[Federal Register Volume 79, Number 111 (Tuesday, June 10, 2014)]
[Rules and Regulations]
[Pages 33057-33072]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-13384]
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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-0063 (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: Final rule.
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SUMMARY: The Food and Drug Administration (FDA or we) is issuing a
final rule that adopts, with some modifications, the interim final rule
(IFR) entitled ``Current Good Manufacturing Practices, Quality Control
Procedures, Quality Factors, Notification Requirements, and Records and
Reports, for Infant Formula'' (February 10, 2014). This final rule
affirms the IFR's changes to FDA's regulations and provides additional
modifications and clarifications. The final rule also responds to
certain comments submitted in response to the request for comments in
the IFR.
DATES: This final rule is effective July 10, 2014. The compliance date
for manufacturers to meet the requirements of Sec. Sec. 106.96(a),
106.96(e), 106.96(i)(5), 106.100(p)(2) and 106.100(q)(2) related to
quality factors for eligible infant formulas is November 12, 2015. The
compliance date for the remaining provisions of this final rule is
September 8, 2014. Submit comments on information collection issues
under the Paperwork Reduction Act of 1995 by July 10, 2014 (see section
VII, the ``Paperwork Reduction Act of 1995'' section of this document).
ADDRESSES: To ensure that comments on the information collection are
received, the 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: 202-395-7285, or emailed to
[email protected]. All comments should be identified with
the OMB control number 0910-0256 and titled ``Infant Formula
Requirements.'' Also include the FDA docket number found in brackets in
the heading of this document.
FOR FURTHER INFORMATION CONTACT: Benson M. Silverman, Office of
[[Page 33058]]
Nutrition, Labeling, and Dietary Supplements (HFS-850), Center for Food
Safety and Applied Nutrition, Food and Drug Administration, 5100 Paint
Branch Pkwy., College Park, MD 20740, 240-402-1451.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background
II. Summary of Changes Made to the Interim Final Rule
III. Comments on the Interim Final Rule
IV. Technical Amendments
V. Executive Order 12866 and Executive Order 13563: Cost Benefit
Analysis
VI. Small Entity Analysis (or Final Regulatory Flexibility Analysis)
VII. Paperwork Reduction Act of 1995
VIII. Analysis of Environmental Impact
IX. Federalism
X. References
I. Background
We are issuing this final rule to establish requirements for
quality factors for infant formulas and good manufacturing practices,
including quality control procedures, under section 412 of the Federal
Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 350a). The final
rule will help prevent the manufacture of adulterated infant formula,
ensure the safety of infant formula, and ensure that the nutrients in
infant formula are present in a form that is bioavailable.
Congress passed the Infant Formula Act of 1980 (the Infant Formula
Act) (Public Law 96-359), which created section 412 of the FD&C Act. 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 practices (CGMP), recordkeeping, and recall
requirements for infant formula. The requirements in the 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 final rule implements the
remaining provisions of the 1986 amendments, including provisions for
CGMPs and quality factor requirements.
This final rule generally affirms the IFR's changes to FDA's
regulations at parts 106 and 107 (21 CFR parts 106 and 107) and
provides additional modifications and clarifications to part 106. The
final rule also responds to certain comments submitted in response to
the request for comments in the IFR (79 FR 7934, February 10, 2014).
II. Summary of Changes Made to the Interim Final Rule
A. Definitions (Sec. 106.3)
1. Eligible Infant Formula
We are amending the definition of ``eligible infant formula'' in
Sec. 106.3. Eligible infant formula means an infant formula that could
be lawfully distributed in the United States on December 8, 2014.
2. Quality Factors
We are clarifying the definition of ``quality factors'' in Sec.
106.3. Under this final rule, quality factors means those factors
necessary to demonstrate the safety of the infant formula and the
bioavailability of its nutrients, as prepared for market and when fed
as the sole source of nutrition, to ensure the healthy growth of
infants.
B. Controls To Prevent Adulteration Caused by Facilities (Sec. 106.20)
We are modifying the language in Sec. 106.20(i) to permit doors to
toilet facilities to open into the plant facilities where infant
formula, ingredients, containers, or closures are processed, handled,
or stored if alternate means have been taken to protect against
contamination.
C. Controls To Prevent Adulteration Caused by Equipment or Utensils
(Sec. 106.30)
We are deleting Sec. 106.30(e)(2)(ii)(A) and combining Sec.
106.30(e)(2)(ii) from the IFR with Sec. 106.30(e)(2)(ii)(B) from the
IFR. The section is designated as Sec. 106.30(e)(2)(ii). In the final
rule, Sec. 106.30(e)(2)(ii) states that ``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[emsp14][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 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.''
D. Controls To Prevent Adulteration Due to Automatic (Mechanical or
Electronic) Equipment (Sec. 106.35)
We are amending Sec. 106.35(a)(4) to clarify that validation can
be accomplished through any suitable means, such as verification
studies or modeling. We are also amending Sec. 106.35(b)(1) to specify
that requirements for the calibration, inspection, and checking of
hardware apply at any point, step, or stage where control is necessary
to prevent adulteration of infant formula.
E. Controls To Prevent Adulteration During Manufacturing (Sec. 106.50)
We are deleting the word ``drafted'' from Sec. 106.50(a)(2) in the
final rule in response to a comment noting that persons other than a
responsible official could draft changes to a master manufacturing
order.
F. General Quality Control (Sec. 106.91)
1. Section 106.91(b)(1)
We are reducing the required frequency of stability testing for new
infant formulas from every 3 months to every 4 months in Sec.
106.91(b)(1)(i) of the final rule because we agree with a comment that
explained that stability testing of new formulas every 3 months, as
required by Sec. 106.91(b)(1) in the IFR, would not provide additional
public health protection over testing every 4 months.
We are modifying Sec. 106.91(b)(1) to provide an exemption from
the testing required by Sec. 106.91(b)(1) of the IFR if the
manufacturer of a new infant formula requests an exemption and provides
analytical data that demonstrate that the stability of the new infant
formula will likely not differ from the stability of formulas with
similar composition, processing, and packaging for which there are
extensive stability data. In doing so, we are renumbering Sec.
106.91(b)(1) of the IFR as Sec. 106.91(b)(1)(i) and creating Sec.
106.91(b)(1)(ii) in the final rule to provide the exemption. The
manufacturer would request the exemption in the 90-day notification for
the new infant formula as required by new Sec. 106.120(b)(7). If the
manufacturer is exempted from the testing required by Sec.
106.91(b)(1)(i), the manufacturer would then be required under Sec.
106.91(b)(1)(ii) to test the first production aggregate of the new
infant formula in accordance with the stability testing requirements
for subsequent production aggregates in Sec. 106.91(b)(2).
2. Section 106.91(b)(2)
We are deleting the requirement to conduct stability testing at the
midpoint of the shelf life for infant formulas tested under Sec.
106.91(b)(2) in response to a comment that questioned how measuring
nutrients at the midpoint of shelf life would provide additional
assurance for formulas for which stability data have been established.
We
[[Page 33059]]
agree with the comment that the critical data are the nutrient levels
present at the end of shelf life and that the midpoint data are not
essential.
3. Section 106.91(b)(3) and (4)
We are making a technical correction to Sec. 106.91(b)(3) of the
final rule to clarify our intent that manufacturers have the option to
adjust the ``Use by'' date on an infant formula container so that such
date is substantiated if the stability data from the testing required
by Sec. 106.91(b)(1) did not substantiate the anticipated shelf life
of the formula. We are also changing Sec. 106.91(b)(3) to provide
flexibility for manufacturers to take other appropriate actions, in
addition to conducting the testing required by Sec. 106.91(b)(1) or
adjusting the ``Use by'' date, when stability testing does not
substantiate the shelf life of the formula. Further, we are clarifying
that the manufacturer must address all production aggregates released
and pending release for distribution that are implicated by the testing
results.
We are making conforming changes to Sec. 106.91(b)(4)(iii) to
clarify that manufacturers also must address all production aggregates
released and pending release for distribution that are implicated by
testing results required by Sec. 106.91(b)(2) that show that any
nutrient that is not present in the production aggregate of infant
formula at the level intended by the manufacturer.
We are making other conforming changes in Sec. 106.91(b)(3) and
(4) as a result of changes made to these provisions in the final rule.
G. Requirements for Quality Factors for Infant Formulas (Sec. 106.96)
We are revising the exemption in Sec. 106.96(c)(2)(ii) so that it
applies when a change to a formula does not impact normal physical
growth. We are also adding section 106.96(g)(3), which states that FDA
will exempt a manufacturer from the requirements of conducting a
protein efficiency ratio (PER) rat bioassay if the manufacturer
requests an exemption and provides assurances, as required under Sec.
106.121(i), that demonstrate that an alternative method to the PER that
is based on sound scientific principles is available to show that the
formula supports the quality factor for the biological quality of the
protein.
H. Records (Sec. 106.100)
We are revising Sec. 106.100(m) to require access to records
``within 24 hours'' in response to a comment.
I. New Infant Formula Submission (Sec. 106.120)
As stated earlier in section II.F.1 of this document, we are
providing an exemption in Sec. 106.91(b)(1)(ii) from the testing
required by Sec. 106.91(b)(1) if the manufacturer of a new infant
formula requests an exemption and provides analytical data that
demonstrate that the stability of the new infant formula will likely
not differ from the stability of formulas with similar composition,
processing, and packaging for which there are extensive stability data.
In doing so, we added Sec. 106.120(b)(7), which states that if the
manufacturer is requesting an exemption under Sec. 106.91(b)(1)(ii),
the manufacturer shall include the scientific evidence that the
manufacturer is relying on to demonstrate that the stability of the new
infant formula will likely not differ from the stability of formulas
with similar composition, processing, and packaging for which there are
extensive stability data.
