[Federal Register Volume 74, Number 236 (Thursday, December 10, 2009)]
[Rules and Regulations]
[Pages 65409-65436]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-29285]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 210, 211, and 212

[Docket No. FDA-2004-N-0449] (formerly Docket No. 2004N-0439)


Current Good Manufacturing Practice for Positron Emission 
Tomography Drugs

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing regulations 
on current good manufacturing practice (CGMP) for positron emission 
tomography (PET) drugs. The regulations are intended to ensure that PET 
drugs meet the requirements of the Federal Food, Drug, and Cosmetic Act 
(the act) regarding safety, identity, strength, quality, and purity. In 
this final rule, we are establishing CGMP regulations for approved PET 
drugs. For investigational and research PET drugs, the final rule 
states that the requirement to follow CGMP may be met by complying with 
these regulations or by producing PET drugs in accordance with the 
United States Pharmacopeia (USP) general chapter on compounding PET 
radiopharmaceuticals. We are establishing these CGMP requirements for 
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, we are announcing the availability of a 
guidance entitled ``PET Drugs--Current Good Manufacturing Practice 
(CGMP).''

DATES: This regulation is effective December 12, 2011. The 
incorporation by reference of a certain publication listed in the rule 
is approved by the Director of the Federal Register as of December 12, 
2011.

FOR FURTHER INFORMATION CONTACT: Brenda Uratani, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Silver Spring, MD 20993-0002, 1-240-328-7621, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction
    A. Background
    B. The Proposed Rule
    C. Changes to the Proposed Rule
II. Unique Aspects of the PET CGMP Regulations
III. Comments on the Proposed Rule
    A. General Comments
    B. Scope of Part 211 (Proposed Sec.  211.1)
    C. Definitions (Proposed Sec.  212.1)
    D. Application (Proposed Sec.  212.5)
    E. Personnel and Resources (Proposed Sec.  212.10)
    F. Production and Process Controls (Proposed Sec.  212.50)
    G. Laboratory Controls (Proposed Sec.  212.60)
    H. Controls and Acceptance Criteria (Proposed Sec.  212.70)
    I. Actions To Be Taken if Product Does Not Conform to 
Specifications (Proposed Sec.  212.71)
    J. Complaint Handling (Proposed Sec.  212.100)
    K. Records (Proposed Sec.  212.110)
IV. Analysis of Economic Impacts
    A. Regulatory Benefits
    B. Regulatory Costs
    C. Compliance Requirements
    D. Growth of the PET Industry
    E. Regulatory Flexibility Analysis
V. Environmental Impact
VI. 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
VII. Federalism
VIII. Effective Date

I. Introduction

    We are adding to our regulations new part 212 (21 CFR part 212) to 
establish CGMP requirements for PET drugs in accordance with section 
121 of the Modernization Act (Public Law 105-115).

A. Background

    In the Federal Register of September 20, 2005 (70 FR 55038) (2005 
proposed

[[Page 65410]]

rule), we published a proposed rule to establish CGMP requirements for 
PET drugs. PET is a medical imaging modality involving the use of a 
unique type of radiopharmaceutical drug product. The majority of PET 
drugs are injected intravenously into patients for diagnostic purposes. 
Section 121(c)(1)(A) of the Modernization Act directed us to establish 
appropriate approval procedures and CGMP requirements for PET drugs. 
During our development of these PET drug CGMP requirements and approval 
procedures, we were to take due account of any relevant differences 
between not-for-profit institutions that compound PET drugs for their 
patients and commercial manufacturers of PET drugs and to consult with 
patient advocacy groups, professional associations, manufacturers, and 
physicians and scientists who make or use PET drugs (section 
121(c)(1)(B) of the Modernization Act). In the preamble to the 2005 
proposal, we described the steps we took and the groups we consulted 
while developing the proposed regulations on PET drug CGMP. We refer 
readers to the preamble of the 2005 proposal for details on these 
events, information on the unique nature of PET drugs, and our 
conclusions regarding the current status of PET drug production in the 
United States.

B. The Proposed Rule

    In the proposed rule, we stated that the proposed CGMP requirements 
would contain the minimum standards needed for PET drug production at 
all types of PET production facilities. We further stated that the 
proposed CGMP regulations were designed 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 drugs differed in 
many significant ways from the CGMP requirements for non-PET drugs 
found in our regulations in parts 210 and 211 (21 CFR parts 210 and 
211). The proposed PET CGMP requirements included differences 
concerning personnel; aseptic processing; quality control of 
components; self-verification of production steps; same-person 
oversight of production, batch record review, and authorization of 
product release; and labeling requirements.

C. Changes to the Proposed Rule

    We received 11 comments on the proposed rule, which we address in 
section III of this document. As a result of the comments, and upon 
further review on our own initiative, we have made several changes to 
the proposed PET CGMP requirements, including the following:
     We have substituted the term ``quality assurance'' for 
``quality control'' and revised the definition.
     We have clarified that the CGMP requirements followed for 
the study of PET drugs under an investigational new drug application 
(IND) or under the review of a Radioactive Drug Research Committee 
(RDRC) (which reviews and approves the use of radioactive drugs for 
certain limited research purposes in accordance with 21 CFR 361.1) may 
be either the regulations in part 212 or the standards in Chapter 823, 
``Radiopharmaceuticals for Positron Emission Tomography--Compounding'' 
of the 32d ed. of the USP (2009) (USP 32).
     We have simplified the requirement for identification of a 
sample received for laboratory testing.
     We have provided more flexibility in method for 
determining that each batch of a PET drug product conforms to 
specifications before final release.
     We revised the circumstances under which conditional final 
release may be acceptable.
    When we published the proposed rule on PET CGMP, we also made 
available a revised draft guidance on CGMP for PET drugs (70 FR 55145, 
September 20, 2005). Elsewhere in this issue of the Federal Register, 
we are announcing the availability of a guidance entitled ``PET Drugs--
Current Good Manufacturing Practice (CGMP)'' to further assist PET 
production facilities in complying with the requirements in the final 
rule.

II. Unique Aspects of the PET CGMP Regulations

    The final rule establishes several differences between CGMP 
requirements for PET drugs and CGMP requirements for other drugs in 
parts 210 and 211. Included among these differences are the following:
     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 assurance 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;
     Greater flexibility in approaches to determining whether 
PET drug products conform to their specifications;
     Specialized quality assurance requirements for PET drugs 
produced in multiple sub-batches; and
     Simplified labeling requirements consistent with the scope 
and complexity of operations.

III. Comments on the Proposed Rule

    We received 11 comments on the proposed rule, including 6 from PET 
drug producers, 3 from industry associations, 1 from a consultant, and 
1 from the USP. A summary of the comments received and our responses 
follow.

A. General Comments

    (Comment 1) Several comments recommended that the title of the 
proposed rule be changed to ``Current Good Manufacturing Practice for 
Positron Emission Tomography Drug Products.'' The comments stated that 
the draft guidance title refers to ``PET Drug Products,'' and the 
comments maintained that the focus of the rule is on drug products.
    (Response) We do not agree with the comments. Section 
121(c)(1)(A)(ii) of the Modernization Act requires us to develop 
appropriate CGMP requirements for PET ``drugs,'' rather than PET ``drug 
products.'' The definition of ``compounded positron emission tomography 
drug'' in section 121(a) of the Modernization Act (codified at section 
201(ii) of the act (21 U.S.C. 321(ii))), encompasses both a PET drug 
product (i.e., a PET drug in finished dosage form) and the active 
pharmaceutical ingredient (API) that is incorporated into a PET drug 
product and enables the product to perform its diagnostic function 
(e.g., the 2-deoxy-2-[18F]fluoro-D-glucose in an FDG F 18 injection 
drug product). Thus, the PET CGMP requirements are applicable to the 
production of a PET API as well as the PET drug product containing that 
API.
    To clarify that the PET CGMP regulations apply to PET drugs, not 
solely to PET drug products, we have made several revisions to the 
proposed rule. To the definition of ``PET drug'' in Sec.  212.1, we 
have added the following statement: ```PET drug' includes a `PET drug 
product' as defined in this

[[Page 65411]]

section.'' We also have revised the definition of ``PET drug product'' 
in Sec.  212.1 to state as follows: ``PET drug product means a finished 
dosage form of a PET drug, whether or not in association with one or 
more other ingredients.'' We have revised Sec. Sec.  212.2 and 212.5 to 
make clear that the PET CGMP requirements apply to PET drugs (not only 
to PET drug products), and, where appropriate, we have revised other 
sections of part 212 accordingly. For those provisions in part 212 that 
are intended to apply only to finished dosage forms of PET drugs, the 
term ``PET drug product'' is used.
    (Comment 2) As noted in the response to the previous comment, 
section 121(a) of the Modernization Act added a definition of 
``compounded positron emission tomography drug'' to the act as section 
201(ii). One comment stated that although section 121(a) of the 
Modernization Act recognizes that PET drugs can be compounded and that 
compounding can occur by or on the order of a practitioner who is 
licensed by a State to compound or order compounding for a PET drug, 
the proposed rule focuses primarily on manufacturing and does not 
appear to recognize the role of professional practitioners in the 
practice of medicine and pharmacy. The comment stated that the agency 
seems to have determined that production of a PET drug is exclusively 
an issue of regulatory adherence, apparently unintentionally removing 
the standard of professional responsibility traditionally established 
for the practice of medicine and pharmacy, and treating all producers 
of PET drugs as manufacturers. The comment referred to the draft 
guidance, which states that: (1) Production of a PET drug includes all 
operations to the point of final release of a finished dosage form, and 
(2) after a PET drug product is received by the receiving facility, 
subsequent dispensing of a patient-specific dose and use of the PET 
drug is regarded as part of the practice of medicine and pharmacy. The 
comment maintained that the rule and the guidance should state that 
they only apply to noncompounded PET drugs and that the compounding of 
PET drugs will continue to be subject to the requirements of the 
various State boards of medicine and pharmacy as well as the PET 
compounding standards and monographs of the USP.
    (Response) We do not agree with the comment that the proposed rule 
did not recognize the practice of medicine and pharmacy with respect to 
PET drugs. The proposed rule did not include regulations on the 
administration or dispensing of PET drug products. The proposed rule 
defined ``production'' of a PET drug as the manufacturing, compounding, 
processing, packaging, labeling, reprocessing, repacking, relabeling, 
and testing of a PET drug. As the comment noted, the draft guidance 
stated that production includes all operations to the point of final 
release of a finished dosage form, and use of a PET drug product after 
receipt by a receiving facility generally is regarded as the practice 
of medicine and pharmacy.
    The Modernization Act does not require separate regulations for 
compounded PET drugs and noncompounded PET drugs. Section 121(b) of the 
Modernization Act states that, until after the later of 4 years after 
the date of enactment of the Modernization Act or 2 years after the 
agency establishes approval procedures and CGMP requirements for PET 
drugs, a compounded PET drug is not adulterated if it is compounded, 
processed, packed, or held in conformity with the PET compounding 
standards and official monographs of the USP. Thus, after the later of 
the two specified times, the CGMP requirements that FDA will have 
established for PET drugs will apply to compounded PET drugs. The fact 
that some production or ``compounding'' of PET drugs is performed by 
physicians, including some academicians and researchers at facilities 
located in universities and other not-for-profit institutions, does not 
remove such production from the scope of the PET CGMP regulations. 
Consistent with the Modernization Act, the final rule ensures that the 
production of compounded PET drugs is subject to the CGMP regulations 
while permitting the dispensing and administration of PET drug products 
in accordance with State regulation of the practice of medicine and 
pharmacy.
    (Comment 3) One comment questioned whether new drug applications 
(NDAs) and abbreviated new drug applications (ANDAs) are needed or 
realistic for very short lived PET drugs that logistically require in-
house preparation, such as those labeled with O-15. The comment 
maintained that the preparation of these drugs falls more closely under 
the definition of compounding than manufacturing because their 
extremely short half-lives preclude marketing and distribution. The 
comment stated that these short half-life PET drugs are individually 
compounded onsite, one dose at a time, for specific individual 
patients, which means that the drugs have no commercial potential and 
thus are not marketed.
    (Response) As stated in our response to comment 2, under the 
Modernization Act, there is no difference between compounding PET drugs 
and producing PET drugs. Having a very short half-life might mean that 
a PET drug could not be distributed to a facility outside of the one in 
which it was produced, but the product could still be produced, 
released for use, and administered to patients within the same 
facility. It is just as important that these PET drugs be produced 
under approved applications--and be subject to CGMP--as it is for PET 
drugs that are produced and distributed to other facilities for 
subsequent administration to patients.
    (Comment 4) One comment stated that although section 121(c)(1)(B) 
of the Modernization Act directs FDA to take due account of the 
relevant differences between not-for-profit institutions that compound 
PET drugs and commercial manufacturers of PET drugs, the agency 
concluded that profit or not-for-profit status does not have a 
significant bearing on the quality of PET drugs that are produced and 
distributed. The comment stated that we seem to have concluded that the 
only way to regulate the production of PET drugs is to require an NDA 
or ANDA. The comment stated that our decisions on how to enforce the 
Modernization Act appear to have been greatly influenced by the 
commercialization of PET drugs and the fact that many PET drugs and 
studies are reimbursed by the government and private insurance payors. 
The comment stated that although we had simplified the approval process 
for 3 PET drugs (fludeoxyglucose (FDG) F 18 injection, ammonia N 13 
injection, and sodium fluoride F 18 injection) for specified 
indications in the notice published in the March 10, 2000, issue of the 
Federal Register (65 FR 12999) (March 2000 Notice), there are other PET 
drugs in use and the USP contains monographs for 12 PET drugs. The 
comment maintained that it will be an almost insurmountable hurdle for 
many facilities to submit NDAs or ANDAs for the PET drugs for which FDA 
has not developed a template, guidance, and instructions for preparing 
marketing applications. The comment added that approved PET drug 
products might have patent and market exclusivity protection, and it 
would be unlikely that commercial PET facilities would invite 
competition.
    (Response) The Modernization Act does not leave the manner in which 
PET drugs are to be regulated completely to FDA's discretion. Rather, 
in section 121(c)(1)(A)(i), Congress directed the agency to develop 
``appropriate procedures for the approval of positron emission 
tomography drugs pursuant to

