[Federal Register Volume 65, Number 103 (Friday, May 26, 2000)]
[Rules and Regulations]
[Pages 34082-34089]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-13210]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 200

[Docket No. 96N-0048]
RIN 0910-AA88


Sterility Requirement for Aqueous-Based Drug Products for Oral 
Inhalation

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations to require that all prescription and over-the-counter (OTC) 
aqueous-based drug products for oral inhalation be manufactured 
sterile. This rule applies to aqueous-based oral inhalation drug 
products in both single-dose and multiple-use primary packaging. 
Pressurized metered-dose inhalers are not subject to this rule. Based 
on reports of adverse drug experiences from contaminated nonsterile 
inhalation drug products and recalls of these products, FDA is taking 
this action to help ensure the safety and effectiveness of these 
products.

DATES: This rule is effective May 27, 2002.

FOR FURTHER INFORMATION CONTACT: Peter H. Cooney, Center for Drug 
Evaluation and Research (HFD-160), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-443-5818.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of September 23, 1997 (62 FR 49638), FDA 
proposed to amend its regulations to require that all inhalation 
solutions for nebulization be manufactured sterile. This action was 
proposed to help ensure the safety and effectiveness of these drug 
products.
    Drug products for oral inhalation are used to treat a variety of 
breathing disorders and are frequently administered to patients who are 
immunocompromised, have cystic fibrosis, or have chronic obstructive 
airway disease. Aqueous-based oral inhalation drug products either in 
single-dose or multiple-use packaging are administered by oral 
inhalation into the lungs as a mist or spray created by a nebulizer 
device. The majority of inhalation drug products on the market are 
manufactured to be sterile. Those products not manufactured to be 
sterile are often manufactured under assigned microbial count limits, 
but current manufacturing methods and safeguards have not prevented 
dangerous microbial contamination.
    Inhalation drug products contaminated with microorganisms are 
likely to cause lung infections because the contaminating organisms are 
introduced with the drug product directly into the lungs through the 
mouth. Thus, microbial contamination of these products may result in 
serious health consequences. Microbial contamination of these products 
may also cause degradation of the drug product.
    Because of contamination problems with several different aqueous-
based drug products for oral inhalation and for the reasons explained 
in the proposed rule, FDA has determined that current manufacturing 
methods and safeguards against contamination, including microbial 
limits tests, have not prevented dangerous microbial contamination of 
nonsterile aqueous-based drug products for oral inhalation.
    The final rule reflects FDA's determination that all aqueous-based 
drug products for oral inhalation be manufactured sterile. Once the 
final rule becomes effective, failure to comply with the sterility 
requirement will 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 will also result in the agency's refusal to 
approve a new or abbreviated application for a product, under section 
505(d)(1), (d)(2), (d)(3), and (j)(4)(A) of the act (21 U.S.C. 
355(d)(1), (d)(2), (d)(3), and (j)(4)(A)).

II. Highlights of the Final Rule

    This final rule amends the regulations governing requirements for 
specific classes of drugs to include new Sec. 200.51 for aqueous-based 
drug products for oral inhalation. Section 200.51(a) requires that all 
prescription and OTC aqueous-based drug products for oral inhalation be 
manufactured sterile. FDA is taking this action to prevent the public 
health consequences of the distribution of contaminated aqueous-based 
drug products for oral inhalation and to help ensure the safety and 
effectiveness of these products.
    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. The agency plans to issue a final rule regarding 
terminal sterilization. When the proposed requirement for terminal 
sterilization becomes final, manufacturers of aqueous-based drug 
products for oral inhalation will be subject to its requirements.
    The agency has revised the proposed regulation in response to 
comments received on the proposed rule. The comments and responses are 
discussed in section III of this document, ``Comments on the Proposed 
Rule.'' The agency is revising the title of proposed Sec. 200.51 from 
``Sterility Requirements for Inhalation Solution Drug Products'' to 
``Aqueous-Based Drug Products for Oral Inhalation.'' The new title 
names the specific class of drugs subject to the rule in conformance 
with the established format of part 200 (21 CFR part 200), subpart C of 
the regulations. The agency is removing the phrases ``inhalation 
solution drug products'' and ``inhalation solutions for nebulization'' 
from proposed Sec. 200.51. These phrases are replaced by the phrase 
``aqueous-based drug products for oral inhalation.'' The agency has 
added the phrase ``for oral inhalation'' to clarify that the rule 
applies to orally administered inhalation drug products and not nasal 
sprays. The agency has added the modifier ``aqueous-based'' to the type 
of drug products covered to exclude metered-dose inhalers from 
coverage. In addition, the agency has made minor edits to the final 
rule in response to the President's June 1, 1998, memorandum on plain 
language in government writing. The agency has increased the amount of 
time for manufacturers to comply with the sterility requirement from 1 
year to 2 years. All manufacturers of nonsterile aqueous-based drug 
products for oral inhalation will have until 2 years after the date of 
publication of the final rule to comply with the sterility requirement. 
As discussed in section IV of this document, ``Effective Date,'' the 
agency believes this effective date more realistically reflects the 
time

