Current Good Manufacturing Practice for Positron Emission Tomography Drugs, 65409-65436 [E9-29285]
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Federal Register / Vol. 74, No. 236 / Thursday, December 10, 2009 / Rules and Regulations
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BILLING CODE 4910–13–P
Current Good Manufacturing Practice
for Positron Emission Tomography
Drugs
Airbus AOT—
VerDate Nov<24>2008
Issued in Renton, Washington, on
November 30, 2009.
Michael J. Kaszycki,
Acting Manager, Transport Airplane
Directorate, Aircraft Certification Service.
[FR Doc. E9–29378 Filed 12–9–09; 8:45 am]
Food and Drug Administration,
HHS.
ACTION:
Final rule.
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
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65409
Evaluation and Research, Food and
Drug Administration, 10903 New
Hampshire Ave., Silver Spring, MD
20993–0002, 1–240–328–7621, e-mail:
Brenda.Uratani@fda.hhs.gov.
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
§ 211.1)
C. Definitions (Proposed § 212.1)
D. Application (Proposed § 212.5)
E. Personnel and Resources (Proposed
§ 212.10)
F. Production and Process Controls
(Proposed § 212.50)
G. Laboratory Controls (Proposed
§ 212.60)
H. Controls and Acceptance Criteria
(Proposed § 212.70)
I. Actions To Be Taken if Product
Does Not Conform to Specifications
(Proposed § 212.71)
J. Complaint Handling (Proposed
§ 212.100)
K. Records (Proposed § 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
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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-forprofit 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
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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;
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• 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
§ 212.1, we have added the following
statement: ‘‘‘PET drug’ includes a ‘PET
drug product’ as defined in this
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section.’’ We also have revised the
definition of ‘‘PET drug product’’ in
§ 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 §§ 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
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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 inhouse 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.
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(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
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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) (§§ 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
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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
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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
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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-forprofit 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
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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
§ 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 § 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.
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(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 § 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
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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
§ 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.,
§ 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.
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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 § 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
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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 § 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 § 212.1.
Target material is thus subject to the
PET CGMP requirements in part 212,
including the provisions on components
of PET drugs in § 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.
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(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 § 212.1
reflect the definition in the
Modernization Act (section 201(ii) of
the act). We believe that the definition
of PET drug in § 212.1 is sufficiently
consistent with the definition of
diagnostic radiopharmaceutical in
§ 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 § 212.5(a) states that
the regulations apply to PET drug
products, the title of § 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., § 212.61 on stability,
§ 212.80 on labeling and packaging), the
term ‘‘PET drug product’’ is used.
Therefore, the title of § 212.40 continues
to refer to ‘‘PET drugs.’’ However,
provisions in § 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
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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 § 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
§ 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 containerclosure 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
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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
§ 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 § 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 § 212.1, using
the definition in USP Chapter 823 to
which the comments referred.
D. Application (Proposed § 212.5)
Proposed § 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 § 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
§ 212.5(b).
Proposed § 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
§ 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 § 212.5 to make clear
that the PET CGMP requirements apply
to PET drugs, not solely to PET drug
products. Correspondingly, we have
revised § 212.5(b) to state that for
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‘‘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 § 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 § 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.
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(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
§ 212.10)
Proposed § 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 § 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.
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F. Production and Process Controls
(Proposed § 212.50)
1. Master Production and Control
Records
Proposed § 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 § 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 wellcontrolled 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 § 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 § 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 § 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
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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
§ 212.50(c)(6) to require inclusion of the
dates of production steps and times of
critical production steps.
G. Laboratory Controls (Proposed
§ 212.60)
Proposed § 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 § 212.60(g)(1) through (g)(5).
Proposed § 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
§ 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 § 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
§ 212.60(g)(4) required a statement of
the results of tests and how the results
compare with established acceptance
criteria. Proposed § 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
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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 § 212.60(g)(1) is more than
adequate. Two comments recommended
revising § 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 § 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
§ 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
§ 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
§ 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
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by referring to information in the master
production and control record or the
batch production and control record.
The revised § 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 § 212.70)
1. Specifications
Proposed § 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 § 212.70(a) to refer to
‘‘pyrogens’’ rather than ‘‘pyrogenicity.’’
In addition, on our own initiative, we
have revised § 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 § 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 § 212.70(c). However, one
comment recommended adding a new
paragraph (g) to § 212.70 to
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accommodate testing of a PET drug
product on something less than a perbatch 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
§ 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 subbatches, 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
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drug product conforms to specifications
under § 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 § 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
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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 § 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 § 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
§ 212.70(d) to state that except as
conditional final release is permitted in
accordance with § 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 § 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
§ 212.70(c), we have revised the first
criterion in § 212.70(d) (i.e.,
§ 212.70(d)(1)) to require completion of
an ‘‘appropriate laboratory
determination under paragraph (c)’’
rather than appropriate laboratory
testing under § 212.70(a).
4. Sterility Testing
Proposed § 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 § 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 § 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.
