[Federal Register: September 20, 2005 (Volume 70, Number 181)]
[Proposed Rules]               
[Page 55038-55062]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr20se05-8]                         

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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availability of the draft guidance entitled ``PET Drug Products--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: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov. 

Follow the instructions for submitting comments.
     Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://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 
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://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 http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://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

[[Page 55041]]

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 record of each complaint 
in a file designated for PET drug product complaints (proposed Sec.  
212.100(c)), including the following information:
    --Name and strength of the PET drug product,
    --Batch number,
    --Name of the complainant,
    --Date the complaint was received,
    --Nature of the complaint,
    --Response to the complaint, and
    --Findings of any investigation and followup.
     PET drug products that are returned because of a complaint 
may not be reprocessed and must be destroyed in accordance with 
applicable Federal and State law (proposed Sec.  212.100(d)).

Q. Records

    Proposed Sec.  212.110 answers the question ``How must I maintain 
records of my production of PET drug products?'' Proposed Sec.  212.110 
would require that:
     PET drug producers maintain all records at the PET 
production facility or another location that is reasonably accessible 
to responsible officials of the production facility and to employees of 
FDA designated to perform inspections (proposed Sec.  212.110(a)). A 
reasonably accessible location is one that would enable the PET center 
to make requested records available to us in a reasonable period of 
time.
     All records, including those not stored at the inspected 
establishment, be legible, stored to prevent deterioration or loss, and 
readily available for review and copying by FDA employees (proposed 
Sec.  212.110(b)).
     PET drug producers maintain all records and documentation 
referenced in part 212 for at least 1 year after the final release or 
conditional final release of a PET drug product (proposed Sec.  
212.110(c)).

III. Analysis of Economic Impacts

    We have considered the potential economic impact of this proposed 
rule under Executive Order 12866 and the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Public 
Law 104-4). 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 the 
benefits (including potential economic, environmental, public health 
and safety, and other advantages; distributive impacts; and equity).
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing, ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $115 million, using the most current (2003) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The agency has determined that this proposed rule is not an 
economically significant rule as described in the Executive order 
because annual impacts on the economy are substantially below $100 
million. Under the Regulatory Flexibility Act, unless an agency 
certifies that a rule will not have a significant impact on a 
substantial number of small entities, the agency must analyze 
regulatory options that would minimize any significant economic impact 
of a rule on small entities. We project that the rule may have a 
significant effect on a substantial number of small entities. A 
regulatory flexibility analysis explaining this finding is presented in 
the following paragraphs.

A. Regulatory Benefits

    The Modernization Act requires us to establish appropriate good 
manufacturing practices for PET drugs. Without minimum manufacturing 
standards, unintentionally inferior PET drug products may be produced 
for human use. The short half-life characteristic of PET drug products 
often limits extensive and complete finished product testing prior to 
administration to humans. Moreover, recalls are usually impossible due 
to this short half-life, which can range from minutes to hours. Most 
PET drug products are marketed without FDA approval, and we have not 
received any official reports of adverse events. Official reports that 
can be relied upon to demonstrate or project the actual number of 
adverse events related to these products therefore do not exist. 
Tracing infections possibly caused by contaminated PET drugs to 
patients is difficult since there are a multitude of other factors that 
can cause infections in hospitalized patients, as well as a time delay 
before infection presents itself. Lacking this information, we are 
unable to quantify this proposal's reduction of risk of adverse events 
associated with PET drug products and the accompanying increase in 
public health benefits.
    This proposed rule would create minimum manufacturing standards to 
ensure the safety, identity, strength, quality, and purity of PET drug 
products. Although, as discussed in section III.B of this document, all 
PET drug producers have adopted some level of good manufacturing 
practices or SOPs, not all producers currently are fully compliant with 
all USP standards. Therefore, compliance with the provisions of the 
proposed rule would ensure that all producers establish and implement 
adequate SOPs for production and quality control, including internal 
procedures for product quality audits, resulting in consistent 
production of quality products. Building quality into the production 
process would permit early detection and correction of problems and 
promote continuous improvement. Activities such as developing 
specifications may result in increased reliability and uniformity of 
PET drug products to patients. Ultimately, this rule would be expected 
to result in a reduction in adverse reactions to PET drug products and 
an increase in overall benefit to the public health.

B. Regulatory Costs

    All PET drug producers have already adopted some level of good 
manufacturing practices or SOPs, although the specificity of the 
written documents may vary. The Modernization Act requires that 
compounded PET drugs conform to USP compounding standards and official 
monographs for PET drugs until CGMP regulations are established for PET 
drugs. For producers already following required USP standards, we would 
expect average compliance costs associated with this proposal to be 
small.
    The proposed CGMP rule is expected to affect all PET drug 
producers, especially those affiliated with hospitals and academic 
medical centers, as well as the small number of unaffiliated regional 
producers that produce FDG F 18. Most of the large corporate PET drug

[[Page 55048]]

producers and hospital PET drug producers associated with these 
corporate entities are expected to already comply to a great degree 
with the proposed CGMP rule. Based on our contacts with industry, we 
have made a general assessment of the current operational status of PET 
drug producers.
    For this cost analysis, we consulted with the PET community, 
including PET drug producers and professional associations, through 
direct contact as well as via public comments at public meetings and 
previously published preliminary proposed rules (for a full description 
of our interactions with the PET community regarding this proposed 
rule, see section I.B of this document). We visited six PET drug 
producers affiliated with academic medical centers and four commercial 
(corporate or regional) operations. Using the knowledge gained from 
these site visits, public meeting comments from industry members 
including the Academy of Molecular Imaging (AMI) (a primary 
professional organization for PET), and agency employee expertise in 
PET drug manufacturing procedures, we estimated the average level of 
effort needed to bring each of the different types of PET drug producer 
into compliance with this proposed rule. Compliance costs (labor costs) 
were then calculated using these estimated levels of effort. In effect, 
we projected compliance costs based on the expected additional labor 
above implicit baseline levels (based on information acquired through 
the site visits by FDA officials).
    The estimated number of U.S. establishments producing PET drug 
products was created by combining an AMI-prepared list of PET centers 
with cyclotrons with a list of PET manufacturing facilities from the 
Society of Nuclear Imaging in Drug Development (which has since merged 
with the AMI), and adding additional facilities that we identified. 
This resulted in the projection that the proposed rule would affect 51 
producers of PET drugs, operating 101 establishments. Fifteen of these 
producers own or operate 65 commercial establishments (16 of which are 
associated with academic hospitals). Of these 15 producers, 11 are 
regional or local unaffiliated producers that have begun to produce PET 
drug products in recent years. The other four commercial producers are 
corporations, each of which has multiple establishments. In total, 
these 4 corporate producers operate 48 establishments. The remaining 36 
producers are part of academic or hospital institutions (see table 1 of 
this document).

                                                              Table 1.--PET Drug Producers
--------------------------------------------------------------------------------------------------------------------------------------------------------
            Producer Type                                 No. of Producers                                        No. of Establishments
--------------------------------------------------------------------------------------------------------------------------------------------------------
Hospital/Academic\1\                                                                        36                                                        36
--------------------------------------------------------------------------------------------------------------------------------------------------------
Commercial-Regional                                                                         11                                                        17
--------------------------------------------------------------------------------------------------------------------------------------------------------
Commercial-Corporate \2\                                                                     4                                                        48
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                       51                                                       101
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Sixteen hospital producers operated by commercial firms are counted under Commercial-Corporate.
\2\ One producer may not be a corporation but is included here due to its multiple sites and longer history of PET drug production.

C. Compliance Requirements

    The proposed CGMP rule would impose compliance requirements 
resulting in two types of costs. From the date of publication of the 
final rule until the effective date, PET drug producers would incur 
one-time costs as each producer is brought into compliance. In 
succeeding years, each producer would be expected to incur only annual 
costs related to maintaining compliance.
    The following proposed sections contain the general requirements of 
the rule:
     Section 212.10: Require qualified and trained personnel.
     Section 212.20: Establish SOPs to define quality 
assurance.
     Section 212.30: Establish SOPs and prepare documents 
related to installation, cleaning, qualification, and maintenance of 
facilities and equipment.
     Section 212.40: Establish SOPs and prepare documents on 
the receipt, identification, storage, handling, testing, and approval 
of components and drug product containers and closures. Establish 
specifications for the components, containers, and closures.
     Section 212.50: Establish written production and process 
control procedures (including in-process parameters) for production of 
a PET drug. Prepare master production record and batch record.
     Section 212.60: Establish written procedures and schedules 
for the calibration, cleaning, and maintenance of laboratory testing 
equipment. Establish testing procedures for components, in-process 
materials and finished PET drug products.
     Section 212.61: Establish written procedures to assess the 
stability characteristics of PET drug products.
     Section 212.70: Establish acceptance criteria and written 
procedures to control the release of products. Prepare SOPs to 
establish system suitability of each test. Prepare documents to record 
tests performed on the PET drug product for final release.
     Section 212.71: Establish procedures to investigate the 
reason for product nonconformance.
     Section 212.80: Establish templates for labeling.
     Section 212.90: Establish procedures and documents for the 
distribution of PET drugs.
     Section 212.100: Establish procedures for the receipt and 
handling of complaints regarding a PET drug product.
    We expect some variation in the exact SOPs that would need to be 
created or revised to comply with the proposal. We expect that the 
various types of producers already comply with the proposed rule to 
different extents. The hospital PET drug producers and the independent 
regional commercial producers would likely require more time and effort 
to comply than would the group of corporate producers. Because of this, 
we estimated average compliance efforts for two separate groups based 
on expected current compliance levels--the corporate