[[Page 34083]]

manufacturers may need to establish the sterility of their products.
    Section 200.51(b) states that manufacturers must comply with the 
requirements of 21 CFR 211.113(b) of FDA's current good manufacturing 
practice (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.
    In addition to the above highlights, the agency notes that persons 
holding an approved new drug application (NDA) or abbreviated 
application for a nonsterile aqueous-based drug product for oral 
inhalation must submit to FDA a supplemental application describing the 
new manufacturing process under Sec. 314.70(b) or Sec. 314.97 (21 CFR 
314.70(b) or 314.97). The proposed rule stated that if a manufacturer 
intended to sterilize a product by terminal sterilization, the 
manufacturer must obtain prior FDA approval for such change under 
Sec. 314.70(b)(2), but if a manufacturer intended to sterilize a 
product by aseptic processing they may make the change at the time a 
supplemental application is submitted under Sec. 314.70(c)(1). The 
agency has now determined that the technological complexity of aseptic 
processing warrants prior approval of any changes in the manufacturing 
process. Accordingly, the agency concludes that all manufacturing 
changes related to sterility requirements require supplemental 
applications to be submitted and approved under Sec. 314.70(b)(2) prior 
to making any changes. In November 1999, a guidance related to this 
topic, entitled ``Changes to an Approved NDA or ANDA,'' became 
available. This guidance states that the agency considers a change in 
the sterilization process, e.g. from aseptic processing to terminal 
sterilization or vice versa, a major change to any approved application 
for which the manufacturer should submit a prior approval supplement. 
The agency notes that a proposed rule entitled ``Supplements and Other 
Changes to an Approved Application,'' published in the Federal Register 
of June 28, 1999 (64 FR 34608). This proposed rule is currently being 
finalized and may further affect the filing of supplemental 
applications related to this rule.
    The following information should be included in a supplemental 
application related to this rule:
    <bullet> Complete validation data for the aseptic process (see 
November 1994 guidance document entitled ``Guidance for Industry for 
the Submission of Documentation for Sterilization Process Validation in 
Applications for Human and Veterinary Drug Products'');
    <bullet> For abbreviated applications, an executed batch record for 
a production batch of the product using the approved formulation;
    <bullet> In-process and release control data;
    <bullet> Updated release specifications that include sterility;
    <bullet> Three months accelerated stability data;
    <bullet> An updated stability protocol to include either sterility 
or container/closure integrity testing initially and at expiry; and
    <bullet> A commitment to place the first three commercial batches 
into the routine stability program and submit the data in annual 
reports.

III. Comments on the Proposed Rule

    The agency received a total of 61 comments on the September 23, 
1997, proposed rule. Forty-nine of those comments were from consumers 
of an OTC aqueous solution of epinephrine sold in a kit with an 
atomizer. Of the remaining 12 comments, 8 were from industry, 2 were 
from associations of health care professionals, 1 was from academia, 
and 1 was from a Federal Government agency. The majority of comments 
requested clarification of the scope of the rule and the drug products 
intended to be covered, and also discussed the economic impacts of the 
proposed rule.

A. Covered Products

    1. The proposed rule stated: ``All inhalation solutions for 
nebulization shall be manufactured to be sterile'' (proposed 
Sec. 200.51(a)). Several comments indicated that the scope of drug 
products intended to be covered by the proposed rule was either unclear 
or overbroad. Some of the comments asked whether intranasal sprays 
would be subject to the rule. One comment asked whether both OTC and 
prescription drugs were covered. Three comments suggested clarifying 
that only aqueous-based drug products are subject to the rule. One 
comment interpreted the proposed rule to cover OTC and prescription 
drugs dispensed out of a manufacturer's primary packaging container 
into a separate, secondary and independent device prior to 
administration to the end user or patient, excluding nebulized or 
atomized sprays for inhalation. The comment stated that primary 
formulations should include both single-dose and multiple-use sterile 
products to eliminate microbial contamination during use. One comment 
suggested that the rule cover inhalation suspension products, stating 
that they contain more nutrients that contaminating microorganisms can 
metabolize than do inhalation solutions, and suggested that the title 
of the rule be modified to reflect this change.
    The agency has considered these comments and agrees that further 
clarification of products covered by the rule is warranted. In response 
to these comments, the agency has revised the final rule to state: 
``All aqueous-based drug products for oral inhalation must be 
manufactured to be sterile.'' Because the rule covers only drug 
products administered orally, it does not cover nasal sprays. Because 
the rule covers only aqueous-based drug products, pressurized metered-
dose inhalers are not covered. All marketed prescription and OTC drugs 
are covered by the rule.
    The agency agrees with the comment that inhalation suspension 
products pose contamination risks at least as great as those of 
inhalation solution products. Aqueous-based suspension drug products 
for oral inhalation would also bypass many of a patient's natural 
defense mechanisms and, if contaminated, pose similar risks. However, 
all currently marketed inhalation suspension drug products are metered-
dose inhalers and, because they are metered-dose inhalers, are not 
subject to this final rule. Any aqueous-based oral inhalation 
suspension drug products approved in the future that are not metered-
dose inhalers are subject to this rule.

