Current Good Manufacturing Practice for Positron Emission Tomography Drugs, 55038-55062 [05-18510]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 70, Number 181 (Tuesday, September 20, 2005)]
[Proposed Rules]
[Pages 55038-55062]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-18510]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 210, 211, and 212

[Docket No. 2004N-0439]


Current Good Manufacturing Practice for Positron Emission 
Tomography Drugs

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing proposed 
regulations on current good manufacturing practice (CGMP) for positron 
emission tomography (PET) drug products. The regulations are intended 
to ensure that PET drug products meet the requirements of the Federal 
Food, Drug, and Cosmetic Act (the act) regarding safety, identity, 
strength, quality, and purity. We are proposing to establish CGMP 
requirements for approved PET drug products. For investigational and 
research PET drugs, the proposed rule states that the requirement to 
follow CGMP may be met by producing PET drugs in accordance with the 
United States Pharmacopeia (USP) general chapter on compounding PET 
radiopharmaceuticals. We are proposing to establish these CGMP 
requirements for all PET drugs under the provisions of the Food and 
Drug Administration Modernization Act of 1997 (the Modernization Act). 
Elsewhere in this issue of the Federal Register, FDA is announcing the 
availability of the draft guidance entitled ``PET Drug Products--
Current Good Manufacturing Practice (CGMP).''

DATES: Submit written or electronic comments by December 19, 2005. 
Submit written comments on the information collection requirements by 
October 20, 2005. See section VII of this document for the proposed 
effective date of a final rule based on this document.

ADDRESSES: You may submit comments, identified by Docket No. 2004N-
0439, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: https://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.

Written Submissions

    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and Docket No(s). or Regulatory Information Number (RIN) for this 
rulemaking. All comments received may be posted without change to 
https://www.fda.gov/ohrms/dockets/default.htm, including any personal 
information provided. For detailed instructions on submitting comments 
and additional information on the rulemaking process, see the 
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this 
document.
    Docket: For access to the docket to read background documents or 
comments received, go to https://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number(s), found in brackets in the heading of 
this document, into the ``Search'' box and follow the prompts and/or go 
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Brenda Uratani, Center for Drug 
Evaluation and Research (HFD-320), Food and Drug Administration, 11919 
Rockville Pike, Rockville, MD 20852, 301-827-8941.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction
    A. Background
    B. The Modernization Act and PET Drugs
    C. The Nature of PET Drug Production and Our Proposed Regulations
II. Description of the Proposed Rule
    A. Exclusion of PET Drug Products From CGMP Regulations in Parts 
210 and 211
    B. Definitions
    C. Describing CGMP Requirements for PET Drugs
    D. Applicability of CGMP Regulations
    E. Adequate Personnel and Resources
    F. Quality Assurance
    G. Facilities and Equipment
    H. Control of Components, Containers, and Closures
    I. Production and Process Controls
    J. Laboratory Testing Requirements
    K. Stability
    L. Controls and Acceptance Criteria for Finished Products
    M. Actions To Be Taken if Product Does Not Conform to 
Specifications
    N. Labeling and Packaging
    O. Distribution Controls
    P. Complaint Handling
    Q. Records
III. Analysis of Economic Impacts
    A. Regulatory Benefits
    B. Regulatory Costs
    C. Compliance Requirements
1. Costs to Establish SOPs
2. Equipment Costs
3. Process Verification Costs

[[Page 55039]]

4. Total Costs
    D. Growth of the PET Industry
    E. Regulatory Flexibility Analysis
1. Objective of the Rule
2. Definition of Small Entities
3. Impact on Small Entities
4. Other Federal Rules
5. Description of Alternatives
IV. Environmental Impact
V. The Paperwork Reduction Act of 1995
    A. Investigational and Research PET Drugs
    B. Batch Production and Control Records
    C. Equipment and Facilities Records
    D. Records of Components, Containers, and Closures
    E. Process Verification
    F. Laboratory Testing Records
    G. Sterility Test Failure Notices
    H. Conditional Final Releases
    I. Out-of-Specification Investigations
    J. Reprocessing Procedures
    K. Distribution Records
    L. Complaints
VI. Federalism
VII. Proposed Effective Date
VIII. Request for Comments

I. Introduction

A. Background

    Positron emission tomography is a medical imaging modality 
involving the use of a unique type of radiopharmaceutical drug product. 
The majority of PET drug products are injected intravenously into 
patients for diagnostic purposes. Most PET drugs are produced using 
cyclotrons and other production equipment at locations that are close 
to the patients to whom the drugs are administered (e.g., in hospitals 
or academic institutions). Due to their short half-lives, PET drugs 
usually are administered to patients within a few minutes or hours of 
production.
    Under section 501(a)(2)(B) of the act (21 U.S.C. 351(a)(2)(B)), a 
drug is adulterated if the methods used in, or the facilities or 
controls used for, its manufacture, processing, packing, or holding do 
not conform to or are not operated or administered in conformity with 
CGMP to ensure 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. 
Our CGMP requirements for non-PET drug products are set forth in parts 
210 and 211 (21 CFR parts 210 and 211).

