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

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

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

D. Growth of the PET Industry

    Although we do not have reliable estimates of the annual number of
PET scans, the number has increased dramatically over the last 10
years, due at least in part to the increased numbers of disease
conditions for which both public and private insurers have extended
coverage. The number of establishments producing PET drugs, and FDG F
18 in particular, has also increased over this time period. As
mentioned previously in this document, the majority of this growth in
establishments reflects commercial operations that focus mainly or
solely on FDG F 18 production.
    As demand for PET scan services and, therefore, PET drugs is
expected to continue to increase, we projected compliance costs over
the next 10 years for the proposed rule. We did not receive comment on
our projection and retain it (with adjustments for

employment cost inflation) for the final rule. We cannot confidently
predict the number of additional PET drug production runs to meet the
additional demand for PET services because of unknown factors. We do
not know the number of additional diseases for which PET will be used
and be reimbursable in the future or possible increases in size of
production batches of PET drugs. Because PET drug producers are not
currently producing to capacity, we believe that increased demand will
be partially met by increasing production runs and batch sizes at
existing establishments rather than proportional increases in the
number of PET drug production establishments. We have therefore
projected average annual PET drug production establishment increases
will range from 3 to 7 percent. Assuming this growth occurs evenly
across producer types, this growth rate implies an increase in
annualized costs from $3.17 million in year one to $4.15 to $5.84
million in year ten. The PET drug risk reduction resulting from this
rule will also apply to the additional volume of PET drug dosages
implied by the 3- to 7-percent annual growth rate in PET drug
establishments.

E. Regulatory Flexibility Analysis

    The Regulatory Flexibility Act requires agencies to examine
regulatory alternatives for small entities if that rule may have a
significant impact on a substantial number of small entities.
1. Objective of the Rule
    The implementation of this rule, in accordance with the
Modernization Act, will help ensure the safety, identity, strength,
quality, and purity of PET drugs by establishing CGMP requirements. The
objective of the rule is to reduce the risk to public health from
adverse events that would be more likely to occur in the absence of
adherence to CGMP for PET drugs.
2. Definition of Small Entities
    A regulatory flexibility analysis (RFA) is required to estimate the
number of small entities to which the rule applies. Since we did not
receive any comments on the proposed rule that addressed the analysis
of impacts on small entities, we retain our analysis for the final
rule, with revisions for inflation. This rule affects producers of PET
drugs, including certain hospitals, clinics, colleges and universities,
and producers of in vivo diagnostic substances. According to the Small
Business Administration (SBA), pharmaceutical preparation manufacturers
with 750 or fewer employees, electromedical and electrotherapeutic
apparatus manufacturers with 500 or fewer employees, drugs and
druggists' sundries wholesalers with 100 or fewer employees, and for-
profit hospitals, clinics, colleges, and universities with $29 million
or less in revenue are considered small businesses or entities. To
estimate the number of U.S. establishments producing PET drugs, we
combined a list of PET centers with cyclotrons from the Academy of
Molecular Imaging (AMI) with a list of PET manufacturing facilities
from the Society of Nuclear Imaging in Drug Development, which has
since merged with the AMI, and added additional facilities that we
identified. We have identified 101 establishments operated by 51 PET
drug producers. In over one-third of the cases, the PET drug is
produced by a hospital. In other instances, a corporate producer
manages production under contract at one or more hospitals with
cyclotrons. PET drugs are also produced at independent establishments
by corporate producers or small regional producers. Total producer
numbers continue to increase as the current corporate producers expand
their number of establishments and more independent regional producers
enter the market.
    Using information from the American Hospital Association (AHA), we
characterized 28 of the hospital producers as one of the following
establishment types:
     Government, non-Federal;
     Government, Federal;
     Non-Government not-for-profit;
     Investor-owned (for-profit).\6\
---------------------------------------------------------------------------

    \6\ ``AHA Guide to the Health Care Field, 1997-98 Edition,''
Healthcare Infosource, Inc., a subsidiary of the American Hospital
Association.
---------------------------------------------------------------------------