B. Pharmacy Compounding

    2. One comment asked whether the proposed rule would cover 
solutions for oral inhalation compounded under applicable practice of 
pharmacy provisions and regulations. Another comment stated that a 
large fraction of nebulizer solutions sold in the United States are 
compounded in pharmacies and suggested that such facilities use 
chemicals of dubious quality, that such solutions are dispensed in 
unsafe vials, and that preservatives used are contraindicated in anti-
asthma products. This comment supported the rule and suggested that the 
rule would resolve issues of compounding in pharmacies which, the 
comment stated, results in millions of dollars in Medicare fraud.
    Compounding occurs when a pharmacist or physician mixes, combines, 
or alters ingredients to create a customized drug product for an 
individual patient. The issue of pharmacy compounding is addressed in 
section 127 of the Food and Drug

[[Page 34084]]

Administration Modernization Act of 1997 (Pub. L. 105-115). Section 127 
adds section 503A to the act (21 U.S.C. 353a). Section 503A(b)(3)(A) of 
the act provides that a drug product may qualify for exemptions from 
certain provisions of the act, including CGMP requirements (section 
501(a)(2)(B) of the act) if, among other conditions, the drug product 
is not identified by regulation as a drug product that presents 
demonstrable difficulties for compounding that reasonably demonstrate 
an adverse effect on the safety or effectiveness of that drug product. 
FDA intends to issue regulations to implement section 503A(b)(3)(A) of 
the act. During the course of that rulemaking, the agency intends to 
consider, among other issues, whether aqueous-based drug products for 
oral inhalation present demonstrable difficulties for compounding that 
reasonably demonstrate an adverse effect on the safety or effectiveness 
of that drug product. Compounded aqueous-based drug products for oral 
inhalation that fail to meet any of the conditions of section 503A of 
the act are subject to the statutory CGMP provision (section 
501(A)(2)(B) of the act) and, therefore, are subject to the 
requirements of this final rule.

C. Packaging

    3. Several comments asked whether the proposed rule addresses 
maintaining the sterility of multiple-use containers after the 
container is opened and closed for later use. These comments stated 
that there is a high risk of contamination of inhalation drug products 
when multiple-use containers, e.g., bottles with droppers, are opened 
and used in a nonsterile environment. One comment asked whether the 
rule would require single-dose containers for one-time use. Two 
comments noted that new packaging is either on the market or in 
development that would eliminate the need to transfer aqueous-based 
drugs into separate secondary receptacles, thus reducing the potential 
for microbial contamination.
    The agency recognizes that multiple-use containers raise issues of 
microbial contamination when aseptic handling procedures are not used 
either by a patient at home or in a hospital setting. However, the 
intent of this rule is to ensure sterility from the point of 
manufacture. The rule is intended to prevent contaminated products from 
being distributed by manufacturers. While the agency encourages the use 
of single-dose containers, the agency is not requiring their use at 
this time. The agency supports innovations in new packaging that would 
reduce the likelihood of microbial contamination. The agency has no 
current plans, however, to require the use of such packaging by 
manufacturers.

D. Antimicrobial Preservatives

    4. One comment suggested that the proposed rule was a ``simplistic 
fix'' for a series of complex problems including inadequate 
antimicrobial preservation systems for in-use contamination control, 
inadequate U.S. Pharmacopeia (USP) microbiological testing methods, and 
defective hospital infection control procedures. The comment questioned 
the adequacy of microbial limits testing, in particular USP procedure 
61>, to reliably detect the prevalent contaminants of inhalation drug 
products. The comment also suggested that there is no evidence for the 
assumption underlying the proposed rule that contaminating organisms 
have developed resistance to the antimicrobial preservative systems 
used. The comment stated that organisms historically known to be 
resistant to benzalkonium chloride have been noted and that mistakes 
have occurred when companies have made errors designing a product's 
antimicrobial preservative system. The comment also noted the 
inadvisability of using a single preservative in the manufacturing 
process and suggested that the proposed rule shows that the agency now 
believes preservatives are to be used to address inadequate 
manufacturing contamination controls that were previously considered to 
be serious CGMP violations.
    Another comment acknowledged that some antimicrobial preservatives 
are no longer effective because resistance to them in certain bacterial 
strains has developed, and expressed concern as to whether this problem 
would be addressed by the rule. Similarly, a different comment noted 
microbial contamination in spite of preservatives. This comment 
indicated support for sterile, additive-free solutions, noting that one 
disadvantage of preservatives is that they may be contraindicated in 
anti-asthmatic products. This comment stated that benzalkonium chloride 
is a known bronchoconstrictor contraindicated in anti-asthmatic 
products and that edetic acid, while not as potent as benzalkonium 
chloride, causes bronchospasm and would not be present in an ideal 
nebulizer solution.
    Antimicrobial preservatives are added to dosage forms to protect 
them from microbial contamination. The USP states that antimicrobial 
agents should not be used solely to reduce the viable microbial count 
as a substitute for good manufacturing practices. The USP sets forth 
tests for estimating the presence, or absence, of microorganisms. USP 
procedure 61> sets forth tests for the estimation of the number of 
viable aerobic microorganisms present and the absence of designated 
microbial species in both raw materials and finished form drug 
products. FDA recognizes that both sterile and nonsterile drug products 
may contain preservative systems to control bacteria and fungi that may 
be inadvertently introduced during manufacturing or use.
    Concerning the comment that the proposed rule represents an 
inappropriate policy change in allowing preservatives to be used to 
address inadequate manufacturing contamination controls, this rule does 
not change the agency's policy of considering such use of preservatives 
a serious CGMP violation. To the extent agency policy is reflected in 
the USP, the USP clearly states that while situations may arise where 
the use of an antimicrobial preservative may be necessary to minimize 
the proliferation of microorganisms, all useful antimicrobial agents 
are toxic substances.
    The agency agrees with the comment acknowledging that some 
antimicrobial preservatives are no longer fully effective because 
certain bacterial strains have developed resistance. The agency 
disagrees with the comment that suggests there is no evidence that 
contaminating organisms have developed resistance to antimicrobial 
preservatives. Bacteria best identified as belonging to the Pseudomonas 
family have been known for many years to survive and grow in commercial 
preparations of quanternary ammonium compounds such as benzalkonium 
chloride. (See, for example, Adair, F.W., S.G. Geftic, and J. Gelzer, 
``Resistance of Pseudomonas to Quaternary Ammonium Compounds: I. Growth 
in Benzalkonium Chloride Solution,'' Applied Microbiology, vol. 18, pp. 
299-302, 1969. See also, Dixon, R.E., et al., ``Aqueous Quaternary 
Ammonium Antiseptics and Disinfectants,'' Journal of the American 
Medical Association, vol. 236, pp. 2415-2417, 1976.) In fact, the 
albuterol sulfate product recalled in January 1994, discussed in the 
proposed rule, contained benzalkonium chloride, an antimicrobial 
preservative, yet the preservative failed to prevent microbial 
contamination of the product. As of October 28, 1997, the agency's 
Spontaneous Reporting System (SRS) reported that this albuterol sulfate 
incident was associated with a total of 2,846 cases including 1,498 
serious cases, 1,163 hospitalizations, and 441 deaths.

