[Federal Register Volume 62, Number 184 (Tuesday, September 23, 1997)]
[Proposed Rules]
[Pages 49638-49642]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-25130]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 200
[Docket No. 96N-0048]
Sterility Requirements for Inhalation Solution Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulations to require that all inhalation solutions for
nebulization be sterile. Inhalation solutions for nebulization, as the
term is used in this document, refers to inhalation solutions
administered as a fine aqueous mist created by an atomizer or
nebulizer. Currently, approximately half of these products are
manufactured to be sterile. Based on reports of adverse drug
experiences from contaminated nonsterile inhalation solutions for
nebulization and recalls of these products, FDA is taking this action
to ensure the safety and effectiveness of these solutions.
DATES: Written comments by December 22, 1997. Submit written comments
on the information collection requirements by October 23, 1997. FDA
proposes that any final rule that may issue based on this proposal
become effective March 23, 1998.
ADDRESSES: Submit written comments on this proposed rule to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Submit written comments on
the information collection requirements to the Office of Information
and Regulatory Affairs, Office of Management and Budget (OMB), New
Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC
20503, Attn: Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT: Carol E. Drew, Center for Drug
Evaluation and Research (HFD-7), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-2041.
SUPPLEMENTARY INFORMATION:
I. Background
Inhalation solutions for nebulization are used to treat a variety
of breathing disorders. Currently, approximately half of the marketed
products are manufactured to be sterile. Those products not
manufactured to be sterile are often manufactured under assigned
[[Page 49639]]
microbial count limits. For the reasons stated below, FDA has
determined that current manufacturing methods and purported safeguards
against contamination, including the microbial limits test, have not
prevented dangerous microbial contamination of nonsterile inhalation
solutions for nebulization. A sterility requirement is needed to
prevent such microbial contamination.
Contaminated inhalation solutions for nebulization are likely to
cause lung infections because the drug product is introduced directly
into the lungs in a manner which at least partially bypasses the
patient's natural defense mechanisms. Many patients using inhalation
solution products for nebulization have chronic obstructive airway
disease or cystic fibrosis, or are immunocompromised. Microbial
contamination of these products may result in serious health
consequences due to opportunistic pathogens entering the lungs or to
the possible inactivation of the drug product by these microorganisms.
Based on the significant health risk to users, FDA is proposing to
require that all aqueous-based inhalation solutions for nebulization be
manufactured as sterile.
Contamination problems with several different inhalation solution
products and numerous adverse experience reports have led to FDA's
determination that a sterility requirement is necessary for these
products. In January 1994, a marketed albuterol sulfate inhalation
solution product was found to be contaminated with a bacterium best
identified as belonging to the Pseudomonas fluorescens/putida group.
The manufacturer voluntarily recalled the product (class I recall to
the consumer level) and issued a press release regarding the recall.
In June 1992, a manufacturer recalled its metaproterenol sulfate
inhalation solution for nebulization when the product was found to
contain excessive microbial growth identified as P. gladioli/cepacia. A
press release was also issued concerning this recall.
In 1987, an FDA investigator identified at least two potential
human fungal pathogens (Aspergillus glaucus and Chrysosporium) in
another albuterol sulfate inhalation solution for nebulization before
market distribution.
A sterility requirement for all inhalation solutions for
nebulization will provide the necessary assurance that these solutions
will not be contaminated. The sterility requirement is necessary for
several reasons.
First, there is a high risk of contamination of inhalation
solutions. Microbial contaminants identified in two of the recalls were
Pseudomonas species (spp.), which are ubiquitous and are commonly found
in pharmaceutical water supplies and nonsterile manufacturing
environments.
Second, most species of Pseudomonas associated with the
contamination of inhalation solutions have the potential to be human
pathogens. Of special concern is the fact that many of the patients
using these products have compromised pulmonary defense mechanisms and
are therefore at a particularly high risk of serious infection.
Third, adherence to current good manufacturing practice (CGMP)
regulations without appropriate sterilization procedures does not
provide an adequate level of assurance that inhalation solutions for
nebulization will not be contaminated. Even if antimicrobial
preservatives are used in a product, they may not be effective because
many bacteria, including Pseudomonas spp., may develop resistance to
these preservatives. The albuterol sulfate product recalled in January
1994, for example, contained benzalkonium chloride, an antimicrobial
preservative, yet the preservative failed to prevent microbial
contamination of the product. Resistance to preservatives is not
species specific; strains of many species are resistant. Furthermore,
use of a single preservative in the manufacture of a nonsterile
inhalation solution for an extended period may actually select for
preservative-resistant strains of Pseudomonas spp. or other bacteria.