[[Page 65412]]

section 505 of the [act] (21 U.S.C. 355)'' (emphasis added). Section 
505 of the act (21 U.S.C. 355) contains the provisions on new drugs, 
including provisions on NDAs and ANDAs. To the extent that increased 
commercialization of PET drugs has affected the size, scope, and 
complexity of PET drug production operations, the PET CGMP regulations 
indirectly reflect this market reality. However, as we stated in the 
proposed rule, not-for-profit versus for-profit status does not (and 
should not) have a significant bearing on the quality of PET drugs 
produced or the facilities and procedures needed to ensure product 
quality. Thus, our approach to the regulation of PET drugs has been 
shaped largely by these statutory and product quality imperatives, 
rather than commercialization or reimbursement concerns.
    Regarding approval procedures for PET drugs, in the proposed rule 
to establish regulations on the evaluation and approval of diagnostic 
radiopharmaceuticals (63 FR 28301, May 22, 1998), we stated that 
although we expected the standards for determining the safety and 
effectiveness of diagnostic radiopharmaceuticals set forth in the 
proposed rule to apply to PET drugs, we would address that issue when 
we published our proposal on PET drugs. On May 17, 1999 (64 FR 26657), 
we published the final rule establishing regulations on the review and 
approval of diagnostic radiopharmaceutical drugs in part 315 (21 CFR 
part 315) and diagnostic radiopharmaceutical biologics in part 601 (21 
CFR part 601) (Sec. Sec.  601.30 through 601.35). These regulations 
complement and clarify the regulations on the approval of drugs and 
biologics in part 314 (21 CFR part 314) and part 601, respectively.
    Part 315 provides considerable detail on what is needed to obtain 
approval of an application for a diagnostic radiopharmaceutical. Part 
315 includes provisions on the following:
     General factors relating to the safety and effectiveness 
of diagnostic radiopharmaceuticals;
     The types of indications for which approval might be 
sought and the evidence needed to support those indications; and
     The factors that we consider in making a safety assessment 
of a diagnostic radiopharmaceutical and the types of information needed 
to demonstrate that a product is safe.
    In addition, we have issued three guidance documents to assist 
developers of medical imaging drug and biological products in planning 
and coordinating their clinical investigations and preparing and 
submitting INDs and marketing applications (69 FR 34683, June 22, 
2004). These guidances on ``Developing Medical Imaging Drug and 
Biological Products'' are as follows: ``Part 1: Conducting Safety 
Assessments;'' ``Part 2: Clinical Indications;'' and ``Part 3: Design, 
Analysis, and Interpretation of Clinical Studies.''
    In the March 2000 Notice, we declared FDG F 18 injection, ammonia N 
13 injection, and sodium fluoride F 18 injection to be safe and 
effective for certain indications when produced under conditions 
specified in approved applications. We took this action after reviewing 
the published literature on these drugs and indications and after 
presenting our preliminary findings at public meetings and before the 
Medical Imaging Drugs Advisory Committee. We issued the March 2000 
Notice to help make it easier for all PET drug producers to obtain 
marketing approval for these commonly used PET drugs. The March 2000 
Notice, along with a draft guidance document entitled ``PET Drug 
Applications--Content and Format for NDAs and ANDAs'' (65 FR 13010, 
March 10, 2000), which we intend to finalize in the near future, 
provides considerable assistance to PET drug producers in submitting 
applications for these commonly used PET drug products.
    In the March 2000 Notice, we noted that, in a future issue of the 
Federal Register, we intended to state our approach to applications for 
approval of other PET drugs and new indications for approved drugs in 
accordance with the Modernization Act. After considering this issue, we 
conclude that it is appropriate to apply part 315 to the review and 
approval of new PET drugs and new indications for approved PET drugs 
under part 314. We believe that the use of PET drugs raises safety and 
effectiveness concerns that are comparable to those posed by other 
diagnostic radiopharmaceuticals. Although PET drugs differ in some ways 
from other diagnostic radiopharmaceuticals, such as in their often very 
short half-lives and limited distribution environment, we find that 
these differences are not so pronounced that they necessitate the 
establishment of separate approval regulations. Therefore, we conclude 
that parts 314 and 315 of the regulations constitute the appropriate 
approval procedures for PET drugs in accordance with section 
121(c)(1)(A)(i) of the Modernization Act.
    We realize that submitting marketing applications for PET drugs 
under parts 314 and 315 will require considerably more resources than 
are needed to submit applications for the PET drug products and 
indications listed in the March 2000 Notice. However, the agency lacks 
the resources to conduct literature reviews to determine the safety and 
effectiveness of all PET drugs and indications that might be used in 
the future. We believe that the guidances on ``Developing Medical 
Imaging Drug and Biological Products'' will greatly assist PET drug 
producers in investigating and seeking approval of new PET drugs and 
new indications for existing drugs in accordance with parts 314 and 
315. We believe that these guidances will lessen the burden of PET drug 
producers in obtaining approval of new products.
    As the comment noted, we acknowledge in the March 2000 Notice that 
PET drugs that we have approved might be protected from competition by 
patents, or by marketing exclusivity granted by us at the time of 
approval. We agree with the comment that these factors could have an 
effect on the availability of certain PET drugs. However, because 
patent and exclusivity rights are protected by statute, revising those 
rights would require Congressional action.
    (Comment 5) One comment stated that the proposed rule failed to 
acknowledge that the size, scope, and complexity of production 
operations that lead to CGMP differences are also an important 
reflection of differences between not-for-profit and commercial 
institutions. The comment claimed that the rule might compel not-for-
profit hospitals and research institutions to divert resources from 
research, health care delivery, and patient services to meet CGMP 
compliance obligations that are not grounded in clinical or safety 
considerations. In particular, the comment stated that subjecting 
hospitals and research institutions to the same inspection regime as 
large commercial producers would be unduly onerous. The comment stated 
that most facilities in hospitals and research institutions produce 
only limited doses of PET drugs for their own clinical use, they do not 
profit from such production, and they may lack the resources to satisfy 
FDA inspection requirements. The comment welcomed the opportunity to 
assist the agency in developing inspection guidelines that would ensure 
that the CGMP requirements and enforcement strategies take due account 
of any relevant differences between not-for-profit and for-profit 
institutions. In particular, the comment stated that, as a matter of 
enforcement discretion and practical implementation, we should only 
inspect not-for-profit facilities that produce PET

[[Page 65413]]

drugs for their own clinical use when we have cause to suspect that 
drug safety or quality has been compromised.
    (Response) As we stated in the proposed rule, although there are 
some differences between not-for-profit and commercial institutions, 
there is some overlap between the two, including when for-profit 
entities manage the production of PET drugs within not-for-profit 
institutions. We concluded that the principal factors influencing 
production and CGMP differences among PET drug producers are the size, 
scope, and complexity of PET drug operations. We designed the CGMP 
regulations with these factors in mind, rather than trying to establish 
different CGMP requirements for several different kinds of producers. 
We believe that the CGMP regulations contain the minimum requirements 
needed to ensure the safety, identity, strength, quality, and purity of 
all PET drugs, regardless of where they are produced. Although we 
recognize that PET drug producers will incur costs in coming into 
compliance with the PET CGMPs (see the analysis of economic impacts in 
section IV of this document), we believe that CGMP expenditures by not-
for-profit institutions and commercial producers will benefit patients 
who receive PET drugs.
    We appreciate the comment's concern about the impact of inspections 
on PET drug producers. In the preamble to the proposed rule, we stated 
that, for PET drugs studied under an IND and PET drugs produced for 
research under the review of an RDRC, we generally would conduct 
inspections only on a for-cause basis. For preapproval inspections and 
inspections of marketed drugs, we will consider such factors as the 
size, scope, and complexity of operations in establishing our 
inspectional approach. We would expect that because many hospitals and 
research institutions have smaller operations, the impact on operations 
that those institutions might experience due to an inspection would be 
less than the impact experienced by a commercial producer with 
significantly larger operations. In any case, we will provide training 
to agency inspectors so that they conduct inspections in a manner that 
is consistent with the regulations yet takes into account relevant 
differences among PET drug producers.
    (Comment 6) One comment expressed support for the incorporation 
into the proposed rule of principles and definitions in the USP general 
chapter on compounding PET radiopharmaceuticals.
    (Response) As we stated in the proposed rule, the fact that Chapter 
823 reflects the views of the PET community and the agency on how to 
properly produce PET drugs makes it appropriate to incorporate 
principles and concepts from Chapter 823 into the CGMP requirements. In 
addition, as discussed in response to comment 25, under Sec.  212.5(b) 
of the final rule, for investigational and research PET drugs, the 
requirement under the act to follow CGMP is met by complying with part 
212 or by producing the drugs in accordance with Chapter 823 of the 
USP's 32d ed. (the current (2009) edition of the USP).
    (Comment 7) One comment stated that, although many regulations 
require drug manufacturers to include pediatric data with their NDA 
submissions, PET drugs by definition are for metabolic and/or 
diagnostic studies and do not elicit pharmacologic effect. The comment 
stated that if the metabolic pathway being studied is functional in 
pediatric patients, it stands to reason that the PET drug will 
appropriately provide the diagnostic data needed. The comment 
maintained that if the pediatric regulations are allowed to impact the 
PET CGMP regulations, many children will be unnecessarily exposed to 
radiation and NDA submissions will be inappropriately delayed, without 
scientific benefit, for the sole purpose of meeting the pediatric 
regulations. Therefore, the comment recommended that part 212 be 
exempted from all regulations that require pediatric data collection or 
submission for primary or continued approval.
    (Response) The question of the application of the statutory and 
regulatory provisions on pediatric study requirements to PET drugs is 
beyond the scope of this rulemaking.

B. Scope of Part 211 (Proposed Sec.  211.1)

    The proposed rule included revisions to parts 210 and 211 to 
exclude PET drugs from the scope of CGMP for the manufacturing, 
processing, packing, or holding of drugs and CGMP for finished 
pharmaceuticals.
    (Comment 8) One comment expressed support for the exclusion of PET 
drugs from the scope of the requirements in parts 210 and 211.
    (Response) Exclusion of PET drugs from the scope of parts 210 and 
211 is necessary and appropriate in light of the establishment of CGMP 
requirements for PET drug products in accordance with the Modernization 
Act.
    (Comment 9) One comment stated that FDA inspectors will need 
retraining to make the exclusion of PET drugs from parts 210 and 211 
clear in practice.
    (Response) We will provide FDA field offices with adequate training 
regarding the new CGMP regulations for PET drugs in part 212 so that 
agency officials can conduct appropriate inspections to determine 
compliance with these regulations.

C. Definitions (Proposed Sec.  212.1)

1. Active Pharmaceutical Ingredient
    In the proposed rule, ``active pharmaceutical ingredient'' was 
defined as 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.
    (Comment 10) Several comments stated that PET drugs by their nature 
as diagnostic drugs should not elicit a pharmacological effect, so they 
recommended deleting ``pharmacological activity'' from the definition. 
One comment specifically recommended substituting ``to furnish the 
physiological pathway'' for ``to furnish pharmacological activity or 
other direct effect.''
    (Response) We do not agree with the comments. Although PET drugs as 
defined in these regulations are intended for diagnostic use and are 
not intended to provide a pharmacological effect, many PET drugs 
provide their diagnostic effect by binding to receptors, which is a 
type of pharmacological activity. In addition, the term ``physiological 
pathway'' would not be appropriate because some PET drugs may not 
actually furnish details of the physiological pathway. Therefore, we 
have not changed the definition of active pharmaceutical ingredient.
    (Comment 11) Two comments stated that we should add ``treatment'' 
of a disease to the definition of active pharmaceutical ingredient 
because a PET drug may be used for tumor therapy.
    (Response) We do not agree with the comment. Under section 121(a) 
of the Modernization Act, a ``compounded positron emission tomography 
drug'' is a drug that ``exhibits spontaneous disintegration of unstable 
nuclei by the emission of positrons and is used for the purpose of 
providing dual photon emission tomographic diagnostic images'' 
(codified as section 201(ii)(1)(A) of the act) (emphasis added). This 
wording in the definition means that the provisions of the 
Modernization Act concerning PET drugs, including the requirement that