[[Page 34085]]

    The agency acknowledges the public health need for sterile, 
additive-free, aqueous-based drug products for oral inhalation for the 
segment of the population for whom antimicrobial products are 
contraindicated (e.g., sensitive patients with asthma and other 
pulmonary diseases). To this end, the agency encourages the manufacture 
of sterile, additive-free, single-dose drug products for oral 
inhalation. However, the agency is not at this time requiring that all 
aqueous-based drug products for oral inhalation be manufactured in 
single-dose containers.
    The agency recognizes that microbial limits tests have not 
prevented serious microbial contamination of nonsterile inhalation drug 
products in the past. Endproduct microbial limits tests performed prior 
to distribution may not be capable of detecting low levels of 
contamination. Products that initially pass the microbial limits test 
may support the growth of contaminating organisms that could later 
increase to unacceptable levels. The agency believes that requiring the 
sterility of such products from the point of manufacture will reduce 
the likelihood of microbial contamination.
    The agency recognizes that contamination of these products may 
occur during usage. Such contamination may occur because of inadequate 
handling procedures, including defective hospital infection control 
procedures, or patient handling errors. The agency notes that the 
National Center for Infectious Diseases of the Centers for Disease 
Control and Prevention is sponsoring initiatives on preventing 
nosocomial transmission of antimicrobial-resistant microorganisms and 
directs those interested to their Internet at www.cdc.gov/ncidod/ for 
related information. The agency encourages hospital personnel and 
patients to follow instructions in the labeling for such products, 
including any precautions for use. The agency emphasizes the importance 
of following proper handling technique when transferring these products 
from their original container into an atomizer or nebulizer. FDA has 
determined that the best way for it to prevent future public health 
problems associated with contaminated aqueous-based drug products for 
oral inhalation is to require sterility at the point of manufacture.

E. Costs of Compliance

    In the proposed rule, FDA estimated that the affected industry 
would incur total annual compliance costs of $192,000 to $1,210,000 
(after amortization over 10 years at a 7 percent interest rate), mostly 
for constructing clean rooms in the five manufacturing facilities 
believed to be using a nonsterile production process. Several of the 
comments addressed aspects of FDA's original analysis of economic 
impacts.
    5. Three comments stated that FDA had underestimated the costs of 
compliance and two comments provided estimates of compliance costs for 
their companies, although they did not provide the bases for these 
estimates.
    FDA has considered these estimates and has revised its compliance 
cost estimates for the final rule, as described in section V of this 
document, ``Analysis of Economic Impacts.'' The agency's full cost 
analysis is based on a report prepared by its contractor, Eastern 
Research Group (ERG) (available in the docket) entitled ``Cost Impact 
on the Pharmaceutical Industry of Final Sterility Requirements for 
Inhalation Solution Products,'' and the comments mentioned above.
    6. The U.S. Small Business Administration (SBA) commented that 
there was insufficient information on the record to evaluate the need 
for the regulation, as measured by the incidence of illness, against 
the enormous cost of compliance.
    The proposed rule listed several incidents of contaminated 
inhalation drug products that jeopardized the public health and safety 
and were the subject of product recalls (62 FR 49638 at 49639). The 
proposed rule did not, however, provide data on adverse events 
associated with these recalls. The agency notes that as of October 28, 
1997, FDA's SRS reported that the albuterol sulfate product recalled in 
January 1994, discussed in the proposed rule, was associated with 2,846 
reports of adverse events including 441 deaths. FDA believes that this 
evidence, along with the resistance to microbial preservatives and the 
growth potential of the Pseudomonas family of bacteria, provides the 
public health and safety justification for this rule. Further, as the 
revised compliance costs of the final rule are estimated at $10.1 
million per year, the agency believes that public health and safety 
concerns outweigh the compliance burdens.

F. Training Costs

    7. SBA noted the lack of training costs for sterility procedures in 
the agency's original cost estimates. FDA agrees with this comment, and 
training costs are now included in its final estimate.

