49638 Federal Register / Vol. 62, No. 184 / Tuesday, September 23, 1997 / Proposed Rules

Regulatory Procedures

Executive Order 12866

We have consulted with the Office of

Management and Budget (OMB) and

determined that these proposed rules

meet the criteria for a significant

regulatory action under Executive Order

12866. Thus, they were subject to OMB

review. There are no program or

administrative costs or savings

associated with these proposed rules.

Therefore, no assessment of costs and

benefits is required.

Regulatory Flexibility Act

We certify that these proposed

regulations will not have a significant

economic impact on a substantial

number of small entities because they

affect only individuals. Therefore, a

regulatory flexibility analysis, as

provided in Public Law 96–354, the

Regulatory Flexibility Act, is not

required.

Paperwork Reduction Act

These proposed regulations will

impose no new reporting or

recordkeeping requirements requiring

OMB clearance.

(Catalog of Federal Domestic Assistance

Program Nos. 96.001, Social Security

Disability Insurance; 96.006, Supplemental

Security Income)

List of Subjects in 20 CFR Part 404

Administrative practice and

procedure, Blind, Death benefits,

Disability benefits, Old-Age, Survivors

and Disability Insurance, Reporting and

recordkeeping requirements, Social

Security.

Dated: June 16, 1997.

John J. Callahan,

Acting Commissioner of Social Security.

For the reasons set out in the

preamble, part 404, subpart P, Chapter

III of Title 20, Code of Federal

Regulations, is proposed to be amended

as set forth below.

PART 404—FEDERAL OLD-AGE,

SURVIVORS AND DISABILITY

INSURANCE (1950– )

1. The authority citation for subpart P

continues to read as follows:

Authority: Secs. 202, 205(a), (b), and (d)–

(h), 216(i), 221(a) and (i), 222(c), 223, 225,

and 702(a)(5) of the Social Security Act (42

U.S.C. 402, 405(a), (b), and (d)–(h), 416(i),

421(a) and (i), 422(c), 423, 425, and

902(a)(5)); sec. 211(b), Pub. L. 104–193, 110

Stat. 2105, 2189.

2. Section 201.00(h), appendix 2,

subpart P, is revised to read as follows:

APPENDIX 2 TO SUBPART P—

MEDICAL-VOCATIONAL GUIDELINES

* * * * *

201.00 Maximum sustained work capability

limited to sedentary work as a result of

severe medically determinable

impairment(s).

* * * * *

(h) The term younger individual is used to

denote an individual age 18 through 49. For

individuals who are age 45–49, age is a less

advantageous factor for making an

adjustment to other work than for those who

are age 18–44. Accordingly, for such

individuals who: (1) are restricted to

sedentary work, (2) are unskilled or have no

transferable skills, (3) have no past relevant

work or who can no longer perform past

relevant work, and (4) are unable to

communicate in English, or are able to speak

and understand English but are illiterate in

English, a finding of ‘‘disabled’’ is warranted.

For individuals who are under age 45, age is

a more advantageous factor for making an

adjustment to other work and is usually not

a significant factor in limiting such

individuals’ ability to make an adjustment to

other work, even an adjustment to unskilled

sedentary work, and even when the

individuals are unable to communicate in

English or are illiterate in English. A finding

of ‘‘disabled’’ is not precluded for those

individuals under age 45 (and those age 45–

49 for whom rule 201.17 does not direct a

decision of disabled) who do not meet all of

the criteria of a specific rule and who do not

have the ability to perform a full range of

sedentary work. However, the inability to

perform the full range of sedentary work does

not necessarily equate with a finding of

‘‘disabled.’’ In deciding whether an

individual who is limited to a partial range

of sedentary work is able to make an

adjustment to work other than any past

relevant work, the adjudicator is required to

make an individualized determination

considering the individual’s remaining

occupational base, age, education, and work

experience. Further, ‘‘sedentary work’’

represents a significantly restricted range of

work, and individuals with a maximum

sustained work capability limited to

sedentary work have very serious functional

limitations. Therefore, a finding that an

individual is limited to less than the full

range of sedentary work will be based on a

careful consideration of the evidence of an

individual’s medical impairment(s) and the

limitations and restrictions attributable

thereto. Such evidence must support the

finding that an individual’s residual

functional capacity is limited to less than the

full range of sedentary work.