[[Page 65414]]

we establish appropriate CGMP requirements for PET drugs, do not apply 
to PET drugs used for therapeutic purposes. Therefore, it would not be 
appropriate to define active pharmaceutical ingredient as including use 
of the substance in the treatment of a disease.
    (Comment 12) One comment expressed support for the exclusion of 
intermediates or chemical precursors used in the synthesis and 
production of PET drugs from the definition of active pharmaceutical 
ingredient. The comment stated that proposed Sec.  212.40(c)(1)(i) 
clarified that finished product testing and reliance on supplier 
certificates of analysis was appropriate to ensure that the correct 
components had been used.
    (Response) Although intermediates are excluded from the definition 
of active pharmaceutical ingredient, we wish to make clear that 
intermediates, as components of PET drugs, are subject to the PET CGMP 
regulations (see, e.g., Sec.  212.40 on control of components, 
containers, and closures).
2. Master Production and Control Record
    We proposed to define ``master production and control record'' as a 
compilation of records containing the procedures and specifications for 
the production of a PET drug.
    (Comment 13) Three comments recommended changes to the proposed 
definition. One comment stated that it inadequately describes the 
relationship of the master formula and batch sheet as used in PET drug 
production; according to the comment, the batch record is the 
documented activity recorded as the result of following the master 
formula. One comment stated that the master production and control 
record should be a detailed step-by-step instruction set, while the 
input and output information from the production batch is recorded in 
the batch record. Both of these comments recommended substituting the 
term ``control procedure'' for ``control record.'' One comment stated 
that to more accurately reflect that batch records need not be exact 
copies of the master production and control document, the term 
``control document'' should be substituted for ``control record'' and 
the definition should be changed to ``a compilation of instructions 
containing the procedures for the production of a PET drug product and 
specifications for the product.''
    (Response) We do not agree that it is appropriate to change the 
term ``control record'' because this is a standard term used in the 
production of drugs. However, we agree that it is appropriate to change 
the definition of master production and control record to a compilation 
of instructions (rather than records) containing the procedures and 
specifications for the production of a PET drug, and we have revised 
the definition accordingly.
3. PET Drug
    We proposed 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 specifically 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. As stated in the proposed rule, this definition closely parallels 
the definition of PET drug in section 121(a) of the Modernization Act 
(codified as section 201(ii) of the act).
    As stated in our response to comment 1, we have added the statement 
```PET drug' includes a `PET drug product' as defined in this section'' 
to the definition of ``PET drug'' in Sec.  212.1.
    (Comment 14) Two comments stated that because a PET drug may also 
be used for tumor therapy, the definition should state that a PET drug 
is used for providing diagnostic images or therapeutic procedures.
    (Response) As stated in our response to comment 11, the provisions 
of the Modernization Act concerning PET drugs do not apply to PET drugs 
used for therapeutic purposes. Therefore, it would not be appropriate 
to define PET drug as including use of the drug for therapeutic 
purposes.
    (Comment 15) Several comments addressed the second sentence of the 
definition of PET drug, which lists certain items that are included in 
the definition. Two comments stated that the second sentence of the 
definition is inaccurate within the practical and technical meaning of 
a drug and, specifically, a PET drug. One comment stated that the 
definition seems overly broad in that it includes both components and 
equipment used to produce the PET drug. Two comments stated that a PET 
drug product does not include the components of a PET drug listed in 
the second sentence of the definition, necessitating a change to the 
definition of ``PET drug'' or ``PET drug product.'' One comment stated 
that generators, accelerators, electronic synthesizers, and computer 
programs should be deleted from the definition because they are not PET 
drugs but ancillary items.
    (Response) Section 201(ii)(2) of the act states that a compounded 
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 such a drug.'' Therefore, it is appropriate that the 
definition of ``PET drug'' in the CGMP regulations for PET drugs 
include these items. However, because a ``PET drug product'' is defined 
as ``a finished dosage form of a PET drug,'' it is not necessary that 
the definition restate the list of items set forth in the definition of 
``PET drug.''
    (Comment 16) Two comments stated that a generator system that 
produces a PET radionuclide from the decay of a longer half-lived 
parent isotope should be regulated under the CGMP requirements in part 
211.
    (Response) The generator system described in the comments is a 
nuclide generator under the definition of PET drug in section 
201(ii)(2) of the act. Therefore, such generator systems are included 
in the definition of PET drug in Sec.  212.1 and are subject to the 
CGMP requirements in part 212. FDA has approved an NDA for a PET drug 
containing a generator (rubidium chloride RB-82 generator).
    (Comment 17) One comment stated that although liquid target 
material for PET production facilities seems to fall under the proposed 
definition of PET drug, the comment did not believe that we intended to 
regulate producers of this material under part 212.
    (Response) Target material is included in the definition of PET 
drug in section 201(ii)(2) of the act. Therefore, it is appropriate to 
include target material in the definition of PET drug in Sec.  212.1. 
Target material is thus subject to the PET CGMP requirements in part 
212, including the provisions on components of PET drugs in Sec.  
212.40. However, with respect to the manufacture of target material 
that is intended to be used as a component of a PET drug, we intend to 
exercise our enforcement discretion by not requiring compliance with 
part 212.
    (Comment 18) One comment stated that an alternative to the proposed 
definition would be to develop consistency with part 315 for diagnostic 
radiopharmaceuticals because PET drugs are radiopharmaceuticals. The 
comment stated that this would help maintain clarity of language when 
discussing all radiopharmaceuticals and eliminate sources of confusion 
in the proposed definition of PET drug.

[[Page 65415]]

    (Response) Section 315.2 of the regulations defines ``diagnostic 
radiopharmaceutical'' as an article that is intended for use in the 
diagnosis or monitoring of a disease or a manifestation of a disease in 
humans and that exhibits spontaneous disintegration of unstable nuclei 
with the emission of nuclear particles or photons, or any 
nonradioactive reagent kit or nuclide generator that is intended to be 
used in the preparation of such an article. Because we are implementing 
these CGMP regulations for PET drugs in accordance with section 121 of 
the Modernization Act, it is appropriate that the definition of PET 
drug in Sec.  212.1 reflect the definition in the Modernization Act 
(section 201(ii) of the act). We believe that the definition of PET 
drug in Sec.  212.1 is sufficiently consistent with the definition of 
diagnostic radiopharmaceutical in Sec.  315.2 that it is unlikely to 
cause confusion.
    (Comment 19) One comment stated that ``PET drug'' and ``PET drug 
product'' are used somewhat interchangeably in the proposed rule. For 
example, the comment noted that although proposed Sec.  212.5(a) states 
that the regulations apply to PET drug products, the title of Sec.  
212.40 refers to ``PET drugs.''
    (Response) As stated in our response to comment 1, we have revised 
the proposed rule to clarify that the PET CGMP regulations apply to PET 
drugs, which include PET drug products (i.e., finished dosage forms of 
PET drugs). Where a provision is intended to apply only to finished 
dosage forms of PET drugs (e.g., Sec.  212.61 on stability, Sec.  
212.80 on labeling and packaging), the term ``PET drug product'' is 
used. Therefore, the title of Sec.  212.40 continues to refer to ``PET 
drugs.'' However, provisions in Sec.  212.40 refer to ``drug product'' 
containers and closures and to finished-product testing of a ``PET drug 
product'' because these provisions are applicable only to finished 
dosage forms of PET drugs.
4. PET Drug Product
    We proposed 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.
    As stated in our response to comment 1, we have redefined ``PET 
drug product'' as a finished dosage form of a PET drug, whether or not 
in association with one or more other ingredients.
    (Comment 20) One comment stated that the definition of PET drug 
product should be revised to ``a finished dosage form suitable for 
administration to humans.'' The comment further stated that for a PET 
drug product to be administered intravenously, it should comply with 
the sterility requirements for parenterals.
    (Response) We do not believe that it is necessary to refer 
specifically to humans in the definition of PET drug product because 
Sec.  212.2 states that CGMP for PET drugs is the minimum requirements 
for the methods to be used in, and the facilities and controls used 
for, the production, quality assurance, holding, or distribution of PET 
drugs intended for human use. With respect to CGMP sterility 
requirements, all injectable PET drugs must meet the requirements for 
sterility testing in Sec.  212.70(e).
5. PET Production Facility
    We proposed to define ``PET production facility'' as a facility 
that is engaged in the production of a PET drug.
    (Comment 21) Two comments stated that the definition of PET 
production facility does not accurately depict the actual function of 
the facility. The comments stated that the definition could be 
interpreted to include a facility for the production of PET scanners or 
for the acquisition of PET images. The comments stated that the term 
``PET drug production facility'' would more precisely reflect the 
proposed definition.
    (Response) We agree with the comments and have substituted ``PET 
drug production facility'' for ``PET production facility.''
6. Quality Control
    We proposed to define ``quality control'' as 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.
    (Comment 22) Several comments recommended substituting ``ensuring'' 
for ``maintaining'' in the definition of quality control. One comment 
stated that quality control activities are more commonly defined as 
intended to ensure quality rather than maintain quality.
    (Response) We agree with the comment and have revised the 
definition accordingly. In addition, on our own initiative we have 
replaced the term ``quality control'' with ``quality assurance.'' We 
believe that the term quality assurance more accurately reflects a 
system that is intended to ensure the quality of active ingredients, 
components, and other elements of PET drug production through the use 
of various procedures, tests, analytical methods, and acceptance 
criteria. Moreover, we believe that this change is consistent with 
subpart C, ``Quality Assurance,'' of the PET CGMP regulations, and 
specifically with Sec.  212.20(e), which requires PET drug producers to 
establish and follow written quality assurance procedures.
7. Sub-batch
    (Comment 23) Three comments recommended that Sec.  212.1 include a 
definition of ``sub-batch,'' as defined in USP Chapter 823: ``A 
quantity of PET drug product having uniform character and quality, 
within specified limits, that is produced during one succession of 
multiple irradiations, using a given synthesis and/or purification 
operation.''
    (Response) We agree with the comments and have included a 
definition of sub-batch in Sec.  212.1, using the definition in USP 
Chapter 823 to which the comments referred.

D. Application (Proposed Sec.  212.5)

    Proposed Sec.  212.5(a) stated part 212 applies only to the 
production, quality control, holding, and distribution of PET drug 
products. It further stated that any human drug product that does not 
meet the definition of a PET drug product must be manufactured in 
accordance with the CGMP requirements in parts 210 and 211. Proposed 
Sec.  212.5(a) also stated that part 212 applies to all PET drug 
products for human use except for investigational and research PET 
drugs as described in Sec.  212.5(b).
    Proposed Sec.  212.5(b) stated that the regulations in part 212 do 
not apply to investigational PET drugs or drug products for human use 
produced under an IND in accordance with part 312 and PET drugs or drug 
products produced with the approval of an RDRC in accordance with part 
361. Proposed Sec.  212.5(b) further stated that for such 
investigational and research PET drugs or drug products, the 
requirement under the act to follow CGMP is met by producing PET drugs 
or drug products in accordance with Chapter 823 of the 28th ed. of the 
USP, which was incorporated by reference in the proposed rule.
    As stated in response to comment 1, we have revised Sec.  212.5 to 
make clear that the PET CGMP requirements apply to PET drugs, not 
solely to PET drug products. Correspondingly, we have revised Sec.  
212.5(b) to state that for

[[Page 65416]]

``investigational PET drugs for human use produced under an IND in 
accordance with part 312'' and ``PET drugs produced with the approval 
of an RDRC in accordance with part 361,'' the requirement to follow 
CGMP is met by producing these drugs in accordance with Chapter 823 of 
the 32d ed. of the USP.
    (Comment 24) One comment expressed support for the exclusion of PET 
drugs studied under an IND or RDRC review from the scope of the PET 
drug CGMP regulations. However, one comment stated that there is an 
understanding within the industry, based on experiences with 
preapproval inspections, that the agency expects that investigational 
drugs for Phase 3 clinical trials will be produced under CGMP 
conditions to link the drugs to production of market batches. 
Therefore, the comment requested that we clarify whether, under Sec.  
212.5(b), CGMP will apply to the production of PET drug products for 
Phase 3 trials.
    (Response) Under the proposed rule, investigational and research 
PET drugs produced in accordance with USP Chapter 823 would be deemed 
to meet CGMP requirements. As we stated in the preamble to the proposed 
rule, we believe that it is appropriate to have more flexible CGMP 
requirements for these drugs during development. Because many PET drugs 
are produced under an IND or RDRC review and most PET drug producers 
are familiar with the standards in Chapter 823, adopting USP 32 Chapter 
823 as an alternative standard for CGMP for investigational and 
research PET drugs should make it easier for PET drug producers to 
comply with the CGMP requirements.
    Nevertheless, we agree with the comment that a PET drug producer 
intending to seek marketing approval for a PET drug or new indication 
should conduct Phase 3 studies on the drug in accordance with the PET 
CGMP requirements in part 212. Therefore, we have revised Sec.  
212.5(b) to state that for investigational and research PET drugs, the 
requirement under the act to follow CGMP is met by complying with part 
212 or by producing PET drugs in accordance with USP 32 Chapter 823. 
This revised provision gives producers of investigational and research 
PET drugs the flexibility of choosing to follow the CGMP requirements 
in part 212 or meeting the standards in USP 32 Chapter 823, depending 
on the purposes of the investigation or research with the PET drug.
    (Comment 25) One comment stated that because the USP is frequently 
updated, the regulations should not refer to a specific edition.
    (Response) We do not agree with the comment. It would not be 
appropriate to permit future changes to Chapter 823 to be incorporated 
into part 212 without conducting notice and comment rulemaking. We 
believe that the current version of Chapter 823 (in the 32d ed. of the 
USP) contains appropriate CGMP standards for investigational and 
research PET drugs. If Chapter 823 is changed in the future, we will 
consider whether it is appropriate to issue a proposed rule to revise 
the PET CGMP regulations to incorporate the revisions to the chapter.

E. Personnel and Resources (Proposed Sec.  212.10)

    Proposed Sec.  212.10 stated that a PET drug producer must have a 
sufficient number of personnel with the necessary education, 
background, training, and experience to perform their assigned 
functions. It further stated that a PET drug producer must have 
adequate resources, including facilities and equipment, to enable its 
personnel to perform their functions.
    (Comment 26) One comment remarked that the discussion of proposed 
Sec.  212.10 in the preamble of the proposed rule stated that 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 drugs or a facility producing 
larger amounts of a PET drug. The comment stated that because there are 
not likely to be any operations (commercial or noncommercial) that 
produce only one or two doses each day (or week), the statement 
unrealistically portrays a simple operation. The comment maintained 
that the draft guidance on PET CGMP (lines 226 through 230) more 
accurately defines a small operation as one that produces only one or 
two batches of a PET drug daily. The comment recommended that the 
wording in the introduction to the final rule be changed to be 
consistent with the draft guidance.
    (Response) We agree with the comment that it is appropriate to 
characterize a small PET drug production operation as one that produces 
only one or two batches each day (or week) of a single PET drug, as 
stated in the final guidance. We note, however, that it is not unusual 
for a batch of a PET drug to consist of very few doses.

F. Production and Process Controls (Proposed Sec.  212.50)

1. Master Production and Control Records
    Proposed Sec.  212.50(b)(1) through (b)(6) listed certain items of 
information that would be required in a master production and control 
record. These included, in proposed Sec.  212.50(b)(6), a statement of 
acceptance criteria on radiochemical yield, i.e., the minimum 
percentage of yield beyond which investigation and corrective action 
are required.
    (Comment 27) One comment recommended deletion of this requirement. 
The comment stated that radiochemical yields can have significant 
variations in a well-controlled PET manufacturing operation and that 
many factors can affect the yield. The comment maintained that 
radiochemical yield is not a significant predictor of product quality. 
According to the comment, discarding useful product and having to 
produce another lot based on arbitrary radiochemical yield increases 
radiation exposure without predicting product quality.
    (Response) We do not agree with the comment. Although a low 
radiochemical yield would not necessarily require the rejection of a 
batch, low radiochemical yield can be a useful predictor of control of 
the production process for a PET drug. For example, a low radiochemical 