B. The Modernization Act and PET Drugs

    On November 21, 1997, the President signed the Modernization Act 
(Public Law 105-115) into law. Section 121 of the Modernization Act 
contains several provisions affecting the regulation of PET drugs. 
Section 121(d) directed us to terminate the application of the 
following three Federal Register documents:
     A notice entitled ``Regulation of Positron Emission 
Tomography Radiopharmaceutical Drug Products; Guidance; Public 
Workshop'' (60 FR 10594, February 27, 1995). This notice stated that 
traditional CGMP requirements in parts 210 and 211 were applicable to 
PET drugs.
     A notice that announced the availability of a draft 
guideline on the production of PET drugs (60 FR 10593, February 27, 
1995).
     A final rule authorizing us to approve exceptions or 
alternatives to the application of CGMP requirements to the production 
of PET drugs (62 FR 19493, April 22, 1997).
    We terminated the application of these three documents in a notice 
(62 FR 66636) and final rule (62 FR 66522) published in the December 
19, 1997, issue of the Federal Register.
    Section 121(c)(1)(A) of the Modernization Act directs us to 
establish appropriate approval procedures and CGMP requirements for PET 
drugs. Section 121(c)(2) of the Modernization Act provides that FDA 
cannot require the submission of a new drug application (NDA) or 
abbreviated new drug application (ANDA) for a PET drug product until 2 
years after the day we publish a final rule establishing CGMP 
requirements for PET drug products.
    Section 121(c)(1)(B) of the Modernization Act states that, in 
adopting CGMP and approval requirements, we must take due account of 
any relevant differences between not-for-profit institutions that 
compound PET drugs for their patients and commercial manufacturers of 
such drugs. We discuss the nature of PET drug production in section I.C 
of this document.
    Section 121(c)(1)(B) of the Modernization Act also directs us, as 
we develop PET drug CGMP requirements and approval procedures, to 
consult with patient advocacy groups, professional associations, 
manufacturers, and physicians and scientists who make or use PET drugs. 
We have taken the following steps in developing the PET drug CGMP 
regulations:
     We presented our initial tentative approach to PET drug 
CGMP requirements and responded to numerous questions and comments 
about that approach at a public meeting on February 19, 1999.
     In accordance with Sec. Sec.  10.40(f)(4) and 10.80(b)(2) 
(21 CFR 10.40(f)(4) and 10.80(b)(2), we announced the availability of 
preliminary draft regulations on PET drug CGMP requirements in the 
September 22, 1999, issue of the Federal Register (64 FR 51274).
     We held a public meeting to discuss the preliminary draft 
regulations on September 28, 1999.
     After considering the comments on the preliminary draft 
regulations, in accordance with Sec. Sec.  10.40(f)(4) and 10.80(b)(2), 
we announced the availability of a preliminary draft proposed rule on 
PET drug CGMP requirements in the April 1, 2002, issue of the Federal 
Register (67 FR 15344).
     We also announced the availability of a draft guidance on 
``PET Drug Products--Current Good Manufacturing Practice for Positron 
Emission Tomography'' on April 1, 2002 (67 FR 15404).
     We held a public meeting to discuss the preliminary draft 
proposed rule and draft guidance on April 21, 2002.
     After considering the comments on the preliminary draft 
proposed rule, we are now issuing this proposed rule on PET drug CGMP 
requirements. Elsewhere in this issue of the Federal Register, we are 
making available for comment a revised draft guidance on CGMP for PET 
drug products.

C. The Nature of PET Drug Production and Our Proposed Regulations

    As directed by Congress in the Modernization Act, to aid our 
development of these proposed regulations, we closely examined the 
operations of many PET drug producers, including not-for-profit 
institutions and commercial manufacturers. Since the Modernization Act 
became law, PET drug production in the United States has significantly 
changed. The number of PET production facilities has increased, as has 
the number of facilities where PET scans are performed. The business of 
PET drug production has changed as well. Historically, PET drug 
products were produced by academicians and researchers at facilities 
located in universities and similar not-for-profit institutions. These 
academically oriented PET production facilities usually produce small 
amounts (a few doses per day) of a few PET drug products for onsite 
patient use and a larger variety of PET drug products for clinical 
investigation and academic research.
    An increasing number of PET production facilities are now operated

[[Page 55040]]

by large, for-profit corporate entities that contract with academic and 
medical institutions (many of which have not-for-profit status) to 
manage the production of PET drugs at those institutions. Most of these 
PET drug products are administered onsite, although there is some 
distribution to other local or regional hospitals.
    In addition, there are a growing number of independent PET 
production facilities that are not affiliated with any university or 
hospital. Typically these are for-profit, independently operated 
facilities, although they are often contractually managed. These 
facilities generally focus on producing one or two PET drug products 
and distribute them to significantly greater numbers of patients, 
sometimes hundreds of miles from the production site.
    Our review of PET drug production leads us to the following 
conclusions:
     A PET drug producer's status as either a not-for-profit or 
for-profit entity does not have a significant bearing on the quality of 
PET drugs that it produces and distributes for administration to 
patients, or the methods, facilities, and controls that a PET 
production facility needs to ensure product quality.
     Production and CGMP differences among PET drug producers 
are primarily a function of the size, scope, and complexity of their 
production operations.
     Certain production standards and controls are necessary to 
ensure the production of quality PET drugs regardless of differences in 
the nature and scope of production among facilities.
    While this proposed rule and the draft guidance primarily reflect 
our familiarity with the current approved PET drugs (fludeoxyglucose 
(FDG) F 18 injection and ammonia N 13 injection), we intend both the 
proposed rule and the draft guidance to apply to future PET drug 
products. We also recognize that the development of new PET drug 
products may require us to amend regulations or guidance to accommodate 
the new products.
    This proposed rule on CGMP requirements contains the minimum 
standards needed for PET drug production at all types of PET production 
facilities. We have designed the CGMP regulations to be sufficiently 
flexible to accommodate not-for-profit, academically oriented 
institutions as well as larger commercial producers.
    In consideration of the unique nature of PET drugs and PET drug 
production, the proposed CGMP requirements for PET drug products differ 
in many significant ways from the CGMP requirements for non-PET drug 
products found in our regulations in part 211. The proposed PET CGMP 
requirements include the following differences:
     Fewer required personnel with fewer organizational 
restrictions consistent with the scope and complexity of operations;
     Allowance for multiple operations (or storage) in the same 
area as long as organization and other controls are adequate;
     Streamlined requirements for aseptic processing consistent 
with the nature of the production process;
     Streamlined quality control requirements for components;
     Self-verification of significant steps in PET drug 
production consistent with the scope and complexity of operations;
     Same-person oversight of production, review of batch 
records, and authorization of product release consistent with the scope 
and complexity of operations;
     Specialized quality control requirements for PET drugs 
produced in multiple sub-batches; and
     Simplified labeling requirements consistent with the scope 
and complexity of operations.
    These and other proposed PET CGMP provisions, designed to reflect 
the unique characteristics of PET drug production, should make it 
easier for PET production facilities to achieve compliance with CGMP 
requirements.
    This proposed rule incorporates principles from Chapter <823>, 
``Radiopharmaceuticals for Positron Emission Tomography--Compounding,'' 
of the 28th edition of the USP (2005) (USP 28). The USP contains 
standards that are of significant regulatory importance for PET drugs. 
Under section 501(a)(2)(C) of the act, a compounded PET drug is 
adulterated unless it is produced in compliance with the USP's PET drug 
compounding standards and the official monograph for the particular PET 
drug. Section 121(b) of the Modernization Act added this provision as a 
safety net while we develop this rule. Under section 121(b) of the 
Modernization Act, however, section 501(a)(2)(C) of the act will expire 
2 years after the date on which we establish final approval procedures 
and CGMP requirements for PET drugs. At that time, compliance with the 
final version of this rule will be required. The USP 28 general chapter 
on PET drug compounding largely reflects the consensus views of the PET 
community and FDA on how to properly produce PET drug products. 
Consequently, we believe it is appropriate to incorporate many of the 
principles and concepts in the USP general chapter into these proposed 
CGMP requirements.
    Moreover, as discussed in section II.D of this document, we believe 
that it is appropriate to designate the provisions of USP 28, Chapter 
<823> as the CGMP requirements for investigational PET drugs produced 
under an investigational new drug application (IND) and research PET 
drugs produced with the approval of a Radioactive Drug Research 
Committee (RDRC) under Sec.  361.1 (21 CFR 361.1). Thus, under the 
proposed rule, investigational and research PET drugs produced in 
accordance with Chapter <823> would be deemed to meet CGMP 
requirements; they would not have to meet the more specific 
requirements in proposed part 212. Because most PET drugs currently are 
produced under an IND or RDRC review, adopting USP 28, Chapter <823> as 
the standard for CGMP for investigational PET drugs should make it 
easier for PET drug producers to comply with the proposed CGMP 
requirements.
    To further assist PET production facilities in complying with the 
requirements in the rule, we have revised the draft guidance document 
entitled ``PET Drug Products--Current Good Manufacturing Practice 
(CGMP).'' For many aspects of CGMP (such as resources, controls, and 
documentation), the draft guidance makes different recommendations 
depending on the size, scope, and complexity of a PET production 
facility's operations. The draft guidance provides practical examples 
of methods and procedures that different types of PET production 
facilities might use to comply with the CGMP requirements.