* * * * *

[FR Doc. 97–25125 Filed 9–22–97; 8:45 am]

BILLING CODE 4190–29–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 200

[Docket No. 96N–0048]

Sterility Requirements for Inhalation

Solution Products

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

amend its regulations to require that all

inhalation solutions for nebulization be

sterile. Inhalation solutions for

nebulization, as the term is used in this

document, refers to inhalation solutions

administered as a fine aqueous mist

created by an atomizer or nebulizer.

Currently, approximately half of these

products are manufactured to be sterile.

Based on reports of adverse drug

experiences from contaminated

nonsterile inhalation solutions for

nebulization and recalls of these

products, FDA is taking this action to

ensure the safety and effectiveness of

these solutions.

DATES: Written comments by December

22, 1997. Submit written comments on

the information collection requirements

by October 23, 1997. FDA proposes that

any final rule that may issue based on

this proposal become effective March

23, 1998.

ADDRESSES: Submit written comments

on this proposed rule to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857. Submit written comments on the

information collection requirements to

the Office of Information and Regulatory

Affairs, Office of Management and

Budget (OMB), New Executive Office

Bldg., 725 17th St. NW., rm. 10235,

Washington, DC 20503, Attn: Desk

Officer for FDA.

FOR FURTHER INFORMATION CONTACT:

Carol E. Drew, Center for Drug

Evaluation and Research (HFD–7), Food

and Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–594–

2041.

SUPPLEMENTARY INFORMATION:

I. Background

Inhalation solutions for nebulization

are used to treat a variety of breathing

disorders. Currently, approximately half

of the marketed products are

manufactured to be sterile. Those

products not manufactured to be sterile

are often manufactured under assigned
Federal Register / Vol. 62, No. 184 / Tuesday, September 23, 1997 / Proposed Rules 49639

microbial count limits. For the reasons

stated below, FDA has determined that

current manufacturing methods and

purported safeguards against

contamination, including the microbial

limits test, have not prevented

dangerous microbial contamination of

nonsterile inhalation solutions for

nebulization. A sterility requirement is

needed to prevent such microbial

contamination.

Contaminated inhalation solutions for

nebulization are likely to cause lung

infections because the drug product is

introduced directly into the lungs in a

manner which at least partially bypasses

the patient’s natural defense

mechanisms. Many patients using

inhalation solution products for

nebulization have chronic obstructive

airway disease or cystic fibrosis, or are

immunocompromised. Microbial

contamination of these products may

result in serious health consequences

due to opportunistic pathogens entering

the lungs or to the possible inactivation

of the drug product by these

microorganisms. Based on the

significant health risk to users, FDA is

proposing to require that all aqueousbased inhalation solutions for

nebulization be manufactured as sterile.

Contamination problems with several

different inhalation solution products

and numerous adverse experience

reports have led to FDA’s determination

that a sterility requirement is necessary

for these products. In January 1994, a

marketed albuterol sulfate inhalation

solution product was found to be

contaminated with a bacterium best

identified as belonging to the

Pseudomonas fluorescens/putida group.

The manufacturer voluntarily recalled

the product (class I recall to the

consumer level) and issued a press

release regarding the recall.

In June 1992, a manufacturer recalled

its metaproterenol sulfate inhalation

solution for nebulization when the

product was found to contain excessive

microbial growth identified as P.

gladioli/cepacia. A press release was

also issued concerning this recall.

In 1987, an FDA investigator

identified at least two potential human

fungal pathogens (Aspergillus glaucus

and Chrysosporium) in another

albuterol sulfate inhalation solution for

nebulization before market distribution.

A sterility requirement for all

inhalation solutions for nebulization

will provide the necessary assurance

that these solutions will not be

contaminated. The sterility requirement

is necessary for several reasons.

First, there is a high risk of

contamination of inhalation solutions.

Microbial contaminants identified in

two of the recalls were Pseudomonas

species (spp.), which are ubiquitous and

are commonly found in pharmaceutical

water supplies and nonsterile

manufacturing environments.