yield might result from a leak in the production system that introduces 
an extraneous substance, resulting in a contaminated product that might 
not be easily purified. Repeated occurrences of low radiochemical yield 
or a downward trend in radiochemical yield should prompt an 
investigation and, if necessary, corrective action. We have revised 
Sec.  212.50(b)(6) to require a statement of action limits, rather than 
acceptance criteria, on radiochemical yield, because exceeding the 
radiochemical yield limits would require investigation and corrective 
action but not necessarily rejection of the batch.
2. Batch Production and Control Records
    Proposed Sec.  212.50(c)(1) to (c)(11) listed the items of 
information that must be included on a batch production and control 
record. These included, in proposed Sec.  212.50(c)(6), the dates and 
time of production steps.
    (Comment 28) One comment stated that recording the time of critical 
production steps is appropriate but recording the date and time of each 
step is not necessary. The comment stated

[[Page 65417]]

that the manufacture of a PET drug takes place over a few hours at 
most. The comment maintained that recording the date once on the batch 
record is sufficient unless production spans 2 days. The comment also 
recommended that recording the time be limited to critical steps, 
contending that doing so for all steps would de-emphasize critical 
steps.
    (Response) We believe that it is appropriate to record the date of 
each production step on the batch production and control record. 
However, we agree with the comment that the time need only be recorded 
for each critical production step (e.g., start of irradiation, 
beginning and end of synthesis). Therefore, we have revised Sec.  
212.50(c)(6) to require inclusion of the dates of production steps and 
times of critical production steps.

G. Laboratory Controls (Proposed Sec.  212.60)

    Proposed Sec.  212.60(g) required each laboratory performing tests 
related to the production of a PET drug to keep complete records of all 
tests performed to ensure compliance with established specifications 
and standards, including examinations and assays. The specific records 
required were set forth in proposed Sec.  212.60(g)(1) through (g)(5). 
Proposed Sec.  212.60(g)(1) required 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. Proposed Sec.  212.60(g)(2) required 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. Proposed Sec.  
212.60(g)(3) required 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. Proposed 
Sec.  212.60(g)(4) required a statement of the results of tests and how 
the results compare with established acceptance criteria. Proposed 
Sec.  212.60(g)(5) required the initials or signature of the person 
performing the test and the date on which the test was performed.
    (Comment 29) Several comments objected to the proposed requirements 
for test records, in particular the description of the sample received 
for testing. One comment stated that the required documentation needs 
streamlining because of limited time and human resources during 
production and quality control activities. The comment maintained that 
the proposed level of documentation is excessive in the presence of 
comprehensive and verified procedures.
    Several comments maintained that the proposed requirements are 
excessive because the testing is conducted in the same room as, 
contiguous to, or in close proximity to the production area, often by 
the same personnel responsible for the production of the drug. One 
comment recommended that the guidance include a reduced requirement for 
when testing is performed contiguous with PET drug production.
    One comment stated that the reference to the batch or lot number in 
proposed Sec.  212.60(g)(1) is more than adequate. Two comments 
recommended revising Sec.  212.60(g)(1) to state simply that samples 
received for testing must be suitably identified to avoid mix-ups.
    Three comments maintained that the information that would be 
required under proposed Sec.  212.60(g)(1) is already in the master 
formula and/or in individual batch records. One comment recommended 
that we clarify that existing documentation could satisfy the 
requirements for test records in Sec.  212.60(g).
    One comment recommended having separate test record requirements 
for: (1) Components, in-process materials, and PET drug products tested 
in a facility physically external to the manufacturing facility and (2) 
PET drug products tested internally. For the first group, the test 
record requirements in proposed Sec.  212.60(g)(1) through (g)(5) would 
apply. The requirements for PET drug products tested internally would 
be the same, except that in lieu of a provision requiring a description 
of the sample received for testing, there would be a provision stating 
that ``[t]est records for PET drug products tested internally shall be 
inclusive to the batch record for that PET drug product.''
    (Response) We agree with the comments that the proposed 
requirements for describing the sample received for testing should be 
changed to reflect the typical production and testing circumstances 
described by the comments. Therefore, we have revised Sec.  
212.60(g)(1) to require a ``suitable identification of the sample 
received for testing.'' Suitable identification of the sample means 
information that will provide complete traceability of the sample to 
the batch or lot from which the sample was taken. We agree with the 
comments that a PET drug producer might be able to meet this 
requirement by referring to information in the master production and 
control record or the batch production and control record. The revised 
Sec.  212.60(g)(1) reflects that the information needed to identify a 
sample might vary depending on the circumstances under which production 
and testing are conducted. In particular, the revised provision 
obviates the need for separate provisions for: (1) Components, in-
process materials, and PET drug products tested in a facility 
physically external to the manufacturing facility and (2) PET drug 
products tested internally.

H. Controls and Acceptance Criteria (Proposed Sec.  212.70)

1. Specifications
    Proposed Sec.  212.70(a) would have required a PET drug producer to 
establish specifications for each batch of a PET drug product, 
including criteria for determining identity, strength, quality, purity, 
and, if appropriate, sterility and pyrogenicity.
    (Comment 30) One comment stated that it seems more appropriate to 
set specifications for apyrogenicity rather than pyrogenicity.
    (Response) An injectable PET drug product will have as part of its 
specifications a test and acceptance criteria for pyrogens. Therefore, 
we have revised Sec.  212.70(a) to refer to ``pyrogens'' rather than 
``pyrogenicity.''
    In addition, on our own initiative, we have revised Sec.  212.70(a) 
to state that a PET drug producer must establish specifications for 
``each PET drug product'' rather than for ``each batch of a PET drug 
product.'' We intend the revision to make clear that the specifications 
are for each PET drug product and that these specifications may not 
differ from batch to batch of the product.
2. Conformance to Specifications
    Proposed Sec.  212.70(c) would have required a PET drug producer, 
before final release, to 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. The proposed 
provision would have further required that, 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.
    (Comment 31) We did not receive any comment specifically referring 
to proposed Sec.  212.70(c). However, one comment recommended adding a 
new paragraph (g) to Sec.  212.70 to

[[Page 65418]]

accommodate testing of a PET drug product on something less than a per-
batch basis. The comment stated that many tests are amenable to daily 
or skip testing. As an example, the comment referred to FDG F 18. The 
comment maintained that the bacterial endotoxin test for FDG F 18 
always generates a nondetectable result because the alumina cartridge 
in the FDG production process removes all endotoxins. The comment also 
claimed that radiation levels for a bombarded target render the target 
and its contents sterilized by ionizing radiation, and repeated passage 
of commercial quantities of FDG F 18 through a production process 
renders the fluid pathway sterilized by ionizing radiation. According 
to the comment, the sterility assurance level achieved by exposure to 
ionizing radiation and passage of the active pharmaceutical ingredient 
through a sterilizing membrane filter renders a retrospective sterility 
test moot. Therefore, the comment recommended adding a provision 
stating as follows: ``You must conduct process verification and 
establish procedures for finished product testing on a daily basis 
rather than every batch of finished product.''
    (Response) We do not agree with the comment that the bacterial 
endotoxin test for FDG F 18 always generates a nondetectable result; we 
are aware of at least one instance in which a batch of FDG F 18 was 
recalled due to endotoxin problems. However, we agree that finished-
product testing is not the only method that can be used to demonstrate 
that a PET drug product conforms to its specifications. Other 
approaches may be appropriate for certain specifications. To reflect 
this, we have revised Sec.  212.70(c) to require, before final release, 
``an appropriate laboratory determination'' to ensure that each batch 
of a PET drug product conforms to specifications, except for sterility. 
For a PET drug product produced in sub-batches, before final release, 
``an appropriate laboratory determination'' is required to ensure that 
each sub-batch conforms to specifications, except for sterility.
    Examples of PET drug product specifications--the measurements of 
critical quality attributes that are indicative of the product's safety 
and effectiveness--include radiochemical identity and purity (including 
chiral purity), assay (including radioconcentration), specific 
activity, radioactive and non-radioactive impurities, and sterility. An 
appropriate laboratory determination to ensure that each batch (or, for 
a product produced in sub-batches, each sub-batch) of a PET drug 
product conforms to specifications under Sec.  212.70(c) could involve 
the following:
     Finished-product testing of each batch;
     In-process testing of an attribute that is equivalent to 
finished-product testing of that attribute;
     Continuous process monitoring of attributes with 
statistical process controls;
     Some combination of these approaches.
    Using finished-product testing alone would require testing each 
batch of a PET drug product for conformance to all specifications. In-
process testing might involve use of an on-line test to determine 
whether an attribute meets an appropriate acceptance criterion, 
provided that the relevant attribute does not change during the 
production of the finished product. Under this scenario, the in-process 
testing of an attribute could be an adequate substitute for the 
finished-product testing for that attribute. Continuous process 
monitoring with statistical process controls involves comprehensive 
testing of attributes using on-line monitoring and corresponding 
adjustments to prevent an upward or downward drift in batch-to-batch 
measurements of an attribute. Depending on the particular PET drug 
product and specification, any of the suggested approaches might be 
appropriate for conducting an appropriate laboratory determination to 
ensure that each batch of the product conforms to the specification. 
The laboratory determination approach for each specification should be 
set forth in the product's marketing application.
    Although Sec.  212.70(c) addresses conformance to specifications, 
we recognize that there may be attributes of a PET drug product that, 
although not as significant as those included in the specifications, 
are nevertheless important in assessing the quality of the product. 
Examples of these noncritical attributes might include radionuclidic 
purity (when potentially contaminating radionuclides do not impact the 
safety or effectiveness of the drug product), as well as certain low-
level nontoxic impurities and class three residual solvents. These 
noncritical attribute tests, referred to as periodic quality indicator 
tests (PQITs), are additional to tests conducted for conformance to 
drug product specifications. A PQIT is performed at predetermined 
intervals rather than on a batch-to-batch basis. A PET drug producer 
generally establishes and refines tests of noncritical attributes 
within its internal quality system. However, the sponsor of a PET drug 
product should seek approval of a PQIT for a noncritical attribute in 
the product's marketing application. FDA will review the frequency of 
PQIT testing during CGMP inspections.
3. Final Release Procedures
    Proposed Sec.  212.70(d) stated that a PET drug producer must 
establish and follow procedures to ensure that a PET drug product is 
not given final release until the following are done: (1) Appropriate 
laboratory testing under Sec.  212.70(a) 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.
    At our own initiative, we have revised Sec.  212.70(d) to state 
that except as conditional final release is permitted in accordance 
with Sec.  212.70(f), a PET drug producer must establish and follow 
procedures to ensure that a each batch of a PET drug product is not 
given final release until the steps in Sec.  212.70(d)(1) through 
(d)(3) are done. This makes clear that compliance with the conditional 
final release procedures for a particular batch constitutes an 
exception to the requirement that each batch comply with final release 
procedures.
    In addition, consistent with the change that we have made to 
proposed Sec.  212.70(c), we have revised the first criterion in Sec.  
212.70(d) (i.e., Sec.  212.70(d)(1)) to require completion of an 
``appropriate laboratory determination under paragraph (c)'' rather 
than appropriate laboratory testing under Sec.  212.70(a).
4. Sterility Testing
    Proposed Sec.  212.70(e) stated that sterility testing need not be 
completed before final release but must be started within 30 hours 
after completion of production; the 30 hours might be exceeded because 
of a weekend or holiday. Proposed Sec.  212.70(e) further stated that 
if the sample for sterility testing is held longer than indicated, the 
PET drug producer 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. Proposed Sec.  
212.70(e) also stated that 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.

[[Page 65419]]

    On our own initiative, we have revised the second sentence of Sec.  
212.70(e) to clarify that if the sample for sterility testing is held 
longer than 30 hours (rather than as ``indicated''), the PET drug 
producer must take the actions specified in that sentence. Also on our 
own initiative, we have revised Sec.  212.70(e) to state that 
``[t]ested samples must be from individual batches and not pooled,'' 
rather than stating that ``[p]roduct samples must be tested 
individually and must not be pooled.'' This clarifies that a sample 
from each batch of a PET drug product must be tested for sterility.
    (Comment 32) Several comments objected to the proposed requirement 
to notify receiving facilities immediately if a PET drug product fails 
the sterility test. Several comments stated that although detection of 
a growth in an inoculated media should prompt an investigation, it does 
not necessarily equate to sterility failure. Two comments stated that 
an investigation of a test failure should lead to an informed 
determination as to whether the batch was not sterile or a technical 
error caused a false positive result, and that notification is 
justified only if nonsterility is confirmed. Two comments stated that 
the results of an investigation into a sterility test failure might not 
be known for 2 to 4 weeks. One comment stated that the notification 
required by proposed Sec.  212.70(e) would occur several days after 
administration of the drug product and critical data, such as species 
identification, would not be available. Three comments stated that 
immediate, unqualified notification would be alarming and unproductive.
    To address concerns about proposed Sec.  212.70(e), four comments 
recommended that this provision require that receiving facilities be 
notified if an investigation into a nonconforming sterility test 
concludes that a drug product was non-sterile. One comment, stating 
that it was questionable what benefit would be served by notification 
at this point and what advice would be appropriate and meaningful, 
asked that we reconsider this requirement or include recommendations in 
the PET CGMP guidance on what to tell the receiving facility.
    (Response) We understand that initial results from conventional 
sterility tests are not definitive, and we appreciate that it takes 
some time to investigate a failed test. However, we believe that it is 
important to convey to the clinician the potential risks to a patient 
when a PET drug product initially fails to meet a criterion for 
sterility. We have revised Sec.  212.70(e) to clarify that, if a 
product fails to meet a criterion for sterility, the PET drug producer 
must immediately notify all facilities that received the product of the 
test results and provide any appropriate recommendations. Consistent 
with the need to keep receiving facilities adequately informed, we have 
added to Sec.  212.70(e) a requirement that, upon completion of an 
investigation into a failure to meet a criterion for sterility, the PET 
drug producer must notify all facilities that received the product of 
the findings from the investigation.
    (Comment 33) Two comments, noting that the draft guidance states 
that sterile PET drugs can be distributed after initiation of an 
endotoxin test but before obtaining test results (provided the results 
are determined to meet acceptance criteria before the drug product is 
administered to humans), requested that this procedure be included in 
the regulations.
    (Response) We do not believe that it necessary to establish a 
regulation as requested. Under Sec.  212.70(c), endotoxin testing must 
be completed before final release of a PET drug product. The guidance 
simply clarifies that, because of the short half-lives of many PET 
drugs, a product can be ``distributed under control after a 
pharmacopeial bacterial endotoxin test is initiated. However, the 
endotoxin results should meet the acceptance criteria before 
administering the product to humans.'' Distribution under control does 
not constitute final release of the product; final release can only 
occur after the completion of the laboratory determination to ensure 
conformance to specifications (except for sterility). Distribution 
control procedures, including any agreements between the PET drug 
producer and receiving facilities, should be specified in a standard 
operating procedures (SOPs) document.
5. Conditional Final Release
    Proposed Sec.  212.70(f) set forth the conditions under which 
conditional final release of a PET drug product would be permitted.
    a. Conditions for release (proposed Sec.  212.70(f)(1)). Proposed 
Sec.  212.70(f)(1) stated that if the PET drug producer cannot complete 
one of the required finished product tests for a PET drug product 
because of a breakdown of analytical equipment, the producer may 
approve the conditional final release of the product if it meets the 
following conditions (listed in proposed Sec.  212.70(f)(1)(i) through 