[[Page 55049]]

producers and the hospital and regional commercial producers.
1. Costs to Establish SOPs
    All PET drug producers are expected to incur some costs associated 
with interpreting the rule, determining the manner of compliance, and 
implementing the compliance method. These costs would be included in 
the efforts of a designated individual or individuals who would be 
primarily responsible for bringing each center into compliance. In this 
case, we have included any general administrative efforts in the time 
required to establish and write the SOPs for the previously listed 
requirements and to prepare templates for CGMP documentation.
    The document entitled ``Sample Formats for Chemistry, 
Manufacturing, and Controls Sections''\1\ provides guidance that may be 
helpful in preparing master production records, finished-product 
release testing records, and in-coming component tracking and testing 
records. PET drug producers would have the option of choosing their own 
format (and the amount of detail) as long as essential information 
required by the CGMPs is included. We believe that the CGMP guidance 
will aid PET drug producers that have little or no experience in 
creating these documents, helping to reduce compliance costs.
---------------------------------------------------------------------------

    \1\ The document is an attachment to the guidance for industry 
entitled ``PET Drug Applications--Content and Format for NDAs and 
ANDAs: Fludeoxyglucose F 18 Injection, Ammonia N 13 Injection, 
Sodium Fluoride F 18 Injection'' (available on the Internet at 
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/guidance).

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

    We estimate that all hospital and regional commercial producers 
will need from 3 to 5 months to establish and write detailed SOPs that 
comply with this rule, even with the guidance provided and the 
understanding that these establishments currently operate under less-
detailed SOPs. We assume that the employee responsible for writing the 
SOPs would be in a management position, either in quality assurance or 
elsewhere, with a salary of up to $100,000 per year. Including an 
additional 35 percent for employee benefits, the cost of an average 4-
month effort would amount to $45,000 for each hospital and regional 
commercial PET drug producer.\2\
---------------------------------------------------------------------------

    \2\ Salary represents upper range of estimate (intended to not 
underestimate costs) provided at FDA site visit to a commercial PET 
drug producer on October 2, 2001. Although there is uncertainty 
concerning salaries paid by academic/hospital producers, we assume 
they would pay a salary similar to those of corporate producers.
---------------------------------------------------------------------------

    Although most corporate PET drug producers are believed to have a 
complete set of SOPs, we believe each would expend some time to verify 
its compliance with this proposal and make minor adjustments to their 
SOPs. We estimate that it would take, on average, 1 month for an 
individual to complete the same undertaking due to the current high 
compliance rates expected at the corporate establishments.\3\ This 
would result in a cost of approximately $11,250 per corporate PET drug 
producer, again using an estimated salary of $100,000 per year plus 
benefits. We assume that corporate producers with multiple 
manufacturing sites would amend a single set of SOPs to cover all of 
their production sites. Since there are currently four corporate 
producers of PET drug products, the cost of the SOP revisions is 
estimated at $45,000 (4 times $11,250).
---------------------------------------------------------------------------

    \3\ Labor hour estimate from FDA site visit to a PET drug 
producer on October 2, 2001.
---------------------------------------------------------------------------

    The SOP establishment or revision work could be performed by 
company personnel or an outside consultant or contractor. Although we 
predict that the use of an outside consultant or contractor would be 
more likely at the hospital and regional commercial PET drug producers, 
we would not expect the total cost of this compliance effort to vary 
considerably.
    Producers would also be expected to provide some additional 
training to at least one person on revisions made to current procedures 
to comply with the CGMP rule. While we do not think extensive training 
would be necessary at most establishments, our experience with PET drug 
production procedures and our 10 producer site visits leads us to 
believe that one person at each establishment could need up to 1 week 
of additional training. The cost of this additional training would 
amount to about $262,000 (101 establishments times 1 week at $135,000 
per year).
    The total cost for initial compliance associated with writing the 
SOPs and creating document forms amounts to approximately $2.42 
million. The 47 hospital and regional commercial producers would incur 
a total of about $2.25 million (47 producers times $45,000 plus 53 
establishments times $2,600). The 4 corporate producers would incur a 
total of about $170,000 (4 producers times $11,250 plus 48 
establishments times $2,600). Annualizing the total one-time cost over 
5 years at a 7-percent discount rate results in annualized costs of 
about $591,000 (at a 3-percent discount rate, the costs are estimated 
to be about $529,000).
    Once procedures are established and documents are in place to 
record PET drug production and events associated with routine 
production of PET drugs, we would expect there to be some additional 
costs for the day-to-day implementation of the CGMP provisions. 
Periodic audits conducted by company personnel to ensure compliance 
with current procedures would have to be expanded to include any 
provisions with which the company was not already in compliance (for 
example, tracking and recordkeeping of incoming components, proper 
documentation of production and laboratory testing, tracking, 
investigation and documentation of products not meeting 
specifications). Additional time would also be spent updating the SOPs 
as the equipment and procedures used in the manufacture of PET drugs 
are upgraded and refined.
    We project the day-to-day implementation of the CGMP rules would 
require, at most, 1 to 2 additional hours per day for an individual at 
each hospital or regional commercial producer. Using the midpoint of 
this range would result in 2.25 additional months of labor each year. 
Using the same estimated annual salary ($100,000 plus benefits), 2.25 
months of labor equates to about $25,300 in annual costs to each PET 
drug production establishment, or about $1.34 million for all 53 
hospital and regional commercial producer establishments. Our 
assessment of corporate PET drug producers is that they comply 
substantially with the proposed rule. For these producers, we project 
that 1 production individual may expend an additional 1 month of effort 
over the course of each year (about 3 hours per week) in order to 
comply with the proposed rule. This month would result in each 
corporate PET center incurring about $11,250 in additional annual 
costs, totaling $540,000 for the 48 corporate PET drug production 
establishments. Some producers would probably opt to use an outside 
consultant to manage the implementation of the new rules in the first 
year. Although we do not know how many producers would hire a 
consultant, we would not expect this to affect the total cost 
considerably, as the cost of the consultant would replace the cost of 
the company employee. Total annual costs for day-to-day implementation 
are estimated at $1.88 million.
    Producers would also be expected to provide some additional 
training in future years on SOPs that were amended to comply with this 
CGMP rule. We would expect that this training (review for current 
employees as well as new employees) would be incorporated into

[[Page 55050]]

current training programs and therefore be less burdensome to 
producers. Nevertheless, we have included the cost for annual training 
for one person per establishment for one-half week. The cost of this 
additional training would amount to about $131,000 (101 establishments 
times one-half week at $135,000 per year).
    Total annual costs associated with daily implementation and 
training amount to $2.01 million. The 53 hospital and regional 
commercial establishments would incur a total of about $1.41 million 
(53 establishments times ($25,300 plus $1,300)). The average cost per 
facility for these provisions is $26,600. The 48 corporate production 
establishments would incur a total of about $602,000 (48 establishments 
times ($11,250 plus $1,300)). The average cost per facility for these 
provisions is $12,600.

                                               Table 2.--CGMP Costs
----------------------------------------------------------------------------------------------------------------
    Rule Requirement          No. of Estab.        Labor (Months)      Wage (Yr. Sal) \1\         Cost \2\
----------------------------------------------------------------------------------------------------------------
One-Time Costs
いいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいい
Establish/Write SOPs      ....................  ....................  ....................  ....................
----------------------------------------------------------------------------------------------------------------
  Academic PET Producers                    47                     3              $135,000            $2,115,000
----------------------------------------------------------------------------------------------------------------
  Commercial PET                             4                     1              $135,000               $45,000
   Producers
----------------------------------------------------------------------------------------------------------------
Training on SOPs
----------------------------------------------------------------------------------------------------------------
  Academic PET Producers                    53                  0.23              $135,000              $138,000
----------------------------------------------------------------------------------------------------------------
  Commercial PET                            48                  0.23              $135,000              $125,000
   Producers
----------------------------------------------------------------------------------------------------------------
Total One-Time Costs                                                                                  $2,422,000
いいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいい
Annual Costs
いいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいいい
Rule Requirement
----------------------------------------------------------------------------------------------------------------
Daily Implementation, Audits, Updates
----------------------------------------------------------------------------------------------------------------
  Academic PET Products                     53                  2.25              $135,000            $1,342,000
----------------------------------------------------------------------------------------------------------------
  Commercial PET                            48                   1.0              $135,000              $540,000
   Products
----------------------------------------------------------------------------------------------------------------
Training
----------------------------------------------------------------------------------------------------------------
  Academic PET Products                     53                  0.11              $135,000               $69,000
----------------------------------------------------------------------------------------------------------------
  Commercial PET                            48                  0.11              $135,000               $62,000
   Products
----------------------------------------------------------------------------------------------------------------
Total Annual Costs                                                                                    $2,013,000
----------------------------------------------------------------------------------------------------------------
\1\ Salary includes 35 percent increase for benefits.
\2\ Cost totals may not sum to rounding.

