34082 Federal Register / Vol. 65, No. 103 / Friday, May 26, 2000 / Rules and Regulations

* * * * *

Dated: May 11, 2000.

L. Robert Lake,

Director of Regulations and Policy, Center

for Food Safety and Applied Nutrition.

[FR Doc. 00–13209 Filed 5–25–00; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 200

[Docket No. 96N–0048]

RIN 0910–AA88

Sterility Requirement for AqueousBased Drug Products for Oral

Inhalation

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

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 singledose 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 aqueousbased 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 § 200.51

for aqueous-based drug products for oral

inhalation. Section 200.51(a) requires

that all prescription and OTC aqueousbased 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

§ 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 § 200.51. These phrases

are replaced by the phrase ‘‘aqueousbased 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

Federal Register / Vol. 65, No. 103 / Friday, May 26, 2000 / Rules and Regulations 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

§ 314.70(b) or § 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 § 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 § 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

§ 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:

• 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’’);

• For abbreviated applications, an

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;

• Three months accelerated stability

data;

• An updated stability protocol to

include either sterility or container/

closure integrity testing initially and at

expiry; and

• 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 § 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 aqueousbased 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 aqueousbased 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

34084 Federal Register / Vol. 65, No. 103 / Friday, May 26, 2000 / Rules and Regulations

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 multipleuse 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.

Federal Register / Vol. 65, No. 103 / Friday, May 26, 2000 / Rules and Regulations 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 contaminantfree 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

34086 Federal Register / Vol. 65, No. 103 / Friday, May 26, 2000 / Rules and Regulations

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 aqueousbased 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 aqueousbased 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 multipleVerDate 11<MAY>2000 23:16 May 25, 2000 Jkt 190000 PO 00000 Frm 00048 Fmt 4700 Sfmt 4700 E:\FR\FM\26MYR1.SGM pfrm13 PsN: 26MYR1
Federal Register / Vol. 65, No. 103 / Friday, May 26, 2000 / Rules and Regulations 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. Onetime 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

34088 Federal Register / Vol. 65, No. 103 / Friday, May 26, 2000 / Rules and Regulations

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 aqueousbased drug products for oral inhalation.

Based on the significant health risk to

users, FDA is requiring that all aqueousbased 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 § 314.70(b) or § 314.97, describing

their new manufacturing process for

achieving sterility of their aqueousbased 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

§ 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.

Federal Register / Vol. 65, No. 103 / Friday, May 26, 2000 / Rules and Regulations 34089

TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN

21 CFR Section No. of Respondents

Annual Frequency per Response

Total Annual

Responses

Hours per Response Total Hours

314.97 7 1 7 160 1,12011

314.70 2 1 2 20 40 2

Total 1,160

1Reporting burden for manufacturers of nonsterile products.

2Reporting 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

21 CFR Section No. of Recordkeepers

Annual Frequency of Recordkeeping

Total Annual

Records

Hours per

Record Total Hours

211.113(b) 9 1 9 2 18

Total 18

1There 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:

§ 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 § 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

DEPARTMENT OF STATE

22 CFR Part 123

[Public Notice 3318]

Exports of Commercial

Communications Satellite

Components, Systems, Parts,

Accessories and Associated Technical

Data

AGENCY: Bureau of Political-Military

Affairs, State.

ACTION: Interim final rule.

SUMMARY: Section 1309(a) of the Foreign

Relations Authorization Act for Fiscal

Years 2000 and 2001 requires the

Department of State to establish a

regulatory regime for the export

licensing to U.S. allies of commercial

satellites, technologies, components,

and systems, which shall include

expedited approval, as appropriate,

while ensuring priority to national

security and U.S. commitments under

the Missile Technology Control Regime.

Section 1302(a) of the same Act

requires the Department to promulgate

regulations in order to ensure timely

reporting to the Department (within 15