(f)(1)(vii)):
     The PET drug producer has 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;
     The PET drug producer determines that all other acceptance 
criteria are met;
     The PET drug producer immediately notifies the receiving 
facility of the incomplete testing;
     The PET drug producer retains a reserve sample of the 
conditionally released batch of drug product;
     The PET drug producer completes the omitted test using the 
reserve sample after the analytical equipment is repaired and documents 
that reasonable efforts have been made to ensure that the problem does 
not recur;
     If an out-of-specification result is obtained when the 
reserve sample is tested, the PET drug producer immediately notifies 
the receiving facility; and
     The PET drug producer documents 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.
    i. Circumstances justifying conditional final release (proposed 
Sec.  212.70(f)(1)). At our own initiative, we have revised Sec.  
212.70(f)(1) to clarify that conditional final release may be 
appropriate when a PET drug producer cannot complete one of the 
required finished-product tests for a particular batch of a PET drug 
product because of a malfunction involving analytical equipment 
(proposed Sec.  212.70(f)(1)(i) and (f)(i)(iv), but not (f)(1), had 
referred to conditionally released batches).
    (Comment 34) Three comments objected to the proposed criteria for 
conditional final release because they believe the criteria are 
partially inconsistent with the Tests and Assays section of the USP's 
General Notices. Two comments stated that according to the Tests and 
Assays section, process validation and in-process controls may provide 
greater assurance that a drug product conforms to release 
specifications than conducting each test on every final product batch. 
One comment stated that proposed Sec.  212.70(f)(1) inaccurately 
implies that every pharmacopeial test is required before release to 
assure quality. Two comments recommended that Sec.  212.70(f)(1) be 
revised to state that if a PET drug producer cannot complete one of the 
finished-product release tests on a timely basis because of an 
analytical equipment breakdown,

[[Page 65420]]

inconclusive result, or invalid condition, the producer may approve 
conditional release of a batch if there is historical evidence to 
substantiate that the product will likely meet the established 
specifications. One comment stated that such a release test should be 
one that is stipulated in an approved application. One comment also 
stated that the producer should be required to implement written 
procedures that: (1) Determine which finished-product tests are 
applicable for conditional release, (2) specify the steps required to 
correct the cause of the invalid condition or equipment failure in a 
timely fashion, and (3) document all conditional release activities.
    (Response) We agree with the comments that the USP does not require 
the completion of every pharmacopeial test on each product batch prior 
to release of the batch. Instead, the USP states that every article, 
when tested, should conform to the monograph. However, Sec.  212.70(c) 
requires that the PET drug producer conduct an appropriate laboratory 
determination to ensure that each batch of a PET drug product conforms 
to specifications, except for sterility, before final release of the 
product. Although many of the critical laboratory tests must be 
completed before final release, we agree that it is appropriate to 
broaden the circumstances under which a PET drug producer may approve 
the conditional final release of a product. Therefore, we have revised 
Sec.  212.70(f)(1) to allow conditional final release if the PET drug 
producer cannot complete one of the required finished-product tests for 
a PET drug product because of a malfunction involving analytical 
equipment, rather than solely a complete breakdown of such equipment. 
For example, gas chromatography equipment might be operating but 
producing inaccurate results because of some malfunction. Conditional 
release due to an equipment malfunction might be appropriate when test 
results are atypical but other process indicators show that release of 
raw materials and production and purification process events have 
occurred as expected. For example, a PET drug producer might observe a 
baseline drift in a high pressure liquid chromatography (HPLC) analysis 
for a product, but if the peak shape is similar to what is normally 
seen and the production and purification events have progressed as 
expected, it might be reasonable to conclude that there is an equipment 
malfunction, rather than that the product is contaminated. In such a 
case, conditional final release of the product would be appropriate. 
For these reasons, the revised Sec.  212.70(f)(1) more accurately 
reflects the range of circumstances under which conditional final 
release might be appropriate.
    However, we do not agree with the proposal to allow conditional 
final release when there is an ``inconclusive result'' or an ``invalid 
condition,'' because those terms are so broad and vague that they might 
permit conditional final release when there is too much uncertainty 
about the safety and quality of the drug product. For similar reasons, 
we do not believe that it is appropriate to allow each PET drug 
producer to determine which finished-product tests may be omitted under 
conditional final release. We do not believe it is necessary to require 
that the approved application specify all the tests that need not be 
completed for conditional final release, as long as conditional final 
release is limited to circumstances in which there is a malfunction 
involving analytical equipment.
    In addition, we do not believe it is necessary for Sec.  212.70(f) 
to specifically require that PET drug producers have written procedures 
for conditional final release, as requested by one comment, because the 
provision itself essentially states those procedures. Consistent with 
the comment, however, Sec.  212.70(f)(vi) requires documentation of all 
actions regarding conditional final release, including corrective 
actions to prevent recurrence of a particular malfunction involving 
analytical equipment.
    We have revised the definition of ``conditional final release'' in 
Sec.  212.1 to correspond to this change by replacing ``breakdown of 
analytical equipment'' with ``malfunction involving analytical 
equipment.''
    ii. Notification of incomplete testing (proposed Sec.  
212.70(f)(1)(iii)). (Comment 35) Several comments recommended deletion 
of the requirement in proposed Sec.  212.70(f)(1)(iii) to immediately 
notify the receiving facility of incomplete testing. Four comments 
stated that the personnel at the receiving facility are not 
knowledgeable of the conditional release allowance and lack the 
expertise to interpret the meaning of such a release in the context of 
patient safety and product efficacy. The comments stated that notifying 
the receiving facility in these circumstances would cause uncertainty 
and undue apprehension, which would not serve the best interest of 
patients. Three comments stated that other provisions in proposed Sec.  
212.70(f)(1) provide adequate protection to patients; for example, 
proposed Sec.  212.70(f)(1)(vi) provides for immediate notification of 
the receiving facility if subsequent testing reveals an out-of-
specification result.
    (Response) We agree that immediate notification of the receiving 
facility of incomplete product testing would not provide sufficient 
information to make the requirement worthwhile. Therefore, we have 
deleted this condition from Sec.  212.70(f)(1).
    iii. Completion of omitted test and efforts to ensure that the 
problem does not recur (proposed Sec.  212.70(f)(1)(v)). At our own 
initiative, we have revised Sec.  212.70(f)(1)(v) (now Sec.  
212.70(f)(1)(iv)) to require that a PET drug producer promptly correct 
the malfunction of analytical equipment, complete the omitted test 
using the reserve sample after the malfunction is corrected (rather 
than after the analytical equipment is repaired, consistent with the 
change to Sec.  212.70(f)(1)), and document that reasonable efforts 
have been made to prevent recurrence of the malfunction. In connection 
with this change, we have added Sec.  212.70(f)(3), which states that a 
PET drug producer may not release another batch of PET drug product 
following the conditional release of a batch of the product until the 
producer has corrected the problem concerning the malfunction of 
analytical equipment and completed the omitted finished-product test. 
We believe that these changes are appropriate to provide assurance that 
patients receive safe and effective PET drug products. We conclude that 
these changes will not impose a significant additional burden on PET 
drug producers because we believe that in most of the rare instances in 
which a malfunction of analytical equipment occurs, PET drug producers 
seek to quickly correct the malfunction and typically do not release 
additional batches of the drug until the problem is corrected. In 
addition, many medical facilities that produce and administer PET drugs 
may be able to obtain PET drugs for their patients from other PET drug 
producers while they are correcting an equipment malfunction in 
accordance with Sec.  212.70(f)(1)(iv). For these reasons, we have 
revised Sec.  212.70(f)(1)(iv) and added Sec.  212.70(f)(3) as stated.
    (Comment 36) Regarding completion of the omitted test under 
proposed Sec.  212.70(f)(1)(v), two comments stated that, depending on 
when analytical equipment is repaired, the PET drug producer might not 
be able to obtain meaningful data for testing (e.g., radionuclidic 
identity or purity) because the radioactivity of the radionuclide might 
be decayed to background level. Therefore, the comments recommended 
revising the provision to state that the

[[Page 65421]]

PET drug producer should complete the omitted test, if possible, using 
the reserve sample after the analytical equipment is repaired.
    (Response) Although we agree that some critical tests cannot be 
performed at a later time (i.e., after correction of an analytical 
equipment malfunction) because of the short half-life of a product, we 
do not believe that it is appropriate to revise Sec.  212.70(f)(1)(v) 
to require completion of the omitted test only ``if possible'' after 
the malfunction is corrected. With respect to radionuclidic identity, a 
dose calibrator is required for testing. If the dose calibrator is not 
functioning properly, we believe that the dose of the product cannot be 
accurately measured. As for radionuclidic purity, we believe that it is 
possible to conduct the test on a decayed sample of the product. We 
recommend that PET drug producers develop alternate tests for 
specifications for which they conclude it is not possible to conduct a 
particular test after an analytical equipment malfunction has been 
corrected. For example, if a dose calibrator malfunctioned and the 
activity of a product could not be assayed, a sample of known dilution 
could be counted using other equipment, and the activity concentration 
could be determined by correcting for counting efficiency and dilution.
    (Comment 37) Three comments stated that it will never be possible 
to ``ensure'' that a breakdown of analytical equipment will not recur, 
as expected in proposed Sec.  212.70(f)(1)(v). Two comments recommended 
substituting ``prevent recurrence of the problem'' for ``ensure that 
the problem does not recur.'' One comment recommended substituting 
``document the repair and corrective and preventive actions'' for 
``document that reasonable efforts have been made to ensure that the 
problem does not recur.''
    (Response) We agree that it is more appropriate to require a PET 
drug producer to document that reasonable efforts have been made to 
prevent recurrence of the malfunction involving analytical equipment. 
Therefore, we have revised Sec.  212.70(f)(1)(v) (now Sec.  
212.70(f)(1)(iv)) accordingly.
    iv. Notification of an out-of-specification result (proposed Sec.  
212.70(f)(1)(vi)). (Comment 38) One comment recommended deletion of the 
requirement for the PET drug producer to immediately notify the 
receiving facility if the producer obtains an out-of-specification 
result when testing the reserve sample. The comment stated that 
personnel at the receiving facility would not have sufficient 
understanding of such regulatory action or expertise to decide whether 
to administer the drug. The comment stated that such notification would 
create confusion and undue concern at the receiving facility.
    (Response) We do not agree. Notifying receiving facilities of out-
of-specification results so that personnel can take appropriate action, 
usually to prevent administration of the drug, is consistent with the 
intent of CGMP to ensure that patients receive appropriate PET drugs. 
This differs from the situation involving notification of incomplete 
product testing under proposed Sec.  212.70(f)(1)(iii), in which it is 
still possible that the batch may actually conform to specifications 
and therefore be appropriate for administration to patients.
    v. Documentation of actions regarding conditional final release 
(proposed Sec.  212.70(f)(1)(vii)). Consistent with the changes to 
Sec.  212.70(f)(1) and (f)(1)(iv), we revised Sec.  212.70(f)(1)(vii) 
(now Sec.  212.70(f)(1)(vi)) to require documentation of all actions 
regarding the conditional final release of the drug product to prevent 
recurrence of the malfunction involving analytical equipment (rather 
than to ensure that the equipment breakdown does not recur).
    b. Inability to perform radiochemical identity/purity test 
(proposed Sec.  212.70(f)(2)). Proposed Sec.  212.70(f)(2) stated that 
even if the criteria in Sec.  212.70(f)(1) were met, a PET drug 
producer could not approve the conditional final release of a PET drug 
product if the breakdown in analytical equipment prevented the 
performance of a radiochemical identity/purity test.
    (Comment 39) One comment stated that Sec.  212.70(f)(2) should also 
disallow conditional final release if the breakdown in analytical 
equipment prevents the determination of the specific activity of a PET 
drug product with mass-dependent target localization and/or potential 
to elicit a physiological effect, where the specific activity limit is 
quantitatively expressed.
    (Response) We agree. Therefore, we have revised Sec.  212.70(f)(2) 
to state that a PET drug producer may not approve the conditional final 
release of a product if the malfunction involving analytical equipment 
prevents the performance of a radiochemical identity/purity test or 
prevents the determination of the product's specific activity.

I. Actions To Be Taken If Product Does Not Conform to Specifications 
(Proposed Sec.  212.71)

    Proposed Sec.  212.71 addressed the actions that a PET drug 
producer must take if a batch of a PET drug product does not conform to 
specifications. Proposed Sec.  212.71(d) stated that, if appropriate, a 
PET drug producer may reprocess a batch of a PET drug product that does 
not conform to specifications. The proposed provision further stated 
that if material that does not meet acceptance criteria is reprocessed, 
the PET drug 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.
    (Comment 40) One comment asked whether such reprocessing was 
required to be specified in the approved NDA for the PET drug product 
or whether it could be done according to an internal process for the 
establishment of production and process controls.
    (Response) Reprocessing a batch of PET drug product that did not 
conform to specifications is only appropriate if the reprocessing is 
included in the approved NDA or ANDA for the product. To clarify this 
provision, we have revised the second sentence of Sec.  212.71(d) to 
state that if material that does not meet acceptance criteria is 
reprocessed, the PET drug producer must follow ``procedures stated in 
the product's approved application'' (which could be either an NDA or 
ANDA).

J. Complaint Handling (Proposed Sec.  212.100)

1. Written Complaint Procedures
    Proposed Sec.  212.100(a) stated that a PET drug producer must 
develop and follow written procedures for the receipt and handling of 
all complaints concerning a PET drug product.
    (Comment 41) Three comments objected to the scope of proposed Sec.  
212.100(a). The comments stated that it would be inappropriate for 
Sec.  212.100(a) to include complaints involving such matters as 
pricing issues, ordering errors, and shipping delays. One comment 
stated that the provision should be limited to complaints concerning 
the quality or purity of, or possible adverse reactions to, a PET drug 
product. In addition to recommending inclusion of complaints about 
adverse reactions, one comment suggested including complaints about the 
quality or labeling of a PET drug product and another comment 
recommended including complaints about the quality or efficacy of a PET 
drug product.
    (Response) We agree with the comments that PET drug producers 
should not be required to have written procedures regarding all 
conceivable

[[Page 65422]]

complaints about a PET drug product. Therefore, we have revised Sec.  
212.100(a) to state that a PET drug producer must develop and follow 
written procedures for the receipt and handling of all complaints 
concerning the quality or purity of, or possible adverse reactions to, 
a PET drug product.
2. Returned Products
    Proposed Sec.  212.100(d) stated that 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.
    (Comment 42) One comment asked us to clarify whether proposed Sec.  
212.100(d) was intended to allow the reprocessing of returns that are 
not the result of complaints.
    (Response) We can conceive of no circumstances under which a 
returned PET drug product could be reusable. Therefore, we have revised 
Sec.  212.100(d) to state that a PET drug product that is returned 
because of a complaint or for any other reason may not be reprocessed 
and must be destroyed in accordance with applicable Federal and State 
law.

K. Records (Proposed Sec.  212.110)

    Proposed Sec.  212.110(c) stated that a PET drug producer must 
maintain all records and documentation referenced in other parts of the 
regulation for a period of at least 1 year from the date of final 
release, including conditional final release, of a PET drug product. On 
our own initiative, we revised this provision to clarify that it 
requires the maintenance of all records and documentation referenced in 
part 212.

IV. Analysis of Economic Impacts

    We have examined the potential economic impact of this final 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 net 
benefits (including potential economic, environmental, public health 
and safety, and other advantages; distributive impacts; and equity). We 
believe that this final rule is not an economically significant action 
under the Executive order.
    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 this rule may have a significant effect on a 
substantial number of small entities. A regulatory flexibility analysis 
explaining this finding is presented below.
    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 $133 million, using the most current (2008) Implicit 
Price Deflator for the Gross Domestic Product. We do not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.

A. Regulatory Benefits

    Comments on the proposed rule did not focus specifically on our 