2. Equipment Costs
    Based on at least 10 site visits to PET drug production facilities 
(both commercial and academic) by FDA personnel, we believe that the 
current laboratory facilities and equipment comply with the 
requirements of the proposed rule. Therefore, additional costs for 
laboratory space or equipment would not be incurred in complying with 
this regulation. Further, we believe that the qualification procedures 
for all current production equipment already occur as a matter of 
current business practice, and further equipment qualification 
procedures would not be required.
3. Process Verification Costs
    In response to public comments to the preliminary draft proposed 
rule, modifications have been made to the process verification 
requirements. For this proposed rule, all PET drug product batches that 
undergo full finished-product testing to ensure that the product meets 
specifications would not be required to verify the production process. 
Currently, all NDA-approved PET drug products undergo finished-product 
testing. We believe that all PET drug products that will receive NDA 
approval in the foreseeable future will undergo finished-product 
testing. This is because it would be difficult, using current PET drug 
technology, to commercialize a PET drug product with a half-life of 
only minutes (which would prevent finished-product testing before 
release). Therefore, the proposed finished-product testing requirement 
would not be expected to impose any additional burden in the near term. 
In the future, however, it is possible that some small percentage of 
PET drugs products with NDA approval may submit only the initial sub-
batch to finished-product testing before release. In such cases, 
producers would have to document their process verification procedures. 
Since we do not know how many, if any, PET drug products such as this 
would be approved in the future, we are unable to estimate any 
additional burden to the industry from process verification 
requirements. Nevertheless, we believe current business practice 
includes process verification, so any burden to producers would result 
from the need to document and organize the verification activities.
4. Total Costs
    Total one-time costs are estimated at about $2.42 million 
(annualized at $591,000 over 5 years at 7 percent, and at $529,000 at 3 
percent), and annual costs at about $2.01 million (see table 3

[[Page 55051]]

of this document). The 53 hospital and regional commercial PET drug 
production establishments would incur about $2.25 million in one-time 
costs and $1.41 million in annual costs. The annualized (annualized 
one-time costs plus annual costs) cost per facility is estimated at 
about $35,700 at a 7-percent discount rate (and at $34,600 at 3 
percent). The 48 corporate PET production facilities would incur about 
$170,000 and $602,000 in one-time and annual costs, respectively. Total 
annualized (annualized one-time costs plus annual costs) costs per 
corporate establishment are estimated at about $13,400 at a 7-percent 
discount rate (and at $13,300 at 3 percent). Total annualized costs for 
all producers are estimated at $2,603,000 at a 7-percent discount rate 
(and at $2,541,000 at 3 percent).

                                                     Table 3.--PET Drug Producers' Compliance Costs
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                 One-Time Cost                                         Annual Cost
--------------------------------------------------------------------------------------------------------------------------------------------------------
Hospital and Regional Commercial Establishments                                     $2,250,000                                                $1,410,000
 (53)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Corporate Establishments (48)                                                         $170,000                                                  $602,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total Cost \1\                                                                      $2,420,000                                                $2,010,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total Annualized Cost \2\                                                                                                                      2,600,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Sum of costs may not equal total cost due to rounding.
\2\ Total annualized cost equal to total one-time cost discounted at 7-percent over 5 years plus total annual cost. Using a 3-percent discount rate
  reduces annualized costs by about $60,000.

D. Growth of the PET Industry

    Although we do not have reliable estimates of the annual number of 
PET scans, the number has increased dramatically over the last 10 
years, due at least in part to the increased numbers of disease 
conditions for which both public and private insurers have extended 
coverage. The number of establishments producing PET drug products, and 
FDG F 18 in particular, has also increased over this time period. As 
mentioned previously in this document, the majority of this growth in 
establishments reflects commercial operations that focus mainly or 
solely on FDG F 18 production.
    As demand for PET scan services and, therefore, PET drug products 
is expected to continue to increase, we have projected compliance costs 
over the next 10 years. We cannot confidently predict the number of 
additional PET drug production runs to meet the additional demand for 
PET services because of unknown factors. We do not know the number of 
additional diseases for which PET will be used and be reimbursable in 
the future or possible increases in size of production batches of PET 
drugs. Because PET drug producers are not currently producing to 
capacity, we believe that increased demand would be partially met by 
increasing production runs and batch sizes at existing establishments 
rather than proportional increases in the number of PET production 
establishments. We have therefore tentatively projected that average 
annual PET drug production establishment increases would range from 3 
to 7 percent. Assuming this growth occurs evenly across producer types, 
this growth rate implies an increase in annualized costs from $2.60 
million currently to $3.40 to $4.79 million in year ten (with a present 
value of $3.37 million at a 7-percent discount rate, and $3.64 million 
at a 3-percent discount rate). The PET drug risk reduction resulting 
from this rule would also apply to the additional volume of PET drug 
dosages implied by the 3 to 7 percent annual growth rate in PET drug 
establishments. We request public comment and data on the annual number 
of PET scans and the expected future growth rate of PET drug products 
and production establishments subject to this proposed rule.

E. Regulatory Flexibility Analysis

    The Regulatory Flexibility Act requires agencies to examine 
regulatory alternatives for small entities if that rule may have a 
significant impact on a substantial number of small entities.
1. Objective of the Rule
    The implementation of this proposed rule, in accordance with the 
Modernization Act, would help ensure the safety, identity, strength, 
quality, and purity of PET drugs by establishing CGMP. The objective of 
the proposal is to reduce the risk to public health from adverse events 
that would be more likely to occur in the absence of adherence to CGMP 
for PET drug products.
2. Definition of Small Entities
    A regulatory flexibility analysis (RFA) is required to estimate the 
number of small entities to which the proposed rule would apply. Under 
the Regulatory Flexibility Act (as amended), the definition of a small 
entity would include a small business as defined under the Small 
Business Administration (SBA) Act, nonprofit organizations, and small 
governmental jurisdictions.
    This rule would affect producers of PET drug products. These 
include certain hospitals, clinics, colleges and universities, and 
producers of in vivo diagnostic substances. According to the SBA, 
pharmaceutical preparation manufacturers with 750 or fewer employees, 
electromedical and electrotherapeutic apparatus manufacturers with 500 
or fewer employees, drugs and druggists' sundries wholesalers with 100 
or fewer employees, and for-profit hospitals, clinics, colleges, and 
universities with $29 million or less in revenue are considered small 
businesses or entities. As stated earlier in this analysis, we 
identified 101 establishments operated by 51 PET drug producers. In 
over one-third of the cases, the PET drug product is produced by a 
hospital. In other instances, a corporate producer manages production 
under contract at one or more hospitals with cyclotrons. PET drug 
products are also produced at independent establishments by corporate 
producers or small regional producers. Total producer numbers continue 
to increase as the current corporate producers expand their

[[Page 55052]]

number of establishments and more independent regional producers enter 
the market.
    Using information from the American Hospital Association (AHA), we 
characterized 28 of the hospital producers as one of the following 
establishment types:
     Government, non-Federal;
     Government, Federal;
     Non-Government not-for-profit; and
     Investor-owned (for-profit).\4\
---------------------------------------------------------------------------

    \4\ ``AHA Guide to the Health Care Field, 1997-98 Edition.'' 
Healthcare Infosource, Inc., a subsidiary of the American Hospital 
Association.
---------------------------------------------------------------------------

    The AHA data did not include information for eight hospitals 
associated with large colleges or universities, but for this analysis, 
these were assumed to be not-for-profit because approximately 93 
percent of all 4-year higher education institutions are public or 
nonprofit institutions.\5\ Census data reports indicate that private 
hospitals (with more than 100 employees) average gross revenues of 
about $36.8 million in 1997. This figure inflates to about $46.0 
million using the Consumer Price Index (CPI) for medical care from 1997 
to 2003. Considering that hospitals producing PET drug products would 
probably be larger than the average private hospital, we consider it 
very likely that the two private hospitals producing PET drugs have 
annual revenues over $29 million and would therefore not be considered 
small entities.\6\ In instances where PET drug producer information is 
not available, this analysis assumes that the PET drug producer is 
owned by the hospital in which it is located.
---------------------------------------------------------------------------

    \5\ ``The Nation: Colleges and Universities,'' The Chronicle of 
Higher Education, 1999-2000, Almanac Issue, volume XVI, no. 1, p. 7, 
August 27, 1999.)
    \6\ ``Hospital Statistics,'' table 3, pp. 8-9, Health Forum, An 
American Hospital Association Company, 1999.
---------------------------------------------------------------------------