J. Quality Factor Assurances for Infant Formulas (Sec. 106.121)
We are making a change to Sec. 106.121 by adding Sec. 106.121(i)
to the final rule, which states that if the manufacturer is requesting
an exemption under Sec. 106.96(g)(3), the manufacturer shall include a
detailed explanation of the alternative method, an explanation of why
the method is based on sound scientific principles, and the data that
demonstrates that the quality factor for the biological quality of the
protein has been met.
III. Comments on the Interim Final Rule
We provided an opportunity for comment in the IFR but indicated
that comments submitted in response to the IFR ``should be limited to
those that present new issues or new information'' (79 FR 7934 at
8056). The preamble to the IFR also stated that ``Comments previously
submitted to the Division of Dockets Management have been considered
and addressed in this IFR and should not be resubmitted'' (id).
We received a number of comments to the IFR. The comments were
generally supportive of the rule. After considering all the comments
submitted to this docket number, we are making minor technical
corrections, clarifications to some provisions in response to comments
that indicate some confusion on the part of industry, and modifications
that increase flexibility with respect to certain requirements included
in the IFR. In addition, we summarize and respond to relevant portions
of comments.
To make it easier to identify comments and FDA's responses, the
word ``Comment,'' in parentheses, appears before the comment's
description, and the word ``Response,'' in parentheses, appears before
FDA's response. Each comment is numbered to help distinguish between
different comments. The number assigned to each comment is purely for
organizational purposes and does not signify the comment's value or
importance.
A. Subpart A--General Provisions
1. Definitions (Sec. 106.3)
(Comment 1) One comment stated that FDA's definition of quality
factors in the IFR introduced a novel concept, i.e., the
``bioavailability . . . of the formula,'' that is inconsistent with
FDA's definition of bioavailability in the IFR and with the scientific
and common meaning of ``bioavailability,'' which refers to absorption
of particular nutrients. The comment continued that the concept of the
bioavailability of a food should be subjected to external nutritional
science input before being given the force and effect of law and
recommended that the definition of quality factors in the 1996 proposed
rule be restored.
(Response) We recognize that the wording of the definition of
quality factors in the IFR inadvertently suggested a ``novel'' concept
of ``bioavailability.'' To clarify and better align the wording in the
definition of quality factors with the definition of bioavailability
used by FDA and the scientific community, we are modifying the wording
of the definition of ``quality factor'' in Sec. 106.3 in the final
rule.
The revised definition still speaks to the safety of the formula
while clarifying that the term ``bioavailability'' refers to nutrients.
We note, however, that the infant formula as a whole, i.e., the matrix
that contains the nutrients, must be formulated, processed, and
packaged such that the nutrients are bioavailable. Changes in an infant
formula matrix can greatly influence nutrient bioavailability (see 79
FR 7934 at 8007). Because infants are fed formula as the sole source of
nutrients, it is imperative that formulas have characteristics that
allow the nutrients to be bioavailable.
We decline to restore the definition of quality factors from the
1996 proposed rule. As discussed in response to comment 23 of the IFR,
the definition of quality factors in the proposed rule caused some
people to interpret
[[Page 33060]]
``healthy growth'' as a separate quality factor (79 FR 7934 at 7950-
7951).
(Comment 2) One comment expressed concern with defining quality
factors to apply to bioavailability of the infant formula as a whole,
but did not explain the basis for its concern. Another comment asserted
that our explanation for why quality factors apply to the
``bioavailability . . . of the formula'' is inconsistent with the
definition of ``bioavailability'' as understood by Congress and fails
to consider other more plausible and well-precedented interpretations
of Congressional intent. The comment stated that FDA's conclusion that
quality factors pertain to the ``bioavailability . . . of the formula''
appears arbitrary in the context of the 1986 Amendments to the Infant
Formula Act of 1980. The comment stated that the statutory language
requiring that the Secretary of Health and Human Services (the
Secretary) establish requirements for quality factors for infant
formulas ``including'' quality factor requirements for the nutrients
required to be contained in infant formula under section 412(i) of the
FD&C Act demonstrates that Congress intended to grant FDA the authority
to establish quality factor requirements for individual nutrients other
than those specified in section 412(i) of the FD&C Act, as well as
quality factor requirements relating to issues other than the
quantitative levels of nutrients as prescribed in section 412(i) of the
FD&C Act (e.g., the bioavailability of distinct forms of individual
nutrients), but not the authority to establish quality factor
requirements for the infant formula as a whole. The comment argued that
the IFR's definition of ``quality factors'' fails the legal analysis
provided by FDA in section VIII.A of the IFR because Congress was not
silent about the meaning of the term quality factors.
(Response) To the extent that either comment relates to the
explanation of bioavailability as set forth in the IFR and the
suggestion that bioavailability relates to the infant formula as a
whole, rather than to the bioavailability of individual nutrients, we
address this issue in our response to comment 1. To the extent these
comments assert that we lack authority to establish a definition of
quality factors that relates to the infant formula as a whole, we
disagree. We also disagree with the assertion that the legal analysis
provided in section VIII.A of the IFR failed to consider all the
possible interpretations of the statutory language or otherwise
provides an insufficient or inaccurate analysis of FDA's authority.
Comment 195 in the preamble to the IFR explicitly challenged FDA's
authority to establish the quality factor of normal physical growth,
which relates to the formula as a whole rather than any individual
nutrient (79 FR 7934 at 8003). In responding to comment 195, we
provided a detailed interpretation of our authority based, in part, on
section 412(b)(1) of the FD&C Act, and we summarize some of this
argument below (79 FR 7934 at 8003 through 8006). We reaffirm our
explanation of our authority as set forth in the response to comment
195 in the preamble to the IFR.
As discussed in the preamble to the IFR, section 412(b)(1) of the
FD&C Act requires the Secretary to ``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 [section
412(i)].'' 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. The
language is silent regarding what the exact quality factors should be.
The 1986 Amendments to the 1980 Infant Formula Act are consistent with
our interpretation that quality factors extend beyond requirements for
individual nutrients. The original language from the Infant Formula Act
of 1980 authorized the Secretary to, by regulation, ``establish
requirements for quality factors for such nutrients [required by
subsection (g)].'' Infant Formula Act of 1980, Public Law 96-359,
section 2, 94 Stat. 1190 (1980). (Subsection (g) of section 412 of the
FD&C Act was subsequently redesignated as subsection (i) of section 412
of the FD&C Act as part of the 1986 Amendments. Anti-Drug Abuse Act of
1986, Public Law 99-570, section 4014(a)(1), 100 Stat. 3207 (1986).) 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 apply to the ``infant
formula'' as a whole as well as to the individual nutrients.
Further, requiring that quality factors relate to the safety of the
infant formula as a whole is reasonable when considering the statutory
scheme as a whole. See FDA v. Brown & Williamson Tobacco Corp., 529
U.S. 120, 133 (2000) (explaining that the words of a statute must be
read in the context of the overall statutory scheme). Our 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, and this purpose is
achieved, in part, through the establishment of requirements for
quality factors that help ensure the safety of the infant formula as a
whole. See Public Law 96-359, 94 Stat. 1190, 1190 (1980).
(Comment 3) One comment expressed concern that the IFR is silent on
what changes, other than major changes, should be submitted to FDA
before processing for FDA's concurrence in the manufacturer's
assessment. The comment stated that because the guidelines issued under
21 CFR 106.30(c)(2) (and incorporated by reference in the 1986 Infant
Formula Act Amendments) discuss changes other than major changes and
have the force and effect of law, we should honor those guidelines.
(Response) We disagree that the IFR is silent on what changes,
other than major changes, a manufacturer should submit to FDA before
first processing (BFP). We addressed this issue in response to comments
256 and 352 of the IFR (79 FR 7934 at 8021 and 8053). As discussed in
the preamble to the IFR, a ``before first processing'' (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.
[[Page 33061]]
As for the comment's assertion that we should honor the guidelines
issued under 21 CFR 106.30(c)(2) with respect to changes other than
major changes, the comment misinterprets the language in section
412(c)(2) of the FD&C Act. Section 412(c)(2) of the FD&C Act only
incorporates the definition of ``major change'' as found in 21 CFR
106.30(c)(2) (as in effect on August 1, 1986) and the guidelines issued
thereunder. Thus, FDA's decision not to codify portions of the
guidelines related to changes other than major changes is not
inconsistent with section 412(c)(2) of the FD&C Act.
(Comment 4) One comment requested that we clarify the notification
requirements of an infant formula submitted after February 10, 2014 (90
days prior to May 12, 2014) under the current 90-day premarket
notification requirements. The comment stated that the requirements for
formulas submitted before July 10, 2014, and especially before May 12,
2014, need to be clarified.
(Response) We recognize the lack of clarity surrounding the
notification requirements for infant formulas submitted after February
10, 2014, based on the definition of eligible infant formula as set
forth in the IFR. To address the issue, we are amending the definition
of ``eligible infant formula'' to mean an infant formula that could be
lawfully distributed in the United States on December 8, 2014. The
change should eliminate the confusion surrounding notification
requirements for new infant formula products that are the subject of a
new infant formula notification submitted after the publication of the
IFR. Under the revised definition, new infant formulas that are the
subject of a notification submitted prior to the compliance date of
September 8, 2014 will be considered eligible.
B. Subpart B--Current Good Manufacturing Practice
1. Production and In-Process Control System (Sec. 106.6)
(Comment 5) One comment stated that FDA had declined to accept
comments submitted on the proposed rule that would limit the areas of
production requiring establishment of specifications to those deemed to
be critical and requested that wording be inserted in Sec. 106.6(a) to
align this section with other parts of the IFR (e.g., Sec.
106.30(d)(1)).
