Current Good Manufacturing Practice for Finished Pharmaceuticals; Positron Emission Tomography

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 211

[Docket No. 94N-0421]

RIN 0910-AA45

Current Good Manufacturing Practice for Finished Pharmaceuticals;

Positron Emission Tomography

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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[[Page 19494]]

SUMMARY: The Food and Drug Administration (FDA) is amending its

regulations to permit FDA to approve requests from manufacturers of

positron emission tomography (PET) radiopharmaceutical drug products

for exceptions or alternatives to provisions of the current good

manufacturing practice (CGMP) regulations. This action is intended to

relieve manufacturers of PET radiopharmaceutical drug products from

regulations that might result in unsafe handling of these products or

that are inapplicable or inappropriate, and that do not enhance safety

or quality in the manufacture of PET radiopharmaceutical drug products.

Elsewhere in this issue of the Federal Register, FDA is amending its

regulations to authorize the Director, Center for Drug Evaluation and

Research (CDER) and CDER's Director of the Office of Compliance to

grant or deny citizen petitions under FDA regulations requesting an

exception or alternative to any requirement pertaining to CGMP.

EFFECTIVE DATE: April 28, 1997.

ADDRESSES: Decisions on the petitions may be seen in the Dockets

Management Branch (HFA-305), Food and Drug Administration, 12420

Parklawn Dr., rm. 1-23, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Robert K. Leedham, Center for Drug

Evaluation and Research (HFD-343), Food and Drug Administration, 7500

Standish Pl., Rockville, MD 20855, 301-594-1026.

SUPPLEMENTARY INFORMATION:

I. Background

PET is a medical imaging modality used to assess the body's

biochemical processes. Radionuclides are manufactured into PET

radiopharmaceutical drug products that are then administered to

patients for medical imaging. The medical images of the body's

biochemical processes are then evaluated, generally for diagnostic

purposes.

PET radiopharmaceutical drug product manufacturing differs in a

number of important ways from the manufacture of conventional drug

products:

1. Because of the short physical half-lives of PET

radiopharmaceutical drug products, PET facilities generally manufacture

the products in response to daily demand for a relatively small number

of patients.

2. Manufacturing may be limited and only a few lots are produced

each day.

3. PET radiopharmaceutical drug products must be administered to

patients within a short period of time after manufacturing because of

the short physical half-lives of the products.

In the Federal Register of February 27, 1995 (60 FR 10517), FDA

proposed to permit manufacturers of PET radiopharmaceutical drug

products to apply to the agency for approval of exceptions or

alternatives to the requirements of the CGMP regulations in part 211

(21 CFR part 211). The agency noted in the proposal that there are

fundamental principles of the CGMP regulations that must be applied to

drug manufacturing processes, including those for PET

radiopharmaceutical drug products, to ensure the safety and efficacy of

the finished products. However, part 211 is primarily directed to

regulating the manufacture of conventional, nonradioactive drug

products, and there are certain aspects of the manufacture of PET

radiopharmaceutical drug products that are unique. Therefore,

regulations in part 211 may contain requirements that could result in

unsafe handling or that are inapplicable or inappropriate to the

manufacture of PET radiopharmaceutical drug products and do not

otherwise enhance drug product quality.

The proposal specified that a request for an exception would be

required to contain an explanation of why compliance with a particular

CGMP provision is unnecessary or cannot be achieved. It also specified

that a request for an alternative would be required to contain an

explanation of how a proposed alternative procedure would satisfy the

purpose of the CGMP requirement. The proposal stated that either the

Director of CDER or CDER's Director of the Office of Compliance could

approve an exception or alternative if it is determined that: (1) The

requestor's compliance with the requirement is unnecessary to protect

the radiopharmaceutical drug product's quality or safety; (2) the

proposed alternative procedures satisfy the purpose of the CGMP

requirement; or (3) the requestor's submission otherwise justified an

exception or alternative. In addition, the proposal would allow either

CDER's Director or CDER's Director of the Office of Compliance to

withdraw the approval of an exception or alternative by issuing a

written notice to the requestor who had obtained approval for the

exception or alternative.

The proposed rule was one of three documents dealing with PET

radiopharmaceutical drug products that FDA published in the Federal

Register of February 27, 1995. Another document announced the

availability of a draft guideline on the manufacture of PET

radiopharmaceutical drug products (60 FR 10593). The third document

announced a March 21, 1995, public workshop and explained the

applicable statutory and regulatory requirements for these products (60

FR 10594). This final rule pertains only to the exceptions and

alternatives to CGMP regulations for PET radiopharmaceutical drug

products and addresses only those comments received on this issue.