Second, most species of Pseudomonas

associated with the contamination of

inhalation solutions have the potential

to be human pathogens. Of special

concern is the fact that many of the

patients using these products have

compromised pulmonary defense

mechanisms and are therefore at a

particularly high risk of serious

infection.

Third, adherence to current good

manufacturing practice (CGMP)

regulations without appropriate

sterilization procedures does not

provide an adequate level of assurance

that inhalation solutions for

nebulization will not be contaminated.

Even if antimicrobial preservatives are

used in a product, they may not be

effective because many bacteria,

including Pseudomonas spp., may

develop resistance to these

preservatives. The albuterol sulfate

product recalled in January 1994, for

example, contained benzalkonium

chloride, an antimicrobial preservative,

yet the preservative failed to prevent

microbial contamination of the product.

Resistance to preservatives is not

species specific; strains of many species

are resistant. Furthermore, use of a

single preservative in the manufacture

of a nonsterile inhalation solution for an

extended period may actually select for

preservative-resistant strains of

Pseudomonas spp. or other bacteria.

Also, the microbial limits test does

not ensure against contamination. Endproduct microbial limits tests performed

prior to distribution may not be capable

of detecting sufficiently low levels of

contamination; a product that initially

passes the microbial limits test may

support the growth of contaminating

organisms, which could later grow to

unacceptable levels.

FDA has therefore determined that all

inhalation solutions for nebulization

should be manufactured as sterile

products. Any failure to comply with

the sterility requirement would result in

a finding that the drug product is

adulterated under section 501(a)(2)(B) of

the Federal Food, Drug, and Cosmetic

Act (the act) (21 U.S.C. 351(a)(2)(B)),

and misbranded under section 502(j) of

the act (21 U.S.C. 352(j)). Failure to

comply with the sterility requirement

would also result in the agency’s refusal

to approve a new or abbreviated

application for the product, pursuant to

section 505(d)(1), (d)(2), (d)(3), and

(j)(3)(A) of the act (21 U.S.C. 355(d)(1),

(d)(2), (d)(3), and (j)(3)(A)).

II. Description of the Proposed

Regulation

This proposal would amend the

regulations governing requirements for

specific classes of drugs to include new

§ 200.51 for inhalation solutions for

nebulization. Proposed § 200.51(a)

would require that all prescription and

over-the-counter (OTC) inhalation

solutions for nebulization be sterile.

Manufacturers may use any appropriate

process to achieve sterility of their

inhalation solution products, as long as

the method is in compliance with

current FDA regulations. In the Federal

Register of October 11, 1991 (56 FR

51354), FDA proposed to require that

manufacturers use a terminal

sterilization process when preparing a

sterile drug unless the process adversely

affects the drug product. The October

11, 1991, proposed rule would require

that manufacturers include in their

applications a written justification for

not using terminal sterilization if such

process is not appropriate. Should that

proposed rule become final,

manufacturers of inhalation solution

products would be subject to its

requirements.

Under this proposal, all

manufacturers of nonsterile inhalation

solutions for nebulization have until 1

year after the date of publication of the

final rule to comply with the sterility

requirement. This effective date reflects

the time that FDA believes applicants

may need to establish the sterility of

their products.

Persons holding an approved

application for a nonsterile inhalation

solution product should submit to FDA

a supplemental application establishing

the sterility of the product. If they

intend to sterilize their product by

terminal sterilization or make other

changes listed under § 314.70(b)(2) (21

CFR 314.70(b)(2)), they must obtain

FDA approval of a supplement under

that section before making the

change(s). If they intend to manufacture

the sterile product by aseptic

processing, to retain the same container

and closure system, and make no

changes other than those listed under

§ 314.70(c)(1), they may submit a

supplemental application under that

section.

The following information should be

included in the supplements: Complete

qualification data for the aseptic

process, executed batch record for a

production batch of the product using

the approved formulation, in-process

and release control data, updated

release specifications that include

sterility, 3 months’ accelerated stability

data, updated stability protocol to
49640 Federal Register / Vol. 62, No. 184 / Tuesday, September 23, 1997 / Proposed Rules

include either sterility or container/

closure integrity testing initially and at

expiry, and commitment to place the

first three commercial batches into the

routine stability program and submit the

data in annual reports.