description of the benefits of the proposed CGMP regulations for PET 
drugs. Further, none of the changes made to the final rule cause us to 
re-examine these benefits. We therefore present the same qualitative 
description of the benefits of the final rule.
    The Modernization Act requires us to establish appropriate good 
manufacturing practices for PET drugs. Without minimum manufacturing 
standards, unintentionally inferior PET drugs may be produced for human 
use. The short half-life characteristic of PET drugs 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 drugs are 
marketed without FDA approval, and we have not received any 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 for the proposed rule, we were unable to 
estimate how much this rule might reduce the risk of adverse events 
associated with PET drugs and consequently improve public health. As 
stated previously, comments on the proposed rule did not offer any data 
concerning the expected level of risk reduction due to compliance with 
the CGMP requirements. Because the final rule is not substantially 
different from the proposed rule, we maintain that the final rule will 
reduce, by an unquantifiable amount, the risk of adverse health events 
associated with PET drugs.
    This rule creates minimum manufacturing standards to ensure the 
safety, identity, strength, quality, and purity of PET drugs. Building 
quality into the production process permits early detection and 
correction of problems and promotes continuous improvement. Activities 
such as developing specifications may result in increased reliability 
and uniformity of PET drugs to patients. Ultimately, this rule is 
expected to result in a reduction in adverse reactions to PET drugs and 
an improvement in overall public health.

B. Regulatory Costs

    Public comments did not specifically address the methodology of the 
analysis of impacts section that was published in the proposed rule. As 
such, we retain it for the analysis of the final rule. For the proposed 
rule, we determined that many PET drug producers had already adopted 
some form of good manufacturing practices or SOPs. The Modernization 
Act required 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 expected average compliance costs associated with the 
proposal to be small.
    We proposed that the CGMP rule would 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. We believed that most of the large corporate PET 
drug producers and hospital PET drug producers associated with these 
corporate entities already complied to a great degree with the proposed 
CGMP rule. Based on our consultations with industry (including PET drug 
producers and professional associations) through direct contact as well 
as public comments at public meetings and previously published 
preliminary proposed rules, we made a general assessment of the current 
operational status of PET drug producers for the proposed rule.
    We estimated that the proposed rule would affect 51 producers of 
PET drugs, operating 101 establishments. Fifteen of these producers 
owned or operated 65

[[Page 65423]]

commercial establishments (16 of which are associated with academic 
hospitals). Of these 15 producers, 11 were regional or local 
unaffiliated producers that had begun to produce PET drug products in 
recent years. The other four commercial producers were corporations, 
each of which had multiple establishments. In total, these 4 corporate 
producers operated 48 establishments. The remaining 36 producers were 
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 or 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

    As with the CGMP proposed rule, the final rule imposes compliance 
requirements resulting in two types of costs. From the date of 
publication of the final rule until the effective date, PET drug 
producers will incur one-time costs as each producer is brought into 
compliance. In succeeding years, each producer is expected to incur 
only annual costs related to maintaining compliance.
    The following sections contain the general requirements of the 
final 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 
PET drugs. 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 drug products.
     Section 212.100: Establish procedures for the receipt and 
handling of complaints regarding a PET drug product.
1. Impact of Changes to the Proposed Rule
    Among the revisions we made to the proposed rule are several 
changes that could affect the compliance costs of the rule. We revised 
Sec.  212.50(c)(6) to require that the time of production of PET drugs 
be recorded only for critical production steps. This is expected to 
slightly reduce the burden of the final rule on PET drug producers. We 
revised Sec.  212.60(g)(1) to require only that any sample of a PET 
drug product received by a laboratory for testing be suitably 
identified, rather than requiring a description of the sample, 
including information that may already be included in the master 
production and control record. Under this change, a reference to the 
information in the master production and control record would simplify 
the identification procedure by eliminating the need for an employee to 
re-enter identical data, which would slightly reduce labor costs for 
PET drug producers.
    We revised Sec.  212.70(c) to allow for more flexibility in the 
determination of batch specificity conformity by not requiring 
finished-product testing in all circumstances. This change represents 
another slight reduction in compliance costs. We revised Sec.  
212.70(e) to require that, upon completion of an investigation into the 
failure to meet a criterion for sterility, all facilities that received 
the PET drug product be notified of the findings of the investigation. 
Because providing this notification appears to be the current practice 
among PET drug producers, no additional compliance costs are expected 
to result from this change. We slightly reduced potential compliance 
costs under Sec.  212.70(f)(1) by broadening the circumstances under 
which conditional final release is permitted to include when there is a 
malfunction involving analytical equipment (instead of only when a 
complete breakdown occurs). Our deletion from Sec.  212.70(f)(1) of the 
requirement that the PET drug producer immediately notify the receiving 
facility if incomplete testing occurs also slightly reduces compliance 
costs. Finally, we revised Sec.  212.70(f)(2) to prohibit approval of 
conditional final release of a PET drug product if an equipment 
malfunction prevents the determination of the product's specific 
activity. Although this revision specifies another circumstance under 
which conditional final release of a PET drug product is not 
permissible (in addition to when a malfunction prevents the performance 
of a radiochemical identity/purity test), the change is consistent with 
current practice and therefore creates no additional compliance burden.
    For the annual costs of the proposed rule, we developed estimates 
based on input from agency resources that a quality control manager of 
a PET drug production facility would put forth from 3 to 7.5 additional 
labor hours weekly to comply with the CGMP regulations. The changes to 
the final rule outlined

[[Page 65424]]

above would likely result in a slightly smaller burden due to reduced 
labor hours that may total only a few minutes weekly. Since the size of 
the reduction in burden is so small and likely within any range of 
uncertainty inherent in the estimates made for the proposal, we have 
not changed the estimated labor hour increases in the analysis of this 
final rule.
    We expect some variation in the exact SOPs that PET drug producers 
will need to create or revise to comply with the rule. We expect that 
the various types of producers already comply with aspects of the rule 
to different extents. The hospital PET drug producers and the 
independent regional commercial producers will likely require more time 
and effort to comply than will 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 producers and the hospital and regional commercial producers.
2. 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 will be included in the 
efforts of a designated individual or individuals who will be primarily 
responsible for bringing each PET drug production establishment into 
compliance. In this case, we 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 titled ``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 incoming component tracking and testing records. PET drug 
producers will 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://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm).
---------------------------------------------------------------------------

    For the final rule, we have increased all employment costs by about 
21.7 percent to account for the employment cost increase from 2001 (the 
year for which we estimated salary and labor costs) to 2007.\2\ We 
estimate that all hospital and regional commercial producers will need 
from 3 to 5 months to write and establish the SOPs, even with the 
guidance provided. We assume that the employee responsible for writing 
the SOPs will be in a management position, either in quality assurance 
or elsewhere, with a salary of up to $121,700 per year; we include an 
additional 35 percent for employee benefits and other costs for an 
annual cost per employee of $164,300 ($121,700 x 1.35). The cost of an 
average 4-month effort will therefore amount to $54,800 for each 
hospital and regional commercial PET drug producer.\3\
---------------------------------------------------------------------------

    \2\ U.S. Department of Labor, Bureau of Labor Statistics, 
private industry, total compensation.
    \3\ 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 or hospital producers, we 
assume they would pay a salary similar to those of corporate 
producers.
---------------------------------------------------------------------------

    Although most corporate PET drug producers are said to have a 
complete set of SOPs, we assume each will expend some time to verify 
its compliance with the rule and make minor adjustments to their SOPs. 
We estimate that it will take, on average, 1 month for an individual to 
verify compliance with the rule and make any needed adjustments to the 
SOPs. This will result in a cost of approximately $13,700 per corporate 
PET drug producer, again using an estimated salary and benefits of 
$164,300 per year. The smaller burden for corporate PET drug producers 
compared with hospitals and regional producers is due to the current 
high compliance rates expected at the corporate establishments.\4\ We 
also assume that corporate producers with multiple manufacturing sites 
will amend a single set of SOPs to cover all of their production sites. 
Since there are currently four corporate producers of PET drugs, the 
cost of the SOP revisions is estimated at $54,800 (4 times $13,700).
---------------------------------------------------------------------------

    \4\ 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 will be 
more likely at the hospital and regional commercial PET drug producers, 
we do not expect the total cost of this compliance effort to vary 
considerably.
    Producers also are 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 will be 
necessary at most establishments, we projected that one person at each 
establishment could need up to 1 week of additional training. The cost 
of this additional training amounts to about $319,000 (101 
establishments times 1 week at $164,300 per year).
    The total cost for initial compliance associated with writing the 
SOPs and creating document forms amounts to approximately $2.95 
million. The 47 hospital and regional commercial producers will incur a 
total of about $2.75 million (47 producers times $54,800 plus 53 
establishments times $3,200). The 4 corporate producers will incur a 
total of about $207,000 (4 producers times $13,700 plus 48 
establishments times $3,200). Annualizing the total one-time cost over 
5 years at a 7 percent discount rate results in annualized costs of 
about $719,000.
    Once procedures are established and documents are in place to 
record PET drug production and events associated with routine 
production of PET drugs, we 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 will have to be expanded to include any provisions with 
which the company is 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 
will 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 rule will 
require, at most, one to two additional hours per day for an individual 
at each hospital or regional commercial producer. Using the midpoint of 
this range results in 2.25 additional months of labor each year. Using 
the same estimated annual salary ($121,700 plus benefits), 2.25 months 
of labor equates to about $30,800 in annual costs to each PET drug 
production establishment, or about $1.63 million for all 53 hospital 
and regional commercial producer establishments.
    Our assessment of corporate PET drug producers is that they already 
comply substantially with the rule. For these

[[Page 65425]]

producers, we project that one production individual will expend an 
additional 1 month of effort over the course of each year (about 3 
hours per week) to comply with the rule. This month will result in each 
corporate PET drug producer incurring about $13,700 in additional 
annual costs, totaling $657,000 for the 48 corporate PET drug 
production establishments. Some producers will probably opt to use an 
outside consultant to manage the implementation of the new regulations 
in the first year. Although we do not know how many producers will hire 
a consultant, we do 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 
for hospitals and regional producers as well as corporate producers are 
estimated at $2.29 million ($1.63 million plus $657,000).
    Producers also are expected to provide some additional training in 
future years on SOPs that were amended to comply with this CGMP rule. 
We expect that this training (review for current employees as well as 
new employees) will be incorporated into current training programs and 
therefore be less burdensome than the initial training to implement the 
rule. Nevertheless, we included the cost for annual training for one 
person per establishment for one-half week. The cost of this additional 
training amounts to about $160,000 annually (101 establishments times 
one-half week at $164,300 per year).
    Total annual costs associated with daily implementation and 
training amount to $2.45 million. The 53 hospital and regional 
commercial establishments will incur a total of about $1.72 million (53 
establishments times ($20,800 plus $1,600)). The average cost per 
facility for these provisions is $32,400. The 48 corporate production 
establishments will incur a total of about $734,000 (48 establishments 
times ($13,700 plus $1,600)). The average cost per facility for these 
provisions is $15,300.
3. Equipment Costs
    Based on numerous site visits to PET drug production facilities by 
FDA personnel, we conclude that the current laboratory facilities and 
equipment comply with the requirements of the final rule. Therefore, 
additional costs for laboratory space or equipment will not be incurred 
in complying with the rule. 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 will not be required.
4. Process Verification Costs
    In response to public comments on the preliminary draft proposed 
rule, we modified the process verification requirements. Not all PET 
drug product batches that undergo full finished-product testing to 
ensure that the product meets specifications will be required to verify 
the production process. Since we believe that all PET drugs that will 
receive NDA approval in the next few years will undergo finished-
product testing, this requirement will not impose any additional 
burden. In later years, however, some PET drugs products with NDA 
approval may submit only the initial sub-batch to finished-product 
testing before release. In such cases, producers will have to document 
their process verification procedures. Since we do not know how many, 
if any, PET drugs such as this will 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.
5. Total Costs
    Total one-time costs are estimated at about $2.95 million 
(annualized at $720,000 over 5 years), and annual costs at about $2.45 
million (see table 2 of this document).

                                       Table 2.--CGMP Costs By Requirement
----------------------------------------------------------------------------------------------------------------
                                                      No. of                         Wage (Yr.
                Rule Requirement                  Establishments  Labor (Months)     Sal.)\1\         Cost\2\
----------------------------------------------------------------------------------------------------------------
One-Time Costs
----------------------------------------------------------------------------------------------------------------
Establishment/Write SOPs                          ..............  ..............  ..............  ..............
----------------------------------------------------------------------------------------------------------------
  Academic PET Producers                                      47               3        $164,300      $2,574,000
----------------------------------------------------------------------------------------------------------------
  Commercial PET Producers                                     4               1        $164,300         $55,000
----------------------------------------------------------------------------------------------------------------
Training on SOPs                                  ..............  ..............  ..............  ..............
----------------------------------------------------------------------------------------------------------------
  Academic PET Producers                                      53             .23        $164,300        $168,000
----------------------------------------------------------------------------------------------------------------
  Commercial PET Producers                                    48             .23        $164,300        $152,000
----------------------------------------------------------------------------------------------------------------
Total One-Time Costs                                                                                  $2,949,000
----------------------------------------------------------------------------------------------------------------
Annual Costs
----------------------------------------------------------------------------------------------------------------
Rule Requirement
----------------------------------------------------------------------------------------------------------------
Daily Implementation, Audits, Updates
----------------------------------------------------------------------------------------------------------------
  Academic PET Producers                                      53            2.25        $164,300      $1,633,000
----------------------------------------------------------------------------------------------------------------
  Commercial PET Producers                                    48             1.0        $164,300        $657,000
----------------------------------------------------------------------------------------------------------------