II. Description of the Proposed Rule

    We are proposing to establish CGMP regulations for PET drug 
products by creating 21 CFR part 212. These regulations are intended to 
ensure that every PET drug product meets the requirements of the act as 
to safety and has the identity and strength, and meets the quality and 
purity characteristics, that it is represented to possess.
    We describe our proposed CGMP regulations for PET drug production 
in the following sections of this document. The format of the proposed 
regulations, including the use of questions in section headings, is in 
accordance with the Presidential Memorandum of June 1, 1998, promoting 
the use of plain language in regulatory writing.

A. Exclusion of PET Drug Products From CGMP Regulations in Parts 210 
and 211

    We propose revising certain sections of parts 210 (CGMP for the 
manufacturing, processing, packing, or

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holding of drugs) and 211 (CGMP for finished pharmaceuticals) to make 
clear that the regulations in those parts do not apply to PET drug 
products. The revisions are in Sec.  210.1 (status of CGMP 
regulations), Sec.  210.2 (applicability of CGMP regulations), and 
Sec.  210.3 (definitions). We propose revising the text of each of 
these sections so that the provisions will only apply to parts 210, 
211, 225, and 226, rather than part 210 and parts 211 through 226. The 
revisions would exclude part 212, which will address PET drug products, 
from the scope of Sec. Sec.  210.1, 210.2, and 210.3. Similarly, we 
propose to revise Sec.  211.1(a) (scope of CGMP for finished 
pharmaceuticals) to clarify that the regulations in part 211 do not 
apply to PET drug products.

B. Definitions

    Proposed Sec.  212.1 sets forth the meaning of several terms used 
in the PET drug CGMP regulations. Most of the definitions are self-
explanatory and well understood by PET producers and the pharmaceutical 
industry. We will discuss here a few of the definitions for which added 
comment may help the reader better understand the provision.
     Acceptance criteria. We propose to define ``acceptance 
criteria'' as numerical limits, ranges, or other criteria for tests 
that are used for or in making a decision to accept or reject a unit, 
lot, or batch of a PET drug product. This varies slightly from the 
definition in part 210, which states that acceptance criteria are the 
``product specifications and acceptance/rejection criteria, such as 
acceptable quality level and unacceptable quality level, with an 
associated sampling plan, that are necessary for making a decision to 
accept or reject a lot or batch (or any other convenient subgroups of 
manufactured units).'' The proposed definition, which does not refer to 
sampling plans, is more appropriate for PET drug production.
     Specifications. We propose a separate definition of 
``specifications'' to mean the tests, analytical procedures, and 
appropriate acceptance criteria to which a PET drug, PET drug product, 
component, container closure system, in-process material, or other 
material used in PET drug production must conform to be considered 
acceptable for its intended use. Conformance to specifications would 
mean that a PET drug, PET drug product, component, container closure 
system, in-process material, or other material used in PET drug 
production, when tested according to the described analytical 
procedures, meets the listed acceptance criteria.
    The definitions for acceptance criteria and specifications are 
intended to be consistent with guidance in ``Q6A Specifications: Test 
Procedures and Acceptance Criteria for New Drug Substances and New Drug 
Products,'' prepared under the auspices of the International Conference 
on Harmonisation for Registration of Pharmaceuticals for Human Use 
(ICH). ICH works to promote the harmonization of technical requirements 
(including definitions, procedures, formats, and standards) for 
approval of pharmaceutical products among the European Union, Japan, 
and the United States.
     Active pharmaceutical ingredient. We propose to define 
``active pharmaceutical ingredient'' (API) for purposes of part 212 as 
a substance (excluding intermediates used in the synthesis of such 
substance) that is intended for incorporation into a finished PET drug 
product and is intended to furnish pharmacological activity or other 
direct effect in the diagnosis or monitoring of a disease or a 
manifestation of a disease in humans. For example, in the case of FDG F 
18 injection drug product, 2-deoxy-2-[18F]fluoro-D-glucose is 
considered the API. In a commonly used production method for FDG F 18 
injection, 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethane sulfonyl-[beta]-
D-mannopyranose (mannose triflate) and O 18 water are considered 
components that yield the API but are not part of the API.
     PET drug. We propose to define ``PET drug'' as a 
radioactive drug that exhibits spontaneous disintegration of unstable 
nuclei by the emission of positrons and is used for providing dual 
photon positron emission tomographic diagnostic images. The definition 
of PET drug includes any nonradioactive reagent, reagent kit, 
ingredient, nuclide generator, accelerator, target material, electronic 
synthesizer, or other apparatus or computer program to be used in the 
preparation of a PET drug. This definition closely parallels the 
statutory definition.
     PET drug product. We propose to define ``PET drug 
product'' as a finished dosage form that contains a PET drug, whether 
or not in association with one or more other ingredients. In other 
words, a PET drug product is the finished dosage form of a PET drug, 
with or without an excipient such as a diluent.
     Receiving facility. We propose to define ``receiving 
facility'' as any hospital, institution, nuclear pharmacy, imaging 
facility, or other entity or part of an entity that accepts a PET drug 
product that has been given final release. A receiving facility may be 
in the same area as or adjacent to the production area, in a different 
area but located in the same building as the production area, or at a 
site that is completely separate from the production area.
     Material release and final release. We propose to define 
``material release'' as the authoritative decision by a responsible 
person in a PET production facility to permit the use of a component, 
container and closure, in-process material, packaging material, or 
labeling in the production of a PET drug product. ``Final release,'' in 
contrast, is defined as the authoritative decision by a responsible 
person in a PET production facility to permit the use of a batch of a 
PET drug product in humans.
     Strength. We propose to define ``strength'' as the 
concentration of the API (radioactivity amount per volume or weight at 
the time of calibration). This proposed definition varies from the 
definition of ``strength'' in part 210 in that it specifies a 
radioactivity to volume (or weight) ratio rather than a weight/weight, 
weight/volume, or unit dose/volume ratio. The definition of strength 
for proposed part 212 reflects that PET drug products have radioactive 
APIs (quantified in units of radioactivity) and generally are produced 
in a solution or gas dosage form.