    Two of the three domestic corporate PET drug producers exceed the 
SBA employee limits within their respective business classifications to 
qualify as small businesses. Employee data were not available for the 
other domestic corporation or any of the 11 regional commercial 
producers, and we therefore assume that these may be small businesses.
    In total, the 51 identified producers of PET drug products are 
classified as follows: 6 Federal, 6 State, 34 small entities, and 5 
large entities. Most of those that were considered small entities were 
classified as such because they are not-for-profit organizations, not 
because they met the employee or revenue limits for small businesses. 
It should be noted that an entity's identification as small or large in 
this analysis does not necessarily indicate the volume of PET drug 
products it produces or the share of the market it holds.
3. Impact on Small Entities
    Another requirement of an RFA is that we estimate the reporting, 
recordkeeping, and other compliance requirements on small entities. 
These requirements are detailed in the regulatory cost section of this 
preamble. Most, if not all, of the PET drug producers currently employ 
individuals who possess skills necessary to establish written 
procedures and prepare documentation as required by this rule. Some may 
choose, as mentioned above, to contract with an outside consultant to 
manage their compliance with the rule.
    At most, a single-establishment PET drug producer may incur one-
time and annual costs of approximately $42,500 and $25,300 per 
operating facility, respectively. The hospital and regional commercial 
producers would incur these higher per-facility costs because these 
establishments are expected to require more time to fully comply with 
the written procedure and recordkeeping requirements. The total of the 
maximum one-time and annual costs per producer equates to significantly 
less than 1 percent of the $88 million ($70.8 million inflated by the 
CPI for medical care from 1997 until 2003) average annual gross revenue 
per nonprofit hospital. In addition, most of the hospitals that would 
be affected by this rule are affiliated with large universities whose 
total revenues are expected to be much higher than the $88 million 
figure cited. The estimated compliance cost would represent an even 
smaller portion of a percent of the entire university's revenues. 
Revenue data were not available for the one possibly small corporate 
producer. This company would incur annual costs of approximately 
$62,700 and one-time costs of about $24,000. The 11 regional commercial 
producers are expected to incur one-time and annual costs of 
approximately $42,500 per producer and $25,300 per operating facility, 
respectively. We lack sufficient data to estimate the expected 
compliance costs as a percent of revenues for the regional commercial 
producers. Accordingly, it is possible that this proposed rule might 
have a significant effect on these small entities. We request comment 
on the extent of the effect that this rule will have on small entities, 
as well as additional data to profile PET drug producers.
4. Other Federal Rules
    We are not aware of any relevant Federal rules that may duplicate, 
overlap, or conflict with the proposed rule. We request any information 
that may show otherwise.
5. Description of Alternatives
    Several alternative provisions were considered but not adopted 
during the formulation of this rule.
    Traditional CGMP. We considered requiring PET drug producers to 
follow traditional CGMP (parts 210 and 211), but because these 
requirements would not allow the flexibility of PET drug CGMP detailed 
in this rule, the compliance costs would have been much greater under 
this alternative. The increased flexibility provided by this proposal 
is believed to be more appropriate because of the special 
characteristics of PET drugs, including their short half-life, small-
scale manufacturing, and limited distribution environment.
    Specific identity testing of PET drug components. We were also 
interested in preventing contamination of PET drugs with components 
that may present a threat to public health. We therefore considered an 
alternative that would have required specific identity testing of PET 
drug components. In the May 2002 preliminary proposed rule, we proposed 
that PET drug producers perform identity testing on raw materials that 
yield a drug substance and each inactive ingredient that is not a 
finished drug product. For FDG F 18 production, this would have 
required that mannose triflate be tested using either infrared 
spectroscopy (IR) or nuclear magnetic spectroscopy (NMR). We were 
unable to estimate the current level of compliance with this provision 
and therefore assumed the level to be zero, although it is possible 
that some PET drug producers currently perform this testing. Contact 
with PET drug producers indicated that the most probable method of 
compliance would have been to use a private laboratory to perform these 
tests under contract to the PET drug producers. Although some 
producers, especially hospital producers, may have IR testing equipment 
or could at least acquire these services from other departments at 
their institutions, we assumed they would also use the services of 
private laboratories.
    We estimated that producers receive from two to six lots of mannose 
triflate annually, and we believe the average number is around three. 
We have estimated the costs of the identity testing alternative 
assuming the use of NMR. Since testing could be done using

[[Page 55053]]

either IR or NMR, with IR being somewhat less expensive, our estimates 
may overstate actual costs. Sample testing using the NMR is expected to 
cost up to $400 including the additional consultation and 
interpretation of the results with the technical staff. Testing three 
lots per year would result in a cost of $1,200 to each PET drug 
producer. We estimate that the total annual cost of identity testing 
the mannose triflate would have been about $121,000 for all PET drug 
producers.
    Identity testing of O 18 water would be performed through the 
cyclotron production run and is believed to be current practice. 
Therefore, no additional compliance costs would have been added for 
identity testing of the O 18 water.
    Many of the hospital PET producers make a small number of 
additional PET drug products and may use other inactive ingredients. 
Almost all excipients and other components are marketed as finished 
drug products and would not have required identification testing under 
this alternative policy. We do not have enough data to estimate 
confidently the average number of additional PET drug products made by 
each establishment, but we conservatively project that two components 
would require identity testing at each of the 36 hospital PET producers 
as well as the 16 hospital producers operated by corporate producers. 
Identity testing of these additional components would have added an 
additional $2,400 per PET drug producer (2 components times $400 per 
test times 3 lots per year), resulting in a total of about $125,000 in 
costs to the industry ($2,400 times 36 academic and hospital producers 
plus 16 hospital producers operated by industry). The total cost of 
identity testing of components would have amounted to about $246,000 
($121,000 for mannose triflate and $125,000 for the other components). 
The regional commercial PET drug producers and the corporate producers 
(excluding hospital producers operated by corporate entities) are 
believed to produce only FDG F 18. These producers would have incurred 
no additional costs under this alternative.
    PET drug producers commented that this alternative requirement 
would still be unnecessary and unduly burdensome because components and 
contaminants would be identified in finished-product testing and a 
certificate of analysis is provided by the supplier. We are in 
substantial agreement with these comments and have removed the 
component identity testing requirement from the proposed rule.
    Verification of the certificate of analysis. A related alternative, 
also proposed in the preliminary draft proposed rule of May 2002, would 
have required producers to verify the component specifications as 
written on the certificate of analysis. We believe that certificate of 
analysis verification would also be completed by independently testing 
the first three lots of each component received. We estimate that this 
would require contract testing of about three components for the 
hospital and regional commercial producers and about two components for 
the corporate producers. The total cost associated with verifying the 
reliability of the component suppliers would be a one-time cost of 
about $306,000. This would include $3,600 (3 lots times 3 components 
times $400) for each hospital and regional commercial producer 
establishment for a total of $191,000, and about $2,400 (3 lots times 2 
components times $400) for corporate producer establishments for a 
total of about $115,000. Using a discount rate of 7 percent over 5 
years, the annualized cost would have amounted to about $75,000.
    Several PET drug producers commented that a requirement for 
verification of the supplier's certificate of analysis would also be 
unnecessary and unduly burdensome. They stated that an established 
track record with a supplier showing no problems in finished-product 
test results should adequately establish the reliability of a supplier. 
As with the component identity testing alternative, we are in 
substantial agreement with PET drug producer comments and have not 
included the certificate of analysis verification requirement in the 
proposed rule.
    Validation of production and process controls. We also considered a 
requirement that production and process controls in every PET drug 
production process be validated according to established procedures. 
This provision was included in the preliminary draft proposed rule. It 
would have provided for retrospective validation in most cases, which 
would have relied on a review of historical data to show that each 
process is sufficiently capable of yielding batches meeting 
specifications. PET drug producers commented that this provision would 
be unnecessarily burdensome for those producers without written 
validation protocols, and finished-product testing would alleviate the 
safety concerns. After considering these comments, we decided not to 
include this provision in the proposed rule. While we did not calculate 
a separate cost for this provision, we believe it could have been 
burdensome for some producers.
    Audit trail capabilities. Another alternative would have been to 
require audit trail capabilities for all computer-operated systems to 
ensure the security of all production and nonproduction records. For 
nonproduction systems, software is available with audit trail 
capabilities and can be run alongside a widely used spreadsheet 
software program. This additional software system would provide PET 
producers with audit trail capabilities for tracking the receipt of 
drug components and in-process materials, the distribution of finished 
products, batch records, complaint files, personnel training, and 
equipment maintenance. Prices for this software, including its base 
price, a validation package, and annual maintenance and support, are 
available on the Internet. The entire package would amount to about 
$7,000 in first year costs for a PET drug producer. A short training 
course provided by the software vendor would increase first year costs 
by about $1,600 for each producer. In order to account for some 
uncertainty and regional price differences for this or similar software 
programs, we increased the estimated costs about 50 percent. Compliance 
costs would therefore be expected to total about $12,900 for each PET 
drug producer ($10,400 for the base license, validation package, and 
first year maintenance and support plus about $2,400 for a short 
training program). We believe there is very little use of software 
providing secure audit trail capabilities. Therefore, we assumed that 
to comply with this provision, all PET drug producers would have had to 
purchase software providing secure audit trail capabilities. The total 
first year cost of this software would have been about $1,303,000 for 
the 101 PET drug production establishments. We further assumed that 50 
percent of the producers would need to purchase the spreadsheet 
software at a cost of about $150 each, adding $7,600 to the software 
costs. Total one-time software costs for non-production equipment would 
have been about $1,310,000.
    The manufacturers of the audit-trail capable software would also 
have been expected to provide on-site maintenance and support of their 
systems, as mentioned above. PET drug producers would have been 
expected to purchase these maintenance and support systems. Based on 
our contact with one such software manufacturer, we estimated that the 
annual cost of such a system would be about $1,000 per year. In order 
to account for the uncertainty in using

[[Page 55054]]

only a single software application in estimating costs, we increased 
this amount to about $1,500 for each PET drug producer for this 
analysis. The estimated total cost for all 101 producers would have 
been about $152,000 annually.
    We also considered requiring the radiochemical synthesis apparatus, 
as well as the HPLC and GC equipment, to have secure audit trail 
software systems with electronic signature capabilities. We believe 
that most of this equipment and programming software currently provides 
date, time, and employee identification capabilities. However, for at 
least some producers we believe that a software update would be 
required to provide, at a minimum, file deletion prevention 
capabilities. While software packages are updated regularly in the 
industry, we did not have enough information to estimate the 
incremental cost of updating all types of production equipment software 
to include audit trail capabilities. Information on electronic 
recordkeeping, which would apply to electronic audit trails, may be 
found in 21 CFR part 11; Electronic Records; Electronic Signatures and 
the draft guidance document entitled ``PET Drug Products--Current Good 
Manufacturing Practice (CGMP).'' We invite public comment and data on 
the scope and cost of creating electronic audit trail capability, 
including data on current audit trail capabilities within the industry.
    The electronic audit trail requirements we have described were 
excluded from the proposed rule because we could not determine if the 
additional level of quality assurance would justify the additional 
compliance costs. We request public comment and data concerning the 
need for electronic audit trail requirements as part of the CGMPs for 
PET drug products.