Proposed § 200.51(b) states that

manufacturers must comply with the

recordkeeping requirements of 21 CFR

211.113(b) of FDA’s CGMP regulations.

This section requires that manufacturers

establish and follow appropriate written

procedures designed to prevent

microbiological contamination of drug

products purporting to be sterile. Such

procedures must include validation of

any sterilization process.

III. Proposed Effective Date

The agency’s proposal would prohibit

all manufacturers of nonsterile

inhalation solution products for

nebulization, including those products

currently approved, from introducing or

delivering for introduction into

interstate commerce any such products

that are nonsterile from 1 year after the

date of publication in the Federal

Register of any final rule based on this

proposal.

Holders of approved new drug

applications (NDA’s) and abbreviated

new drug applications (ANDA’s) must

submit data to FDA to establish sterility

of these products within 1 year after the

publication in the Federal Register of

any final rule based on this proposal.

This effective date reflects the time that

FDA believes applicants may need to

establish the sterility of their products.

Any NDA or ANDA for a nonsterile

inhalation solution for nebulization

under review by FDA on or after the

date of publication of the final rule but

before the effective date of the final rule

may be approved if the application is

otherwise approvable and the applicant

agrees to establish the sterility of its

product by the effective date. On or after

the effective date of the final rule, FDA

will refuse to approve an NDA or ANDA

for a nonsterile inhalation solution for

nebulization if the applicant has not

established the sterility of the product.

IV. Environmental Impact

The agency has determined under 21

CFR 25.24(a)(8) that this action is of a

type that does not individually or

cumulatively have a significant effect on

the human environment. Therefore,

neither an environmental assessment

nor an environmental impact statement

is required.

V. Analysis of Impacts

FDA has examined the impacts of the

proposed rule under Executive Order

12866, under the Regulatory Flexibility

Act (5 U.S.C. 601–612), and under the

Unfunded Mandates Reform Act (Pub.

L. 104–4). Executive Order 12866

directs agencies to assess all costs and

benefits of available regulatory

alternatives and, when regulation is

necessary, to select regulatory

approaches that maximize net benefits

(including potential economic,

environmental, public health and safety,

and other advantages; distributive

impacts; and equity). Unless an agency

certifies that a rule will not have a

significant economic impact on a

substantial number of small entities, the

Regulatory Flexibility Act requires an

analysis of regulatory options that

would minimize any significant impact

of a rule on small entities. The

Unfunded Mandates Reform Act

requires that agencies prepare an

assessment of anticipated costs and

benefits before proposing any rule that

may result in an annual expenditure by

State, local, and tribal governments, in

the aggregate, or by the private sector, of

$100,000,000 (adjusted annually for

inflation).

The expected aggregate costs of this

proposed rule, and the anticipated

impact of the rule on small entities, are

described in the analysis below. The

agency believes that the proposed rule

is consistent with the regulatory

philosophy and principles identified in

the Executive Order. This rule is not a

significant regulatory action as defined

by the Executive Order, does not impose

any mandates on State, local, or tribal

governments, and is not a significant

regulatory action under the Unfunded

Mandates Reform Act. Based on the

following analysis, FDA estimates that

this rule will have significant adverse

effects on about four to five small firms

that currently manufacture nonsterile

inhalation solutions for nebulization.

However, since the exact number of

firms manufacturing nonsterile

inhalation solutions is not certain, FDA

invites comments from firms that

believe they would be affected by the

proposed rule. The statutory basis for

FDA’s authority to issue the rule is

presented previously in this preamble.

FDA has not identified any other

Federal rules that duplicate, overlap, or

conflict with the proposed rule.

As described in section I of this

document, the objective of the proposed

rule is to ensure that all inhalation

solutions for nebulization are

manufactured as sterile products and

are thus safe and effective for use.