C. Describing CGMP Requirements for PET Drugs

    Proposed Sec.  212.2 answers the question ``What is current good 
manufacturing practice for PET drugs?'' Proposed Sec.  212.2 states 
that CGMP for PET drug products is the minimum requirements for the 
methods to be used in, and the facilities and controls used for, the 
production, quality control, holding, or distribution of PET drug 
products intended for human use. CGMP is intended to ensure that each 
PET drug product meets the requirements of the act as to safety and has 
the identity and strength, and meets the quality and purity 
characteristics, that it is supposed to have.

D. Applicability of CGMP Regulations

    Proposed Sec.  212.5 answers the question ``To what drugs do the 
regulations in this part apply?'' Proposed Sec.  212.5(a) states that:
     Part 212 applies only to the production, quality control, 
holding, and distribution of PET drug products.
     Any human drug product that does not meet the definition 
of a PET drug product must be manufactured in accordance with the CGMP

[[Page 55042]]

requirements in parts 210 and 211 of this chapter.
     Part 212 contains CGMP requirements for all PET drug 
products for human use, but proposed Sec.  212.5(b) specifies different 
CGMP requirements for investigational and research PET drugs.
    We believe that it is appropriate to have less detailed CGMP 
requirements for investigational and research PET drugs to allow for 
more flexibility in the production of these drugs. We also recognize 
that many investigational PET drugs may not have commercial potential. 
Therefore, proposed Sec.  212.5(b) states that the regulations in part 
212 do not apply to investigational PET drugs for human use produced 
under an IND in accordance with part 312 and research PET drugs 
produced with the approval of an RDRC in accordance with Sec.  361.1. 
Instead, proposed Sec.  212.5(b) states that, for investigational and 
research PET drugs, the requirement under the act to follow CGMP is met 
by producing drugs in accordance with USP 28 Chapter <823>, which is 
incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR 
part 51. Chapter <823> sets forth requirements on several aspects of 
PET drug production, including control of components, materials, and 
supplies, verification of procedures, stability testing and expiration 
dating, quality control, and sterilization and sterility assurance. 
Because most PET drug producers are very familiar with the requirements 
in USP 28 Chapter <823>, adopting the Chapter <823> provisions as the 
CGMP requirements for investigational and research PET drugs should 
greatly facilitate producers' compliance with those requirements. 
Although the provisions in USP 28 Chapter <823>, including those on 
documentation, are generally less specific and explicit than the 
requirements in proposed part 212, we believe that they are adequate to 
ensure that investigational and research PET drugs are produced safely 
under appropriate conditions, consistent with section 501(a)(2)(B) of 
the act. We are interested in any comments that suggest appropriate 
standards, other than USP 28 Chapter <823>, for PET drugs and drug 
products produced under an IND or with the approval of an RDRC.
    Although we propose that USP 28 Chapter <823>, rather than part 
212, would constitute the minimum CGMP requirements for investigational 
and research PET drugs, FDA retains the authority under section 704 of 
the act (21 U.S.C. 374) to inspect facilities where investigational or 
research PET drugs are produced to verify compliance with USP 28 
Chapter <823>. However, as with inspection of investigational studies 
of non-PET drugs, we generally would conduct inspections of facilities 
that produce investigational or research PET drugs only on a for-cause 
basis. An example of a situation that could lead to a for-cause 
inspection would be when we become aware of a potential safety concern 
related to the production of an investigational or research PET drug.

E. Adequate Personnel and Resources

    Proposed Sec.  212.10 answers the question ``What personnel and 
resources must I have?'' The proposal would require:
     A sufficient number of personnel with the necessary 
education, background, training, and experience to enable those 
personnel to perform their assigned functions, and
     Adequate resources, including facilities and equipment, to 
enable personnel to perform their functions.
    What constitutes ``adequate'' personnel and resources will depend 
in part on the size and complexity of the PET drug producer's 
operations. A PET production facility having a simple operation that 
produces only one or two doses each day (or week) of a single PET drug 
would need fewer personnel and other resources than a facility having a 
more complex operation that produces multiple PET drug products or a 
facility producing larger amounts of a PET drug product.