(Response) The comment's assertion that we declined to accept
recommendations to limit the areas of production that require
specifications to be established to those deemed to be critical is
incorrect. This issue is addressed in Sec. 106.6(c), which limits the
establishment of specifications to be met ``to any point, step, or
stage in the production process where control is necessary to prevent
adulteration.'' We indicated in the response to comment 41 in the
preamble to the IFR (see 79 FR 7934 at 7957-7958) that ``FDA does not
intend that the control procedures established under Sec. 106.6(c)
would address every theoretical risk of technical adulteration'' and
further stated that ``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.'' The response continued that ``certain
actions (e.g., the establishing of specifications) are not required at
every step in the manufacturer's process . . . [and] it is the
responsibility of the manufacturer to identify those points at which
control is necessary to prevent adulteration of infant formula
products.'' (79 FR 7934 at 7958).
(Comment 6) One comment stated that specifications necessary to
prevent adulteration during production are currently established and
contended that additional controls such as warehousing conditions and
trailer temperatures during distribution are not expected to cause
adulteration and should be out of the scope of the IFR. The comment
asked us to clarify whether additional non-process related
specifications beyond what manufacturers currently do are required and,
if so, which non-process related specifications, or the criteria to
make this determination, are needed. The comment said that
manufacturers need this information to assess their ability to comply
and determine related costs. The comment further stated that compliance
with Sec. 106.6 of the IFR would not be feasible by the effective date
of the IFR because, if additional specifications need to be developed
for areas the comment asserted are not critical to preventing product
adulteration, much more time than 150 days will be required to draft,
finalize, implement, and train employees. The comment requested that we
provide relief through an announcement and exercise of enforcement
discretion, a delayed compliance date, or a formal delay for this
provision to align with the compliance date for eligible infant
formulas.
(Response) We do not agree that warehousing conditions and trailer
temperatures during distribution can be dismissed as a potential cause
of adulteration. For example, temperatures that are too cold during
storage and distribution may result in breaking of the emulsion of an
infant formula, causing separation of the fat and liquid portions of
the products and rendering the products inappropriate/unfit for
consumption by infants. Temperatures that are too hot may result in
growth of thermophilic organisms (organisms that need high temperatures
for proliferation or that thrive at high temperature) that render the
products unpalatable and inappropriate/unfit for infant consumption. As
another example, during storage and distribution, rats that may gain
access to warehouses and/or trailers could gnaw through cardboard
cartons and plastic containers containing infant formula, which would
result in adulteration of the product under section 402(a) of the FD&C
Act.
The comment did not define non-process related specifications or
provide additional examples of non-process related specifications
beyond what manufacturers currently do. Therefore, we cannot respond to
the comment's request for additional information. However, we remind
manufacturers that Sec. 110.93 of Part 110--Current Good Manufacturing
Practice in Manufacturing, Packing, or Holding Human Food requires that
storage and transportation of finished food shall be under conditions
that will protect food against physical, chemical, and microbiological
contamination as well as deterioration of the food and the container.
We expect that infant formula manufacturers have already instituted
practices, whether or not they are currently identified as
specifications, to prevent adulteration and maintain product integrity
during storage and distribution as a necessary step in fulfilling their
responsibility to ensure that their formulas reach the consumer in a
condition that is safe and appropriate for consumption. Creating
written specifications as required by Sec. 106.6(b) for such practices
should not involve extensive effort or extra cost, and we see no basis
for announcing the exercise of enforcement discretion or a formal delay
for this provision to align with the compliance date for eligible
infant formulas. Nonetheless, with the exception of the compliance date
for certain requirements related to quality factors for eligible infant
formulas, the final rule adopts a compliance date of September 8, 2014
to facilitate manufacturer compliance with all requirements of this
final rule.
[[Page 33062]]
2. Controls To Prevent Adulteration Caused by Facilities (Sec. 106.20)
(Comment 7) One comment said that the requirements of Sec.
106.20(i), which addresses controls to prevent adulteration from in-
plant toilet facilities, are more restrictive than the provisions for
toilet facilities in the food GMPs (21 CFR 110.37(d)(4)), which allows
for doors in in-plant toilet facilities to open into enumerated areas
if alternate means have been taken to protect against contamination
(such as double doors or positive air-flow systems). The comment
continued that FDA did not establish a public health need for the more
restrictive requirements and claimed that infant formula manufacturers
will have to move or otherwise reconfigure their in-plant toilet
facilities if the IFR is interpreted not to permit the alternate means
in the food GMPs or exempt facilities in areas where product is not
subject to airborne contamination. The comment further stated that
compliance with Sec. 106.20 of the IFR would not be feasible by the
effective date of the IFR if the comment's proposed changes to Sec.
106.20 were not accepted and requested that we provide relief through
an announcement and exercise of enforcement discretion, a delayed
compliance date, or a formal delay for this provision to align with the
compliance date for eligible infant formulas.
(Response) We agree with the aspect of the comment that suggests
that it should be permissible for doors in in-plant toilet facilities
to open into certain areas if alternate means have been taken to
protect against contamination. However, we disagree that airborne
contamination is the only source of contamination from toilet
facilities. Contamination can come from hands, clothing, and footwear
of employees exiting the toilet facilities, and it is likely that
measures such as foot baths and footwear and garment changes in
addition to double doors and positive air-flow systems will be needed
to prevent contamination from in-plant toilet facilities. We are
revising Sec. 106.20(i) to permit doors to toilet facilities to open
into the plant facilities if alternate means have been taken to protect
against contamination. With this change to Sec. 106.20(i), we see no
basis for announcing the exercise of enforcement discretion or a formal
delay for this provision to align with the compliance date for eligible
infant formulas. Nonetheless, with the exception of the compliance date
for certain requirements related to quality factors for eligible infant
formulas, the final rule adopts a compliance date of September 8, 2014
to facilitate manufacturer compliance with all requirements of this
final rule.
3. Controls To Prevent Adulteration Caused by Equipment or Utensils
(Sec. 106.30)
(Comment 8) One comment agreed with FDA that controlling the
temperature of infant formula is important to prevent adulteration,
requested clarification regarding the equipment covered by Sec.
106.30(e)(2), and requested that we modify the provision to apply only
to cold bulk liquid storage. The comment stated that, with this change,
ingredient receipt through blending would not be classified as in-
process infant formula or finished infant formula until the components
are mixed and introduced into the cold storage vessel. In support of
the requested modification, the comment pointed to FDA's report
``Analysis of Results for FDA Food Defense Vulnerability Assessments
and Identification of Activity Types,'' in which we defined liquid
storage as follows: ``Bulk liquid storage refers to any medium-long
term storage silo or tank where liquid product may be stored prior to
introduction into the product stream or to hold finished product prior
to loading for outbound shipping.''
(Response) We do not agree with the modification recommended in
this comment. The report to which the comment refers, ``Analysis of
Results for FDA Food Defense Vulnerability Assessments and
Identification of Activity Types,'' identifies liquid storage/hold/
surge tanks as a key activity type found in most production
environments. However, in addition to the category of bulk liquid
storage described in the comment, the report describes a second
category of non-bulk holding and surge tanks, which ``refer to any
storage tanks used to hold product for a short period or surge tanks.
Non-bulk tanks can be used to store non-bulk liquid ingredients, hold
liquid product for sample testing and other QC activity, or to control
flow rates of liquid ingredients/product through the production
system.'' The report also specifies that liquid storage ``refers to any
processing step where liquid ingredient (emphasis added) or
intermediate/finished liquid product is stored in either bulk storage
tanks or smaller secondary holding tanks or surge tanks.'' Thus, the
report does not provide a basis for restricting cold storage in Sec.
106.30(e)(2)(i) to cold bulk liquid storage, so we decline to revise
Sec. 106.30(e)(2)(i) as suggested by the comment.
(Comment 9) One comment asked us to allow a less restrictive
approach to meet the showing required underSec. 106.30(e)(2)(ii)
(i.e., meeting both of the conditions listed in Sec. 106.30(e)(2)(ii)
of the IFR). Under Sec. 106.30(e)(2)(ii) in the IFR, 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[emsp14][deg]F (F) for a defined period of time if the manufacturer
has scientific data and other information to demonstrate that (a)
compliance with Sec. 106.30(e)(2)(i) (which established
40[emsp14][deg]F or below as the temperature level for all areas of
cold storage) would have an adverse effect on the quality of the in-
process or final infant formula 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. The comment argued that the changes we
made in the IFR do not fully encompass our stated rationale for the
provision ``to minimize the growth of pathogens and the deterioration
of liquid ingredients'' (79 FR 7934 at 7964).
(Response) In response to the comment's concern, we have revised
Sec. 106.30(e)(2)(ii) of the IFR. We are deleting Sec.
106.30(e)(2)(ii)(A) and combining Sec. 106.30(e)(2)(ii) from the IFR
with Sec. 106.30(e)(2)(ii)(B) from the IFR. The section will be
designated as Sec. 106.30(e)(2)(ii) in the final rule. In the final
rule, Sec. 106.30(e)(2)(ii) states that ``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[emsp14][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 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.''
(Comment 10) One comment requested that we align section Sec.
106.30(e)(2)(ii) with the Pasteurized Milk Ordinance, which specifies
45 [deg]F as the maximum storage temperature of pasteurized milk and
milk products. The comment stated that any capital improvements to
facilities needed to comply with Sec. 106.30(e)(2) will take
considerably longer than the 150 days until the effective date.
(Response) The language in Sec. 106.30(e)(2)(ii) of this final
rule (see
[[Page 33063]]
response to comment 9) allows the 45 [deg]F temperature permitted for
pasteurized milk and milk products for in-process or final infant
formula for a defined period of time provided that the manufacturer has
scientific information to demonstrate that 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. We discussed in the responses to comments 65 and 66 in the IFR
our reasons why the time and temperature conditions established in the
IFR are sufficient to ensure product safety and the reasons for the 40
[deg]F requirement. Furthermore, because infant formula is consumed by
a vulnerable population, food safety and public health considerations
do not justify further relaxing of the requirements of Sec.