IV. Environmental Impact

    We have determined under 21 CFR 25.30(j) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

V. The Paperwork Reduction Act of 1995

    This proposed rule contains information collection requirements 
that are subject to review by OMB under the Paperwork Reduction Act of 
1995 (the PRA) (44 U.S.C. 3501-3520). The title, description, and 
respondent description of the information collection provisions 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 each 
collection of information.
    We invite comments on these topics: (1) Whether the collection of 
information is necessary for the proper performance of our functions, 
including whether the information will have practical utility; (2) the 
accuracy of our estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    Title: Current Good Manufacturing Practice for Positron Emission 
Tomography Drugs
    Description: In accordance with the Modernization Act, the proposed 
rule would establish CGMP requirements for PET drugs. The proposed CGMP 
requirements are designed to take into account the unique 
characteristics of PET drugs, including their short half-lives and the 
fact that most PET drugs are produced at locations that are very close 
to the patients to whom the drugs are administered. The estimate is 
based on there being 51 PET drug producers operating 36 hospital or 
academic facilities and 65 commercial facilities for a total of 101 PET 
drug production facilities.
    The proposed regulations are intended to ensure that approved PET 
drug products meet the requirements of the act as to safety, identity, 
strength, quality, and purity. The proposed regulations address the 
following matters: Personnel and resources; quality control; facilities 
and equipment; control of components, in-process materials, and 
finished products; production and process controls; laboratory 
controls; acceptance criteria; labeling and packaging controls; 
distribution controls; complaint handling; and recordkeeping.
    The proposed CGMP regulations would establish several recordkeeping 
requirements for the production of PET drugs. In making our estimates 
of the time spent in complying with these proposed requirements, we 
relied on communications we have had with PET producers, visits by our 
staff to PET facilities, and our familiarity with both PET and general 
pharmaceutical manufacturing practices.
    Description of Respondents: Academic institutions, hospitals, 
commercial manufacturers, and other entities that produce PET drug 
products.
    Burden Estimate: Table 4 of this document provides an estimate of 
the annual recordkeeping burdens associated with the proposed rule. We 
are not proposing any reporting requirements. All of our recordkeeping 
burden estimates are based on there being 101 PET production 
facilities, with each of the 36 academic or hospital facilities 
producing 3 different PET drug products and each of the 65 commercial 
facilities producing 1 PET drug product, resulting in an estimated 173 
total PET drug products. Our estimates are also based on a 250-day work 
year with an average yearly production of 500 batches for each 
facility. We have also taken into account that time spent on recording 
procedures, processes, and specifications may be somewhat higher in the 
year in which these records are first established and correspondingly 
lower in subsequent years, when only updates and revisions would be 
required.

A. Investigational and Research PET Drug Products

    Proposed Sec.  212.5(b)(2) provides that for investigational PET 
drugs or drug products produced under an IND and research PET drugs or 
drug products produced with approval of an RDRC, the requirement under 
the act to follow current good manufacturing practice is met by 
complying with USP 28 Chapter <823>. We believe that PET production 
facilities producing drugs under INDs and RDRCs are currently 
substantially complying with the recordkeeping requirements of USP 28 
Chapter <823> (see section 121(b) of the Modernization Act), and 
accordingly, we have not estimated any recordkeeping burden for this 
provision of this proposed rule.

B. Batch Production and Control Records

    Proposed Sec. Sec.  212.20(c) through (e), 212.50(a) through (c), 
and 212.80(c) set out requirements for batch and production records as 
well as written control records. We estimate that it would take 20 
hours annually for each PET production facility to prepare and maintain 
written production and control procedures and to create and maintain 
master batch records for each PET drug product produced. We also 
estimate that there will be a total of 173 PET drug products produced, 
with a total estimated recordkeeping burden of 3,460 hours. We estimate 
that it would

[[Page 55055]]

take a PET production facility an average of 30 minutes to complete a 
batch record for each of 500 batches. Our estimated burden for 
completing batch records is 25,250 hours.

C. Equipment and Facilities Records

    Proposed Sec. Sec.  212.20(c), 212.30(b), 212.50(d), and 212.60(f) 
contain requirements for records dealing with equipment and physical 
facilities. We estimate that it would take 1 hour to establish and 
maintain these records for each piece of equipment in each PET 
production facility. We estimate that the total burden for establishing 
procedures for these records would be 1,515 hours. We estimate that 
recording maintenance and cleaning information would take 5 minutes a 
day for each piece of equipment, with a total recordkeeping burden of 
31,436 hours.

D. Records of Components, Containers, and Closures

    Proposed Sec. Sec.  212.20(c), 212.40(a) through (b) and (e) 
contain requirements on records regarding receiving and testing of 
components, containers, and closures. We estimate that the annual 
burden for establishing these records would be 202 hours. We estimate 
that each facility would receive 36 shipments annually and would spend 
10 minutes per shipment entering records. The annual burden for 
maintaining these records would be 604 hours.

E. Process Verification

    Proposed Sec.  212.50(f)(2) would require that any process 
verification activities and results be recorded. Because process 
verification would only be required when results of the production of 
an entire batch are not fully verified through finished-product 
testing, we believe that process verification will be a very rare 
occurrence, and we have not estimated any recordkeeping burden for 
documenting process verification.

F. Laboratory Testing Records

    Proposed Sec. Sec.  212.20(c), 212.60(a) through (b) and (g), 
212.61(a) through (b), and 212.70(a) through (b) and (d) set out 
requirements for documenting laboratory testing and specifications 
referred to in laboratory testing, including final release testing and 
stability testing. We estimate that each commercial PET production 
facility will need to establish procedures and create forms for 20 
different tests for the 1 product they produce. Each hospital and 
academic PET drug production facility will need to establish procedures 
and create forms for a total of 34 different tests for the 3 products 
they produce. We estimate that it will take each facility an average of 
1 hour to establish procedures and create forms for one test. The 
estimated annual burden for establishing procedures and creating forms 
for these records would be 2,525 hours, and the annual burden for 
recording laboratory test results would be 8,383 hours.

G. Sterility Test Failure Notices

    Proposed Sec.  212.70(e) would require PET drug producers to notify 
all receiving facilities if a batch fails sterility tests. We also 
believe that sterility test failures will be a very rare occurrence, 
and we have estimated no recordkeeping burden for the notices. If such 
an event were to occur, we believe that PET drug producers would use e-
mail and facsimile transmission to notify the receiving facilities of 
the test failure. Providing notice should take less than 1 hour per 
failure.

H. Conditional Final Releases

    Proposed Sec.  212.70(f) would require PET drug producers to 
document any conditional final releases of a product. We believe that 
conditional final releases would be fairly uncommon, but for purposes 
of the PRA, we have estimated that each PET production facility would 
have one conditional final release a year and would spend 1 hour 
documenting the release and notifying receiving facilities.

I. Out-of-Specification Investigations

    Proposed Sec. Sec.  212.20(c) and 212.71(a) and (b) would require 
PET drug producers to establish procedures for investigating products 
that do not conform to specifications and conduct these investigations 
as needed. We estimate that it would take 1 hour annually to record and 
update these procedures for each PET production facility. We also 
estimate, for purposes of the PRA, that one out-of-specification 
investigation would be conducted at each facility each year and that it 
would take 1 hour to document the investigation.

J. Reprocessing Procedures

    Proposed Sec. Sec.  212.20(c) and 212.71(d) would require PET drug 
producers to establish and document procedures for reprocessing PET 
drug products. We estimate that it would take 1 hour a year to document 
these procedures for each PET production facility. We have not 
estimated a separate burden for recording the actual reprocessing, both 
because we believe it would be an uncommon event and because the 
recordkeeping burden has been included in our estimate for batch 
production and control records.

K. Distribution Records

    Proposed Sec. Sec.  212.20(c) and 212.90(a) would require that 
written procedures regarding distribution of PET drug products be 
established and maintained. We estimate that it would take 1 hour 
annually to establish and maintain records of these procedures for each 
PET production facility. Proposed Sec.  212.90(b) would require that 
distribution records be maintained. We estimate that it would take 15 
minutes to create an actual distribution record for each batch of PET 
drug products, with a total burden of 1,375 hours for all PET 
producers.