Nonsterile inhalation solutions have

been found to result in serious health

consequences to users. By ensuring

sterilization, the proposed rule is

expected to yield benefits from the

elimination of extended patient

suffering and hospitalization associated

with contaminated nonsterile inhalation

solution products. In addition, the

industry would benefit by avoiding

liability claims from persons harmed

due to the contamination of nonsterile

inhalation solution products.

A. Affected Entities

This proposed rule would affect only

those manufacturers of inhalation

solutions for nebulization that do not

already manufacture the products to be

sterile. Based on its compliance data

base, FDA believes that all innovator

prescription products are currently

manufactured as sterile. Of the

approximately 28 generic and OTC

firms that manufacture inhalation

solutions, FDA estimates that up to five

firms may still use nonsterile

manufacturing processes and will be

affected by this proposed rule. (The

remainder are believed to have either

implemented sterile processes

themselves or to have contracted out the

manufacturing of their inhalation

products to firms that use a sterile

process.) All of these affected firms may

be small entities as defined by the

Regulatory Flexibility Act.

B. Compliance Requirements and Costs

To comply with this rule, the affected

firms must implement a sterile process

for manufacturing their inhalation

products, either by converting their inhouse manufacturing operations to

ensure that the products are sterile, or

by arranging to have these products

manufactured under contract by a firm

that can do so under sterile conditions.

In addition, affected firms must: (1)

Develop appropriate written procedures

designed to prevent contamination of

the products, including validation of the

new inhalation solution processes; and

(2) submit to FDA a supplemental

application establishing the sterility of

the product.

Firms choosing to convert in-house

manufacturing operations would need

to set up an in-plant sterilization

process by constructing a clean room

especially designated for the inhalation

solution product. FDA finds that the

cost of building a new clean room may

amount to almost $600 per square foot.

The size of pharmaceutical clean rooms

is reported to vary widely, from 200 to

2,500 square feet. Thus, the estimated

cost of installing a clean room in a

manufacturing facility may range from

$120,000 to $1,500,000 per firm. Since

affected firms would presumably

contract out their manufacturing process

if to do so would lower their costs of
Federal Register / Vol. 62, No. 184 / Tuesday, September 23, 1997 / Proposed Rules 49641

complying with this proposed rule, this

figure is an upper bound.

Firms would also need to validate the

new inhalation solution processes at an

estimated cost of $75,000 to $100,000

per product. The firms that would need

to complete these validation procedures

produce an average of approximately

two inhalation products each, leading to

validation costs per firm of

approximately $150,000 to $200,000.

Each firm would also be required to

incur the paperwork costs associated

with filing a supplemental application

for each product with FDA.

Thus, overall costs for implementing

and validating a sterile manufacturing

process for inhalation products would

total approximately $270,000 to

$1,700,000 per affected firm. Assuming

that five firms are affected, the costs of

complying with this rule would range

from approximately $1,350,000 to

$8,500,000. Amortized over 10 years at

a 7 percent interest rate implies total

annualized costs of $192,000 to

$1,210,000. In addition, affected firms

will incur any costs associated with

preparing and submitting a

supplemental application.

Affected firms will need to acquire

some new professional skills, since this

rule deals with a new manufacturing

process that will require technicians to

have a knowledge of sterility

procedures, specifically the asceptic

sterilization process. Any other skills

necessary for implementation of this

proposal (e.g., skills associated with

preparing the application) should

already exist within the firms and

should not need to be newly acquired.

C. Minimizing the Impact on Small

Entities

FDA initially considered requiring

conversion to sterile procedures to take

place within 6 months of the

publication of a final rule, due to the

health hazards associated with existing

unsterilized inhalation products.

However, the agency is concerned that

this short timeframe would give affected

firms an inadequate opportunity to

implement aseptic manufacturing

processes and might force some small

firms to temporarily suspend

production. Thus, this proposed rule

allows 1 year for the manufacturing

conversion to take place.

Exempting small businesses from the

rule is not a feasible alternative, since

all of the firms believed to still be using

nonsterile manufacturing for these

products are small. A size-based

exemption would thus defeat the

purpose of this proposed rule.