106.30(e)(2)(ii) of this final rule.
With regard to the comment's concern that compliance will take
considerably longer than 150 days, we disagree. Section 106.30(e)(2) of
this final rule allows a manufacturer the flexibility to store in-
process and final product at temperatures up to and including 45
[deg]F, provided that the manufacturer has scientific data and other
information to demonstrate that 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.
The comment provided no information that would lead us to believe that
compiling such scientific data would prove difficult or burdensome.
4. Controls To Prevent Adulteration Due to Automatic (Mechanical or
Electronic) Equipment (Sec. 106.35)
(Comment 11) One comment noted that the concept under Sec.
106.30(d)(1), which requires only those instruments and controls at
points where control is necessary to prevent adulteration to be
accurate and maintained, including by calibration, should be applied to
Sec. 106.35(b)(1).
(Response) To the extent this comment requests consistency between
the language in the two provisions, we agree that the use of consistent
language would be beneficial, and we are amending Sec. 106.35(b)(1) to
provide that a manufacturer shall ensure, at any point, step, or stage
where control is necessary to prevent adulteration of infant formula,
that all hardware is routinely inspected and checked according to
written procedures and that hardware that is capable of being
calibrated is routinely calibrated according to written procedures. We
note, however, that we are not aware of hardware currently in use in
the infant formula manufacturing process that is capable of calibration
that is not used at a point, step, or stage where control is necessary
to prevent adulteration of infant formula. Infant formula manufacturing
plants contain many automatic measuring devices that are capable of
being calibrated, and they must be calibrated at whatever frequency is
necessary to ensure accurate measurement. No device should be providing
inaccurate data that could lead to adulteration of the infant formula.
(Comment 12) One comment stated that Sec. 106.35(b)(4) would
require revalidation of any system that is modified and suggested an
alternative definition of validation in Sec. 106.35(a)(4) to add the
phrase ``either through validation or verification of all components or
through the validation of the system.'' The comment stated that
industry supports the requirement for full system validation. The
comment acknowledged that our response to comments in the IFR contains
references to ``appropriate regression testing'' and ``validation
analysis'' but said that the IFR ultimately points to revalidation of
the entire system. The comment suggested revising the final rule to
clarify that verification is a sufficient method of ensuring control
for some components in a system.
(Response) The preamble to the IFR included an extensive discussion
of validation of automatic equipment and FDA's reasons for establishing
the definition of validation in Sec. 106.35(a)(4) in the IFR (79 FR
7934 at 7968-7971). We do not agree with the alternative definition
proposed because it would permit the initial validation of a system
through verification of all components. Complete validation of an
automatic system is required initially; however, FDA did not intend
that a whole system would always need to be completely revalidated with
every change. For example, there may be operations upstream from
another part of a system that is being changed that are not affected
when the part of the system that is downstream has changed. In such
cases, it may be possible to revalidate those parts of the system that
are being changed or impacted by the change by other means such as
verification studies or modeling. In response to the comment, we are
revising Sec. 106.35(a)(4) to clarify that validation can be
accomplished through any suitable means, such as verification studies
or modeling. However, we note that such verification studies differ
from the nutrient testing of the final product, which is a form of
verification of a system's proper operation. Finished product testing
for nutrients does not eliminate the need for system validation.
(Comment 13) One comment stated that 150 days is insufficient time
to conduct all the validations required by Sec. 106.35(b)(3). The
comment stated that automation, validation, and change control that is
currently used would meet the requirements of ``consistently produces a
product meeting predetermined specifications'' and that validation
analyses are performed to determine the extent and impact of the change
on the system. The comment stated that this is further augmented by the
ongoing monitoring of critical control points. The comment requested
that, with regard to the requirements of Sec. 106.35, we announce the
exercise of enforcement discretion or a formal delay for this provision
to align with the compliance date for eligible infant formulas.
Nonetheless, with the exception of the compliance date for certain
requirements related to quality factors for eligible infant formulas,
the final rule adopts a compliance date of September 8, 2014 to
facilitate manufacturer compliance with all requirements of this final
rule.
(Response) We note that the validation requirement in Sec.
106.35(b)(3) applies to new infant formulas that have not yet been
released. As such, manufacturers will not need to conduct a complete
system validation for formulas that are already on the market when this
rule becomes effective. However, we also note that manufacturers will
still need to ensure that all systems are designed, installed, tested,
and maintained in a manner that will ensure that they are capable of
performing their intended function and of producing and analyzing
infant formula in accordance with the CGMP and quality control
procedures as required by Sec. 106.35(b). Given that the requirement
in Sec. 106.35(b)(3) applies to new infant formulas, complying with
the section by the effective date of the rule should not be an issue.
We therefore decline the request to announce the exercise of
enforcement discretion, a delayed compliance date, or a formal delay
for this provision to align with the compliance date for eligible
infant formulas.
5. Controls To Prevent Adulteration During Manufacturing (Sec. 106.50)
(Comment 14) One comment noted that Sec. 106.50(a)(2) of the IFR
could be
[[Page 33064]]
interpreted to require a ``responsible official'' to draft changes to
the master manufacturing order and recommended that we delete the term
``drafted.''
(Response) Although a responsible official is required to review
and approve changes in a master manufacturing order, we agree that
persons other than a responsible official could draft changes to a
master manufacturing order. Accordingly, we have deleted the word
``drafted'' from Sec. 106.50(a)(2) in the final rule.
(Comment 15) One comment recommended adding some examples (e.g.,
physical separation or another system of segregation) to Sec.
106.50(f)(4) to make it consistent with Sec. 106.20(b)(2), which deals
with facilities and separation of raw materials, in-process materials
and final product. Section 106.50(f)(4) requires, in part, that
rejected in-process materials be controlled under a quarantine system
designed to prevent the use of the materials in manufacturing or
processing operations.
(Response) Section 106.20(b)(2) requires separate areas or another
system of separation such as a computerized inventory control, a
written card system, or an automated system of segregation for holding
raw materials, in-process materials, and final infant formula product
after rejection for use in, or as, infant formula. As noted in the IFR,
``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'' (79 FR 7934 at 7956). As such, we do not believe
that adding examples is needed in Sec. 106.50(f)(4) and, therefore,
are not making the change recommended in the comment.
6. Controls To Prevent Adulteration From Microorganisms (Sec. 106.55)
(Comment 16) A comment stated that a 95% level of confidence
interval means that up to approximately 5% of C. sakazakii-contaminated
production aggregates may test negative with FDA's proposed testing
scheme and be released to market. The comment said that because
thousands of production aggregates are released to market each year,
this risk is not inconsiderable. The comment further stated that
contamination can occur as clumps and clusters, and this contamination
could be missed when the production aggregate is tested. The comment
expressed concern that powdered infant formula presents a potential
risk to the health of infants of all ages.
(Response) Although we consider the concerns expressed in this
comment to be important, the comment appears to mischaracterize the
meaning of confidence interval in the quantitative risk analysis. A
confidence interval is a range of values in which there is a specified
probability that the value of a parameter lies within it. The
confidence level does not indicate the percentage of adulterated infant
formula that will reach the market.
For purposes of our response, we assume that this comment is
referring to the finished product testing required under Sec.
106.55(c). Finished product testing under Sec. 106.55(c) is but one
means of assuring the safety of powdered infant formula. The purpose of
CGMPs is to have a system that produces products that are consistent in
quality and safety and to collectively provide additional safeguards.
In the preamble to the IFR, we explained that the sampling plan is
intended to help manufacturers identify unacceptable production
aggregates at the finished product stage. The sampling plan is a
statistical approach based on a quantitative risk analysis and was
extensively discussed in the IFR (79 FR 7934 at 7984-7988).
(Comment 17) One comment noted that peer-reviewed articles
published after 2011 are not cited and discussed in the IFR and that no
articles published after 2011 appear to have been taken into
consideration in formulating the IFR. The comment also noted that
significant progress has been made in clarifying sources of and risk
groups for Cronobacter, particularly C. sakazakii. The comment noted a
2012 publication in the American Association of Pediatrics to support
this statement. The comment urged FDA to review publications after
2011, in particular with regard to C. sakazakii.
(Response) Although the IFR did not provide literature citations
after 2011, we monitor the scientific literature closely with respect
to data and studies that affect infant formula. The comment did not
identify, and we are not aware of, any articles published after 2011,
including the 2012 publication by Jason cited in the comment, that
would have suggested a need to change the IFR's requirements or the
requirements of this final rule.
(Comment 18) One comment recommends that the rule clarify that
technologies currently used by manufacturers cannot produce a sterile
formula but that there are technologies capable of producing a sterile
powdered infant formula without damaging the product's nutritional
value, if these technologies were applied by manufacturers.
(Response) We discussed in the preamble to the IFR (79 FR 7934 at
7980-7981) the use of technology to eradicate Cronobacter spp. To the
extent this comment suggests we mandate which production method to use,
we disagree. To a large extent, the IFR, as well as this final rule,
gives manufacturers the flexibility to establish controls,
specifications, and other operations and does not require the use of
specific technologies. Given the pace at which technological changes
can occur, we believe this more flexible approach is more practical to
address the use of changing technologies and best practices.
7. Audits of Current Good Manufacturing Practice (Sec. 106.90)
(Comment 19) One comment agreed with FDA that audits should be
performed by individuals who have as little bias as possible and who do
not have a direct interest in the outcome of the audit. The comment
also noted that the determination of who satisfies these criteria is
largely subjective unless the audit is conducted by a third party, and
the comment requested some examples of situations where an audit might
be conducted by an individual that is not a third party (e.g., the Head
of Quality Assurance auditing a facility) that would be acceptable to
FDA.