F. Quality Assurance

    Proposed Sec.  212.20 answers the question ``What activities must I 
perform to ensure product quality?'' Under proposed Sec.  212.20, PET 
drug product producers would be required to:
     Oversee production operations to ensure that each PET drug 
product meets the requirements of the act as to safety and has the 
identity and strength, and meets the quality and purity 
characteristics, that it is supposed to have (proposed Sec.  
212.20(a)). Each PET drug producer will determine what personnel should 
perform the quality assurance function; at some PET production 
facilities, it may be reasonable for the same personnel to be involved 
in both production and quality assurance.
     Examine and approve or reject components, containers, 
closures, in-process materials, packaging materials, labeling, and 
finished dosage forms to ensure compliance with procedures and 
specifications affecting the identity, strength, quality, or purity of 
a PET drug product (proposed Sec.  212.20(b)).
     Approve or reject, before implementation, any initial 
specifications, methods, processes, or procedures, and any proposed 
changes to existing specifications, methods, processes, or procedures, 
to ensure that they maintain the identity, strength, quality, and 
purity of the PET drug product when they are implemented. PET drug 
producers must demonstrate that any change does not adversely affect 
the identity, strength, quality, or purity of any PET drug product 
(proposed Sec.  212.20(c)).
     Review production records to determine whether errors have 
occurred. If errors have occurred or a production batch or any of its 
components fails to meet any of its specifications, the producer must 
determine the need for an investigation, conduct investigations when 
necessary, and take appropriate corrective action (proposed Sec.  
212.20(d)). Possible errors include miscalculating yield, omitting a 
production step, or transcription mistakes.
     Establish and follow written quality assurance procedures 
to ensure that quality assurance responsibilities are known to all 
personnel involved in PET drug product production (proposed Sec.  
212.20(e)).

G. Facilities and Equipment

    Proposed Sec.  212.30 answers the question ``What requirements must 
my facilities and equipment meet?'' Under proposed Sec.  212.30, a PET 
drug producer would be required to:
     Provide adequate facilities to ensure the orderly handling 
of materials and equipment, the prevention of mixups, and the 
prevention of contamination of equipment or product by substances, 
personnel, or environmental conditions that could reasonably be 
expected to have an adverse effect on product quality (proposed Sec.  
212.30(a)).
     Implement procedures to ensure that all equipment that 
could reasonably be expected to adversely affect the strength, quality, 
or purity of a PET drug product (such as a laminar airflow workbench or 
sterilizing filters) or give erroneous or invalid test results when 
improperly used or maintained (such as high pressure liquid 
chromatography (HPLC) devices) is clean, suitable for its intended 
purposes, properly installed, maintained, and capable of repeatedly 
producing valid results. PET production facilities must document their 
activities in accordance with these procedures (proposed Sec.  
212.30(b)).
     Ensure that equipment is constructed and maintained so 
that surfaces that contact components, in process materials, or PET 
drug products are not reactive, additive, or absorptive

[[Page 55043]]

so as to alter the quality of PET drug products (proposed Sec.  
212.30(c)).

H. Control of Components, Containers, and Closures

    Proposed Sec.  212.40 answers the question ``How must I control the 
components I use to produce PET drugs and the containers and closures I 
package them in?'' Under proposed Sec.  212.40, PET drug producers 
would be required to:
     Establish, maintain, and follow written procedures 
describing the receipt, login, identification, storage, handling, 
testing, approval, and rejection of components and drug product 
containers and closures. The procedures must be adequate to ensure that 
the components, containers, and closures are suitable for their 
intended use (proposed Sec.  212.40(a)).
     Establish appropriate written specifications for the 
identity, quality, and purity of components and for the identity and 
quality of drug product containers and closures (proposed Sec.  
212.40(b)).
    Proposed Sec.  212.40(c) specifies that:
     Upon receipt, each lot of components and containers and 
closures must be uniquely identified and tested or examined to 
determine whether it complies with the PET production facility's 
specifications.
     Any lot that does not meet its specifications, including 
any expiration date if applicable, or that has not yet received its 
material release, must not be used in PET drug production.
     Any incoming lot must be appropriately designated as 
either quarantined, accepted, or rejected.
     PET drug producers must use a reliable supplier as a 
source of each lot of each component, container, and closure.
    We are proposing to establish different requirements for 
examination and testing of components required under proposed Sec.  
212.40(c) depending on whether a PET drug producer conducts finished-
product testing that includes testing to ensure that the correct 
components have been used:
     When the finished-product testing of a PET drug product 
includes testing to ensure that the correct components have been used, 
the PET drug producer need only determine that each lot of incoming 
components complies with written specifications by examining a 
certificate of analysis provided by the supplier (proposed Sec.  
212.40(c)(1)(i)). We believe that the use of this type of finished-
product testing makes specific identity testing of components redundant 
and unnecessary. For example, when identity of the F 18 radionuclide is 
established as part of the finished-product testing and the method of 
production used is well-documented and understood (e.g., as in the 
\18\O (p,n) \18\F nuclear reaction), it can be reasonably argued that 
the component that yields this radionuclide is likely to be O 18 water. 
In this case, a specific identity test for O 18 water is not necessary 
before the lot is used in production. Similarly, a specific identity 
test before using a lot of mannose triflate may be redundant and 
unnecessary when: (1) A well-understood method of synthesis of FDG F 18 
is used, (2) a test to confirm the radiochemical identity is performed 
in the finished drug product, and (3) the mannose triflate was obtained 
from a reliable supplier with whom a relationship has been previously 
established.
     If the finished-product testing of a PET drug product does 
not include testing to ensure that the correct components have been 
used, the following provisions (proposed Sec.  212.40(c)(1)(ii)) would 
apply:
    --The PET drug producer would be required to conduct identity 
testing, using a test that is specific to the component, on each lot of 
a component that yields an active ingredient and each lot of an 
inactive ingredient.
    --For any other component, such as solvents or reagents, the PET 
drug producer would determine that each lot complies with written 
specifications by examining a certificate of analysis provided by the 
supplier.
    --If the PET drug producer prepares an inactive ingredient on site, 
the producer would be required to perform an identity test on the 
components used to make the inactive ingredient before those components 
could be released for use.
    However, if the PET drug producer uses as an inactive ingredient a 
product that is marketed as a finished drug product intended for 
intravenous administration, the producer would not need to perform a 
specific identity test on that ingredient.
    We are also proposing that PET drug producers would be required to 
do the following:
     Examine a representative sample of each lot of containers 
and closures for conformity to its written specifications (proposed 
Sec.  212.40(c)(2)).
     Perform at least a visual identification of each lot of 
containers and closures (proposed Sec.  212.40(c)(2)).
     Handle and store components, containers, and closures in a 
manner that prevents contamination, mixups, and deterioration and 
ensures that these items are and remain suitable for their intended use 
(proposed Sec.  212.40(d)).
     Keep a record of each shipment of each lot of components, 
containers, and closures they receive (proposed Sec.  212.40(e)), 
including the following information:
    --Identity and quantity of each shipment,
    --Supplier's name and lot number,
    --Date of receipt,
    --Results of any testing performed,
    --Disposition of rejected material, and
    --Expiration date, where applicable. (Some components may not have 
expiration dates.)