G. Enforcement of CGMP Regulations

    8. One comment suggested that enforcement of CGMP regulations and 
monitoring of unethical repackaging operations would be more effective 
and less costly then requiring firms to convert to sterile processes.
    The agency has determined that adherence to CGMP regulations 
without appropriate sterilization procedures does not provide an 
adequate level of assurance that aqueous-based drug products for oral 
inhalation will be free of contaminants. Based on past incidents of 
serious health risks to users, the agency has determined that 
enforcement of CGMP's is not enough to ensure these products are 
contaminant-free when they leave the manufacturer for distribution. 
Antimicrobial preservatives used in these products may not be effective 
because many bacteria, including Pseudomonas spp., have developed 
resistance to these preservatives. The albuterol sulfate product 
recalled in January 1994, discussed in the proposed rule, 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 a 
nonsterile inhalation drug product for an extended period may actually 
select for preservative-resistant strains of Pseudomonas spp. or other 
bacteria. Similarly, although the agency recognizes the importance of 
the enforcement of repackaging regulations, this rule is intended to 
help ensure that products are sterile at the point of manufacture.

H. Hazard Analysis and Critical Control Point (HACCP) Program

    9. SBA recommended the use of a HACCP program, like that used for 
the food industry. SBA stated that a HACCP program would reduce 
compliance costs.
    HACCP is a preventive system of hazard control used primarily in 
the food industry. The HACCP concept is a systematic approach to the 
identification and assessment of the risk of biological, chemical, and 
physical hazards that may occur in a particular production process or 
practice and the control of those hazards. Under HACCP, the producer 
develops a plan that anticipates and identifies the points in the 
production process where a failure would likely result in a hazard 
being created or allowed to persist. These points are referred to as 
critical control points (CCP's). Under HACCP, identified CCP's are 
systematically monitored to ensure that critical limits are not 
exceeded, and records are kept

[[Page 34086]]

of that monitoring. Corrective actions are taken when control of a CCP 
is lost and these actions are documented. The effectiveness of HACCP is 
also systematically verified by the processor.
    Because of the potential public health consequences of contaminated 
aqueous-based drug products for oral inhalation, as shown by the 
incidents cited earlier in this document, the agency concludes that a 
HACCP system is not an adequate substitute for sterilization 
requirements.

I. Clean Rooms

    10. Another comment stated that the proposed rule would limit the 
use of each clean room to one product and questioned the necessity of 
this.
    FDA is aware that the trade press has reported that the proposed 
rule would require one product per clean room. FDA is clarifying that 
this interpretation of the proposed rule is inaccurate. FDA did not 
intend to limit, and is not limiting, each clean room to the 
manufacture of only one inhalation product.

J. Specific OTC Drug Product

    11. The agency received 49 comments from consumers of an OTC asthma 
inhalant, Breatheasy, as well as one comment from the manufacturer of 
the Breatheasy product, Pascal Co., Inc., of Bellevue, WA. Pascal Co., 
Inc., distributed a letter to consumers of its product stating the 
agency's new policy would require that all inhalants be manufactured in 
clean rooms and suggesting that overhead costs to produce clean rooms 
would far exceed annual sales of this product. Pascal stated that the 
rule would be cost prohibitive for the company and would require it to 
discontinue manufacture of the product. The 49 letters from consumers 
of this product indicated that they had been informed by Pascal Co., 
Inc., that the new policy would require the manufacturer to discontinue 
manufacture of the product. These letters testified to individual 
experiences with the product, stating duration of use, some for as many 
as 50 or 60 years, lack of any ill effects or quality problems, unique 
needs met by the product exclusive of any other available remedy, and 
the low cost of the product.
    The agency has reviewed the concerns of individuals who have used 
this product for many years and who are understandably concerned about 
it being discontinued. The agency contacted Pascal, Inc., and reviewed 
the labeling of the product to determine if it is the type of product 
intended to be covered by the rule.
    The Breatheasy product is a 2-percent buffered aqueous solution of 
epinephrine that comes in a kit that contains an atomizer. Breatheasy 
is the type of product that has raised serious concerns about the 
health and safety of individuals using such products and it is an 
example of the type of product intended to be covered by the final 
rule. The agency has determined that other, alternative OTC epinephrine 
inhalation products, which do not raise the safety concerns of this 
product, are available on the market to treat the symptoms of these 
individuals. Should Breatheasy become unavailable, the agency suggests 
that individuals consult their health care practitioners for the 
identity of an appropriate alternative OTC product.

IV. Effective Date

    12. Two comments stated that the time for implementation was too 
short and impractical for conversion to sterile processes. Both 
comments requested up to a 2-year phase-in period to allow development 
time for packaging, stability data, and facility modifications. SBA 
stated that allowing a 1-year transition period, as proposed, was not 
sufficient. The comment requested a transition period of 2 years.
    FDA has considered these comments and has decided to lengthen the 
effective date to 2 years after publication of the final rule to give 
each firm a longer period of time to implement the new sterility 
requirements.
    The final rule prohibits all manufacturers of nonsterile aqueous-
based drug products for oral inhalation, including those products 
currently approved, from introducing or delivering for introduction 
into interstate commerce any such products that are nonsterile 
beginning 2 years after the date of publication of the final rule in 
the Federal Register.
    Holders of approved NDA's and abbreviated new drug applications 
(ANDA's) must submit supplemental applications to FDA to establish 
sterility of these products within 2 years after the publication of the 
final rule in the Federal Register.
    Any NDA or ANDA for a nonsterile aqueous-based drug product for 
oral inhalation 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 drug product in a 
supplemental application by the effective date. On or after the 
effective date of the final rule, FDA will refuse to approve an NDA or 
ANDA for an aqueous-based drug product for oral inhalation if the 
applicant has not established the sterility of the product.

V. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612) (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Pub. L. 104-121)), and the Unfunded Mandates Reform Act of 1995 
(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). Under the Regulatory Flexibility Act, if a rule has a 
significant impact on a substantial number of small entities, an agency 
must analyze regulatory options that would minimize any significant 
impact of the rule on small entities. The Unfunded Mandates Reform Act 
requires agencies to prepare an assessment of anticipated costs and 
benefits before enacting any rule that may result in an expenditure in 
any one year by State, local, and tribal governments, in the aggregate, 
or by the private sector, of $100 million (adjusted annually for 
inflation).
    FDA concludes that this final rule is consistent with the 
principles set forth in the Executive Order and in these two statutes. 
FDA estimates that the final rule would impose annual compliance costs 
on industry of about $10.1 million. In addition, the final rule is a 
significant regulatory action as defined by the Executive Order and was 
subject to review under the Executive Order. FDA has also determined, 
as explained later in this section, that the final rule may have a 
significant economic impact on a substantial number of small entities. 
This section, along with the report by FDA's contractor ERG, 
constitutes the agency's final regulatory flexibility analysis as 
required under the Regulatory Flexibility Act. Further, because this 
final rule makes no mandates on government entities and will result in 
expenditures of less than $100 million in any one year, FDA need not 
prepare additional analyses under the Unfunded Mandates Reform Act.

B. Compliance Requirements and Costs

    FDA is amending its regulations to require that all prescription 
and OTC aqueous-based inhalation solutions or suspensions in single-
dose or multiple-

[[Page 34087]]

use primary packaging administered orally via a secondary device or 
other ancillary hardware (e.g., an atomizer, nebulizer, or pump), be 
manufactured to be sterile. This does not include inhalation solutions 
administered by pressurized metered dose inhalers. FDA believes this 
action is necessary to help ensure the safety and efficacy of these 
products, due to reports of adverse drug experiences from contaminated 
nonsterile inhalation solutions and recalls of these products.
    In the preamble to the proposed rule published September 23, 1997, 
FDA estimated that the affected industry would incur total annual 
compliance costs of $192,000 to $1,210,000 (after amortization over 10 
years at a 7 percent interest rate), mostly for constructing clean 
rooms in the five manufacturing facilities believed to be using a 
nonsterile production process. Several of the comments to the proposed 
rule addressed aspects of FDA's original analysis of economic impacts. 
These comments are addressed in section III of this document and below.
    FDA has reviewed its original compliance cost estimates in light of 
the comments to the proposed rule, and has determined that it 
underestimated compliance costs to industry. The agency's revised 
estimates are fully described in the ERG report on compliance costs 
(available in the docket).
    In the proposed rule, FDA estimated that up to five firms may still 
be using a nonsterile manufacturing process for inhalation solutions. 
ERG found that eight firms would be affected by the final rule because 
they use nonsterile manufacturing processes. The ERG estimate assumes 
that some products with an uncertain classification were actually 
nonsterile.
    ERG concluded that the final rule would impose a total annual cost 
of $10.1 million (after amortization of capital costs over 10 years at 
a 7 percent interest rate). The majority of these annual costs ($8 
million) are attributed to the increase in annual operating costs for 
two large manufacturers. This estimate was derived from the comment of 
one of the large companies, which indicated that its operating costs 
would increase by $4 million, primarily due to the lower labor 
productivity that results from the extra activities necessary when 
operating in a sterile environment. One-time capital and related costs 
are estimated at about $8.3 million for converting to the sterile 
production process, including the planning, constructing and equipping 
of clean rooms, training of employees, and revalidation of production 
processes. On an annualized basis (after amortizing over 10 years at a 
7 percent discount rate), these costs are projected at $600,000 per 
year for each of these two large manufacturers.
    The other six manufacturers, which produce nonsterile inhalation 
products with much lower annual revenues (about $1 million or less), 
are not expected to convert their production processes, due to the 
relatively high compliance costs compared to the revenues from these 
products. Instead, ERG projected that one-half of these firms would 
transfer production of these products to a contract manufacturer, with 
an estimated increase in manufacturing costs of about 30 percent, 
resulting in an additional $900,000 per year in costs. The other one-
half of these small volume manufacturers, those with the smallest 
revenues, are expected to discontinue these products altogether. 
Consumers of the discontinued products are expected to switch to 
alternative products. FDA believes, based on the small volume of 
affected sales, the wide availability of competing products, and the 
probable low elasticity of product demand, that the loss of consumer 
and producer value due to this regulation would be extremely small.
    After further review, FDA also decided to require inhalation 
suspension products, other than suspensions in pressurized metered dose 
inhalers, to be sterile although they had not been included in the 
proposal. There are currently five approved inhalation suspension 
products. Because they are all metered-dose inhalers, however, they are 
not covered under the final rule. Further, FDA does not expect to 
receive any new applications for inhalation suspensions that are 
nonsterile, as the current procedures for new products are likely to 
include a sterilization process. Thus, FDA has not raised its 
compliance cost estimates due to the addition of inhalation suspension 
products for oral inhalation in the final rule.