(Response) As the comment noted, the determination of the
objectivity of an in-house employee for performing audits involves
subjective as well as objective evaluation of the suitability of the
individual for a particular audit. Such assessments must be made on a
case-by-case basis. As explained in response to comment 166 in the IFR
(79 FR 7934 at 7994), in evaluating whether an audit might be conducted
by an individual that is not a third party, the manufacturer should
consider factors such 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. Therefore, we decline to
give examples as requested by the comment.
C. Subpart C--Quality Control Procedures
1. General Quality Control (Sec. 106.91)
a. Premix Testing
(Comment 20) One comment stated that infant formula manufacturers
should be allowed to rely on a premix supplier's certificate of
analysis to provide analytical information on all
[[Page 33065]]
nutrients in a premix. The comment continued that our proposed rules on
Current Good Manufacturing Practice and Hazard Analysis and Risk-Based
Preventive Controls for Human Food (78 FR 3646 (January 16, 2013)) and
Foreign Supplier Verification Programs for Importers of Food for Humans
and Animals (78 FR 45729 (July 29, 2013)) (part of our implementation
of the Food Safety Modernization Act (FSMA)) would require food
manufacturers to conduct supplier verification activities with respect
to their premix suppliers. The comment predicted that the FSMA-mandated
supplier verification requirements will adequately address any
potential concerns related to whether nutrient premixes comply with an
infant formula manufacturer's specifications and should be taken into
account in determining the extent of premix testing that should be
required in the IFR.
(Response) We disagree that infant formula manufacturers should be
allowed to rely on a premix supplier's certificate of analysis to
provide information on the composition of a premix. Section
412(b)(3)(B) of the FD&C Act stipulates that ``[e]ach nutrient premix
used in the manufacture of an infant formula shall be tested for each
relied upon nutrient required by subsection (i) which is contained in
such premix to ensure that such premix is in compliance with its
specifications or certifications by a premix supplier.'' (Emphasis
added.) The statutory language makes it clear that a premix
manufacturer's certification is not to be relied upon by the
manufacturer of the infant formula to establish the analytical
composition of a premix. Further, the statute does not allow other
options as substitutes for the testing of premixes by infant formula
manufacturers. Therefore, we decline to revise Sec. 106.91(a)(1) as
suggested by the comment.
b. Stability Testing and Frequency
(Comment 21) One comment stated that the recipe (the manufacturing
order) should be the unit of production used for setting stability
testing requirements rather than the production aggregate required by
Sec. 106.91(b).
(Response) Under section 412(a) of the FD&C Act, an infant formula
that does not provide nutrients as required by section 412(i) is deemed
to be adulterated. Section 106.91(b) of the IFR established the
production aggregate as the quantity of formula to be used for setting
stability testing requirements to provide direct evidence that nutrient
levels are maintained throughout the shelf life of all of the product
in the marketplace. A requirement to use the recipe (manufacturing
order) as the unit of production for setting stability testing
requirements, as requested in the comment, could be interpreted to mean
that after stability testing was conducted one time on the quantity of
formula produced from the recipe, no more stability testing would be
required for that formula. Using such a basis for stability testing
would not provide evidence that nutrient levels are maintained
throughout the shelf life in all formula in the marketplace. Therefore,
we are not revising the unit of production to be used for setting
stability testing requirements in response to this comment. The
production aggregate is the quantity of infant formula from which
manufacturers must take a representative sample for the stability
testing required by Sec. 106.91(b)(1) and (2) in the final rule.
(Comment 22) One comment asked us to clarify the frequency of
stability testing needed for batch processing operations.
(Response) When manufacturers produce their formulas using batch
production, they typically manufacture a ``batch'' during a single
cycle of manufacture, which would correspond to what we have defined as
the production unit in Sec. 106.3 of the IFR (i.e., a specific
quantity of an infant formula produced during a single cycle of
manufacture that has uniform composition, character, and quality,
within specified limits). The individual ``batches'' (i.e., production
units) are stored in containers (often referred to as totes) until the
formula is packaged. Comingling of the individual ``batches''
(production units) occurs when the contents of the individual storage
containers are combined during the packaging process, thereby resulting
in a larger quantity of formula that is intended to have uniform
composition, character, and quality, consistent with the definition of
``production aggregate'' in the IFR. The larger quantity of the formula
that is comingled and packaged in one packaging run would be considered
the production aggregate for manufacturers using batch production. Each
such production aggregate would be subject to the stability testing
requirements as applicable under Sec. 106.91.
(Comment 23) One comment stated that the requirement to conduct
stability testing for every production aggregate of infant formula
disregards extensive data from longstanding stability programs and
treats each production aggregate as an independent sample.
(Response) FDA appreciates that infant formula manufacturers have
been conducting stability testing on their infant formulas since the
passage of the Infant Formula Act of 1980 and recognizes that a
manufacturer may have extensive stability data for existing products
that may be applicable to new infant formulas. We realize the potential
value of such data and consider that manufacturers may be able to rely
on such data in some instances rather than always conducting the de
novo stability testing of new infant formulas required by Sec.
106.91(b)(1). For this reason, and in order to reduce the amount of
comprehensive stability testing required for new products, we are
providing an exemption in Sec. 106.91(b)(1)(ii) from the testing
required by Sec. 106.91(b)(1)(i) in this final rule if the
manufacturer of a new infant formula requests an exemption and provides
analytical data that demonstrate that the stability of the new infant
formula will likely not differ from the stability of non-new formulas
with similar composition, processing, and packaging for which there are
extensive stability data. Under Sec. 106.91(b)(1)(ii) of the final
rule, the manufacturer would request the exemption in the 90-day
notification for the new infant formula under Sec. 106.120(b)(7). If
the manufacturer is exempted from the testing required by Sec.
106.91(b)(1)(i), the manufacturer would then be required under Sec.
106.91(b)(1)(ii) of the final rule to test the first production
aggregate in accordance with the requirements for routine stability
testing of all subsequent production aggregates of infant formula under
Sec. 106.91(b)(2).
(Comment 24) One comment stated that stability testing of new
formulas every 3 months as required by Sec. 106.91(b)(1) of the IFR is
unnecessary. The comment contended that an analytical value at an
isolated point in time may misrepresent the shelf life of the product
as determined through a manufacturer's existing stability programs. The
comment also said that the rate of degradation early in shelf life is
not relevant to product safety if the product meets nutrient
specifications at the end of the shelf life period.
(Response) We agree that an unexpected analytical value at one
point in time may not necessarily be predictive of the shelf life of
the product. We disagree, however, that the rate of nutrient
degradation early in shelf life is irrelevant to product safety. If the
product does not meet nutrient specifications at the end of the shelf
life period, the knowledge that nutrient degradation is occurring more
rapidly than predicted by previous data
[[Page 33066]]
provides a valuable early indicator that possible action may be
required to avoid having an adulterated product in the marketplace. We
have further considered the requirement that stability testing of new
infant formulas be conducted every 3 months (four times a year) in
Sec. 106.91(b)(1) of the IFR and conclude that satisfactory data could
still be obtained if the frequency of testing is reduced to every 4
months (3 times a year). Therefore, we have reduced the required
frequency of stability testing for new infant formulas to every 4
months in Sec. 106.91(b)(1)(i) of the final rule.
(Comment 25) One comment questioned the benefit in requiring that
every production aggregate after the first undergo stability testing,
as such requirement would represent a large increase in the number of
samples undergoing stability testing on a routine basis. The comment
stated this testing requirement would have a significant impact on the
industry and questioned the value of such testing. Another comment
questioned how measuring nutrients at the midpoint of shelf life will
provide additional assurance for formulas for which stability data have
been established.
(Response) The purpose of stability testing of subsequent
production aggregates for nutrients as required by Sec. 106.91(b)(2)
is to confirm that the nutrients present in an infant formula at the
finished product stage do not degrade below minimum levels over the
shelf life of the product. Every production aggregate must be at or
above such minimum levels at the end of the shelf life of the product.
The evidence that nutrient levels have been maintained at or above such
minimum levels in each production aggregate is provided by the results
of stability testing at the end of the shelf life of each production
aggregate. This testing requirement will provide direct evidence that
nutrient levels are maintained throughout the shelf life of infant
formula products. We agree that the critical data are the nutrient
levels present at the end of shelf life and that the midpoint data are
not essential in subsequent production aggregates. Therefore, we have
deleted the requirement to conduct stability testing at the midpoint of
the shelf life for infant formulas tested under Sec. 106.91(b)(2).
(Comment 26) One comment stated that routine stability testing
should not include analysis of nutrients that are not labile (i.e.,
easily broken down). The comment recommended that we limit routine
stability testing to reliable indicator nutrients and supplement such
testing with periodic comprehensive testing.
(Response) We do not agree that the routine stability testing
required at the end of shelf life under Sec. 106.91(b)(2) should
include only labile nutrients or that the purpose of stability testing
would be met by the comment's suggested approach. It is essential to
have proof that all nutrients, including those that deteriorate more
slowly, are present at or above the minimum required levels at the end
of shelf life to demonstrate that the product is not adulterated. We
note, however, that Sec. 106.91(b)(5) waives evaluation of the levels
of minerals from the testing required by Sec. 106.91(b)(1) and (2)
because these nutrients do not degrade in infant formula. We decline to
revise the final rule in response to this comment.
(Comment 27) One comment stated that the requirements of Sec.
106.91(b)(3) are too prescriptive and pointed out that market
withdrawal of the product was another option. The comment further
stated that the manufacturer should be allowed to determine the
disposition of a product that does not maintain its required nutrient
levels throughout shelf life and recommended that Sec. 106.91(b)(3) be
deleted.
(Response) We made an inadvertent error in the language of Sec.
