[Federal Register Volume 60, Number 38 (Monday, February 27, 1995)]
[Proposed Rules]
[Pages 10517-10520]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-4690]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 211
[Docket No. 94N-0421]
RIN 0905-AE63
Current Good Manufacturing Practice for Finished Pharmaceuticals;
Positron Emission Tomography
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its regulations to permit manufacturers of positron emission tomography
(PET) radiopharmaceuticals to apply to the agency for approval of an
exception or alternative to the requirements of the current good
manufacturing practice (CGMP) regulations. This action is intended to
relieve PET manufacturers, nearly all of whom are small entities, from
regulations that might result in unsafe handling of PET
radiopharmaceuticals, that are inapplicable or inappropriate, or that
otherwise do not enhance safety or quality in the manufacture of PET
radiopharmaceuticals.
DATES: Written comments by March 29, 1995. FDA proposes that any final
rule that may issue based on this proposal become effective on its date
of publication in the Federal Register.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: John W. Levchuk, Center for Drug
Evaluation and Research (HFD-322), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301-594-0095.
SUPPLEMENTARY INFORMATION:
I. Introduction
PET is a diagnostic imaging modality consisting of onsite
production of radionuclides that are intravenously injected into
patients for diagnostic purposes. The potential usefulness of a PET
radiopharmaceutical is based upon [[Page 10518]] the product's
interaction with a biochemical process in the body. For example, the
product may be substituted for glucose in anaerobic glycolysis,
theoretically localizing in ischemic tissues where glucose metabolism
is the predominant energy source (epileptic foci, acute vascular
insufficiency states).
The manufacture of PET radiopharmaceuticals consists of a process
that takes place within a few hours. A target material is irradiated by
a cyclotron; chemical synthesis takes place in a programmed, automated
apparatus; and the final solution is compounded and filled. The
biological distribution of a PET radiopharmaceutical in the body is
monitored by a positron tomograph, or PET scanner, which detects the
photons emitted as a result of the radioactive decay of the PET
radiopharmaceutical.
PET manufacturing procedures differ in a number of important ways
from those associated with the manufacture of conventional drug
products:
Because of the short half-lives of PET
radiopharmaceuticals (some of which are only minutes long), PET
facilities generally manufacture the products in response to daily
demand for a relatively small number of patients.
Manufacturing is typically done on a small scale and only
a few lots are produced each day. Thus, the daily production of a PET
facility is normally handled by few employees, sometimes by one
production operator and a part-time support person.
PET radiopharmaceuticals must be administered to patients
in a short period of time because of the brief half-lives of the
products. Any prolonged manufacturing time or testing or release delays
would reduce the useful clinical life of the product.
Unlike most pharmaceuticals, PET radiopharmaceuticals
usually do not enter a general drug distribution chain. An entire lot
(one vial) is usually distributed directly from the PET facility to a
single medical department, to a physician for administration to
patients, to a radiopharmacy for dispensing, or to another site close
to the PET facility. The receiving facilities are in a geographic
proximity that will allow for receipt and use within the product's
half-life parameters.
The agency believes that there are fundamental principles of the
CGMP regulations that need to be applied to drug manufacturing
processes, including those for PET radiopharmaceuticals, to ensure the
safety and efficacy of the finished products. However, as just noted,
certain features are unique to the manufacture of PET products. Part
211 (21 CFR part 211), which is primarily directed to the regulation of
conventional drug products, contains requirements and specific language
which might result in unsafe handling of PET radiopharmaceuticals, are
inapplicable or inappropriate, or which otherwise do not enhance drug
product quality in the manufacture of PET radiopharmaceuticals.
FDA is therefore proposing to amend its regulations to permit
manufacturers of PET radiopharmaceuticals to apply to the agency for
approval of an exception or alternative to the requirements of part 211
as they apply to the manufacture of PET radiopharmaceuticals. A request
for an exception or alternative must contain either an explanation why
compliance with a particular requirement of the CGMP regulations is
unnecessary or cannot be achieved, or a description of alternative
procedures or controls that satisfy the purpose of the CGMP
requirement. Both of these must include all necessary supporting data.
Alternatively, the request may include other information justifying an
exception or alternative. The request for an exception or alternative
may be approved by the agency if it is determined that 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 it has the identity and strength and meets the quality and purity
characteristics that it purports or is represented to possess, or if
compliance with the requirement cannot be achieved. In addition, the
request for an exception or alternative may be approved if the
requestor's alternative procedures or controls satisfy the purpose of
the CGMP requirement, or if the requestor's submission otherwise
justifies an exception or alternative. The agency may withdraw approval
of an exception or alternative if it finds, on the basis of new
information, that the criteria for approval are no longer met. Such
withdrawal will be accomplished by providing written notice, and the
reasons for the action, to the original requestor.
The agency will also periodically provide guidance to the industry
on the application of the CGMP regulations to PET radiopharmaceuticals.
Elsewhere in this issue of the Federal Register, FDA is publishing:
(1) A notice of availability of a draft guideline to assist persons in
determining whether certain manufacturing practices, procedures, and
facilities used for PET radiopharmaceuticals are in compliance with
FDA's CGMP regulations; and (2) a notice of a public workshop and FDA
guidance on the regulation of PET radiopharmaceuticals.