Training                                          ..............  ..............  ..............  ..............
----------------------------------------------------------------------------------------------------------------

[[Page 65426]]

 
  Academic PET Producers                                      53             .11        $164,300         $84,000
----------------------------------------------------------------------------------------------------------------
  Commercial PET Producers                                    48             .11        $164,300         $76,000
----------------------------------------------------------------------------------------------------------------
Total Annual Costs                                                                                    $2,450,000
----------------------------------------------------------------------------------------------------------------
\1\ Salary includes 35 percent increase for benefits.
\2\ Cost totals may not sum due to rounding.

    As shown in table 3 of this document, the 53 hospital and regional 
commercial PET drug production establishments will incur about $2.74 
million in one-time costs and $1.72 million in annual costs. The 
annualized (annualized one-time costs plus annual costs) cost per 
facility is estimated at about $43,600. The 48 corporate PET drug 
production facilities will incur about $207,000 and $733,000 in one-
time and annual costs, respectively. Total annualized (annualized one-
time costs plus annual costs) costs per corporate establishment are 
estimated at about $16,300. Total annualized costs for all producers 
are estimated at $3,170,000.

              Table 3.--CGMP Costs By Type of Establishment
------------------------------------------------------------------------
                                      One-Time Cost       Annual Cost
------------------------------------------------------------------------
Hospital and Regional Commercial           $2,740,000         $1,720,000
 Establishments (53)
------------------------------------------------------------------------
Corporate Establishments (48)                $207,000           $733,000
------------------------------------------------------------------------
Total Cost\1\                              $2,947,000         $2,453,000
------------------------------------------------------------------------
Total Annualized Cost\2\                                      $3,170,000
------------------------------------------------------------------------
\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.

    For the proposed rule, we estimated, with some uncertainty, that 
101 PET drug producers were in operation. While preparing the impacts 
analysis of the final rule, we requested information from an 
association of radiopharmaceutical manufacturers about the number of 
PET drug producers. The association responded with a count showing an 
estimated 135 to 145 sites operating cyclotrons that are capable of 
producing FDG F 18.\5\ We are not certain that each of these 135 to 145 
cyclotrons currently produces PET drugs, nor do the data identify the 
actual sites. However, we use the midpoint of this range, or 140 
cyclotron sites, as the upper bound of the range of possible PET drug 
production sites. The association's data are not as detailed as the 
data we presented in the proposed rule, as the former do not show the 
distribution of production facilities among the different establishment 
types. We will, therefore, retain the relative distribution of 
production facilities we presented for the proposed rule and increase 
total industry costs by the relative increase in possible PET drug 
production sites, or 38.6 percent ((140 sites - 101sites) / 101 sites). 
If these additional 39 sites produce PET drugs, the total annualized 
costs would be as high as $4.40 million. Although our estimates of 
total industry costs would increase due to this adjustment (which we 
anticipated to some extent in the analysis of the proposed rule by 
projecting an annual 5-percent increase in the number of facilities), 
compliance costs per PET drug manufacturing facility will not increase 
with the larger estimate of total facilities.
---------------------------------------------------------------------------

    \5\ Correspondence to FDA from Council on Radionuclides and 
Radiopharmaceuticals, Inc., dated October 3, 2006.
---------------------------------------------------------------------------

    We received one comment on our estimate of total costs. The comment 
expressed concern that subjecting hospitals and research institutions 
to the same inspection regime as large commercial producers would be 
unduly onerous, requiring those institutions to shift limited resources 
away from health care delivery and research to satisfy regulatory 
obligations that the comment believes are not warranted by clinical or 
safety considerations. A footnote to the comment stated that the 
proposed rule's compliance costs (e.g., $2.42 million one-time costs 
and $2 million in annual costs per hospital or corporate facility) were 
of particular concern.
    We note that the $2.95 million in revised one-time costs and the 
approximately $2.45 million in revised annual costs represent totals 
for all PET drug establishments, not individual hospitals or corporate 
facilities. In addition, the cost figures reflect all costs associated 
with compliance with PET CGMP requirements, not simply costs related to 
FDA inspections, which is the focus of the comment's concern. Finally, 
we have addressed the comment's concern regarding inspections in our 
response to comment 6 in section III.A of this document.

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 drugs, 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 drugs is 
expected to continue to increase, we projected compliance costs over 
the next 10 years for the proposed rule. We did not receive comment on 
our projection and retain it (with adjustments for

[[Page 65427]]

employment cost inflation) for the final rule. 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 will 
be partially met by increasing production runs and batch sizes at 
existing establishments rather than proportional increases in the 
number of PET drug production establishments. We have therefore 
projected average annual PET drug production establishment increases 
will range from 3 to 7 percent. Assuming this growth occurs evenly 
across producer types, this growth rate implies an increase in 
annualized costs from $3.17 million in year one to $4.15 to $5.84 
million in year ten. The PET drug risk reduction resulting from this 
rule will also apply to the additional volume of PET drug dosages 
implied by the 3- to 7-percent annual growth rate in PET drug 
establishments.

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 rule, in accordance with the 
Modernization Act, will help ensure the safety, identity, strength, 
quality, and purity of PET drugs by establishing CGMP requirements. The 
objective of the rule 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 drugs.
2. Definition of Small Entities
    A regulatory flexibility analysis (RFA) is required to estimate the 
number of small entities to which the rule applies. Since we did not 
receive any comments on the proposed rule that addressed the analysis 
of impacts on small entities, we retain our analysis for the final 
rule, with revisions for inflation. This rule affects producers of PET 
drugs, including certain hospitals, clinics, colleges and universities, 
and producers of in vivo diagnostic substances. According to the Small 
Business Administration (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. To 
estimate the number of U.S. establishments producing PET drugs, we 
combined a list of PET centers with cyclotrons from the Academy of 
Molecular Imaging (AMI) with a list of PET manufacturing facilities 
from the Society of Nuclear Imaging in Drug Development, which has 
since merged with the AMI, and added additional facilities that we 
identified. We have identified 101 establishments operated by 51 PET 
drug producers. In over one-third of the cases, the PET drug is 
produced by a hospital. In other instances, a corporate producer 
manages production under contract at one or more hospitals with 
cyclotrons. PET drugs 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 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;
     Investor-owned (for-profit).\6\
---------------------------------------------------------------------------

    \6\ ``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.\7\ 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 $57.7 
million using the Consumer Price Index (CPI) for medical care from 1997 
to 2007. Considering that hospitals producing PET drugs probably are 
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 are therefore not considered small entities.\8\ 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.
---------------------------------------------------------------------------

    \7\ ``The Nation: Colleges and Universities,''The Chronicle of 
Higher Education, 1999-2000, Almanac Issue, volume XVI, no. 1, p. 7, 
August 27, 1999.
    \8\ ``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 drugs 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 drugs it 
produces or the share of the market it holds.
3. Impact on Small Entities
    The reporting, recordkeeping, and other compliance requirements on 
small entities 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 PET drug producer may incur one-time and annual 
costs of approximately $57,900 and $32,400, respectively, per 
production facility. The hospital and regional commercial producers 
will incur these higher per-facility costs because these establishments 
are expected to have higher noncompliance rates 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 $111 million ($70.8 million inflated by the CPI for 
medical care from 1997 to 2007) average annual gross revenue per 
nonprofit hospital. In addition, most of the hospitals that are 
affected by this rule are affiliated with large universities whose 
total revenues are expected to be much higher than the $111 million 
figure cited. The estimated compliance cost represents an even

[[Page 65428]]

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 is expected to incur annual costs of 
approximately $70,100 and one-time costs of about $16,800. The 11 
regional commercial producers are expected to incur one-time and annual 
costs of approximately $57,900 per producer and $32,400 per production 
facility. We lack sufficient data to estimate the expected compliance 
costs as a percentage of revenues for the regional commercial 
producers. Although no comments on the proposed rule directly addressed 
our estimates of the expected impact of compliance costs on small 
facilities, it is possible that this final rule will have a significant 
effect on these small entities.
4. Other Federal Rules
    We are not aware of any relevant Federal rules that may duplicate, 
overlap, or conflict with the rule.
5. Analysis of Alternatives
    Several alternative provisions were considered in addition to those 
of the proposed rule. These included using traditional CGMPs, requiring 
specific identity testing of PET drug components, requiring 
verification of certificates of analyses of PET drug components, 
validating production and process controls, and requiring audit trail 
capabilities for all computer-operated systems. These alternative 
provisions were not included in the proposed rule because they were 
determined to be unnecessary, unduly burdensome, or both.
    (Comment 43) We received one comment on electronic audit trail 
capabilities. The comment stated that, as we estimated, there is very 
little if any software of this nature in use by PET drug producers. The 
comment stated that many items of production equipment are incapable of 
the necessary software upgrades due to age and existing operating 
systems. The comment maintained that requiring the use of electronic 
audit trail software would be unduly burdensome for the PET community, 
and it recommended that we not require an electronic audit trail as 
part of PET CGMP provisions.
    (Response) We agree that the additional level of quality assurance 
that might be provided through the use of electronic audit trail 
capability does not warrant the additional costs that would be imposed 
to implement this capability. Therefore, the CGMP requirements for PET 
drugs do not include electronic audit trail requirements.
    We did not receive any public comments on the proposed rule 
concerning the analyses of the other alternative provisions of the 
proposed PET CGMP rule.

V. 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.

VI. Paperwork Reduction Act of 1995

    This final rule contains information collection requirements that 
are subject to review by the Office of Management and Budget (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.
    Title: Current Good Manufacturing Practice for Positron Emission 
Tomography Drugs
    Description: In accordance with the Modernization Act, the final 
rule establishes CGMP requirements for PET drugs. The 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 estimated annual recordkeeping and 
third-party disclosure burden 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 CGMP regulations are intended to ensure that approved PET drugs 
meet the requirements of the act as to safety, identity, strength, 
quality, and purity. The regulations address the following matters: 
Personnel and resources; quality assurance; 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 CGMP regulations establish several recordkeeping requirements 
for the production of PET drugs. In making our estimates of the time 
spent in complying with these 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 drugs.
    Burden Estimate: Table 4 of this document provides an estimate of 
the annual recordkeeping burdens associated with the final rule. Table 
5 of this document provides an estimate of the annual third-party 
disclosure burdens associated with the final rule. 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, resulting in an estimated 
173 total PET drugs. 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 will be 
required.

A. Investigational and Research PET Drugs

    Section 212.5(b)(2) provides that for investigational PET drugs 
produced under an IND and research PET drugs produced with approval of 
an RDRC, the requirement under the act to follow current good 
manufacturing practice is met by complying with the regulations in part 
212 or with USP 32 Chapter 823. We believe that PET production 
facilities producing drugs under INDs and RDRCs are currently 
substantially complying with the recordkeeping requirements of USP 32 
Chapter 823 (see section 121(b) of the Modernization Act), and 
accordingly, we have not estimated any recordkeeping burden for this 
provision of the rule.

B. Batch Production and Control Records

    Sections 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

[[Page 65429]]

maintain written production and control procedures and to create and 
maintain master batch records for each PET drug produced. We also 
estimate that there will be a total of 173 PET drugs produced, with a 
total estimated recordkeeping burden of 3,460 hours. We estimate that 
it would 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

    Sections 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

    Sections 212.20(c) and 212.40(a), (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

    Section 212.50(f)(2) requires that any process verification 
activities and results be recorded. Because process verification is 
only 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

    Sections 212.20(c), 212.60(a), (b), and (g), 212.61(a) through (b), 
and 212.70(a), (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 is 2,525 
hours, and the annual burden for recording laboratory test results is 
8,383 hours.

G. Sterility Test Failure Notices

    Section 212.70(e) requires PET drug producers to notify all 
receiving facilities if a batch fails sterility tests. We believe that 
sterility test failures might occur in only 0.05 percent of the 
estimated 50,500 batches of PET drugs produced each year (about 25 
times each year). Therefore, we have estimated that each PET drug 
producer will need to provide 0.25 sterility test failure notice per 
year to receiving facilities. The notice would be provided using e-mail 
or facsimile transmission and should take no more than 1 hour.

H. Conditional Final Releases

    Section 212.70(f) requires PET drug producers to document any 
conditional final releases of a product. We believe that conditional 
final releases will be fairly uncommon, but for purposes of the PRA, we 
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.
    (Comment 44) One comment expressed concern about the estimate of 
the frequency of conditional final release of PET drug products. The 
comment noted that the preamble to the proposed rule stated that 
conditional final release should not be necessary except in ``very rare 
circumstances''; the comment also noted the statement in the preamble 
that 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'' within the 
meaning of proposed Sec.  212.70(f)(1)(v). The comment disagreed with 
the estimate of one conditional final release per year for each 
facility, stating that there appeared to be no consideration for size 
or production volume. The comment maintained that the use of 
conditional release should be tracked by producers to look for trends 
in equipment failures that need corrective actions, and the diligence 
applied in these corrective actions should be the measure for taking 
reasonable efforts to ensure that the problem does not recur.
    (Response) We believe that the estimate of one conditional final 
release per year per facility is an appropriate average number because 
we believe that many facilities might have no conditional final 
releases while others might have only a few. We agree with the comment 
that an assessment of ``reasonable efforts'' to prevent recurrence of a 
malfunction involving analytical equipment, under Sec.  
212.70(f)(1)(iv) of the final rule, would not focus primarily on the 
specific number of equipment failures. Instead, the reasonableness of 
the efforts relates to the steps that a producer takes to remedy a 
particular equipment problem and to identify and address trends in 
equipment malfunctions.

I. Out-of-Specification Investigations

    Sections 212.20(c) and 212.71(a) and (b) 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 will 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.
    (Comment 45) One comment maintained that the number of out-of-
specification investigations is significantly underestimated (at one 
investigation per facility each year). The comment stated that a true 
failure might only occur once each year but an out-of-specification 
investigation is necessary each time a single item in the final product 
testing process results in a nonconformance to specifications. The 
comment stated that because quality control on each batch is executed 
quickly, most out-of-specification conditions are directly due to 
operator or equipment failure and are rectified by retesting. The 
comment maintained that out-of-specification investigations actually 
occur two to three times per month; therefore, the comment recommended 
that we use an estimate of 36 investigations per facility each year.