106.91(b)(3) by including the words ``shelf life label statement.'' We
intended that manufacturers would have the option of making changes to
the ``use by'' date, not the ``shelf life label statement,'' if the
stability data from the testing required by Sec. 106.91(b)(1) did not
substantiate the anticipated shelf life of the formula. We have revised
Sec. 106.91(b)(3) accordingly.
We realize that there may be some situations when manufacturers may
find that actions other than those provided for in Sec. 106.91(b)(3)
in the IFR may be appropriate when the stability testing of a new
infant formula required by Sec. 106.91(b)(1) does not substantiate the
shelf life of the formula. Consequently, we have revised Sec.
106.91(b)(3) of the final rule to clarify our intent that manufacturers
have the option to adjust the ``use by'' date so that such date is
substantiated if the stability data from the testing required by Sec.
106.91(b)(1) did not substantiate the anticipated shelf life of the
formula. FDA also is providing flexibility for manufacturers to take
other appropriate actions in Sec. 106.91(b)(3)--other than conducting
the testing required by Sec. 106.91(b)(1) or adjusting the ``use by''
date--when stability testing does not substantiate the shelf life of
the formula. We also are clarifying in Sec. 106.91(b)(3) that the
manufacturer must address all production aggregates released and
pending release for distribution that are implicated by the testing
results.
We also are making a conforming change to Sec. 106.91(b)(4)(iii)
to clarify that manufacturers must address all production aggregates
released and pending release for distribution that are implicated by
testing results required by Sec. 106.91(b)(2) that show that any
required nutrient is not present in the production aggregate of infant
formula 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
labels for the finished products from the production aggregate of
infant formula.
(Comment 28) One comment stated that FDA should give further
consideration to periodic testing as a complement to stability testing
rather than requiring stability testing of each production aggregate.
The comment also requested that we change the requirement of the IFR to
require that the manufacturer collect representative samples of
formulas every 3 months for stability testing.
(Response) We considered whether to require periodic testing in
establishing the requirements for quality control procedures in the
IFR. However, we concluded that periodic testing was not necessary
because the testing required by Sec. 106.91(a) of the IFR ``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'' (79 FR 7934 at 7993).
Adding a requirement for periodic testing would result in unnecessary
testing. Further, periodic testing (e.g., testing representative
samples of formula every 3 months) would not provide sufficient
evidence that nutrient levels in each production aggregate are being
maintained. As stated in the response to comment 25, the purpose of
routine stability testing for nutrients is to confirm that the
nutrients present in an infant formula at the finished product stage do
not degrade below minimum levels over the shelf life of the product.
Every production aggregate must be at or above such minimum levels at
the end of the shelf life of the product. Implementation of the
approach requested in the comment would not provide evidence that
nutrient levels have been maintained at or above such minimum levels in
each production aggregate. Therefore, we are not making either of the
changes requested by this comment.
[[Page 33067]]
(Comment 29) One comment stated that the requirement in Sec.
106.91(b) to do stability testing on every production aggregate is
overly burdensome and unnecessary. The comment stated that this
requirement would generate redundant data and would add considerable
costs for formulas.
(Response) We note that under Sec. 106.91(a)(4), manufacturers
must test every production aggregate of finished infant formula for all
nutrients required by Sec. 107.100 and any other nutrient added by the
manufacturer before distribution of the product. Testing at this point
is already mandated by section 412(b)(2)(B)(i) of the FD&C Act, and the
results of this testing can also serve as the initial stability data.
Under the final rule, manufacturers must also conduct stability testing
on each subsequent production aggregate only at the end of shelf life.
In addition, we are providing for an exemption in Sec.
106.91(b)(1)(ii) from the comprehensive stability testing required for
new infant formulas by Sec. 106.91(b)(1)(i) if a manufacturer of a new
infant formula requests an exemption and provides analytical data that
demonstrate that the stability of the new infant formula will likely
not differ from the stability of non-new formulas with similar
composition, processing and packaging for which there exist extensive
stability data.
As such, we do not consider that a requirement for testing of every
production aggregate generates redundant data. Each production
aggregate is produced independently and verification is needed that an
infant formula is not adulterated when it reaches the end of its shelf
life as well as at the time of production. Because infant formula
serves as the sole source of nutrition for infants, we disagree that
such a requirement is overly burdensome or unnecessary.
(Comment 30) One comment stated that the testing required in Sec.
106.91(a)(4) and (b)(1) is limited to the nutrients in Sec. 107.100
because section 412(b)(3)(D) of the FD&C Act specifies that if the
Secretary adds a nutrient to the list of nutrients provided in section
412(i) of the FD&C Act, the Secretary shall by regulation require that
the manufacturer of an infant formula test each batch of such formula
for such new nutrient in accordance with subparagraphs (A), (B), and
(C) of section 412(b)(3) of the FD&C Act. The comment argued that
section 412(b)(3)(D) of the FD&C Act means that if FDA has not deemed
the nutrient to be essential by requiring its addition to infant
formula, then testing for the nutrient is also not essential.
(Response) To the extent this comment asserts that we intended to
limit the testing required in Sec. 106.91(a)(4) and (b)(1) to those
nutrients specified in Sec. 107.100, we disagree. We discuss this
issue in detail in our response to comment 173 in the preamble to the
IFR (79 FR 7934 at 7996). To the extent this comment suggests that we
lack the authority to impose testing requirements on nutrients other
than those specified in Sec. 107.100, we also disagree. The statutory
language in section 412(b)(3)(D) of the FD&C Act is not our sole
authority to establish requirements for nutrient testing. As explained
in the IFR, 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 must 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).
(Comment 31) One comment stated that compliance with Sec. 106.91
by the effective date of the IFR cannot realistically be achieved and
requested that we announce and exercise enforcement discretion, delay
the compliance date, or formally delay the provisions of Sec. 106.91
to align with the compliance date for eligible infant formula. The
comment asserted that the requirements of Sec. 106.91 are burdensome
but did not provide specific information about why compliance with
Sec. 106.91 by the effective date of the IFR would be impractical.
(Response) As discussed in our responses to other comments relating
to Sec. 106.91, we are taking some steps in this final rule to
increase flexibility and lessen the burden of some of the requirements
in Sec. 106.91. This increased flexibility should address any concerns
about complying with Sec. 106.91 by the effective date of this rule.
Therefore, we are rejecting the request to announce and exercise
enforcement discretion or formally delay the provisions of Sec. 106.91
to align with the compliance date for eligible infant formula.
Nonetheless, with the exception of the compliance date for certain
requirements related to quality factors for eligible infant formulas,
the final rule adopts a compliance date of September 8, 2014 to
facilitate manufacturer compliance with all requirements of this final
rule.
D. Subpart E--Quality Factors for Infant Formula
(Comment 32) One comment stated that FDA's expansion of the
definition of ``Quality Factors'' in the IFR to require a growth
monitoring study on the ``bioavailability'' of an infant formula as a
whole was not consistent with current scientific knowledge, as
specified in section 412(b)(1) of the FD&C Act. The comment included an
extended discussion of current scientific knowledge of the effects of
specific nutrients on infant growth and alternative methods for
evaluating infant formulas, such as animal studies.
(Response) The preamble to the IFR (see 79 FR 7934 at 7951-7952)
explored the concept of healthy growth and explained why normal
physical growth as a quality factor is not flawed. As that discussion
indicates, infant growth is steady and predicable, and physical growth
and normal maturation should occur together. If the infant formula does
not have all the nutrients needed by an infant in a form that is
bioavailable, the infant will not grow. Monitoring of physical growth
of infants has long been recognized as an indicator of healthy growth.
For example, the 1980 report of the Committee on Nutrition of the
American Academy of Pediatrics cited in the IFR 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'' (79 FR
7934 at 7951), thereby recognizing the critical nature of this period
of unparalleled growth. More recently, the 2004 report of the Institute
of Medicine of the National Academy of Sciences concluded that ``Growth
is well recognized as a sensitive, but nonspecific indicator of the
overall health and nutritional status of an infant'' (79 FR 7934 at
8006).
[[Page 33068]]
In the preamble to the IFR, we stated that ``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 (79 FR 7934 at 8008). Assessments
described in the comment would require invasive procedures that would
increase the level of risk associated with a human study of an infant
formula applying such measures. The information provided in the comment
also suggested that the evaluation of an infant formula should be
accomplished by studying animals. We understand that animal studies can
be very useful in determining the bioavailability of nutrients and
establishing the safety of ingredients, as well as exploring metabolic
pathways. However, as we concluded in the IFR, FDA is not aware of an
animal model that is a suitable substitute for the infants in a growth
monitoring study (79 FR 7934 at 8008), and the information provided in
the comment did not discuss this issue. Therefore, we are maintaining
the requirement to conduct a growth monitoring study in this final
rule.
(Comment 33) One comment noted that the IFR identified two quality
factors, normal physical growth and sufficient biological quality of
the formula's protein component. The comment interpreted the IFR to
mean that of the many different functional requirements, the only one
to be assessed for infant formula is its efficacy in leading to
adequate physical growth in the short term, and if the infant leads to
adequate growth over a period of fifteen weeks, the infant formula is
of good quality. The comment also stated that it should not be
suggested that quality on a single dimension is sufficient when an
infant must perform well on many different dimensions, and it is
misleading to suggest that a short-term measure of infants' physical
growth can reasonably be viewed as a measure of the overall quality of
infant formula.
(Response) The quality factor requirements are meant to provide the
assurance that, when fed as the sole source of nutrition, the infant
formula in its entirety will support healthy growth. We understand that
the quality factors of normal physical growth and sufficient biological
quality of the formula's protein component have limitations and that
there are other ``dimensions'' that are relevant to infant formula. The
preamble to the IFR (79 FR 7934 at 7953) discussed the limitations of
both quality factors, as demonstrated by the growth study and the PER.
Although we are aware of these limitations, at this time other methods
are not available or are impracticable. As discussed in the IFR, FDA
will consider amending the quality factor regulations as new
methodology and appropriate reference criteria become available (79 FR
7934 at 7950).