I. Production and Process Controls

    Proposed Sec.  212.50 answers the question ``What production and 
process controls must I have?'' Proposed Sec.  212.50 states that PET 
drug producers must have adequate production and process controls to 
ensure the consistent production of a PET drug product that meets the 
applicable standards of identity, strength, quality, and purity. 
Proposed Sec.  212.50 would require PET drug producers to have the 
following controls:
     Written production and process control procedures,
     Master production and control records,
     Batch and production control records,
     Production area and equipment checks,
     In-process materials controls, and
     Depending on finished-product testing, process 
verification.
    The proposed written production and process control procedures 
would ensure and document that all key process parameters are 
controlled and that any deviations from the procedures are justified 
(proposed Sec.  212.50(a)).
    The proposed master production and control records would document 
all steps in the PET drug product production and would include the 
following information (proposed Sec.  212.50(b)):
     The name and strength of the PET drug product;
     If applicable, the name and radioactivity or other 
measurement of each API and each inactive ingredient per batch or per 
unit of radioactivity or other measurement of the drug product, and a 
statement of the total radioactivity or other measurement of any dosage 
unit;
     A complete list of components designated by names and 
codes sufficiently specific to indicate any special quality 
characteristic;
     Identification of all major pieces of equipment used in 
production;

[[Page 55044]]

     An accurate statement of the weight or measurement of each 
component, using the same weight system (metric, avoirdupois, or 
apothecary) for each component (with reasonable variations permitted in 
the amount of component necessary if specified in the master production 
and control records);
     A statement of acceptance criteria on radiochemical yield, 
i.e., the minimum percentage of yield beyond which investigation and 
corrective action are required;
     Complete production and control instructions, sampling and 
testing procedures, specifications, special notations, and precautions 
to be followed; and
     A description of the PET drug product containers, 
closures, and packaging materials, including a specimen or copy of each 
label and all other labeling.
    The creation of a unique batch and production control record would 
be required each time a batch of a PET drug product is produced 
(proposed Sec.  212.50(c)), including the following information:
     The name and strength of the PET drug product,
     An identification number or other unique identifier of the 
specific batch that was produced,
     The name and radioactivity or other measure of each API 
and each inactive ingredient per batch or per unit of radioactivity or 
other measurement of the drug product,
     Each major production step (obtained from the approved 
appropriate master production and control record),
     Weights and identification codes of components,
     Dates and time of production steps,
     Identification of major pieces of equipment used in 
production of the batch,
     Testing results,
     Labeling,
     Initials or signatures of persons performing or checking 
each significant step in the operation, and
     Results of any investigations conducted.
    Proposed Sec.  212.50(d) would require production area and 
equipment checks to ensure cleanliness and suitability immediately 
before use, and a record of the checks.
    Proposed Sec.  212.50(e) specifies that process controls for PET 
production facilities include control of in-process materials to ensure 
that the materials are controlled until required tests or other 
verification activities have been completed or necessary approvals are 
received and documented.
    Proposed Sec.  212.50(f) would establish different requirements for 
process verification depending on whether a PET drug producer conducts 
full finished-product testing on a particular PET drug product:
     Proposed Sec.  212.50(f)(1) would exempt a PET drug 
product from these process verification requirements if each batch of 
that PET drug product, prior to human administration, undergoes full 
finished-product testing to ensure that the product meets all 
specifications. For example, process verification under proposed Sec.  
212.50(f)(2) would not be required for the production of FDG F 18 
where: (1) The entire batch is made in a single vial, (2) a sample from 
the vial is withdrawn for full finished-product testing, and (3) the 
finished product passes all established specifications (except for 
sterility) prior to human administration.
     When the results of the production of an entire batch of a 
PET drug product are not fully verified through finished-product 
testing or when only the initial sub-batch in a series is tested, 
process verification would be required. The PET drug producer would be 
required to demonstrate that the process for producing the PET drug 
product is reproducible and is capable of producing a drug product that 
meets the predetermined acceptance criteria (proposed Sec.  
212.50(f)(2)). While currently most, if not all, batches of PET drug 
products are fully verified through finished-product testing, future 
PET drug products may not be suitable for finished-product testing of 
an entire batch due to the short half-life of the radionuclide, and 
process verification would be required.
     When process verification activities are conducted, the 
PET drug producer would be required to document activities and results, 
including the date and signature of the individual(s) performing the 
verification, the monitoring and control methods and data, and the 
major equipment qualified (proposed Sec.  212.50(f)(2)).
    For a PET facility that has an established history of producing a 
particular PET drug product, verification of that production process 
may be conducted retrospectively provided that the process has not 
changed and has not resulted in process-related failures. However, when 
a PET drug product is not fully verified through finished-product 
testing or when only the initial sub-batch in a series is tested, 
process verification would be required for any new production process 
and after any significant change to a qualified process.

J. Laboratory Testing Requirements

    Proposed Sec.  212.60 answers the question ``What requirements 
apply to the laboratories where I test components, in process 
materials, and finished PET drug products?'' Under proposed Sec.  
212.60, the following requirements would apply to laboratories used to 
conduct testing of components, in process materials, and finished PET 
drug products:
     Each laboratory must have and follow written procedures 
for the conduct of each test and for the documentation of the results 
(proposed Sec.  212.60(a)).
     Each laboratory must have sampling and testing procedures 
designed to ensure that components, in process materials, and PET drug 
products conform to appropriate standards, including established 
standards of identity, strength, quality, and purity (proposed Sec.  
212.60(b)).
     Laboratory analytical methods must be suitable for their 
intended use and must be sufficiently sensitive, specific, accurate, 
and reproducible (proposed Sec.  212.60(c)).
    If a compendial test is used, the testing laboratory should verify 
that the method works under the actual conditions of use and that the 
drug product as formulated can be analyzed using the compendial method. 
This verification is recommended because many compendial methods for 
PET drug products lack specific information (for example, they do not 
describe specific equipment used), the method may not have been 
developed in the context of the production method actually being used, 
and the PET production facility may not be using the same equipment 
that was used in the compendial method.
     The identity, purity, and quality of reagents, solutions, 
and supplies used in testing must be adequately controlled, and all 
solutions prepared by the PET production facility must be labeled with 
their identity and expiration date (proposed Sec.  212.60(d)).
     All testing equipment must be suitable for its intended 
purposes and capable of producing valid results (proposed Sec.  
212.60(e)).
     Each laboratory must have and follow written procedures to 
ensure that equipment is routinely calibrated, inspected, checked, and 
maintained, and these activities must be documented (proposed Sec.  
212.60(f)).
     Each laboratory performing tests related to the production 
of a PET drug product must keep complete records of all tests performed 
to ensure compliance with established specifications and