Also, the microbial limits test does not ensure against
contamination. End-product microbial limits tests performed prior to
distribution may not be capable of detecting sufficiently low levels of
contamination; a product that initially passes the microbial limits
test may support the growth of contaminating organisms, which could
later grow to unacceptable levels.
FDA has therefore determined that all inhalation solutions for
nebulization should be manufactured as sterile products. Any failure to
comply with the sterility requirement would result in a finding that
the drug product is adulterated under section 501(a)(2)(B) of the
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C.
351(a)(2)(B)), and misbranded under section 502(j) of the act (21
U.S.C. 352(j)). Failure to comply with the sterility requirement would
also result in the agency's refusal to approve a new or abbreviated
application for the product, pursuant to section 505(d)(1), (d)(2),
(d)(3), and (j)(3)(A) of the act (21 U.S.C. 355(d)(1), (d)(2), (d)(3),
and (j)(3)(A)).
II. Description of the Proposed Regulation
This proposal would amend the regulations governing requirements
for specific classes of drugs to include new Sec. 200.51 for inhalation
solutions for nebulization. Proposed Sec. 200.51(a) would require that
all prescription and over-the-counter (OTC) inhalation solutions for
nebulization be sterile. Manufacturers may use any appropriate process
to achieve sterility of their inhalation solution products, as long as
the method is in compliance with current FDA regulations. In the
Federal Register of October 11, 1991 (56 FR 51354), FDA proposed to
require that manufacturers use a terminal sterilization process when
preparing a sterile drug unless the process adversely affects the drug
product. The October 11, 1991, proposed rule would require that
manufacturers include in their applications a written justification for
not using terminal sterilization if such process is not appropriate.
Should that proposed rule become final, manufacturers of inhalation
solution products would be subject to its requirements.
Under this proposal, all manufacturers of nonsterile inhalation
solutions for nebulization have until 1 year after the date of
publication of the final rule to comply with the sterility requirement.
This effective date reflects the time that FDA believes applicants may
need to establish the sterility of their products.
Persons holding an approved application for a nonsterile inhalation
solution product should submit to FDA a supplemental application
establishing the sterility of the product. If they intend to sterilize
their product by terminal sterilization or make other changes listed
under Sec. 314.70(b)(2) (21 CFR 314.70(b)(2)), they must obtain FDA
approval of a supplement under that section before making the
change(s). If they intend to manufacture the sterile product by aseptic
processing, to retain the same container and closure system, and make
no changes other than those listed under Sec. 314.70(c)(1), they may
submit a supplemental application under that section.
The following information should be included in the supplements:
Complete qualification data for the aseptic process, executed batch
record for a production batch of the product using the approved
formulation, in-process and release control data, updated release
specifications that include sterility, 3 months' accelerated stability
data, updated stability protocol to
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include either sterility or container/closure integrity testing
initially and at expiry, and commitment to place the first three
commercial batches into the routine stability program and submit the
data in annual reports.
Proposed Sec. 200.51(b) states that manufacturers must comply with
the recordkeeping requirements of 21 CFR 211.113(b) of FDA's CGMP
regulations. This section requires that manufacturers establish and
follow appropriate written procedures designed to prevent
microbiological contamination of drug products purporting to be
sterile. Such procedures must include validation of any sterilization
process.
III. Proposed Effective Date
The agency's proposal would prohibit all manufacturers of
nonsterile inhalation solution products for nebulization, including
those products currently approved, from introducing or delivering for
introduction into interstate commerce any such products that are
nonsterile from 1 year after the date of publication in the Federal
Register of any final rule based on this proposal.
Holders of approved new drug applications (NDA's) and abbreviated
new drug applications (ANDA's) must submit data to FDA to establish
sterility of these products within 1 year after the publication in the
Federal Register of any final rule based on this proposal. This
effective date reflects the time that FDA believes applicants may need
to establish the sterility of their products.
Any NDA or ANDA for a nonsterile inhalation solution for
nebulization under review by FDA on or after the date of publication of
the final rule but before the effective date of the final rule may be
approved if the application is otherwise approvable and the applicant
agrees to establish the sterility of its product by the effective date.
