[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

[[Page 49640]]

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

[[Page 49641]]

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).

[[Page 49642]]

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]
BILLING CODE 4160-01-F