[[Page 55045]]

standards, including examinations and assays (proposed Sec.  
212.60(g)).
    The records required under proposed Sec.  212.60(g) would include 
the following:
     A description of the sample received for testing, 
including its source, the quantity, the batch or lot number, the date 
(and time, if appropriate) the sample was taken, and the date (and 
time, if appropriate) the sample was received for testing;
     A description of each method used in the testing of the 
sample, a record of all calculations performed in connection with each 
test, and a statement of the weight or measurement of the sample used 
for each test;
     A complete record of all data obtained in the course of 
each test, including all graphs, charts, and spectra from laboratory 
instrumentation, properly identified to show the specific component, 
in-process material, or drug product for each lot tested;
     A statement of the results of tests and how the results 
compare with established acceptance criteria; and
     The initials or signature of the person performing the 
test and the date on which the test was performed.

K. Stability

    Proposed Sec.  212.61 answers the question ``What must I do to 
ensure the stability of my PET drug products through expiry?'' Proposed 
Sec.  212.61 would provide the following requirements to ensure the 
stability of PET drug products:
     PET production facilities must establish, follow, and 
maintain a written testing program to assess the stability 
characteristics of their PET drug products (proposed Sec.  212.61(a)).
     Test methods must be reliable, meaningful, and specific 
(i.e., they must be capable of determining the stability 
characteristics of the PET drug product) (proposed Sec.  212.61(a)).
     Samples tested for stability must be representative of the 
lot or batch from which they were obtained and must be stored under 
suitable conditions (proposed Sec.  212.61(a)).
     Results of the stability testing must be documented and 
used in determining appropriate storage conditions and expiration dates 
and times for each PET drug product (proposed Sec.  212.61(b)).

L. Controls and Acceptance Criteria for Finished Products

    Proposed Sec.  212.70 answers the question ``What controls and 
acceptance criteria must I have for my finished PET drug products?'' 
These controls and acceptance criteria are the requirements that must 
be met before a PET production facility may give final release to a 
finished PET drug product. We propose to establish the following 
requirements regarding controls and acceptance criteria:
     PET production facilities would be required to establish 
specifications for each batch of a PET drug product, including criteria 
for identity, strength, quality, purity, and, if appropriate, sterility 
and pyrogenicity (proposed Sec.  212.70(a)). Most, but not all, PET 
drugs are sterile injectable products, and such products would be 
required to have specifications for sterility and pyrogenicity.
     Before a PET drug producer implements a test procedure in 
a specification, the producer would be required to establish and 
document the accuracy, sensitivity, specificity, and reproducibility of 
the procedure (proposed Sec.  212.70(b)).
     If the PET drug producer uses an established compendial 
test procedure in a specification, the producer would be required to 
first verify and document that the test works under the conditions of 
actual use (proposed Sec.  212.70(b)).
     PET drug producers would be required to conduct laboratory 
testing of a representative sample of each batch of a PET drug product 
before final release to ensure that the batch conforms to its 
specifications, except for sterility. For a PET drug product produced 
in sub-batches (e.g., ammonia N 13 injection), at least each initial 
sub-batch that is representative of the entire batch must conform to 
specifications, except for sterility, before final release (proposed 
Sec.  212.70(c)).
     Under proposed Sec.  212.70(d), producers would be 
required to establish and follow procedures to ensure that a PET drug 
product is not given final release until:
    --Appropriate laboratory testing under paragraph (a) of this 
section is completed,
    --Associated laboratory data and documentation are reviewed (review 
may be performed by a second person or self-verified in a one-person 
operation) and they demonstrate that the PET drug product meets 
specifications, except for sterility, and
    --A designated qualified individual authorizes final release by 
dated signature.
    In many cases, the short half-life of a PET radionuclide precludes 
the completion and review of all laboratory testing before release of 
the PET drug product for distribution to a receiving facility. In such 
cases, release for distribution in accordance with previously 
established and documented procedures is acceptable as long as all 
testing and review, except for sterility, is completed before final 
release of the drug product. The PET production facility should 
document the communication of this authoritative decision to the 
receiving facility.
    We are proposing special requirements for sterility testing because 
of the short half-lives of PET radionuclides. Proposed Sec.  212.70(e) 
provides that:
     Sterility testing need not be completed before final 
release but must be performed within 30 hours after completion of 
production. Sterility testing should normally be started within 24 
hours after production. We propose the additional 6 hours in response 
to the concerns of some PET drug producers that a 24-hour test 
initiation period would coincide with the peak activity for PET 
production the following day. Proposed Sec.  212.70(e) would allow the 
30-hour period to be exceeded in certain cases, such as weekends or 
holidays, provided it is shown that the extended period will not affect 
the stability or viability of the contaminants in the product or 
otherwise yield a potentially inaccurate result.
     Product samples must be tested individually and must not 
be pooled.
     If the product fails the sterility test, all receiving 
facilities must be notified of the results immediately.
     The notification must include any appropriate 
recommendations and must be documented.
    We are also including in this proposal a provision to allow the 
conditional final release of PET drug products under certain 
conditions. At the September 28, 1999, public meeting on PET drug 
product CGMP, some comments stated that the regulations should allow 
PET drug producers to release a PET drug product if they experience an 
unanticipated, temporary failure of analytical equipment that prevents 
them from completing final release testing. The comments maintained 
that having duplicative equipment was difficult for smaller PET 
production facilities. They stated that having to cancel scheduled PET 
scans because of analytical equipment failure would inconvenience 
physicians and patients, some of whom may have traveled long distances 
to undergo the diagnostic procedure.
    In our preliminary draft proposed rule, we requested comments on 
whether the regulations should allow the conditional final release of 
PET drug products in case of equipment breakdown and, if so, what 
conditions should apply to such release. Nearly all the comments that 
we received on this matter requested that conditional final release be 
permitted. After

