[Federal Register Volume 62, Number 77 (Tuesday, April 22, 1997)]
[Rules and Regulations]
[Pages 19493-19497]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-10341]


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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

[[Page 19496]]

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:

[[Page 19497]]

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]
BILLING CODE 4160-01-F