FDA is requesting written comments within 30 days after the date of
publication of this proposed rule. In addition, FDA is proposing that
any final rule that may publish as a result of this proposal become
effective on its date of publication in the Federal Register. The
proposed rule would permit manufacturers of PET radiopharmaceuticals to
apply to FDA for approval of an exception or alternative to the
requirements of the CGMP regulations. Accordingly, the proposed rule,
if finalized, 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 21 CFR 10.40(c)(4)(i).) In addition, the
Commissioner of Food and Drugs finds good cause under 21 CFR
10.40(a)(2) for providing 30 days for comments instead of 60 days and
under 5 U.S.C. 553(d)(3) and 21 CFR 10.40(c)(4)(ii) for making a final
rule based on this proposal effective upon its publication in the
Federal Register. The manufacturing process for PET
radiopharmaceuticals is sufficiently different from that of other
regulated products that application of certain CGMP requirements to PET
radiopharmaceuticals is impractical. Because PET radiopharmaceuticals
are already in use, a longer comment period or a later effective date
may delay FDA approval or hinder appropriate application of CGMP
regulations to PET radiopharmaceuticals, that are necessary to protect
the integrity of the drug manufacturing process.
II. Request for Comments
Interested persons may, on or before March 29, 1995, submit to the
Dockets Management Branch (HFA-305), Food and Drug Administration, rm.
1-23, 12420 Parklawn Dr., Rockville, MD 20857, 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.
III. 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 [[Page 10519]] nor an environmental impact
statement is required.
IV. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
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). The agency believes that
this proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the proposed
rule is not a significant regulatory action as defined by the Executive
Order and so is not subject to review under the Executive Order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. The agency certifies that the proposed rule will not
have a significant impact on a substantial number of small entities.
Therefore, under the Regulatory Flexibility Act, no further analysis is
required.
For the reasons explained above, FDA proposes that any final rule
based on this proposal become effective on the date of publication in
the Federal Register.
V. Paperwork Reduction Act of 1980
This proposed rule contains information collections that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1980. The title, description, and
respondent description of the information collection are shown below
with an estimate of the annual reporting and recordkeeping burden.
Included in the estimate is the time for reviewing instructions,
searching existing data sources, gathering and maintaining the data
needed, and completing and reviewing the collection of information.
Title: Current Good Manufacturing Practice for Finished
Pharmaceuticals: Positron Emission Tomography
Description: The proposal would permit manufacturers of PET
products to apply to the agency for approval of an exception or
alternative to the requirements of the CGMP regulations. The regulation
is intended to relieve PET manufacturers, nearly all of whom are small
entities, from regulations that might result in unsafe handling of PET
radiopharmaceuticals, that are inapplicable or inappropriate, or that
otherwise do not enhance safety or quality in the manufacture of PET
radiopharmaceuticals.
Description of Respondents: Businesses; small businesses.
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ESTIMATED ANNUAL REPORTING BURDEN:
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No. of Responses Per
Section Number of Respondents Respondents Total Annual Responses Hours Per Response Total Hours
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21 CFR 211.1(d)........ 60 1 60 4 240
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We have submitted a copy of this proposed rule to OMB for its
review of these information collections. Send comments regarding this
burden estimate or any other aspect of this collection of information,
including suggestions for reducing this burden, to the agency official
designated for this purpose whose name appears in this preamble, and to
the Office of Information and Regulatory Affairs, OMB, Washington, D.C.
20503.
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, it is
proposed that 21 CFR part 211 be 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:
Sec. 211.1 Scope.
* * * * *
(d) The Director of the Center for Drug Evaluation and Research or
the Director of the Office of Compliance, Center for Drug Evaluation
and Research, may approve an exception or alternative to any
application of this part to the manufacture of positron emission
tomography (PET) radiopharmaceuticals. Requests for such exceptions or
alternatives should ordinarily be made in writing. However, in certain
circumstances, such requests may be made orally and permission may be
granted orally. Oral requests and oral approvals must be followed by
written requests and written approvals. Approval of a request for an
exception or alternative must be obtained from either specified
Director prior to the use of any affected PET radiopharmaceutical.
(1) A request for an exception or alternative is required to
contain one of the following:
(i) An explanation, with supporting data as necessary, why
compliance with a particular requirement of this part is unnecessary or
cannot be achieved;
(ii) A description, with supporting data as necessary, of
alternative procedures or controls that satisfy the purpose of the
requirement; or
(iii) Other information justifying an exception or alternative.
(2) The Director may approve a request for an exception or
alternative if the Director finds one of the following:
(i) The requestor's compliance with the 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 cannot be achieved;
(ii) The requestor's alternative procedures or controls satisfy the
purpose of the requirement; or
(iii) The requestor's submission otherwise justifies an exception
or alternative.
(3) The Director may withdraw approval of an exception or
alternative if the Director finds, on the basis of new information,
that the criteria for approval in paragraph (d)(2) of this section are
no longer met. Withdrawal of approval shall be accomplished by
providing written notice of such [[Page 10520]] withdrawal, and the
reasons for the withdrawal, to the original requestor.
Dated: February 17, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-4690 Filed 2-24-95; 8:45 am]
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