[[Page 55046]]

consideration of the comments, we propose to allow the conditional 
final release of PET drug products under certain conditions.
    Under proposed Sec.  212.70(f), a PET drug producer that cannot 
complete one of the required finished product tests for a PET drug 
product because of a breakdown of analytical equipment may approve the 
conditional final release of the product if the conditions in proposed 
Sec.  212.70(f)(1) through (f)(7) are met. These conditions would 
require the PET drug producer to do the following:
     Have data to document that preceding consecutive batches, 
produced using the same method of production as the conditionally 
released batch, demonstrate that the conditionally released batch will 
likely meet the established specifications,
     Determine that all other acceptance criteria are met,
     Notify the receiving facility of the incomplete testing,
     Retain a reserve sample of the conditionally released 
batch of drug product,
     Complete the omitted test using the reserve sample after 
the analytical equipment is repaired and document that reasonable 
efforts have been made to ensure that the problem does not recur,
     Immediately notify the receiving facility if an out-of-
specification result is obtained when testing the reserve sample, and
     Document all actions regarding the conditional final 
release of the drug product, including the justification for the 
release, all followup actions, results of completed testing, all 
notifications, and corrective actions to ensure that the equipment 
breakdown does not recur.
    Conditional final release should be a rare occurrence. In general, 
we believe that a PET drug producer should be prepared for equipment 
failures. Conditional final release would not be permissible when 
certain types of equipment fail. If a PET drug producer could not 
perform a radiochemical identity/purity test on the API of a PET drug 
product, conditional final release of a PET drug product would not be 
allowed. There are, however, certain tests, such as the gas 
chromatography (GC)-based residual solvent determination in FDG F 18, 
where an equipment failure could result in the authorization of a 
conditional final release if all the criteria in proposed Sec.  
212.70(f) were met. Conditional final release would not generally be 
appropriate for certain tests where it is difficult to envision 
equipment failing or where equipment should be very easy to replace 
(for example, in the case of FDG F 18, the hydrogen-ion concentration 
(pH) test, test for kryptofix, thin layer chromatography based 
radiochemical identity and purity tests). Alternate test methods can be 
developed and used when these problems occur, so conditional final 
release should not be necessary except in very rare circumstances. 
Repeated conditional final releases based on the unavailability of 
equipment that is difficult to envision failing or that is easily 
replaced could be considered to be a failure to take ``reasonable 
efforts * * * to ensure that the problem does not recur'' and could 
lead to FDA taking enforcement action.

M. Actions To Be Taken if Product Does Not Conform to Specifications

    Proposed Sec.  212.71 answers the question ``What actions must I 
take if a batch of PET drug product does not conform to 
specifications?'' Proposed Sec.  212.71(a) states that:
     If a batch of a PET drug product does not conform to 
specifications, the PET drug producer must reject it.
     The producer must identify and segregate the nonconforming 
product to avoid mixups.
     The producer must have and follow procedures to 
investigate the causes of the nonconforming product.
     The investigation must include examination of processes, 
operations, records, complaints, and other relevant sources of 
information concerning the nonconforming product.
    Under the proposal, PET drug producers also would be required to:
     Document the investigation of a PET drug product that does 
not conform to specifications, including the results of the 
investigation and what happened to the rejected PET drug product 
(proposed Sec.  212.71(b)), and
     Take action to correct any identified problems to prevent 
recurrence of a nonconforming product or other quality problem 
(proposed Sec.  212.71(c)).
    PET drug producers would be permitted, if appropriate, to reprocess 
a batch of a PET drug product that does not conform to specifications 
(proposed Sec.  212.71(d)). To reprocess material that does not meet 
acceptance criteria:
     The producer must follow preestablished procedures (set 
forth in production and process controls) and
     The finished product must conform to specifications, 
except for sterility, before final release.
    Examples of reprocessing could include a second passage through a 
purification column to remove an impurity or a second passage through a 
filter if the original filter failed the integrity test.

N. Labeling and Packaging

    Proposed Sec.  212.80 answers the question ``What are the 
requirements associated with labeling and packaging PET drug 
products?'' Under proposed Sec.  212.80, the following requirements 
would apply:
     PET drug products must be suitably labeled and packaged to 
protect the product from alteration, contamination, and damage during 
the established conditions of shipping, distribution, handling and use 
(proposed Sec.  212.80(a)).
     Labels must be legible and applied so they will remain 
legible and affixed during the established conditions of processing, 
storage, handling, distribution, and use (proposed Sec.  212.80(b)).
     Information stated on each label must also be contained in 
each batch production record (proposed Sec.  212.80(c)).
     Labeling and packaging operations must be controlled to 
prevent product and labeling mixups (proposed Sec.  212.80(d)).

O. Distribution Controls

    Proposed Sec.  212.90 answers the question ``What actions must I 
take to control the distribution of PET drug products?'' This section 
would primarily apply to PET production facilities that distribute PET 
drug products beyond the immediate vicinity of the production site. 
Under proposed Sec.  212.90, PET drug producers would be required to:
     Establish, maintain, and follow written procedures for the 
control of distribution of PET drug products shipped from the PET 
production facility to ensure that shipping will not adversely affect 
the identity, purity, or quality of the PET drug product (proposed 
Sec.  212.90(a)).
     Maintain distribution records for each PET drug product 
(proposed Sec.  212.90(b)), including the following information:
    --Name, address, and telephone number of the receiving facility 
that received each batch of a PET drug product,
    --Name and quantity of the PET drug product shipped,
    --Lot number, control number, or batch number for the PET drug 
product shipped, and
    --Date and time the PET drug product was shipped.

P. Complaint Handling

    Proposed Sec.  212.100 answers the question ``What do I do if I 
receive a complaint about a PET drug product produced at my facility?'' 
We propose

[[Page 55047]]

the following requirements regarding complaints:
     PET drug producers must develop and follow written 
procedures for the receipt and handling of all complaints concerning a 
PET drug product (proposed Sec.  212.100(a)).
     The procedures must include review by a designated person 
of any complaint involving the possible failure of a PET drug product 
to meet any of its specifications and an investigation to determine the 
cause of the failure (proposed Sec.  212.100(b)).
     Producers must maintain a written reco