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On our own initiative, we have
revised the second sentence of
§ 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
§ 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
§ 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
§ 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
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§ 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 § 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 § 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 § 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
§ 212.70(f)(1)). Proposed § 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
§ 212.70(f)(1)(i) through (f)(1)(vii)):
• The PET drug producer has data
documenting that preceding consecutive
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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
§ 212.70(f)(1)). At our own initiative, we
have revised § 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 § 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
§ 212.70(f)(1) inaccurately implies that
every pharmacopeial test is required
before release to assure quality. Two
comments recommended that
§ 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,
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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, § 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 § 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
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product would be appropriate. For these
reasons, the revised § 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 finishedproduct 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 § 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, § 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 § 212.1 to
correspond to this change by replacing
‘‘breakdown of analytical equipment’’
with ‘‘malfunction involving analytical
equipment.’’
ii. Notification of incomplete testing
(proposed § 212.70(f)(1)(iii)). (Comment
35) Several comments recommended
deletion of the requirement in proposed
§ 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 § 212.70(f)(1) provide
adequate protection to patients; for
example, proposed § 212.70(f)(1)(vi)
provides for immediate notification of
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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
§ 212.70(f)(1).
iii. Completion of omitted test and
efforts to ensure that the problem does
not recur (proposed § 212.70(f)(1)(v)). At
our own initiative, we have revised
§ 212.70(f)(1)(v) (now § 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
§ 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 § 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 finishedproduct 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 § 212.70(f)(1)(iv). For
these reasons, we have revised
§ 212.70(f)(1)(iv) and added
§ 212.70(f)(3) as stated.
(Comment 36) Regarding completion
of the omitted test under proposed
§ 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
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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 § 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 § 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 § 212.70(f)(1)(v) (now
§ 212.70(f)(1)(iv)) accordingly.
iv. Notification of an out-ofspecification result (proposed
§ 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 outof-specification result when testing the
reserve sample. The comment stated
that personnel at the receiving facility
would not have sufficient
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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-ofspecification 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 § 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
§ 212.70(f)(1)(vii)). Consistent with the
changes to § 212.70(f)(1) and (f)(1)(iv),
we revised § 212.70(f)(1)(vii) (now
§ 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
§ 212.70(f)(2)). Proposed § 212.70(f)(2)
stated that even if the criteria in
§ 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 § 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 § 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 § 212.71)
Proposed § 212.71 addressed the
actions that a PET drug producer must
PO 00000
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Fmt 4700
Sfmt 4700
65421
take if a batch of a PET drug product
does not conform to specifications.
Proposed § 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
§ 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
§ 212.100)
1. Written Complaint Procedures
Proposed § 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
§ 212.100(a). The comments stated that
it would be inappropriate for
§ 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
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complaints about a PET drug product.
Therefore, we have revised § 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 § 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 § 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 § 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.
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K. Records (Proposed § 212.110)
Proposed § 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
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16:49 Dec 09, 2009
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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
PO 00000
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Fmt 4700
Sfmt 4700
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
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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
65423
remaining 36 producers were part of
academic or hospital institutions (see
table 1 of this document).
TABLE 1.—PET DRUG PRODUCERS
No.
of Producers
Producer Type
No.
of Establishments
Hospital or Academic1
36
36
Commercial—Regional
11
17
4
48
51
101
Commercial—Corporate2
Total
1 Sixteen
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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
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16:49 Dec 09, 2009
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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 § 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 § 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 § 212.70(c) to allow for
more flexibility in the determination of
batch specificity conformity by not
requiring finished-product testing in all
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Fmt 4700
Sfmt 4700
circumstances. This change represents
another slight reduction in compliance
costs. We revised § 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 § 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 § 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 § 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
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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
mstockstill on DSKH9S0YB1PROD with RULES
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 https://www.fda.gov/
Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/default.htm).
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16:49 Dec 09, 2009
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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
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).
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.
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.
4 Labor hour estimate from FDA site visit to a PET
drug producer on October 2, 2001.
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Sfmt 4700
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
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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
65425
modified the process verification
requirements. Not all PET drug product
batches that undergo full finishedproduct 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 Establishments
Rule Requirement
Labor
(Months)
Wage (Yr.
Sal.)1
Cost2
One-Time Costs
Establishment/Write SOPs
Academic PET Producers
47
3
$164,300
$2,574,000
4
1
$164,300
$55,000
Academic PET Producers
53
.23
$164,300
$168,000
Commercial PET Producers
48
.23
$164,300
$152,000
Commercial PET Producers
Training on SOPs
Total One-Time Costs
$2,949,000
Annual Costs
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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
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TABLE 2.—CGMP COSTS BY REQUIREMENT—Continued
No. of Establishments
Rule Requirement
Labor
(Months)
Wage (Yr.
Sal.)1
Cost2
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
2 Cost
includes 35 percent increase for benefits.