(Comment 34) One comment requested that we revise the designation
of normal physical growth to limit the quality factor to changes in
formulations that may have an effect on growth. The comment noted that
Sec. 106.96(b) sets the default requirement of a growth monitoring
study (GMS) for all new formulas. The comment continued that although
Sec. 106.96(c) provides exemptions from the requirements of paragraph
Sec. 106.96(b) under three conditions, the condition set forth in
Sec. 106.96(c)(2)(ii)--that the change from the existing formula does
not affect the bioavailability of the formula or bioavailability of
nutrients in the formula--is circular because FDA defined the quality
factor as normal physical growth, not as bioavailability of the
nutrients in the formula. The comments stated that the exemption from
the GMS requirement should be provided when there is evidence that a
change to the infant formula would not affect physical growth. The
comment stated that neither bioavailability of the infant formula nor
the nutrients in the formula is directly measured in the GMS. The
comment concluded that to require a GMS across all new formulas even
when it is known that measurement of physical growth will not be able
to detect inadequacies of many nutrients risks the institutionalization
of an insensitive, unreliable measure of formula quality that does
nothing to ensure the health of formula-fed infants.
(Response) FDA agrees that the exemption from the GMS study should
be provided when a change to an existing infant formula would not
affect the ability of the formula to support physical growth
specifically, instead of when the change to the formula does not affect
bioavailability. We agree that bioavailability of individual nutrients
is not directly measured in the GMS. We understand that every
formulation change may not need a GMS and clearly indicated in the
preamble to the IFR that a GMS ``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'' (79 FR
7934 at 8005). We are revising the exemption in Sec. 106.96(c)(2)(ii)
so that it applies when a change to an existing infant formula would
not affect the ability of the formula to support normal physical
growth, and are also making conforming changes to the notification
requirements in Sec. 106.121(d).
(Comment 35) Two comments urged us to provide greater detail for
studies supporting quality factors, particularly in areas of the size
and representativeness of the population of infants studied. The
comments requested that we develop additional guidance beyond what was
published in February 2014 regarding the structure and methodology that
should be used in the studies.
(Response) The preamble to the IFR provided a basis for structuring
and conducting an adequate and well-controlled growth monitoring study
to demonstrate that a new infant formula supports normal physical
growth in infants when fed as the sole source of nutrition (79 FR 7934
at 8007-8021). This information provided the scientific basis for how a
growth monitoring study should be designed and methodological concerns
that included sample size considerations. We would consider future
development of additional guidance to expand upon the information in
the preamble of the IFR regarding conduct of a growth monitoring study.
We are satisfied, however, that the standards set forth in the preamble
to the IFR provide sufficient guidance with which to conduct adequate
and well-controlled growth monitoring studies.
(Comment 36) One comment expressed concern regarding the voluntary
citizen petition process by which manufacturers of eligible infant
formula can provide to FDA the basis on which they have concluded that
their eligible infant formulas satisfy the quality factors for physical
growth and/or protein efficiency ratio (PER). The comment stated that
the citizen petition option under Sec. 106.96(i)(3) for eligible
infant formulas would make information public to competitors,
consumers, and others. The comment continued that it would be difficult
for a manufacturer not to submit a citizen petition because there would
be a public expectation that the manufacturers do so. The comment
further stated that formulas on the market have been through FDA review
and have had to satisfy all the requirements of the Infant Formula Act
and subsequent amendments. The comment stated that if there is any
additional information that the Agency feels is needed from
manufacturers, the Agency should include such details in the new
notification requirements in the provisions of Sec. 106.120 and Sec.
106.121,
[[Page 33069]]
consistent with good administrative procedures for notice and comment.
The comment requested clarification of the reasons an additional
process was created and how manufacturers would receive a response from
FDA. The comment also expressed concern about the manufacturers'
ability to submit petitions for each formula by the November 2015
compliance date. The comment noted that because the citizen petition is
a voluntary process, it provides no assurance that the Agency will
obtain any outstanding information the Agency requires. The comment
concluded that the citizen petition process is not necessary, is
redundant, and provides no additional benefit to the Agency, the
manufacturer, or the public, and that Sec. 106.96(i)(3) should be
deleted.
(Response) We disagree that Sec. 106.96(i)(3) should be removed.
The preamble to the IFR described the basis for the voluntary citizen
petition process and further explained that all formulas, new or not
new (i.e., currently marketed products), must meet the quality factors
requirements (79 FR 7934 at 8028). We reiterate that the citizen
petition process under Sec. 106.96(i)(3) is voluntary and transparent;
however, meeting the quality factor requirements is not voluntary.
Meeting the quality factor requirements is mandatory under section
412(a)(2) of the FD&C Act, and an infant formula that does not meet
quality factor requirements is an adulterated product.
We consider the citizen petition process to be a beneficial
opportunity for the manufacturer of an eligible infant formula to
describe how the quality factors have been met before the compliance
date for eligible infant formulas (79 FR 7934 at 8005). We described in
further detail in an accompanying draft guidance document how the
process works, including information about how FDA will respond to
petitioners. Additionally, we indicated that we are available to meet
with manufacturers and discuss their particular concerns regarding the
citizen petition process. We note that FDA will protect the
confidentiality of information submitted through the citizen petition
process in accordance with the Freedom of Information Act (5 U.S.C.
552) and FDA's regulations (see, e.g., 21 CFR 20.61). In addition, we
are providing more detailed information regarding the process for
submitting a citizen petition to meet the quality factor requirements
for eligible infant formulas in a guidance document posted on FDA's Web
site at http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm400036.htm. However, we also
note that because the citizen petition process is voluntary, we would
not consider the absence of such a petition negatively. Finally, we
note that new infant formula notifications submitted prior to the
compliance date of September 8, 2014 would not necessarily have
demonstrated satisfaction of the quality factor requirements in this
final rule. As such, we disagree that providing this voluntary
opportunity to describe how the quality factors have been met is
redundant.
(Comment 37) One comment requested that additional language be
added to Sec. 106.96(f) regarding the methodology required to
determine the biological protein quality. The comment suggested the
addition of the phrase ``or by other appropriate method(s)'' be added
to Sec. 106.96(f) and Sec. 106.96(i)(2)(ii). The comment continued
that by incorporating this change of language into the final rule,
there would be an opportunity for the use of other scientifically valid
methods for determining protein quality beyond what exists currently
and for the possibility of other methods that may be developed in the
future.
(Response) FDA acknowledges that currently and in the future there
may be other methods that could be used for determining protein
quality. To address this issue, we added an exemption to Sec.
106.96(g)(3) to allow manufacturers of new infant formulas to use
alternative methods based on sound scientific principles to demonstrate
protein quality. FDA is also adding language to Sec. 106.121(i) of
this final rule, consistent with this change, to explain the
information that must be included in a new infant formula notification
if the manufacturer is requesting this exemption.
(Comment 38) Several comments understood the protein efficiency
ratio (PER) to be a quality factor and indicated this was not an
appropriate quality factor.
(Response) We note that the comments have misidentified the quality
factor as the PER. The quality factor is the biological quality of the
protein, and the PER is a method used to assure such quality.
D. Subpart F--Records and Reports
(Comment 39) One comment stated that the term ``immediate'' is
unclear in Sec. 106.100(m). Section 106.100(m) of the IFR described
various means of recordkeeping and stated, in relevant part, that the
records are to be maintained in a manner that ensures that both the
manufacturer and FDA can be provided with ``immediate access'' to the
records. The comment would revise Sec. 106.100(m) by replacing
``immediate'' with ``within 24 hours'' to be consistent with records
access in Sec. 106.100(k)(5)(v).
(Response) We agree that access to records within 24 hours is
reasonable and have revised the wording in Sec. 106.100(m) in the
final rule to require access within 24 hours.
IV. Technical Amendments
In addition to the changes we are making in response to the
comments, we are making minor technical corrections to Sec.
106.96(c)(1) and (g) to provide more specific cross references to other
provisions of the rule. Also, consistent with our discussion in the IFR
explaining our decision to use the terms ``production unit'' and
``production aggregate'' instead of ``batch'' and ``lot'' (79 FR 7934
at 7942-7944), we are eliminating the use of the words ``batch'' and
lot'' in Sec. 106.100(f)(4), (k)(5)(ii), and (o) to ensure consistency
with the terminology used elsewhere in the IFR and final rule. Finally,
we are deleting an unnecessary reference to Sec. 106.3 from what was
Sec. 106.91(b)(1) in the IFR, which has been redesignated as Sec.
106.91(b)(1)(i) in this final rule.
V. Executive Order 12866 and Executive Order 13563: Cost Benefit
Analysis
On February 10, 2014, FDA issued an IFR amending certain
requirements in the regulation on the current good manufacturing
practices, quality control procedures, quality factors, notification
requirements, and records and reports, for infant formula (79 FR 7934).
The Economic Impact Analysis in the IFR explained and further revised
the analysis set forth in the proposed rule by addressing the economic
impact of the changes to the regulations at parts 106 and 107. We did
not receive any comments that would warrant further revising the
economic analysis of the IFR.
FDA has examined the impacts of this 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
[[Page 33070]]
believe that the final rule is not a significant regulatory action
under Executive Orders 12866 and 13563.
The Regulatory Flexibility Act requires Agencies to determine
whether a final rule will have a significant impact on small entities
when an Agency issues a final rule ``after being required . . . to
publish a general notice of proposed rulemaking.'' We certify that this
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 (2013) Implicit
Price Deflator for the Gross Domestic Product. We do not expect this
final rule to result in any 1-year expenditure that would meet or
exceed this amount.