    (Response) We agree with the comment's reasoning and we have 
revised the annual frequency of out-of-specification investigations 
from 1 to 36, which results in an annual hourly burden of 3,636 (101 
producers times 36

[[Page 65430]]

investigations times 1 hour for documentation equals 3,636 hours).

J. Reprocessing Procedures

    Sections 212.20(c) and 212.71(d) require PET drug producers to 
establish and document procedures for reprocessing PET drugs. We 
estimate that it will take 1 hour a year to document these procedures 
for each PET production facility. We did not estimate 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

    Sections 212.20(c) and 212.90(a) require that written procedures 
regarding distribution of PET drug products be established and 
maintained. We estimate that it will take 1 hour annually to establish 
and maintain records of these procedures for each PET production 
facility. Section 212.90(b) requires that distribution records be 
maintained. We estimate that it will take 15 minutes to create an 
actual distribution record for each batch of PET drug products, with a 
total burden of 12,625 hours for all PET producers.

L. Complaints

    Sections 212.20(c) and 212.100 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 will take 1 hour 
annually for each PET production facility and that each facility will 
receive one complaint a year and will spend 30 minutes recording how 
the complaint was dealt with.

                                                     Table 4.--Estimated Annual Recordkeeping Burden
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                              No. of       Annual Frequency  of     Total Annual        Hours per
                    21 CFR Section                        Recordkeepers        Recordkeeping          Records          Recordkeeper       Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.20(c) and (e),                                                    101                  1.71                173                 20              3,460
212.50(a) and (b)
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.20(d) and (e), 212.50(c), 212.80(c)                               101                   500             50,500                 .5             25,250
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.20(c), 212.30(b), 212.50(d), 212.60(f)                            101                    15              1,515                  1              1,515
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.30(b), 212.50(d), 212.60(f)                                       101                 3,750            378,750               .083             31,436
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.20(c), 212.40(a) and (b)                                          101                     2                202                  1                202
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.40(e)                                                             101                    36              3,636               .166                604
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.20(c), 212.60(a) and (b), 212.61(a), 212.70(a),                   101                    25              2,525                  1              2,525
 (b), and (d)
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.60(g), 212.61(b), 212.70(d)(2) and (d)(3)                         101                   500             50,500               .166              8,383
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.70(f)                                                             101                     1                101                  1                101
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.20(c), 212.71(a)                                                  101                    36              3,636                  1              3,636
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.71(b)                                                             101                     1                101                  1                101
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.20(c), 212.71(d)                                                  101                     1                101                  1                101
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.20(c), 212.90(a)                                                  101                     1                101                  1                101
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.90(b)                                                             101                   500             50,500                .25             12,625
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.20(c), 212.100(a)                                                 101                     1                101                  1                101
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.100(b) and (c)                                                    101                     1                101                 .5                 50
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                             90,191
--------------------------------------------------------------------------------------------------------------------------------------------------------


                                               Table 5.--Estimated Annual Third-Party Disclosure Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                              No. of         No. of Responses                           Hours per
                    21 CFR Section                         Respondents        per Respondent      Total  Responses       Response         Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
212.70(e)                                                             101                   .25                 25                  1                 25
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                                 25
--------------------------------------------------------------------------------------------------------------------------------------------------------


[[Page 65431]]

    The information collection provisions of this final rule have been 
submitted to the Office of Management and Budget (OMB) for review, as 
required under section 3507(d) of the PRA. Prior to the effective date 
of this final rule, FDA will publish a notice in the Federal Register 
announcing OMB's decision to approve, modify, or disapprove the 
information collection provisions in this final rule. An agency may not 
conduct or sponsor, and a person is not required to respond to, a 
collection of information unless it displays a currently valid OMB 
control number.

VII. Federalism

    We have analyzed this rule in accordance with the principles set 
forth in Executive Order 13132. We have 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. Accordingly, we have concluded that the 
rule does not contain policies that have federalism implications as 
defined in the order and, consequently, a federalism summary impact 
statement is not required.

VIII. Effective Date

    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. As stated in the proposed rule, section 121(b)(1) of the 
Modernization Act added this provision as a safety net while we 
developed the CGMP regulations for PET drugs. Section 121(b)(2) of the 
Modernization Act specifies that section 501(a)(2)(C) of the act will 
expire 2 years after the date on which we establish appropriate 
approval procedures and CGMP requirements for PET drugs in accordance 
with section 121(c)(1)(A) of the Modernization Act. For this reason, 
this final rule on CGMP for PET drugs will become effective 2 years 
after the date on which the rule is published in the Federal Register. 
(See the DATES section of this document.) Beginning on that date, PET 
drug producers will be required to produce PET drugs in accordance with 
the CGMP requirements set forth in part 212.
    We also note that section 121(c)(2)(A) of the Modernization Act 
provides that we cannot require the submission of an NDA or ANDA for a 
PET drug until 2 years after the date on which we establish appropriate 
approval procedures and CGMP requirements for PET drugs. With the 
publication of this final rule, we have established CGMP requirements 
for PET drugs in accordance with section 121(c)(1)(A)(ii) of the 
Modernization Act. As discussed in section III.A of this document, we 
have established approval procedures for PET drugs in accordance with 
section 121(c)(1)(A)(i) of the Modernization Act. Therefore, in 
accordance with section 121(c)(2)(A) of the Modernization Act, the 
requirements in the act and FDA regulations concerning NDAs and ANDAs 
will become applicable to PET drugs 2 years from the date of 
publication of this final rule. (See the DATES section of this 
document.) After that date, PET drug producers will be required to 
submit either an NDA or ANDA for each of their PET drugs.

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.

0
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, 21 CFR chapter I is amended as follows:

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

0
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]

0
2. Amend Sec.  210.1 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]

0
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]

0
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

0
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.

0
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 drugs) for administration to humans or 
animals.
* * * * *

0
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 drug 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-

[[Page 65432]]

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 drugs?

    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 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.
    Component means any ingredient intended for use in the production 
of a PET drug, 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 malfunction 
involving 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 in humans.
    Inactive ingredient means any intended component of the PET drug 
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.
    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 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 number means 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 can be determined.
    Master production and control record means a compilation of 
instructions containing the procedures and specifications for the 
production of a PET drug.
    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.
    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'' includes a ``PET 
drug product'' as defined in this section.
    PET drug product means a finished dosage form of a PET drug, 
whether or not in association with one or more other ingredients.
    PET drug production facility means a facility that is engaged in 
the production of a PET drug.
    Production means the manufacturing, compounding, processing, 
packaging, labeling, reprocessing, repacking, relabeling, and testing 
of a PET drug.
    Quality assurance means a system for ensuring the quality of active 
ingredients, PET drugs, 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).
    Sub-batch means a quantity of PET drug having uniform character and 
quality, within specified limits, that is produced during one 
succession of multiple irradiations, using a given synthesis and/or 
purification operation.
    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 drugs is the minimum 
requirements for the methods to be used

[[Page 65433]]

in, and the facilities and controls used for, the production, quality 
assurance, holding, or distribution of PET drugs intended for human 
use. Current good manufacturing practice is intended to ensure that 
each PET 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 is supposed to have.


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

    (a) Application solely to PET drugs. The regulations in this part 
apply only to the production, quality assurance, holding, and 
distribution of PET drugs. Any human drug that does not meet the 
definition of a PET drug must be manufactured in accordance with the 
current good manufacturing practice requirements in parts 210 and 211 
of this chapter.
    (b) Investigational and research PET drugs. For investigational PET 
drugs for human use produced under an investigational new drug 
application in accordance with part 312 of this chapter, and PET drugs 
produced with the approval of a Radioactive Drug Research Committee in 
accordance with part 361 of this chapter, the requirement under the act 
to follow current good manufacturing practice is met by complying with 
the regulations in this part or by producing PET drugs in accordance 
with Chapter 823, ``Radiopharmaceuticals for Positron Emission 
Tomography--Compounding,'' May 1, 2009, pp. 365-369, 32d ed. of the 
United States Pharmacopeia (USP) National Formulary (NF) (USP 32/NF 27) 
(2009). The Director 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 a copy from the United States Pharmacopeial 
Convention, Inc., 12601 Twinbrook Pkwy., Rockville, MD 20852, Geeta M. 
Tirumalai, 301-816-8352, e-mail: [email protected], Internet address: http://www.usp.org/USPNF/notices. You may inspect a copy at the Food and Drug 
Administration Biosciences Library, 10903 New Hampshire Ave., Silver 
Spring, MD, 20993-0002, 301-796-3504, 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://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, 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 drug quality?

    (a) Production operations. You must oversee production operations 
to ensure that each PET 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 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.
    (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.
    (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 mix-ups, 
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, 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 drugs are not reactive, additive, or 
absorptive so as to alter the quality of PET drugs.

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 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 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

[[Page 65434]]

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, mix-
ups, 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 that meets the applicable 
standards of identity, strength, quality, and purity.
    (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 
production process. The master production and control records must 
include the following information:
    (1) The name and strength of the PET drug;
    (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 action limits 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 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;
    (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 of production steps and times of critical 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 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 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 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

[[Page 65435]]

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 must keep complete records of all tests 
performed to ensure compliance with established specifications and 
standards, including examinations and assays, as follows:
    (1) A suitable identification of the sample 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, and 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.


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


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 PET 
drug product, including criteria for determining identity, strength, 
quality, purity, and, if appropriate, sterility and pyrogens.
    (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 an appropriate laboratory determination to ensure that each 
batch of a PET drug product conforms to specifications, except for 
sterility. For a PET drug product produced in sub-batches, before final 
release, you must conduct an appropriate laboratory determination to 
ensure that each sub-batch conforms to specifications, except for 
sterility.
    (d) Final release procedures. Except as conditional final release 
is permitted in accordance with paragraph (f) of this section, you must 
establish and follow procedures to ensure that each batch of a PET drug 
product is not given final release until the following are done:
    (1) An appropriate laboratory determination under paragraph (c) 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 30 hours, 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. Tested samples must be 
from individual batches and not pooled. If the product fails to meet a 
criterion for sterility, you must immediately notify all facilities 
that received the product of the test results and provide any 
appropriate recommendations. The notification must be documented. Upon 
completion of an investigation into the failure to meet a criterion for 
sterility, you must notify all facilities that received the product of 
the findings from the investigation.
    (f) Conditional final release. (1) If you cannot complete one of 
the required finished-product tests for a batch of a PET drug product 
because of a malfunction involving 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 retain a reserve sample of the conditionally released 
batch of drug product;
    (iv) You promptly correct the malfunction of analytical equipment, 
complete the omitted test using the reserve sample after the 
malfunction is corrected, and document that reasonable efforts have 
been made to prevent recurrence of the malfunction;
    (v) If you obtain an out-of-specification result when testing the 
reserve sample, you immediately notify the receiving facility; and
    (vi) 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 prevent recurrence of the 
malfunction involving analytical equipment.
    (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 malfunction involving analytical equipment prevents

[[Page 65436]]

the performance of a radiochemical identity/purity test or prevents the 
determination of the product's specific activity.
    (3) You may not release another batch of the PET drug product until 
you have corrected the problem concerning the malfunction of analytical 
equipment and completed the omitted finished-product test.


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

    (a) Rejection of 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 mix-ups. 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 
procedures stated in the product's approved application 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 mix-ups.

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 drug 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 the quality or purity of, or possible adverse reactions to, 
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 or for any other reason 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 
drugs?

    (a) Record availability. Records must be maintained at the PET drug 
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 this part for a period of at least 1 year 
from the date of final release, including conditional final release, of 
a PET drug product.

    Dated: December 3, 2009.
David Horowitz,
Assistant Commissioner for Policy.
[FR Doc. E9-29285 Filed 12-9-09; 8:45 am]
BILLING CODE 4160-01-S