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 onetime 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
Hospital and Regional Commercial Establishments (53)
$2,740,000
Total Annualized
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2 Total
Cost2
$733,000
$2,947,000
Total Cost1
$1,720,000
$207,000
Corporate Establishments (48)
1 Sum
Annual Cost
$2,453,000
$3,170,000
of costs may not equal total cost due to rounding.
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
5 Correspondence to FDA from Council on
Radionuclides and Radiopharmaceuticals, Inc.,
dated October 3, 2006.
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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.
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
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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
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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.
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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
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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 onethird 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
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
6 ‘‘AHA Guide to the Health Care Field, 1997–98
Edition,’’ Healthcare Infosource, Inc., a subsidiary
of the American Hospital Association.
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.
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65427
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.
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 perfacility 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
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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.
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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 computeroperated 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.
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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, inprocess 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
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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
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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.
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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
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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 § 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
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65429
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
§ 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-ofspecification 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 outof-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-ofspecification investigations from 1 to 36,
which results in an annual hourly
burden of 3,636 (101 producers times 36
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K. Distribution Records
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.
L. Complaints
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.
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
Recordkeepers
21 CFR Section
Annual Frequency
of Recordkeeping
Total Annual
Records
Hours per
Recordkeeper
Total Hours
212.20(c) and (e),
212.50(a) and (b)
101
1.71
173
20
3,460
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), (b), and (d)
101
25
2,525
1
2,525
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 BURDEN1
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21 CFR Section
No. of
Respondents
212.70(e)
No. of Responses
per Respondent
101
.25
Total
Responses
Hours per
Response
25
1
Total
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Total Hours
25
25
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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.
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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
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16:49 Dec 09, 2009
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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.
■ 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
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.
§ 210.1
[Amended]
2. Amend § 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’’.
■
§ 210.2
[Amended]
3. Amend § 210.2(a) and (b) by
removing the phrase ‘‘211 through 226’’
■
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both times it appears and by adding in
its place the phrase ‘‘211, 225, and 226’’.
§ 210.3
[Amended]
4. Amend § 210.3 in paragraphs (a)
and (b) introductory text by removing
the phrase ‘‘211 through 226’’ and
adding in its place the phrase ‘‘211, 225,
and 226’’.
■
PART 211—CURRENT GOOD
MANUFACTURING PRACTICE FOR
FINISHED PHARMACEUTICALS
5. The authority citation for 21 CFR
part 211 continues to read as follows:
■
Authority: 21 U.S.C. 321, 351, 352, 355,
360b, 371, 374; 42 U.S.C. 216, 262, 263a, 264.
6. Amend § 211.1 by revising
paragraph (a) to read as follows:
■
§ 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.
*
*
*
*
*
■ 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-
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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
mstockstill on DSKH9S0YB1PROD with RULES
§ 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
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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
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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.
§ 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
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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.
mstockstill on DSKH9S0YB1PROD with RULES
§ 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:
gt@usp.org, Internet address: https://
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 https://www.archives.gov/federal
_register/code_of_federal_regulations/
ibr_locations.html.
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16:49 Dec 09, 2009
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Subpart B—Personnel and Resources
§ 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
§ 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
§ 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
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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, inprocess 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
§ 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
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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 finishedproduct 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
§ 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
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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
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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 subbatch 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
§ 212.60 What requirements apply to the
laboratories where I test components, inprocess materials, and finished PET drug
products?
(a) Testing procedures. Each
laboratory used to conduct testing of
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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.
§ 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
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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
§ 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
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65435
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-ofspecification 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
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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 finishedproduct test.
§ 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
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§ 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.
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(d) Labeling and packaging operations
must be controlled to prevent labeling
and product mix-ups.
Subpart J—Distribution
§ 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
§ 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.
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Subpart L—Records
§ 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
DEPARTMENT OF DEFENSE
Office of the Secretary
[DoD–2009–HA–0151; 0720–AB37]
32 CFR Part 199
Civilian Health and Medical Program of
the Uniformed Services (CHAMPUS)/
TRICARE: Inclusion of Retail Network
Pharmacies as Authorized TRICARE
Providers for the Administration of
TRICARE Covered Vaccines
AGENCY: Office of the Secretary,
Department of Defense (DoD).
ACTION: Interim final rule.
SUMMARY: This interim final rule allows
a TRICARE retail network pharmacy to
be an authorized provider for the
administration of three TRICAREcovered vaccines in the retail pharmacy
setting. The three immunizations are
H1N1 vaccine, seasonal influenza
vaccine, and pneumococcal vaccine. In
addition, this interim final rule solicits
public comment on also including other
TRICARE-covered immunizations in the
future for which retail network
pharmacies will be authorized
providers. As part of DoD preparations
for a possible public health emergency
involving H1N1 influenza this fall and
winter, this is being issued as an interim
final rule.
DATES: This interim final rule is
effective December 10, 2009. Written
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]]>Agencies
[Federal Register Volume 74, Number 236 (Thursday, December 10, 2009)]
[Rules and Regulations]
[Pages 65409-65436]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E9-29285]
=======================================================================
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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:
Brenda.Uratani@fda.hhs.gov.
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
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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,