VI. The Paperwork Reduction Act of

1995

This proposed rule contains

information collection provisions that

are subject to review by OMB under the

Paperwork Reduction Act of 1995 (44

U.S.C. 3501–3520). Therefore, in

accordance with 44 U.S.C. 3506(c)(2)(B)

and 5 CFR part 1320, FDA is providing

the following title, description, and

respondent description of the

information collection contained in this

proposal, along with an estimate of the

resulting annual collection of

information burden. This estimate

includes the time needed for reviewing

instructions, gathering and maintaining

the data needed, and completing and

reviewing the collection of information.

With respect to the following

collection of information, FDA invites

comments on: (1) Whether the proposed

collection of information is necessary

for proper performance of FDA’s

functions, including whether the

information will have practical utility;

(2) the accuracy of FDA’s estimate of the

burden of the proposed collection of

information, including the validity of

the methodology and assumptions used;

(3) ways to enhance the quality, utility,

and clarity of the information to be

collected; and (4) ways to minimize the

burden of the collection of information

on respondents, including through the

use of automated collection techniques,

when appropriate, and other forms of

information technology.

Title: Sterility requirements for

inhalation solution products.

Description: The proposal would

require that all inhalation solution

products, including those currently

approved, be manufactured as sterile.

Applicants will have 1 year after the

date of publication of the final rule to

comply with the sterility requirement.

Description of Respondents: Drug

manufacturers.

As indicated in the accompanying

chart, the proposed one-time reporting

requirement would require that most

firms commit about 160 additional

hours per product to report the sterility

information in a supplement to a drug

application (20 hours for certain

manufacturers of sterile products) and

about 2 additional hours per product to

document sterility of their inhalation

products.

The expected burden under the

proposed rule is as follows:

ESTIMATED ANNUAL REPORTING BURDEN

21 CFR Section No. of

Respondents

Annual Frequency per

Response

Total Annual

Responses

Hours per Response Total Hours

314.97 5 1 5 160 8001

314.70 2 1 2 20 402

1 Reporting burden for manufacturers of nonsterile products.

2 Reporting burden for manufacturers of sterile products.

ESTIMATED ANNUAL RECORDKEEPING BURDEN

21 CFR Section No. of

Recordkeepers

Annual

Frequency per

Recordkeeping

Total Annual

Records

Hours per

Recordkeeper Total Hours

211.113(b) 7 1 1 2 14

There are no capital costs or operating and maintenance costs associated with this proposed rule.

The agency has submitted a copy of

this proposed rule to OMB for its review

and approval of this information

collection. Interested persons are

requested to send comments regarding

this collection of information to the

Office of Information and Regulatory

Affairs (address above).
49642 Federal Register / Vol. 62, No. 184 / Tuesday, September 23, 1997 / Proposed Rules

VII. Request for Comments

Interested persons may, on or before

December 22, 1997, submit to the

Dockets Management Branch (address

above) written comments regarding this

proposal. Two copies of any comments

are to be submitted, except that

individuals may submit one copy.

Comments are to be identified with the

docket number found in brackets in the

heading of this document. Received

comments may be seen in the office

above between 9 a.m. and 4 p.m.,

Monday through Friday.

List of Subjects in 21 CFR Part 200

Drugs, Prescription drugs.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs, it is proposed that

21 CFR part 200 be amended as follows:

PART 200—GENERAL

1. The authority citation for 21 CFR

part 200 continues to read as follows:

Authority: Secs. 201, 301, 501, 502, 503,

505, 506, 507, 508, 515, 701, 704, 705 of the

Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,

358, 360e, 371, 374, 375).

2. New § 200.51 is added to subpart C

to read as follows:

§ 200.51 Sterility requirements for

inhalation solution drug products.

(a) All inhalation solutions for

nebulization shall be manufactured to

be sterile.

(b) Manufacturers shall also comply

with the recordkeeping requirements in

§ 211.113(b) of this chapter.

Dated: September 12, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–25130 Filed 9–22–97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 600 and 606

[Docket No. 97N–0242]

Biological Products; Reporting of

Errors and Accidents in Manufacturing

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

amend the regulations requiring

licensed manufacturers of biological

products to report errors and accidents

in manufacturing that may affect the

safety, purity, or potency of a product.