Thus, this economic analysis affirms the economic impact analysis
of the IFR. For a full explanation of the economic impact analysis of
this final rule, we direct interested persons to the text of the
economic impact analyses in the IFR (79 FR 7934, February 10, 2014,
Ref. 92). The analyses that we have performed to examine the impacts of
this 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 for the final rule (Ref. 1).
VI. Small Entity Analysis (or Final Regulatory Flexibility Analysis)
A regulatory flexibility analysis is required only when an Agency
must publish a notice of proposed rulemaking (5 U.S.C. 603, 604). FDA
published the IFR after publishing a notice of proposed rulemaking in
1996 (61 FR 36154; July 9, 1996) and reopening of the comment period in
2003 (68 FR 22341; April 28, 2003) and 2006 (71 FR 43392; August 1,
2006). We have conducted such an analysis and examined the economic
implications of this final rule on small entities. This final rule is
not a significant regulatory action as defined by Executive Order
12866. FDA also certifies that this final rule will not have a
significant impact on a substantial number of small entities.
VII. Paperwork Reduction Act of 1995
This final rule contains information collection provisions 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). 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.
1). 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.
We had included a section titled ``Paperwork Reduction Act of
1995'' in the preamble to the IFR (79 FR 7934 at 8055-8056). Any
comments on our analysis of the burdens presented in that section were
submitted to OMB. We will not address these comments in this document.
We are resubmitting the information collection provisions of this final
rule to OMB because the final rule provides additional modifications
and clarifications to 21 CFR part 106.
In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3507(d)), we have submitted the information collection provisions of
this final rule to OMB for review. Interested persons are requested to
submit comments regarding information collection to OMB (see DATES and
ADDRESSES).
We will publish a notice in the Federal Register announcing OMB's
decision to approve, modify, or disapprove the information collection
provisions in this 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.
VIII. Analysis of Environmental Impact
We have carefully considered the potential environmental effects of
this action. FDA has concluded 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.
IX. Federalism
We have analyzed this 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, we conclude 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.
X. Reference
The following reference has 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.
1. FDA. Current Good Manufacturing Practices, Quality Control
Procedures, Quality Factors, Notification Requirements, and Records
and Reports, for Infant Formula. Regulatory Impact Analysis for
Final Rule. FDA-1995-N-0063 (formerly 95N-0309), 2014.
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.
Accordingly, the interim final rule amending 21 CFR parts 106 and
107, which was published at 79 FR 7933 on February 10, 2014, is adopted
as a final rule with the following changes:
PART 106--INFANT FORMULA REQUIREMENTS PERTAINING TO CURRENT GOOD
MANUFACTURING PRACTICE, QUALITY CONTROL PROCEDURES, QUALITY
FACTORS, RECORDS AND REPORTS, AND NOTIFICATIONS
0
1. The authority citation for 21 CFR part 106 continues to read as
follows:
Authority: 21 U.S.C. 321, 342, 350a, 371.
0
2. In Sec. 106.3, revise the definitions for ``Eligible infant
formula'' and ``Quality factors'' to read as follows:
Sec. 106.3 Definitions.
* * * * *
Eligible infant formula means an infant formula that could be
lawfully distributed in the United States on December 8, 2014.
* * * * *
[[Page 33071]]
Quality factors means those factors necessary to demonstrate the
safety of the infant formula and the bioavailability of its nutrients,
as prepared for market and when fed as the sole source of nutrition, to
ensure the healthy growth of infants.
* * * * *
0
3. In Sec. 106.20, revise paragraph (i) to read as follows:
Sec. 106.20 Controls to prevent adulteration caused by facilities.
* * * * *
(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 toilet facility shall not open into areas where
infant formula, ingredients, containers, or closures are processed,
handled, or stored, except where alternate means have been taken to
protect against contamination.
0
4. In Sec. 106.30, revise paragraph (e)(2)(ii) to read as follows:
Sec. 106.30 Controls to prevent adulteration caused by equipment or
utensils.
* * * * *
(e) * * *
(2)(i) * * *
(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[emsp14][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 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.
* * * * *
0
5. In Sec. 106.35, revise paragraphs (a)(4) and (b)(1) to read as
follows:
Sec. 106.35 Controls to prevent adulteration due to automatic
(mechanical or electronic) equipment.
(a) * * *
(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. Validation can be accomplished through any suitable
means, such as verification studies or modeling.
(b) * * *
(1) A manufacturer shall ensure, at any point, step, or stage where
control is necessary to prevent adulteration of the infant formula,
that all hardware is routinely inspected and checked according to
written procedures and that hardware that is capable of being
calibrated is routinely calibrated according to written procedures.
* * * * *
0
6. In Sec. 106.50, revise paragraph (a)(2) to read as follows:
Sec. 106.50 Controls to prevent adulteration during manufacturing.
(a) * * *
(2) Changes made to the master manufacturing order shall be
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.
* * * * *
0
7. In Sec. 106.91, revise paragraphs (b)(1), (b)(2), (b)(3),
(b)(4)(ii), (b)(4)(iii), and (b)(4)(iv) to read as follows:
Sec. 106.91 General quality control.
* * * * *
(b) * * *
(1)(i) For an infant formula that is a new infant formula 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 4 months thereafter throughout the shelf life of the product.
(ii) The Food and Drug Administration will exempt the manufacturer
from the requirements of paragraph (b)(1)(i) of this section if the
manufacturer of a new infant formula requests an exemption and provides
analytical data, as required under Sec. 106.120(b)(7), that
demonstrates that the stability of the new infant formula will likely
not differ from the stability of formulas with similar composition,
processing, and packaging for which there are extensive stability data.
A manufacturer exempt from the requirements of paragraph (b)(1)(i) of
this section would be required to test the first production aggregate
according to the requirements of Sec. 106.91(b)(2).
(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 of this chapter
and all other nutrients added by the manufacturer. The manufacturer
shall repeat such testing 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 address, as appropriate, all production
aggregates of formula released and pending release for distribution
that are implicated by the testing results, such as by conducting the
testing required by paragraph (b)(1) of this section on a subsequently
produced production aggregate to substantiate the shelf life of the
infant formula or revising the use by date for such product so that
such date is substantiated by the stability testing results.
(4) * * *
(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 and pending release for distribution that are implicated by
the testing results; and
(iv) Determine whether it is necessary to conduct the testing
required by paragraph (b)(1) of this section.
* * * * *
0
8. In Sec. 106.96, revise paragraphs (c)(1), (c)(2)(ii), (g)(1), and
(g)(2), and add paragraph (g)(3) to read as follows:
Sec. 106.96 Requirements for quality factors for infant formulas.
* * * * *
(c) * * *
(1) The manufacturer requests an exemption and provides assurances,
as required under Sec. 106.121(b), 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) * * *
(ii) The change made by the manufacturer to an existing formula
does not affect the ability of the formula to support normal physical
growth; or
* * * * *
(g) * * *
(1) The manufacturer requests an exemption and provides assurances
as required under Sec. 106.121(g) that the changes made by the
manufacturer to an
[[Page 33072]]
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(h), that demonstrate that the change
made by the manufacturer to an existing formula does not affect the
bioavailability of the protein.
(3) The manufacturer requests an exemption and provides assurances,
as required under Sec. 106.121(i), that demonstrate that an
alternative method to the PER that is based on sound scientific
principles is available to demonstrate that the formula supports the
quality factor for the biological quality of the protein.
* * * * *
0
9. In Sec. 106.100, revise paragraphs (f)(4), (k)(5)(ii), (m), and (o)
to read as follows:
Sec. 106.100 Records.
* * * * *
(f) * * *
(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 production aggregate
number of each 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.
* * * * *
(k) * * *
(5) * * *
(ii) The production aggregate number;
* * * * *
(m) A manufacturer shall maintain all records required under this
part in a manner that ensures that both the manufacturer and the Food
and Drug Administration can be provided with access to such records
within 24 hours. The manufacturer may maintain the records required
under this part as original records, as true copies such as
photocopies, microfilm, microfiche, or other accurate reproductions of
the original records, or as electronic records. Where reduction
techniques, such as microfilming, are used, suitable reader and
photocopying equipment shall be readily available. All electronic
records maintained under this part shall comply with part 11 of this
chapter.
* * * * *
(o) The manufacturer shall maintain quality control records that
contain sufficient information to permit a public health evaluation of
any production aggregate of infant formula.
* * * * *
0
10. In Sec. 106.120, add paragraph (b)(7) to read as follows:
Sec. 106.120 New infant formula submission.
* * * * *
(b) * * *
* * * * *
(7) If the manufacturer is requesting an exemption under Sec.
106.91(b)(1)(ii), the manufacturer shall include the scientific
evidence that the manufacturer is relying on to demonstrate that the
stability of the new infant formula will likely not differ from the
stability of formulas with similar composition, processing, and
packaging for which there are extensive stability data.
* * * * *
0
11. In Sec. 106.121 revise paragraphs (d) and (i) and add paragraph
(j) to read as follows:
Sec. 106.121 Quality factor assurances for infant formulas.
* * * * *
(d) If the manufacturer is requesting an exemption under Sec.
106.96(c)(2)(ii), the manufacturer shall include a detailed description
of the change and an explanation of why the change made by the
manufacturer to an existing infant formula does not the affect the
ability of the formula to support normal physical growth.
* * * * *
(i) If the manufacturer is requesting an exemption under Sec.
106.96(g)(3), the manufacturer shall include a detailed explanation of
the alternative method, an explanation of why the method is based on
sound scientific principles, and the data that demonstrate that the
quality factor for the biological quality of the protein has been met.
(j) A statement certifying that the manufacturer has collected and
considered all information and data concerning the ability of the
infant formula to meet the requirements for quality factors and that
the manufacturer is not aware of any information or data that would
show that the formula does not meet the requirements for quality
factors.
Dated: June 4, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-13384 Filed 6-9-14; 8:45 am]
BILLING CODE 4160-01-P