instrument shows that a specification at a point, step, or stage in the 
production process where control is deemed necessary to prevent 
adulteration has not been met, a written evaluation of all affected 
product, and any actions that need to be taken with respect to that 
product, shall be made.
    (3) Records, in accordance with Sec.  106.30(e)(3)(iii).
    (4) Records, in accordance with Sec.  106.30(f), on equipment 
cleaning, sanitizing, and maintenance that show the date and time of 
such cleaning, sanitizing, and maintenance and the lot number of each 
production aggregate of infant formula processed between equipment 
startup and shutdown for cleaning, sanitizing, and maintenance. The 
person performing and checking the cleaning, sanitizing, and 
maintenance shall date and sign or initial the record indicating that 
the work was performed.
    (5) Records, in accordance with Sec.  106.35(c), on all mechanical 
and electronic equipment used in the production or quality control of 
infant formula. These records shall include:
    (i) A list of all systems used with a description of the computer 
files and the defined capabilities and inherent limitations of each 
system;
    (ii) A copy of all software used;
    (iii) Records that document installation, calibration, testing or 
validation, and maintenance of the systems used;
    (iv) A list of all persons authorized to create or modify software;
    (v) Records that document modifications to software, including the 
identity of the person who modified the software;
    (vi) Records that document retesting or revalidation of modified 
systems; and
    (vii) A backup file of data entered into a computer or related 
system. The backup file shall consist of a hard copy or alternative 
system, such as duplicate electronic records, tapes, or microfilm, 
designed to ensure that backup data are exact and complete, and that 
they are secure from alteration, inadvertent erasures, or loss.
    (6) Records, in accordance with Sec.  106.40(g), on ingredients, 
containers, and closures used in the manufacture of infant formula. 
These records shall include:
    (i) The identity and quantity of each lot of ingredients, 
containers, and closures;
    (ii) The name of the supplier;
    (iii) The supplier's lot numbers;
    (iv) The name and location of the manufacturer of the ingredient, 
container, or closure, if different from the supplier;
    (v) The date of receipt;
    (vi) The receiving code as specified; and
    (vii) The results of any test or examination (including retesting 
and reexamination) performed on the ingredients, containers, or 
closures and the conclusions derived there from and the disposition of 
all ingredients, containers, or closures.
    (7) A full description of the methodology used to test powdered 
infant formula to verify compliance with the microbiological quality 
standards of Sec.  106.55(c) and the methodology used to do quality 
control testing, in accordance with Sec.  106.91(a).
    (g) A manufacturer shall maintain all records pertaining to 
distribution of the infant formula, including records that show that 
formula produced for export only is exported. Such records shall 
include all information and data necessary to effect and monitor 
recalls of the manufacturer's infant formula products in accordance 
with subpart E of part 107 of this chapter.

[[Page 8070]]

    (h) The manufacturer shall maintain all records pertaining to the 
microbiological quality and purity of raw materials and finished 
powdered infant formula.
    (i) [Reserved]
    (j) The manufacturer shall make and retain records pertaining to 
regularly scheduled audits, including the audit plans and procedures, 
the findings of the audit, and a listing of any changes made in 
response to these findings. The manufacturer shall make readily 
available for authorized inspection the audit plans and procedures and 
a statement of assurance that the regularly scheduled audits are being 
conducted. The findings of the audit and any changes made in response 
to these findings shall be maintained for the time period required 
under paragraph (n) of this section, but need not be made available to 
the Food and Drug Administration.
    (k) The manufacturer shall maintain procedures describing how all 
written and oral complaints regarding infant formula will be handled. 
The manufacturer shall follow these procedures and shall include in 
them provisions for the review of any complaint involving an infant 
formula and for determining the need for an investigation of the 
possible existence of a hazard to health.
    (1) For purposes of this section, every manufacturer shall 
interpret a ``complaint'' as any communication that contains any 
allegation, written or oral, expressing dissatisfaction with a product 
for any reason, including concerns about the possible existence of a 
hazard to health and about appearance, taste, odor, and quality. 
Correspondence about prices, package size or shape, or other matters 
that could not possibly reveal the existence of a hazard to health 
shall not, for compliance purposes, be considered a complaint and 
therefore need not be made available to a Food and Drug Administration 
investigator.
    (2) When a complaint shows that a hazard to health possibly exists, 
the manufacturer shall conduct an investigation into the validity of 
the complaint. Where such an investigation is conducted, the 
manufacturer shall include in its file on the complaint the 
determination as to whether a hazard to health exists and the basis for 
that determination. No investigation is necessary when the manufacturer 
determines that there is no possibility of a hazard to health. When no 
investigation is necessary, the manufacturer shall include in the 
record the reason that an investigation was found to be unnecessary and 
the name of the responsible person making that determination.
    (3) When there is a reasonable possibility of a causal relationship 
between the consumption of an infant formula and an infant's death, the 
manufacturer shall, within 15 days of receiving such information, 
conduct an investigation and notify the Agency as required in Sec.  
106.150.
    (4) The manufacturer shall maintain in designated files all records 
pertaining to the complaints it receives. The manufacturer shall 
separate the files into two classes:
    (i) Those complaints that allege that the infant became ill from 
consuming the product or required treatment by a physician or health 
care provider and
    (ii) Those complaints that may involve a possible existence of a 
hazard to health but do not refer to an infant becoming ill or the need 
for treatment by physician or a health care provider.
    (5) The manufacturer shall include in a complaint file the 
following information concerning the complaint:
    (i) The name of the infant formula;
    (ii) The batch number;
    (iii) The name of complainant;
    (iv) A copy of the complaint or a memo of the telephone 
conversation or meeting and all correspondence with the complainant;
    (v) By reference or copy, all the associated manufacturing records 
and complaint investigation records needed to evaluate the complaint. 
When copies of such records are not maintained in the complaint file, 
they must be available within 24 hours when requested by a Food and 
Drug Administration official.
    (vi) All actions taken to followup on the complaint; and
    (vii) All findings and evaluations of the complaint.
    (6) The manufacturer should maintain the files regarding infant 
formula complaints at the establishment where the infant formula was 
manufactured, processed, or packed. When the manufacturer wishes to 
maintain all consumer complaints for the entire firm at one location 
other than at the facility where an infant formula was manufactured, 
processed, or packed, the manufacturer may do so as long as all records 
required by this section are available within 24 hours of request for 
inspection at that facility. However, all records of consumer 
complaints, including summaries, any reports, and any files, maintained 
at the manufacturing facility or at any other facility shall be m