L. Complaints

    Proposed Sec. Sec.  212.20(c) and 212.100 would require that PET 
drug producers establish written procedures for dealing with 
complaints, as well as document how each complaint is handled. We 
estimate that establishing and maintaining written procedures for 
complaints would take 1 hour annually for each PET production facility 
and that each facility would receive one complaint a year and would 
spend 30 minutes recording how the complaint was dealt with.
    We invite comments on this analysis of information collection 
burdens.

           Table 4.--Estimated Annual Recordkeeping Burden \1\
------------------------------------------------------------------------
                                Annual      Total
   21 CFR        No. of     Frequency per   Annual    Hours per    Total
  Section    Recordkeepers  Recordkeeping  Records  Recordkeeper   Hours
------------------------------------------------------------------------
212.20(c)    101            1.71           173      20            3,460
 and (e),
212.50(a)
 and (b)
------------------------------------------------------------------------

[[Page 55056]]


212.20(d)    101            500            50,500   .5            25,250
 and (e),
212.50(c),
212.80(c)
------------------------------------------------------------------------
212.20(c),   101            15             1,515    1             1,515
212.30(b),
212.50(d),
212.60(f)
------------------------------------------------------------------------
212.30(b),   101            3,750          378,750  .083          31,436
212.50(d),
212.60(f)
------------------------------------------------------------------------
212.20(c),   101            2              202      1             202
212.40(a)
 and (b)
------------------------------------------------------------------------
212.40(e)    101            36             3,636    .166          604
------------------------------------------------------------------------
212.20(c),   101            25             2,525    1             2,525
212.60(a)
 and (b),
212.61(a),
212.70(a),
 (b), and
 (d)
------------------------------------------------------------------------
212.60(g),   101            500            50,500   .166          8,383
212.61(b),
212.70(d)(2
 ) and
 (d)(3)
------------------------------------------------------------------------
212.70(f)    101            1              101      1             101
------------------------------------------------------------------------
212.20(c),   101            1              101      1             101
 212.71(a)
------------------------------------------------------------------------
212.71(b)    101            1              101      1             101
------------------------------------------------------------------------
212.20(c),   101            1              101      1             101
 212.71(d)
------------------------------------------------------------------------
212.20(c),   101            1              101      1             101
 212.90(a)
------------------------------------------------------------------------
212.90(b)    101            500            50,500   .25           12,625
------------------------------------------------------------------------
212.20(c),   101            1              101      1             101
 212.100(a)
------------------------------------------------------------------------
212.100(b)   101            1              101      .5            50
 and (c)
------------------------------------------------------------------------
Total        .............  .............  .......  ............  86,656
------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs
  associated with this collection of information.

    In compliance with the PRA, we have submitted the information 
collection requirements of this proposed rule to OMB for review. 
Interested persons are requested to send comments regarding information 
collection to the Office of Information and Regulatory Affairs, OMB.
    Submit written comments on the information collection provisions to 
the Office of Information and Regulatory Affairs, OMB. OMB is still 
experiencing significant delays in the regular mail, including first 
class and express mail, and messenger deliveries are not being 
accepted. To ensure that comments on the information collection are 
received, OMB recommends that written comments be faxed to the Office 
of Information and Regulatory Affairs, OMB, Attn: Fumie Yokota, Desk 
Officer for FDA, FAX: 202-395-6974.

VI. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. We have tentatively 
determined that the rule does not contain policies that have 
substantial direct effects on the States, on the relationship between 
the National Government and the States, or on the distribution of power 
and responsibilities among the various levels of government. 
Consequently, we do not currently plan to prepare a federalism summary 
impact statement for this rulemaking procedure. We invite comments on 
the federalism implications of this proposed rule.

VII. Proposed Effective Date

    In accordance with section 121 of the Modernization Act, we propose 
that any final rule that may issue based on this proposal become 
effective 2 years after the date on which we issue the final rule.

VIII. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this proposal. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper 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 
Division

[[Page 55057]]

of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects

21 CFR Part 210

    Drugs, Packaging and containers.

21 CFR Part 211

    Drugs, Labeling, Laboratories, Packaging and containers, 
Prescription drugs, Reporting and recordkeeping requirements, 
Warehouses.

21 CFR Part 212

    Current good manufacturing practice, Drugs, Incorporation by 
reference, Labeling, Laboratories, Packaging and containers, Positron 
emission tomography drugs, Prescription drugs, Reporting and 
recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, the Food 
and Drug Modernization Act of 1997, and under authority delegated to 
the Commissioner of Food and Drugs, it is proposed that 21 CFR chapter 
I be amended as follows:

PART 210--CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, 
PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL

    1. The authority citation for 21 CFR part 210 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 
U.S.C. 216, 262, 263a, 264.


Sec.  210.1  [Amended]

    2. Amend Sec.  210.1(a), (b), and (c) by removing the phrase ``211 
through 226'' each time it appears and by adding in its place the 
phrase ``211, 225, and 226''.


Sec.  210.2  [Amended]

    3. Amend Sec.  210.2(a) and (b) by removing the phrase ``211 
through 226'' both times it appears and by adding in its place the 
phrase ``211, 225, and 226''.


Sec.  210.3  [Amended]

    4. Amend Sec.  210.3 in paragraphs (a) and (b) introductory text by 
removing the phrase ``211 through 226'' and adding in its place the 
phrase ``211, 225, and 226''.

PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED 
PHARMACEUTICALS

    5. The authority citation for 21 CFR part 211 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 
U.S.C. 216, 262, 263a, 264.
    6. Amend Sec.  211.1 by revising paragraph (a) to read as follows:


Sec.  211.1  Scope.

    (a) The regulations in this part contain the minimum current good 
manufacturing practice for preparation of drug products (excluding 
positron emission tomography drug products) for administration to 
humans or animals.
* * * * *
    7. Add part 212 to read as follows:

PART 212--CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION 
TOMOGRAPHY DRUGS

Subpart A--General Provisions

Sec.
212.1 What are the meanings of the technical terms used in these 
regulations?
212.2 What is current good manufacturing practice for PET drugs?
212.5 To what drugs do the regulations in this part apply?

Subpart B--Personnel and Resources

212.10 What personnel and resources must I have?

Subpart C--Quality Assurance

212.20 What activities must I perform to ensure product quality?

Subpart D--Facilities and Equipment

212.30 What requirements must my facilities and equipment meet?

Subpart E--Control of Components, Containers, and Closures

212.40 How must I control the components I use to produce PET drugs and 
the containers and closures I package them in?

Subpart F--Production and Process Controls

212.50 What production and process controls must I have?

Subpart G--Laboratory Controls

212.60 What requirements apply to the laboratories where I test 
components, in-process materials, and finished PET drug products?
212.61 What must I do to ensure the stability of my PET drug products 
through expiry?

Subpart H--Finished Drug Product Controls and Acceptance Criteria

212.70 What controls and acceptance criteria must I have for my 
finished PET drug products?
212.71 What actions must I take if a batch of PET drug product does not 
conform to specifications?

Subpart I--Packaging and Labeling

212.80 What are the requirements associated with labeling and packaging 
PET drug products?

Subpart J--Distribution

212.90 What actions must I take to control the distribution of PET drug 
products?

Subpart K--Complaint Handling

212.100 What do I do if I receive a complaint about a PET drug product 
produced at my facility?

Subpart L--Records

212.110 How must I maintain records of my production of PET drug 
products?

    Authority: 21 U.S.C. 321, 351, 352, 355, 371, 374; Sec. 121, 
Pub. L. 105-115, 111 Stat. 2296.

Subpart A--General Provisions


Sec.  212.1  What are the meanings of the technical terms used in these 
regulations?

    The following definitions apply to words and phrases as they are 
used in this part. Other definitions of these words may apply when they 
are used in other parts of this chapter.
    Acceptance criteria means 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.
    Act means the Federal Food, Drug, and Cosmetic Act, as amended (21 
U.S.C. 321 et seq.).
    Active pharmaceutical ingredient means a 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, but does not include intermediates used in the synthesis of 
such substance.
    Batch means a specific quantity of PET drug product intended to 
have uniform character and quality, within specified limits, that is 
produced according to a single production order during the same cycle 
of production.
    Batch production and control record means a unique record that 
references an accepted master production and control record and 
documents specific details on production, labeling, and quality control 
for a single batch of a PET drug product.
    Component means any ingredient intended for use in the production 
of a

[[Page 55058]]

PET drug product, including any ingredients that may not appear in the 
final PET drug product.
    Conditional final release means a final release made prior to 
completion of a required finished product test because of a breakdown 
of analytical equipment.
    Final release means 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.
    Inactive ingredient means any intended component of the PET drug 
product other than the active pharmaceutical ingredient.
    In-process material means any material fabricated, compounded, 
blended, or derived by chemical reaction that is produced for, and is 
used in, the preparation of a PET drug product.
    Lot means a batch, or a specifically identified portion of a batch, 
having uniform character and quality within specified limits. In the 
case of a PET drug product produced by continuous process, a lot is a 
specifically identified amount produced in a unit of time or quantity 
in a manner that ensures its having uniform character and quality 
within specified limits.
    Lot number, control number, or batch numbermeans any distinctive 
combination of letters, numbers, or symbols from which the complete 
history of the production, processing, packing, holding, and 
distribution of a batch or lot of a PET drug product can be determined.
    Master production and control record means a compilation of records 
containing the procedures and specifications for the production of a 
PET drug product.
    Material release means 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.
    PET means positron emission tomography.
    PET drug means 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 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.
    PET drug product means a finished dosage form that contains a PET 
drug, whether or not in association with one or more other ingredients.
    PET production facility means a facility that is engaged in the 
production of a PET drug product.
    Productionmeans the manufacturing, compounding, processing, 
packaging, labeling, reprocessing, repacking, relabeling, and testing 
of a PET drug product.
    Quality control means a system for maintaining the quality of 
active ingredients, PET drug products, intermediates, components that 
yield an active pharmaceutical ingredient, analytical supplies, and 
other components, including container-closure systems and in-process 
materials, through procedures, tests, analytical methods, and 
acceptance criteria.
    Receiving facility means 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, but does 
not include a common or contract carrier that transports a PET drug 
product from a PET production facility to a receiving facility.
    Specifications means 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 means 
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.
    Strength means the concentration of the active pharmaceutical 
ingredient (radioactivity amount per volume or weight at the time of 
calibration).
    Verification means confirmation that an established method, 
process, or system meets predetermined acceptance criteria.