On or after the effective date of the final rule, FDA will refuse to
approve an NDA or ANDA for a nonsterile inhalation solution for
nebulization if the applicant has not established the sterility of the
product.
IV. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) 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.
V. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612),
and under the Unfunded Mandates Reform Act (Pub. L. 104-4). Executive
Order 12866 directs 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). Unless an agency
certifies that a rule will not have a significant economic impact on a
substantial number of small entities, the Regulatory Flexibility Act
requires an analysis of regulatory options that would minimize any
significant impact of a rule on small entities. The Unfunded Mandates
Reform Act requires that agencies prepare an assessment of anticipated
costs and benefits before proposing any rule that may result in an
annual expenditure by State, local, and tribal governments, in the
aggregate, or by the private sector, of $100,000,000 (adjusted annually
for inflation).
The expected aggregate costs of this proposed rule, and the
anticipated impact of the rule on small entities, are described in the
analysis below. The agency believes that the proposed rule is
consistent with the regulatory philosophy and principles identified in
the Executive Order. This rule is not a significant regulatory action
as defined by the Executive Order, does not impose any mandates on
State, local, or tribal governments, and is not a significant
regulatory action under the Unfunded Mandates Reform Act. Based on the
following analysis, FDA estimates that this rule will have significant
adverse effects on about four to five small firms that currently
manufacture nonsterile inhalation solutions for nebulization. However,
since the exact number of firms manufacturing nonsterile inhalation
solutions is not certain, FDA invites comments from firms that believe
they would be affected by the proposed rule. The statutory basis for
FDA's authority to issue the rule is presented previously in this
preamble. FDA has not identified any other Federal rules that
duplicate, overlap, or conflict with the proposed rule.
As described in section I of this document, the objective of the
proposed rule is to ensure that all inhalation solutions for
nebulization are manufactured as sterile products and are thus safe and
effective for use. Nonsterile inhalation solutions have been found to
result in serious health consequences to users. By ensuring
sterilization, the proposed rule is expected to yield benefits from the
elimination of extended patient suffering and hospitalization
associated with contaminated nonsterile inhalation solution products.
In addition, the industry would benefit by avoiding liability claims
from persons harmed due to the contamination of nonsterile inhalation
solution products.
A. Affected Entities
This proposed rule would affect only those manufacturers of
inhalation solutions for nebulization that do not already manufacture
the products to be sterile. Based on its compliance data base, FDA
believes that all innovator prescription products are currently
manufactured as sterile. Of the approximately 28 generic and OTC firms
that manufacture inhalation solutions, FDA estimates that up to five
firms may still use nonsterile manufacturing processes and will be
affected by this proposed rule. (The remainder are believed to have
either implemented sterile processes themselves or to have contracted
out the manufacturing of their inhalation products to firms that use a
sterile process.) All of these affected firms may be small entities as
defined by the Regulatory Flexibility Act.
B. Compliance Requirements and Costs
To comply with this rule, the affected firms must implement a
sterile process for manufacturing their inhalation products, either by
converting their in-house manufacturing operations to ensure that the
products are sterile, or by arranging to have these products
manufactured under contract by a firm that can do so under sterile
conditions. In addition, affected firms must: (1) Develop appropriate
written procedures designed to prevent contamination of the products,
including validation of the new inhalation solution processes; and (2)
submit to FDA a supplemental application establishing the sterility of
the product.
Firms choosing to convert in-house manufacturing operations would
need to set up an in-plant sterilization process by constructing a
clean room especially designated for the inhalation solution product.
FDA finds that the cost of building a new clean room may amount to
almost $600 per square foot. The size of pharmaceutical clean rooms is
reported to vary widely, from 200 to 2,500 square feet. Thus, the
estimated cost of installing a clean room in a manufacturing facility
may range from $120,000 to $1,500,000 per firm. Since affected firms
would presumably contract out their manufacturing process if to do so
would lower their costs of
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complying with this proposed rule, this figure is an upper bound.
Firms would also need to validate the new inhalation solution
processes at an estimated cost of $75,000 to $100,000 per product. The
firms that would need to complete these validation procedures produce
an average of approximately two inhalation products each, leading to
validation costs per firm of approximately $150,000 to $200,000. Each
firm would also be required to incur the paperwork costs associated
with filing a supplemental application for each product with FDA.