    The AHA data did not include information for eight hospitals
associated with large colleges or universities, but for this analysis,
these were assumed to be not-for-profit because approximately 93
percent of all 4-year higher education institutions are public or
nonprofit institutions.\7\ Census data reports indicate that private
hospitals (with more than 100 employees) average gross revenues of
about $36.8 million in 1997. This figure inflates to about $57.7
million using the Consumer Price Index (CPI) for medical care from 1997
to 2007. Considering that hospitals producing PET drugs probably are
larger than the average private hospital, we consider it very likely
that the two private hospitals producing PET drugs have annual revenues
over $29 million and are therefore not considered small entities.\8\ In
instances where PET drug producer information is not available, this
analysis assumes that the PET drug producer is owned by the hospital in
which it is located.
---------------------------------------------------------------------------

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

    Two of the three domestic corporate PET drug producers exceed the
SBA employee limits within their respective business classifications to
qualify as small businesses. Employee data were not available for the
other domestic corporation or any of the 11 regional commercial
producers, and we therefore assume that these may be small businesses.
    In total, the 51 identified producers of PET drugs are classified
as follows: 6 Federal, 6 State, 34 small entities, and 5 large
entities. Most of those that were considered small entities were
classified as such because they are not-for-profit organizations, not
because they met the employee or revenue limits for small businesses.
It should be noted that an entity's identification as small or large in
this analysis does not necessarily indicate the volume of PET drugs it
produces or the share of the market it holds.
3. Impact on Small Entities
    The reporting, recordkeeping, and other compliance requirements on
small entities are detailed in the regulatory cost section of this
preamble. Most, if not all, of the PET drug producers currently employ
individuals who possess skills necessary to establish written
procedures and prepare documentation as required by this rule. Some may
choose, as mentioned above, to contract with an outside consultant to
manage their compliance with the rule.
    At most, a single PET drug producer may incur one-time and annual
costs of approximately $57,900 and $32,400, respectively, per
production facility. The hospital and regional commercial producers
will incur these higher per-facility costs because these establishments
are expected to have higher noncompliance rates with the written
procedure and recordkeeping requirements. The total of the maximum one-
time and annual costs per producer equates to significantly less than 1
percent of the $111 million ($70.8 million inflated by the CPI for
medical care from 1997 to 2007) average annual gross revenue per
nonprofit hospital. In addition, most of the hospitals that are
affected by this rule are affiliated with large universities whose
total revenues are expected to be much higher than the $111 million
figure cited. The estimated compliance cost represents an even

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

V. Environmental Impact

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

VI. Paperwork Reduction Act of 1995

    This final rule contains information collection requirements that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). The title, description, and respondent description of the
information collection provisions are shown below with an estimate of
the annual reporting and recordkeeping burden. Included in the estimate
is the time for reviewing instructions, searching existing data
sources, gathering and maintaining the data needed, and completing and
reviewing each collection of information.
    Title: Current Good Manufacturing Practice for Positron Emission
Tomography Drugs
    Description: In accordance with the Modernization Act, the final
rule establishes CGMP requirements for PET drugs. The CGMP requirements
are designed to take into account the unique characteristics of PET
drugs, including their short half-lives and the fact that most PET
drugs are produced at locations that are very close to the patients to
whom the drugs are administered. The estimated annual recordkeeping and
third-party disclosure burden is based on there being 51 PET drug
producers operating 36 hospital or academic facilities and 65
commercial facilities for a total of 101 PET drug production
facilities.
    The CGMP regulations are intended to ensure that approved PET drugs
meet the requirements of the act as to safety, identity, strength,
quality, and purity. The regulations address the following matters:
Personnel and resources; quality assurance; facilities and equipment;
control of components, in-process materials, and finished products;
production and process controls; laboratory controls; acceptance
criteria; labeling and packaging controls; distribution controls;
complaint handling; and recordkeeping.
    The CGMP regulations establish several recordkeeping requirements
for the production of PET drugs. In making our estimates of the time
spent in complying with these requirements, we relied on communications
we have had with PET producers, visits by our staff to PET facilities,
and our familiarity with both PET and general pharmaceutical
manufacturing practices.
    Description of Respondents: Academic institutions, hospitals,
commercial manufacturers, and other entities that produce PET drugs.
    Burden Estimate: Table 4 of this document provides an estimate of
the annual recordkeeping burdens associated with the final rule. Table
5 of this document provides an estimate of the annual third-party
disclosure burdens associated with the final rule. All of our
recordkeeping burden estimates are based on there being 101 PET
production facilities, with each of the 36 academic or hospital
facilities producing 3 different PET drug products and each of the 65
commercial facilities producing 1 PET drug, resulting in an estimated
173 total PET drugs. Our estimates are also based on a 250-day work
year with an average yearly production of 500 batches for each
facility. We have also taken into account that time spent on recording
procedures, processes, and specifications may be somewhat higher in the
year in which these records are first established and correspondingly
lower in subsequent years, when only updates and revisions will be
required.