FDA is proposing to establish a

reporting period for licensed biological

products; require that error and accident

reports be submitted for products that

have been made available for

distribution, and amend the current

good manufacturing practice (CGMP)

regulations for blood and blood

components to require error and

accident reporting by unlicensed

registered blood establishments and

transfusion services which are currently

reporting on a voluntary basis. The

proposed reporting requirements are

intended to expedite reporting of errors

and accidents in manufacturing of

biological products; provide FDA with a

more accurate surveillance of the

nation’s blood supply, thereby enabling

FDA to monitor actions taken in

response to the errors and accidents

detected for all establishments involved

in manufacturing of blood and blood

components; and facilitate a rapid

response where the public health may

be at risk.

DATES: Submit written comments on the

proposed rule by December 22, 1997.

Submit written comments on the

information collection provisions by

October 23, 1997. The agency is

proposing that any final rule that may

issue based upon this proposed rule

become effective March 23, 1998.

ADDRESSES: Submit written comments

to the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 12420 Parklawn Dr.,

rm. 1–23, Rockville, MD 20857. Submit

written comments on the information

collection provisions to the Office of

Information and Regulatory Affairs,

OMB, New Executive Office Bldg., 725

17th St. NW., Washington, DC 20503.

ATTN: Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT:

Paula S. McKeever, Center for Biologics

Evaluation and Research (HFM–630),

Food and Drug Administration, 1401

Rockville Pike, suite 200N, Rockville,

MD 20852–1448, 301–594–3074.

SUPPLEMENTARY INFORMATION:

I. Introduction

Establishments that engage in the

manufacture, preparation, propagation,

compounding, or processing of drug and

device products, including biological

products, must register with the FDA

under section 510 of the Federal Food,

Drug, and Cosmetic Act (the act) ( 21

U.S.C. 360), unless specifically

exempted by regulation.

Establishments propagating or

manufacturing and preparing biological

products for interstate commerce are

subject to licensing under the Public

Health Service Act (PHS Act) (42 U.S.C.

262(a)). These licenses are issued by

FDA only upon a showing that the

establishment and the product for

which a license is desired meet

applicable standards designed to ensure

the continued safety, purity, and

potency of such products prescribed in

the regulations (42 U.S.C. 262(d)(1)).

Blood and blood products are

regulated as drugs under section 201(g)

of the act (21 U.S.C. 321(g)) and

biologicals are regulated under 42

U.S.C. 262 of the PHS Act.

Establishments manufacturing blood

and blood components are required to

register with FDA and to comply with

the CGMP (parts 211 and 606 (21 CFR

parts 211 and 606)). Transfusion

services which do not routinely collect

or process blood and blood components

are exempted from registering as blood

establishments (§ 607.65(f) (21 CFR

607.65(f))), but are required under 42

CFR 493.1273(a) to comply with parts

606 and 640 (21 CFR part 640) as they

pertain to the performance of

manufacturing activities, such as

compatibility testing, storage, labeling,

and recordkeeping, or any other process

involving manufacturing.

A product is considered adulterated

under the act when the methods used in

its manufacture, processing, packing, or

holding do not conform to the CGMP

(section 501(a)(1) of the act (21 U.S.C.

351(a)(1))). By applying the CGMP,

firms assure that the products meet the

requirements for safety, have the

identity and strength, and meet the

quality and purity characteristics which

they purport or are represented to

possess (section 501(a)(2)(B) of the act).

A product is also adulterated if its

strength differs from, or purity or

quality falls below what it is purported

or represented to possess (section 501(c)

of the act). A product is considered

misbranded if its labeling is false or

misleading in any particular (section

502(a) of the act (21 U.S.C. 352(a))) or

if the product is dangerous to health

when used as labeled under section

502(j) of the act. The introduction or

delivery for introduction of adulterated

and/or misbranded biological products

into interstate commerce is prohibited

under section 301(a) of the act (21

U.S.C. 331(a)). It is also a prohibited act

to adulterate and/or misbrand biological

products while held for sale after receipt

of shipment in interstate commerce

(section 301(k) of the act). These

prohibited acts are punishable by

prescribed penalties under the act.