Sec.  212.2  What is current good manufacturing practice for PET drugs?

    Current good manufacturing practice 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. Current good 
manufacturing practice 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.


Sec.  212.5  To what drugs do the regulations in this part apply?

    (a) Application solely to PET drug products. The regulations in 
this part apply 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 current good manufacturing practice requirements in 
parts 210 and 211 of this chapter. The regulations in this part apply 
to all PET drug products for human use except for investigational and 
research PET drugs as described in paragraph (b) of this section.
    (b) Investigational and research PET drugs. The regulations in this 
part do not apply to investigational PET drugs or drug products for 
human use produced under an investigational new drug application in 
accordance with part 312 of this chapter and PET drugs or drug products 
produced with the approval of a Radioactive Drug Research Committee in 
accordance with part 361 of this chapter. For such investigational and 
research PET drugs or drug products, the requirement under the act to 
follow current good manufacturing practice is met by producing PET 
drugs or drug products in accordance with Chapter 823, 
``Radiopharmaceuticals for Positron Emission Tomography--Compounding,'' 
of the 28th edition of the United States Pharmacopeia (2005), which is 
incorporated by reference. The Director of the Office of the Federal 
Register approves this incorporation by reference in accordance with 5 
U.S.C. 552(a) and 1 CFR part 51. You may obtain copies from the United 
States Pharmacopeial Convention, Inc., 12601 Twinbrook Pkwy., 
Rockville, MD 20852, or you may examine a copy at the Center for Drug 
Evaluation and Research's Division of Medical Library, 5600 Fishers 
Lane, rm. 11B-40, Rockville, MD, or at the National Archives and 
Records Administration (NARA). For information on the availability of 
this material at NARA, call 202-741-6030, or go to: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html
.


Subpart B--Personnel and Resources


Sec.  212.10  What personnel and resources must I have?

    You must have a sufficient number of personnel with the necessary 
education,

[[Page 55059]]

background, training, and experience to perform their assigned 
functions. You must have adequate resources, including facilities and 
equipment, to enable your personnel to perform their functions.

Subpart C--Quality Assurance


Sec.  212.20  What activities must I perform to ensure product quality?

    (a) Production operations. You must 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.
    (b) Materials. You must 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.
    (c) Specifications and processes. You must 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 a PET drug. You must 
demonstrate that any change does not adversely affect the identity, 
strength, quality, or purity of any PET drug product.
    (d) Production records. You must review production records to 
determine whether errors have occurred. If errors have occurred, or a 
production batch or any component of the batch fails to meet any of its 
specifications, you must determine the need for an investigation, 
conduct investigations when necessary, and take appropriate corrective 
actions.
    (e) Quality assurance. You must establish and follow written 
quality assurance procedures.

Subpart D--Facilities and Equipment


Sec.  212.30  What requirements must my facilities and equipment meet?

    (a) Facilities. You must 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.
    (b) Equipment procedures. You must implement procedures to ensure 
that all equipment that could reasonably be expected to adversely 
affect the identity, strength, quality, or purity of a PET drug 
product, or give erroneous or invalid test results when improperly used 
or maintained, is clean, suitable for its intended purposes, properly 
installed, maintained, and capable of repeatedly producing valid 
results. You must document your activities in accordance with these 
procedures.
    (c) Equipment construction and maintenance. Equipment must be 
constructed and maintained so that surfaces that contact components, 
in-process materials, or PET drug products are not reactive, additive, 
or absorptive so as to alter the quality of PET drug products.

Subpart E--Control of Components, Containers, and Closures


Sec.  212.40  How must I control the components I use to produce PET 
drugs and the containers and closures I package them in?

    (a) Written procedures. You must establish, maintain, and follow 
written procedures describing the receipt, login, identification, 
storage, handling, testing, and acceptance and/or 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.
    (b) Written specifications. You must establish appropriate written 
specifications for the identity, quality, and purity of components and 
for the identity and quality of drug product containers and closures.
    (c) Examination and testing. Upon receipt, each lot of components 
and containers and closures must be uniquely identified and tested or 
examined to determine whether the lot complies with your 
specifications. You must not use in PET drug product production any lot 
that does not meet its specifications, including any expiration date if 
applicable, or that has not yet received its material release. Any 
incoming lot must be appropriately designated as either quarantined, 
accepted, or rejected. You must use a reliable supplier as a source of 
each lot of each component, container, and closure.
    (1)(i) If you conduct finished-product testing of a PET drug 
product that includes testing to ensure that the correct components 
have been used, you must determine that each lot of incoming components 
used in that PET drug product complies with written specifications by 
examining a certificate of analysis provided by the supplier. You are 
not required to perform a specific identity test on any of those 
components.
    (ii) If you do not conduct finished-product testing of a PET drug 
product that ensures that the correct components have been used, you 
must conduct identity testing on each lot of a component that yields an 
active ingredient and each lot of an inactive ingredient used in that 
PET drug product. This testing must be conducted using tests that are 
specific to each component that yields an active ingredient and each 
inactive ingredient. For any other component, such as a solvent or 
reagent, that is not the subject of finished-product testing, you must 
determine that each lot complies with written specifications by 
examining a certificate of analysis provided by the supplier; if you 
use such a component to prepare an inactive ingredient on site, you 
must perform an identity test on the components used to make the 
inactive ingredient before the components are released for use. 
However, if you use as an inactive ingredient a product that is 
approved under section 505 of the act (21 U.S.C. 355) and is marketed 
as a finished drug product intended for intravenous administration, you 
need not perform a specific identity test on that ingredient.
    (2) You must examine a representative sample of each lot of 
containers and closures for conformity to its written specifications. 
You must perform at least a visual identification of each lot of 
containers and closures.
    (d) Handling and storage. You must handle and store components, 
containers, and closures in a manner that prevents contamination, 
mixups, and deterioration and ensures that they are and remain suitable 
for their intended use.
    (e) Records. You must keep a record for each shipment of each lot 
of components, containers, and closures that you receive. The record 
must include the identity and quantity of each shipment, the supplier's 
name and lot number, the date of receipt, the results of any testing 
performed, the disposition of rejected material, and the expiration 
date (where applicable).

Subpart F--Production and Process Controls


Sec.  212.50  What production and process controls must I have?

    You 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.

[[Page 55060]]

    (a) Written control procedures. You must have written production 
and process control procedures to ensure and document that all key 
process parameters are controlled and that any deviations from the 
procedures are justified.
    (b) Master production and control records. You must have master 
production and control records that document all steps in the PET drug 
product production process. The master production and control records 
must include the following information:
    (1) The name and strength of the PET drug product;
    (2) If applicable, the name and radioactivity or other measurement 
of each active pharmaceutical ingredient 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;
    (3) A complete list of components designated by names and codes 
sufficiently specific to indicate any special quality characteristic;
    (4) Identification of all major pieces of equipment used in 
production;
    (5) An accurate statement of the weight or measurement of each 
component, using the same weight system (metric, avoirdupois, or 
apothecary) for each component. Reasonable variations are permitted in 
the amount of component necessary if they are specified in the master 
production and control records;
    (6) A statement of acceptance criteria on radiochemical yield, 
i.e., the minimum percentage of yield beyond which investigation and 
corrective action are required;
    (7) Complete production and control instructions, sampling and 
testing procedures, specifications, special notations, and precautions 
to be followed; and
    (8) A description of the PET drug product containers, closures, and 
packaging materials, including a specimen or copy of each label and all 
other labeling.
    (c) Batch production and control records. Each time a batch of a 
PET drug product is produced, a unique batch production and control 
record must be created. The batch production record must include the 
following information:
    (1) Name and strength of the PET drug product;
    (2) Identification number or other unique identifier of the 
specific batch that was produced;
    (3) The name and radioactivity or other measure of each active 
pharmaceutical ingredient and each inactive ingredient per batch or per 
unit of radioactivity or other measurement of the drug product;
    (4) Each major production step (obtained from the approved 
appropriate master production and control record);
    (5) Weights (or other measure of quantity) and identification codes 
of components;
    (6) Dates and time of production steps;
    (7) Identification of major pieces of equipment used in production 
of the batch;
    (8) Testing results;
    (9) Labeling;
    (10) Initials or signatures of persons performing or checking each 
significant step in the operation; and
    (11) Results of any investigations conducted.
    (d) Area and equipment checks. The production area and all 
equipment in the production area must be checked to ensure cleanliness 
and suitability immediately before use. A record of these checks must 
be kept.
    (e) In-process materials controls. Process controls must 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.
    (f) Process verification. (1) For a PET drug product for which each 
entire batch undergoes full finished-product testing to ensure that the 
product meets all specifications, process verification, as described in 
paragraph (f)(2) of this section, is not required.
    (2) 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, the PET drug 
producer must 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. Process verification 
activities and results must be documented. Documentation must include 
the date and signature of the individual(s) performing the 
verification, the monitoring and control methods and data, and the 
major equipment qualified.

