[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]
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