This final rule will become effective 5 days after the date of

publication in the Federal Register. This final rule is a substantive

rule which, in the discretion of the agency, grants or recognizes an

exemption or relieves a restriction. (See 5 U.S.C. 553(d)(1) and

Sec. 10.40(c)(4)(i) (21 CFR 10.40(c)(4)(i).) In addition, the

Commissioner of Food and Drugs finds good cause for making a final

rule, based on the proposal, effective 5 days after the date of

publication in the Federal Register. (See 5 U.S.C. 553(d)(3) and

Sec. 10.40(c)(4)(ii).) The manufacturing process for PET

radiopharmaceutical drug products is sufficiently different from that

of other regulated products that application of certain CGMP

requirements to the PET manufacturing process may be impractical.

Because PET radiopharmaceutical drug products are already in use, a

later effective date may delay FDA approval of exceptions or

alternatives or hinder appropriate application of the CGMP regulations

necessary to protect the integrity of the PET radiopharmaceutical

manufacturing process.

II. Comments on the Proposed Rule

FDA gave interested persons until March 29, 1995, to comment on the

proposed rule. The agency received comments from pharmaceutical

manufacturers, health professionals, professional organizations, and

State regulatory agencies. A summary of these comments and FDA's

responses follows.

A. Application of CGMP Regulations to PET Radiopharmaceutical Drug

Products

Several comments questioned the need to apply CGMP regulations to

PET radiopharmaceutical drug products. One comment stated that there

had not been an adequate explanation of why PET radiopharmaceutical

drug products needed to be governed by CGMP regulations. Several

comments suggested alternative standards for the regulation of PET

radiopharmaceutical drug products such as the United States

Pharmacopeia, the American Pharmaceutical Association Practice

Standards for PET Nuclear Pharmacists, or standards set by State boards

of pharmacy. Another comment suggested that FDA, in conjunction with

the PET

[[Page 19495]]

radiopharmaceutical community, develop a regulation specifically for

PET radiopharmaceutical drug products.

This rule does not trigger the applicability of CGMP regulations.

CGMP regulations apply to PET radiopharmaceutical drug products by

virtue of the fact that, under section 201(g) of the Federal Food,

Drug, and Cosmetic Act (the act) (21 U.S.C. 321(g)), these products are

drugs and are, therefore, subject to the drug provisions of the act. In

a notice published in the Federal Register of February 27, 1995 (60 FR

10594 at 10595), FDA reiterated this fact concerning the regulation of

PET radiopharmaceutical drug products. Under section 501(a)(2)(B) of

the act (21 U.S.C. 351(a)(2)(B)), drugs are deemed adulterated unless

manufactured in conformity with CGMP requirements. PET

radiopharmaceutical drug products are subject to each of the

adulteration provisions of the act, including CGMP requirements, even

if they are prepared in pharmacies or by pharmacists. (See

Professionals & Patients for Customized Care v. Shalala, 847 F. Supp.

1359, 1364 (S.D. Tex. 1994), aff'd, 56 F.3d 592 (5th Cir. 1995).)

Therefore, all PET radiopharmaceutical drug products must be

manufactured in compliance with CGMP regulations. The regulations in

part 211 contain minimum manufacturing practices to be followed by

manufacturers of all drug products. Thus, in the absence of this rule,

all CGMP requirements would apply to the manufacturing of PET drug

products.

FDA's experience has shown that the CGMP regulations are flexible

enough to accommodate most drug products and that it is generally

unnecessary to create specific CGMP regulations for particular classes

of drug products. Such regulations would necessarily contain a large

number of provisions identical to, and redundant with, those already

present in part 211. Where a CGMP regulation has been shown to be

unnecessary or does not enhance the safety or quality of the

manufacturing process for certain drug classes, FDA has revised the

application of that regulation for that class. For example, in the

Federal Register of November 28, 1980 (45 FR 79089), FDA amended

Sec. 211.170 to reduce the time that manufacturers are required to

retain reserve samples of radioactive drugs and to exempt such drugs

from the requirement for annual visual examination of reserve samples.

Although the fundamental principles embodied in the CGMP

regulations are applicable to the PET radiopharmaceutical drug product

manufacturing process, there are certain provisions that may not apply

because of unique manufacturing characteristics. As a result, this

final rule permits FDA to allow exceptions or alternatives to the CGMP

regulations for PET radiopharmaceutical drug products. In addition, FDA

is considering making further revisions to part 211, through rulemaking

including adding a new subpart to the CGMP regulations to deal with

exceptions or alternatives applicable to all PET radiopharmaceutical

drug products.