Subpart G--Laboratory Controls


Sec.  212.60  What requirements apply to the laboratories where I test 
components, in-process materials, and finished PET drug products?

    (a) Testing procedures. Each laboratory used to conduct testing of 
components, in-process materials, and finished PET drug products must 
have and follow written procedures for the conduct of each test and for 
the documentation of the results.
    (b) Specifications and standards. 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.
    (c) Analytical methods. Laboratory analytical methods must be 
suitable for their intended use and must be sufficiently sensitive, 
specific, accurate, and reproducible.
    (d) Materials. The identity, purity, and quality of reagents, 
solutions, and supplies used in testing procedures must be adequately 
controlled. All solutions that you prepare must be properly labeled to 
show their identity and expiration date.
    (e) Equipment. All equipment used to perform the testing must be 
suitable for its intended purposes and capable of producing valid 
results.
    (f) Equipment maintenance. Each laboratory must have and follow 
written procedures to ensure that equipment is routinely calibrated, 
inspected, checked, and maintained, and that these activities are 
documented.
    (g) Test records. 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 standards, including examinations and assays, as follows:
    (1) 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.
    (2) 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.
    (3) A complete record of all data obtained in the course of each 
test, including the date and time the test was conducted, 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.
    (4) A statement of the results of tests and how the results compare 
with established acceptance criteria.
    (5) The initials or signature of the person performing the test and 
the date on which the test was performed.

[[Page 55061]]

Sec.  212.61  What must I do to ensure the stability of my PET drug 
products through expiry?

    (a) Stability testing program. You must establish, follow, and 
maintain a written testing program to assess the stability 
characteristics of your PET drug products. The test methods must be 
reliable, meaningful, and specific. The samples tested for stability 
must be representative of the lot or batch from which they were 
obtained and must be stored under suitable conditions.
    (b) Storage conditions and expiration dates. The results of such 
stability testing must be documented and used in determining 
appropriate storage conditions and expiration dates and times for each 
PET drug product you produce.

Subpart H--Finished Drug Product Controls and Acceptance Criteria


Sec.  212.70  What controls and acceptance criteria must I have for my 
finished PET drug products?

    (a) Specifications. You must establish specifications for each 
batch of a PET drug product, including criteria for determining 
identity, strength, quality, purity, and, if appropriate, sterility and 
pyrogenicity.
    (b) Test procedures. Before you implement a new test procedure in a 
specification, you must establish and document the accuracy, 
sensitivity, specificity, and reproducibility of the procedure. If you 
use an established compendial test procedure in a specification, you 
must first verify and document that the test works under the conditions 
of actual use.
    (c) Conformance to specifications. Before final release, you must 
conduct laboratory testing of a representative sample of each batch of 
a PET drug product to ensure that the product conforms to 
specifications, except for sterility. For a PET drug product produced 
in sub-batches, at least each initial sub-batch that is representative 
of the entire batch must conform to specifications, except for 
sterility, before final release.
    (d) Final release procedures. You must establish and follow 
procedures to ensure that a PET drug product is not given final release 
until the following is done:
    (1) Appropriate laboratory testing under paragraph (a) of this 
section is completed;
    (2) Associated laboratory data and documentation are reviewed and 
they demonstrate that the PET drug product meets specifications, except 
for sterility; and
    (3) A designated qualified individual authorizes final release by 
dated signature.
    (e) Sterility testing. Sterility testing need not be completed 
before final release but must be started within 30 hours after 
completion of production. The 30-hour requirement may be exceeded due 
to a weekend or holiday. If the sample for sterility testing is held 
longer than indicated, you must demonstrate that the longer period does 
not adversely affect the sample and the test results obtained will be 
equivalent to test results that would have been obtained if the test 
had been started within the 30-hour time period. 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. The notification must be documented.
    (f) Conditional final release. (1) If you cannot complete one of 
the required finished product tests for a PET drug product because of a 
breakdown of analytical equipment, you may approve the conditional 
final release of the product if you meet the following conditions:
    (i) You have data documenting that preceding consecutive batches, 
produced using the same methods used for the conditionally released 
batch, demonstrate that the conditionally released batch will likely 
meet the established specifications;
    (ii) You determine that all other acceptance criteria are met;
    (iii) You immediately notify the receiving facility of the 
incomplete testing;
    (iv) You retain a reserve sample of the conditionally released 
batch of drug product;
    (v) You complete the omitted test using the reserve sample after 
the analytical equipment is repaired and you document that reasonable 
efforts have been made to ensure that the problem does not recur;
    (vi) If you obtain an out-of-specification result when testing the 
reserve sample, you immediately notify the receiving facility; and
    (vii) You 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.
    (2) Even if the criteria in paragraph (f)(1) of this section are 
met, you may not approve the conditional final release of the product 
if the breakdown in analytical equipment prevents the performance of a 
radiochemical identity/purity test.


Sec.  212.71  What actions must I take if a batch of PET drug product 
does not conform to specifications?

    (a) Rejection of a nonconforming product. You must reject a batch 
of a PET drug product that does not conform to specifications. You must 
have and follow procedures to identify and segregate the product to 
avoid mixups. You must have and follow procedures to investigate the 
cause(s) of the nonconforming product. The investigation must include, 
but is not limited to, examination of processes, operations, records, 
complaints, and any other relevant sources of information concerning 
the nonconforming product.
    (b) Investigation. You must document the investigation of a PET 
drug product that does not meet specifications, including the results 
of the investigation and what happened to the rejected PET drug 
product.
    (c) Correction of problems. You must take action to correct any 
identified problems to prevent recurrence of a nonconforming product or 
other quality problem.
    (d) Reprocessing. If appropriate, you may reprocess a batch of a 
PET drug product that does not conform to specifications. If material 
that does not meet acceptance criteria is reprocessed, you 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.

Subpart I--Packaging and Labeling


Sec.  212.80  What are the requirements associated with labeling and 
packaging PET drug products?

    (a) A PET drug product 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.
    (b) Labels must be legible and applied so as to remain legible and 
affixed during the established conditions of processing, storage, 
handling, distribution, and use.
    (c) All information stated on each label must also be contained in 
each batch production record.
    (d) Labeling and packaging operations must be controlled to prevent 
labeling and product mixups.

[[Page 55062]]

Subpart J--Distribution


Sec.  212.90  What actions must I take to control the distribution of 
PET drug products?

    (a) Written distribution procedures. You must establish, maintain, 
and follow written procedures for the control of distribution of PET 
drug products shipped from the PET production facility to ensure that 
the method of shipping chosen will not adversely affect the identity, 
purity, or quality of the PET drug product.
    (b) Distribution records. You must maintain distribution records 
for each PET drug product that include or refer to the following:
    (1) The name, address, and telephone number of the receiving 
facility that received each batch of a PET drug product;
    (2) The name and quantity of the PET drug product shipped;
    (3) The lot number, control number, or batch number for the PET 
drug product shipped; and
    (4) The date and time you shipped the PET drug product.

Subpart K--Complaint Handling


Sec.  212.100  What do I do if I receive a complaint about a PET drug 
product produced at my facility?

    (a) Written complaint procedures. You must develop and follow 
written procedures for the receipt and handling of all complaints 
concerning a PET drug product.
    (b) Complaint review. 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.
    (c) Complaint records. A written record of each complaint must be 
maintained in a file designated for PET drug product complaints. The 
record must include the name and strength of the PET drug product, the 
batch number, the name of the complainant, the date the complaint was 
received, the nature of the complaint, and the response to the 
complaint. It must also include the findings of any investigation and 
followup.
    (d) Returned products. A PET drug product that is returned because 
of a complaint may not be reprocessed and must be destroyed in 
accordance with applicable Federal and State law.

Subpart L--Records


Sec.  212.110  How must I maintain records of my production of PET drug 
products?

    (a) Record availability. Records must be maintained at the PET 
production facility or another location that is reasonably accessible 
to responsible officials of the production facility and to employees of 
FDA designated to perform inspections.
    (b) Record quality. All records, including those not stored at the 
inspected establishment, must be legible, stored to prevent 
deterioration or loss, and readily available for review and copying by 
FDA employees.
    (c) Record retention period. You must maintain all records and 
documentation referenced in other parts of this regulation for a period 
of at least 1 year from the date of final release, including 
conditional final release, of a PET drug product.

    Dated: September 1, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-18510 Filed 9-15-05; 8:45 am]

BILLING CODE 4160-01-S