[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]



=======================================================================
-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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.

--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                           ESTIMATED ANNUAL REPORTING BURDEN:                                                           
---------------------------------------------------------------------------------------------------------------------------------------------------------
                                                   No. of Responses Per                                                                                 
        Section          Number of Respondents         Respondents          Total Annual Responses      Hours Per Response            Total Hours       
--------------------------------------------------------------------------------------------------------------------------------------------------------
21 CFR 211.1(d)........                    60                          1                        60                         4                        240 
--------------------------------------------------------------------------------------------------------------------------------------------------------

    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]
BILLING CODE 4160-01-F