B. Exceptions and Alternatives to CGMP Regulations

Several comments criticized FDA's proposed procedures to receive

and evaluate requests for exceptions or alternatives to the CGMP

regulations for PET radiopharmaceutical drug products. The comments

objected to the proposed requirement that each manufacturer must

separately describe and justify each proposed specific exception or

alternative. One comment stated that FDA should identify those specific

CGMP provisions from which all PET manufacturers could generally be

excepted. Another comment stated that excepting some PET

radiopharmaceutical drug manufacturers and not others might cause

problems. A third comment stated that it is important that any

alternatives and exceptions be made public and that the CGMP

regulations be applied consistently and equally to all PET

radiopharmaceutical drug manufacturing centers.

At this time, FDA believes that it is necessary to review

individualized requests to determine whether exceptions or alternatives

to CGMP regulations requested for PET radiopharmaceutical drug product

manufacturing are consistent with the basic principles of the CGMP

regulations and whether differences in existing PET manufacturing

techniques, or the volume of product produced, may have an impact on

product quality. Any procedure used in the manufacture of PET

radiopharmaceutical drug products must provide a reasonable degree of

certainty that products will be manufactured with consistent quality.

The agency will periodically provide guidance to industry on the

application of the CGMP regulations to PET radiopharmaceutical drug

products.

FDA agrees that it is important that exceptions and alternatives be

applied consistently to all PET radiopharmaceutical drug product

manufacturers. To promote such consistency, FDA has withdrawn the

provision in proposed Sec. 211.1(d) that would have, under certain

circumstances, expressly allowed oral requests for exceptions and

alternatives and also would have allowed FDA to issue oral decisions on

such requests. The agency believes that it is important to keep written

records to maintain consistency, to adequately evaluate requests for

exceptions and alternatives, and to prevent misunderstandings.

FDA also agrees that information on exceptions and alternatives

should be publicly available. To maintain a publicly available record

of requests for exceptions and alternatives, and agency action on such

requests, FDA believes that exceptions and alternatives should be

submitted in the form of a citizen petition under Sec. 10.30 (21 CFR

10.30). A request for an exception or alternative should be clearly

identified as a ``PET Request for Exception or Alternative to the CGMP

Regulations.'' Decisions with respect to such petitions will be

maintained for public review in the Dockets Management Branch (address

above) between 9 a.m. and 4 p.m., Monday through Friday.

Elsewhere in this issue of the Federal Register, FDA is amending 21

CFR 5.31 to authorize the Director of CDER and CDER's Director of the

Office of Compliance to grant or deny citizen petitions under

Sec. 10.30 requesting an exception or alternative to any requirement in

part 211 pertaining to CGMP for PET radiopharmaceutical drug products.

The proposed rule specifically listed elements that would be

required to be included in a request for exception or alternative and

also specifically listed the factors pertaining to FDA's decision

whether to grant such a request. In response to comments that the

procedure in the proposed rule was too burdensome, the final rule

provides greater flexibility in that it does not require that any

particular element be included in a request for exception or

alternative, and does not narrowly constrain FDA's discretion to grant

such a request.

Although the codified language of the regulation no longer contains

specific required elements, the agency expects that a citizen petition

requesting an exception or alternative would be approved if the agency

determined, based upon a request, including supporting data as

necessary, that: (1) The requestor's compliance with the CGMP

requirement is unnecessary to provide suitable assurance that the drug

meets the requirements of the act as to safety and has the identity and

strength and meets the quality and purity characteristics that it

purports or is represented to possess, or compliance with the

requirement is not possible to

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achieve; (2) alternative procedures or controls suggested and

sufficiently described by the requestor satisfy the purpose of the

requirement; or (3) the requestor's submission otherwise justifies an

exception or alternative. Although no longer specified in the

regulation, these factors, pertaining to FDA's decisions on requests

for exceptions and alternatives, provide guidance both to assist PET

manufacturers in preparing requests and to assist FDA in consistently

evaluating those requests. As further guidance, citizen petitions for

an exception or alternative may be submitted by manufacturers or trade

associations individually or as a group, as long as the facts presented

are sufficiently individualized for each manufacturer seeking the

exception or alternative.

C. Usefulness of the Rule

Several comments objected to the proposed provision for requesting

an exception or alternative to the CGMP regulations, arguing that it

would not likely achieve its goal of reducing the burden on PET

radiopharmaceutical drug products and would not be cost-effective.