C. Affected Entities

    As stated above, the Regulatory Flexibility Act requires agencies 
to analyze regulatory options that would minimize any significant 
impact of a rule on small entities, unless the rule is not expected to 
have a significant economic impact on a substantial number of small 
entities.
    SBA limits the definition of small businesses in the pharmaceutical 
industry to those with less than 750 employees. ERG estimated that five 
small manufacturers with a total of eight products will be affected by 
this rule, although the data necessary to make this determination are 
scarce and often rely on sales volume rather than number of employees. 
About one-half of these manufacturers (two or three) are expected to 
transfer production to a contract manufacturer, which is estimated to 
increase operating costs by about $180,000 each per year per product. 
In addition, these companies may experience a loss of jobs as these 
products are transferred to the contract manufacturers. The other two 
or three companies are expected to cease production of their product 
completely, thereby incurring the loss of profits on those products. 
While neither ERG nor FDA has quantified these impacts, it expects them 
to be low due to the low product sales volume.
    Affected firms will need to acquire some new professional skills, 
because this rule deals with a new manufacturing process that will 
require technicians to have a knowledge of sterility procedures. Any 
other skills necessary for implementation of this rule (e.g., skills 
associated with preparing the supplemental application) should already 
exist within the firms and should not need to be newly acquired. No 
other compliance costs are estimated for these manufacturers.

D. Alternatives Considered

    FDA has considered alternatives to this rule. FDA considered 
exempting small entities. However, as stated in the proposal, the 
alternative of exempting small businesses from the rule is not 
feasible, because most firms using a nonsterile process are small firms 
and thus granting small businesses an exemption would negate the 
purpose of the rule.
    One alternative mentioned in the comments discussed in section 
III.H of this document was the creation of a HACCP program whereby the 
most critical points in the production process would be monitored for 
microbial safety problems, possibly resulting in lower compliance costs 
for small businesses. As discussed above, FDA has rejected a HACCP 
program for these drug products because of the potential public health 
consequences of contaminated products, as shown by the cited earlier 
incidents involving aqueous-based drug products for oral inhalation.
    Another alternative to the final rule would have been to retain the 
1-year effectiveness date as required by the proposed rule. Instead, 
FDA has responded to public comments by delaying the effectiveness date 
an extra year in order to give industry members additional time to 
adjust to the new requirements and mitigate costs as much as possible. 
In doing so, FDA has

[[Page 34088]]

eliminated compliance costs for 1 year, the present value of which is 
$10.1 million.
    Another alternative mentioned in the comments and discussed in 
section III.G of this document was more uniform enforcement of CGMP's 
and monitoring of unethical repackaging. Based on past incidents of 
serious health risk to users, the agency has determined that 
enforcement of CGMP's is not enough to ensure these products are 
contaminant free when they leave the manufacturer for distribution. 
Similarly, one comment suggested end-testing the product in batches 
prior to shipment from the manufacturing facility. This comment 
incorrectly stated that all contaminated products to date have been 
caught prior to reaching or harming patients. As discussed in section 
III.E of this document, contaminated products have caused serious harm 
to patients. For this reason, the agency has determined that end-
testing and/or enforcement of CGMP's are not adequate to address the 
serious public health and safety concerns raised by such incidents.
    Due to contamination problems with several different inhalation 
solution drug products and adverse experience reports, FDA has 
determined that current manufacturing methods and safeguards against 
contamination, including microbial limits tests, have not prevented 
dangerous microbial contamination of nonsterile aqueous-based drug 
products for oral inhalation. Based on the significant health risk to 
users, FDA is requiring that all aqueous-based drug products for oral 
inhalation be manufactured sterile.
    One alternative considered was to supply consumers and providers 
with information related to the potential risks of aqueous-based drug 
products for oral inhalation that are not manufactured to be sterile, 
instead of mandating sterility in this market. FDA is concerned that 
many prescribers and consumers may not understand the potential risks 
of such products, given that these products are approved and therefore 
regarded as safe and effective when used according to the labeling. In 
many circumstances, additional information would assist prescribers and 
users in making informed choices, and if it were possible to provide 
correct and complete information to all prescribers and consumers in 
this market, they should make the optimal choice for their situation. 
However, FDA does not believe that such information could be developed 
for nonsterile aqueous-based oral inhalation drug products that would 
be consistent with FDA's mandate under the Federal Food, Drug, and 
Cosmetic Act to assure that drug products are safe and effective. 
Additionally, even if such information could be developed, the cost 
associated with providing the information to the relevant parties would 
be too large, and FDA believes that these costs would overshadow any 
expected benefits of allowing fully informed consumers to make their 
own choice in this market.

VI. Environmental Impact

    The agency previously considered the environmental effects of this 
rule as announced in the proposed rule (62 FR 49638). At that time, the 
agency determined under 21 CFR 25.30(h) that this action is of a type 
that does not individually or cumulatively have a significant effect on 
the human environment. No new information or comments have been 
received that would affect the agency's previous determination that 
there is no significant impact on the human environment. Therefore, 
neither an environmental assessment nor an environmental impact 
statement is required.