Thus, overall costs for implementing and validating a sterile
manufacturing process for inhalation products would total approximately
$270,000 to $1,700,000 per affected firm. Assuming that five firms are
affected, the costs of complying with this rule would range from
approximately $1,350,000 to $8,500,000. Amortized over 10 years at a 7
percent interest rate implies total annualized costs of $192,000 to
$1,210,000. In addition, affected firms will incur any costs associated
with preparing and submitting a supplemental application.
Affected firms will need to acquire some new professional skills,
since this rule deals with a new manufacturing process that will
require technicians to have a knowledge of sterility procedures,
specifically the asceptic sterilization process. Any other skills
necessary for implementation of this proposal (e.g., skills associated
with preparing the application) should already exist within the firms
and should not need to be newly acquired.
C. Minimizing the Impact on Small Entities
FDA initially considered requiring conversion to sterile procedures
to take place within 6 months of the publication of a final rule, due
to the health hazards associated with existing unsterilized inhalation
products. However, the agency is concerned that this short timeframe
would give affected firms an inadequate opportunity to implement
aseptic manufacturing processes and might force some small firms to
temporarily suspend production. Thus, this proposed rule allows 1 year
for the manufacturing conversion to take place.
Exempting small businesses from the rule is not a feasible
alternative, since all of the firms believed to still be using
nonsterile manufacturing for these products are small. A size-based
exemption would thus defeat the purpose of this proposed rule.
VI. The Paperwork Reduction Act of 1995
This proposed rule contains information collection provisions that
are subject to review by OMB under the Paperwork Reduction Act of 1995
(44 U.S.C. 3501-3520). Therefore, in accordance with 44 U.S.C.
3506(c)(2)(B) and 5 CFR part 1320, FDA is providing the following
title, description, and respondent description of the information
collection contained in this proposal, along with an estimate of the
resulting annual collection of information burden. This estimate
includes the time needed for reviewing instructions, gathering and
maintaining the data needed, and completing and reviewing the
collection of information.
With respect to the following collection of information, FDA
invites comments on: (1) Whether the proposed collection of information
is necessary for proper performance of FDA's functions, including
whether the information will have practical utility; (2) the accuracy
of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Sterility requirements for inhalation solution products.
Description: The proposal would require that all inhalation
solution products, including those currently approved, be manufactured
as sterile. Applicants will have 1 year after the date of publication
of the final rule to comply with the sterility requirement.
Description of Respondents: Drug manufacturers.
As indicated in the accompanying chart, the proposed one-time
reporting requirement would require that most firms commit about 160
additional hours per product to report the sterility information in a
supplement to a drug application (20 hours for certain manufacturers of
sterile products) and about 2 additional hours per product to document
sterility of their inhalation products.
The expected burden under the proposed rule is as follows:
Estimated Annual Reporting Burden
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Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Respondents Response Responses Response
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314.97 5 1 5 160 800\1\
314.70 2 1 2 20 40\2\
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\1\ Reporting burden for manufacturers of nonsterile products.
\2\ Reporting burden for manufacturers of sterile products.
Estimated Annual Recordkeeping Burden
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Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Recordkeepers Recordkeeping Records Recordkeeper
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211.113(b) 7 1 1 2 14
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There are no capital costs or operating and maintenance costs associated with this proposed rule.
The agency has submitted a copy of this proposed rule to OMB for
its review and approval of this information collection. Interested
persons are requested to send comments regarding this collection of
information to the Office of Information and Regulatory Affairs
(address above).
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VII. Request for Comments
Interested persons may, on or before December 22, 1997, submit to
the Dockets Management Branch (address above) written comments
regarding this proposal. Two copies of any comments are to be
submitted, except that individuals may submit one copy. Comments are to
be identified with the docket number found in brackets in the heading
of this document. Received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday.
List of Subjects in 21 CFR Part 200
Drugs, Prescription drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 200 be amended as follows:
PART 200--GENERAL
1. The authority citation for 21 CFR part 200 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 508,
515, 701, 704, 705 of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 358, 360e, 371, 374,
375).
2. New Sec. 200.51 is added to subpart C to read as follows:
Sec. 200.51 Sterility requirements for inhalation solution drug
products.
(a) All inhalation solutions for nebulization shall be manufactured
to be sterile.
(b) Manufacturers shall also comply with the recordkeeping
requirements in Sec. 211.113(b) of this chapter.
Dated: September 12, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-25130 Filed 9-22-97; 8:45 am]
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