FDA disagrees with these comments. As explained above, the purpose

of the rule is to relieve PET radiopharmaceutical drug product

manufacturers from regulatory provisions that might result in unsafe

handling of PET radiopharmaceutical drug products, that are

inapplicable or inappropriate, or that do not enhance the safety or

quality of PET radiopharmaceutical drug products. The agency believes

that, with the added flexibility provided by this final rule, the CGMP

regulations can be applied to PET radiopharmaceutical drug products in

a way that accommodates their unique manufacturing aspects while still

protecting the integrity of the manufacturing process. The agency will

continue to work with these manufacturers in an effort to apply CGMP

requirements to PET radiopharmaceutical drug products in ways that are

practical and achievable.

III. Environmental Impact

The agency has determined under 21 CFR 25.24(a)(10) 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.

IV. Analysis of Impacts

FDA has examined the impacts of the final 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 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 is expected to have a significant economic

impact on a substantial number of small entities, the agency must

analyze regulatory options that would minimize any significant economic

impact of the 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 million or more (annually adjusted

for inflation).

The agency has reviewed this final rule and has determined that the

rule is consistent with the principles set forth in the Executive

Order. FDA finds that the rule is not a significant regulatory action

under the Executive Order. In addition, the agency finds that the rule

does not impose any mandates on State, local, or tribal governments, or

the private sector that will result in an annual expenditure of $100

million or more.

The fact that PET radiopharmaceuticals are drugs requires

compliance with the CGMP requirements under section 501(a)(2)(B) of the

act, and all finished pharmaceuticals are subject to the requirements

imposed by the CGMP regulations set forth in this part. This rule will

allow FDA to approve requests from manufacturers of PET

radiopharmaceutical drug products for exceptions or alternatives to the

CGMP requirements as they apply to the unique characteristics of PET

radiopharmaceutical drug product manufacturing, without compromising

CGMP standards that are necessary to meet the CGMP requirements.

FDA estimates that there are approximately 70 facilities that

manufacture PET radiopharmaceutical drug products, and the agency

assumes for the purposes of this analysis that each facility is a small

entity within the meaning of the Regulatory Flexibility Act. The only

costs associated with this rule are the possible costs associated with

requesting an exception or alternative.

FDA estimates that it will take approximately 20 hours, or less,

for each facility to develop its request for exceptions or

alternatives. Assuming that each of the 70 facilities submits one

request, the burden would total 1,400 hours. Using the 1995 median

weekly earnings of $524\1\ for clinical laboratory technologists and

technicians, and adding 40 percent for fringe benefits, the average

hourly earnings would be $18.34. Thus, the combined costs for all

facilities would total less than $26,000. FDA concludes that these

incidental one time costs of approximately $367 per facility would

constitute an insignificant percentage of gross revenue, even for a

small entity.

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\1\ Employment and Earnings, U.S. Department of Labor, Bureau of

Labor Statistics, vol. 43, No. 1, p. 206, January 1996.

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In addition, it is expected that some facilities will collaborate

with each other, or with trade associations, to submit bundled

requests, as long as the facts presented are sufficiently

individualized for each manufacturer seeking the exception or

alternative. Moreover, because the filing of a request for an exception

or alternative is voluntary, it is unlikely that a facility will file

such a request unless it expects the benefit derived to exceed the cost

of preparing and filing the request. Consequently, FDA believes that

the rule will, in fact, provide a net economic savings for each

facility that chooses to request an exception or alternative to a CGMP

requirement. Therefore, under the Regulatory Flexibility Act, 5 U.S.C.

605(b), the Commissioner of Food and Drugs certifies that this final

rule will not have a significant economic impact on a substantial

number of small entities.

List of Subjects in 21 CFR Part 211

Drugs, Labeling, Laboratories, Packaging and containers,

Prescription drugs, Reporting and recordkeeping requirements,

Warehouses.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, 21 CFR part

211 is amended as follows:

PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED

PHARMACEUTICALS

1. The authority citation for 21 CFR part 211 continues to read as

follows:

Authority: Secs. 201, 501, 502, 505, 506, 507, 512, 701, 704 of

the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352,

355, 356, 357, 360b, 371, 374).

2. Section 211.1 is amended by adding new paragraph (d) to read as

follows:

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Sec. 211.1 Scope.

* * * * *

(d)(1) The Director of the Center for Drug Evaluation and Research

(CDER) and the CDER Director of the Office of Compliance each may

approve a request from a manufacturer of positron emission tomography

(PET) drug products for an exception or alternative to any requirement

of this part pertaining to current good manufacturing practice for PET

drug products.

(2) An approval under paragraph (d)(1) of this section may be

withdrawn if either Director finds that such exception or alternative

is no longer justified. Withdrawal of such approval shall be

accomplished by providing written notice of such withdrawal, and the

reasons for the withdrawal, to the original requestor.

Dated: April 15, 1997.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 97-10341 Filed 4-21-97; 8:45 am]

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