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). The title, 
description, and respondent description of the information collection 
provisions are shown below with an estimate of the annual reporting and 
recordkeeping burden. Included in the estimate is the time for 
reviewing instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    Title: Sterility Requirements for Aqueous-based drug products for 
oral inhalation.
    Description: The final rule requires that all aqueous-based drug 
products for oral inhalation, including those currently approved, be 
manufactured sterile. Respondents will be required to submit a 
supplemental application under Sec. 314.70(b) or Sec. 314.97, 
describing their new manufacturing process for achieving sterility of 
their aqueous-based drug products for oral inhalation. FDA needs this 
information to determine compliance with this new regulation and will 
use information collected to make decisions on approval of supplemental 
applications. Applicants will have 2 years after the date of 
publication of the final rule to comply with the sterility requirement.
    Description of Respondents: Respondents are businesses engaged in 
the manufacture of aqueous-based drug products for oral inhalation.
    The collection of information described in the proposed rule was 
approved by OMB under control number 0910-0353. However, based on new 
data collected by its contractor, ERG, FDA has revised its estimate of 
the number of respondents in the original proposal for reporting and 
recordkeeping burden. Because the number of respondents has changed, 
the estimate of the total hours has changed. The economic analysis of 
the proposed rule estimated 5 manufacturers, while the economic 
analysis of the final rule estimates 8 manufacturers with 11 nonsterile 
products based on new data collected by ERG (see Ref. 1). However, four 
of the manufacturers are estimated to cease manufacturing, leaving four 
companies manufacturing seven products. These companies are estimated 
to cease manufacturing because they may lack the in-house technical 
capability to convert their operations or might find the prospective 
investments in sterile production technologies to be unattractive. 
Because each nonsterile product will require an annual report (21 CFR 
314.81(b)(2)(iv)), the number of annual responses for nonsterile 
products has increased to seven. Based on a review of FDA's past 
experience with applicants submitting supplemental applications under 
Sec. 314.97, we estimate 160 hours to prepare a supplemental 
application. Therefore, due to the increased estimate of respondents, 
the total hours for the annual reporting burden for manufacturers of 
nonsterile products has increased from 800 hours in the proposed rule 
to 1,120 hours in the final rule. The agency's review of the estimated 
reporting burden for manufacturers of sterile products in the proposed 
rule and its experience with the annual reporting burden for 
manufacturers of sterile products supported the estimate provided in 
the proposed rule. Therefore, the estimated reporting burden for 
manufacturers of sterile products in the final rule is the same as in 
the proposed rule.

[[Page 34089]]



                                   Table 1.--Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
                                         Annual
   21 CFR Section        No. of       Frequency per   Total Annual      Hours per            Total Hours
                       Respondents      Response        Responses       Response
----------------------------------------------------------------------------------------------------------------
314.97                     7               1               7             160              1,1201\1\
314.70                     2               1               2              20                 40 \2\
Total                                                                                        1,160
----------------------------------------------------------------------------------------------------------------
\1\Reporting burden for manufacturers of nonsterile products.
\2\Reporting burden for manufacturers of sterile products.

    Because of the estimated increase from the proposed rule to the 
final rule in the number of respondents for nonsterile products, the 
number of recordkeepers in the recordkeeping burden of Table 2 has 
increased by two from the proposed rule. FDA estimated a total of seven 
recordkeepers in the proposed rule and now estimates a total of nine 
recordkeepers as a result of new data collected by ERG. The proposed 
rule estimated 2 hours per record, and FDA's review of that estimate 
and its experience with the control and validation of microbiological 
contamination supports this proposed estimate. Therefore, the total 
number of hours for the recordkeeping burden has increased from 14 
hours to 18 hours.

                               Table 2.--Estimated Annual Recordkeeping Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                      Annual
         21 CFR Section               No. of       Frequency of    Total Annual      Hours per      Total Hours
                                   Recordkeepers   Recordkeeping      Records         Record
----------------------------------------------------------------------------------------------------------------
211.113(b)                              9               1               9               2              18
Total                                                                                                 18
----------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.

    Individuals and organizations may submit comments on these burden 
estimates or on any other aspect of these information collection 
provisions, including suggestions for reducing the burden, and should 
direct them to the Dockets Management Branch (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    The information collection provisions of this final rule have been 
submitted to OMB for review. Prior to the effective date of this final 
rule, FDA will publish a notice in the Federal Register announcing 
OMB's decision to approve, modify, or disapprove the information 
collection provisions in this 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. Federalism

    FDA has 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 federalism implications as defined 
in the order and, consequently, a federalism summary impact statement 
is not required.

IX. Reference

    The following reference is on display in the Dockets Management 
Branch (address above) and may be seen by interested persons between 9 
a.m. and 4 p.m., Monday through Friday.
    1. Eastern Research Group, ``Cost Impact on the Pharmaceutical 
Industry of Final Sterility Requirements for Inhalation Solution 
Products,'' 1998.

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, 21 CFR part 
200 is amended as follows:

PART 200--GENERAL

    1. The authority citation for 21 CFR part 200 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360e, 
371, 374, 375.


    2. Section 200.51 is added to subpart C to read as follows:


Sec. 200.51  Aqueous-based drug products for oral inhalation.

    (a) All aqueous-based drug products for oral inhalation must be 
manufactured to be sterile.
    (b) Manufacturers must also comply with the requirements in 
Sec. 211.113(b) of this chapter.

    Dated: February 1, 2000.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-13210 Filed 5-25-00; 8:45 am]
BILLING CODE 4160-01-F