A. Investigational and Research PET Drugs

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

B. Batch Production and Control Records

    Sections 212.20(c) through (e), 212.50(a) through (c), and
212.80(c) set out requirements for batch and production records as well
as written control records. We estimate that it would take 20 hours
annually for each PET production facility to prepare and

maintain written production and control procedures and to create and
maintain master batch records for each PET drug produced. We also
estimate that there will be a total of 173 PET drugs produced, with a
total estimated recordkeeping burden of 3,460 hours. We estimate that
it would take a PET production facility an average of 30 minutes to
complete a batch record for each of 500 batches. Our estimated burden
for completing batch records is 25,250 hours.

C. Equipment and Facilities Records

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

D. Records of Components, Containers, and Closures

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

E. Process Verification

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

F. Laboratory Testing Records

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

G. Sterility Test Failure Notices

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

H. Conditional Final Releases

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

I. Out-of-Specification Investigations

    Sections 212.20(c) and 212.71(a) and (b) require PET drug producers
to establish procedures for investigating products that do not conform
to specifications and conduct these investigations as needed. We
estimate that it will take 1 hour annually to record and update these
procedures for each PET production facility. We also estimate, for
purposes of the PRA, that one out-of-specification investigation would
be conducted at each facility each year and that it would take 1 hour
to document the investigation.
    (Comment 45) One comment maintained that the number of out-of-
specification investigations is significantly underestimated (at one
investigation per facility each year). The comment stated that a true
failure might only occur once each year but an out-of-specification
investigation is necessary each time a single item in the final product
testing process results in a nonconformance to specifications. The
comment stated that because quality control on each batch is executed
quickly, most out-of-specification conditions are directly due to
operator or equipment failure and are rectified by retesting. The
comment maintained that out-of-specification investigations actually
occur two to three times per month; therefore, the comment recommended
that we use an estimate of 36 investigations per facility each year.
    (Response) We agree with the comment's reasoning and we have
revised the annual frequency of out-of-specification investigations
from 1 to 36, which results in an annual hourly burden of 3,636 (101
producers times 36

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

J. Reprocessing Procedures

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

K. Distribution Records

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

L. Complaints

    Sections 212.20(c) and 212.100 require that PET drug producers
establish written procedures for dealing with complaints, as well as
document how each complaint is handled. We estimate that establishing
and maintaining written procedures for complaints will take 1 hour
annually for each PET production facility and that each facility will
receive one complaint a year and will spend 30 minutes recording how
the complaint was dealt with.

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

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

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

VII. Federalism

    We have analyzed this rule in accordance with the principles set
forth in Executive Order 13132. We have determined that the rule does
not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, we have concluded that the
rule does not contain policies that have federalism implications as
defined in the order and, consequently, a federalism summary impact
statement is not required.

VIII. Effective Date

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

List of Subjects

21 CFR Part 210

    Drugs, Packaging and containers.

21 CFR Part 211

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

21 CFR Part 212

    Current good manufacturing practice, Drugs, Incorporation by
reference, Labeling, Laboratories, Packaging and containers, Positron
emission tomography drugs, Prescription drugs, Reporting and
recordkeeping requirements.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act, the Food and
Drug Modernization Act of 1997, and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR chapter I is amended as follows:

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

0
1. The authority citation for 21 CFR part 210 continues to read as
follows:

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

Sec.  210.1  [Amended]

0
2. Amend Sec.  210.1 by removing the phrase ``211 through 226'' each
time it appears and by adding in its place the phrase ``211, 225, and
226''.

Sec.  210.2  [Amended]

0
3. Amend Sec.  210.2(a) and (b) by removing the phrase ``211 through
226'' both times it appears and by adding in its place the phrase
``211, 225, and 226''.

Sec.  210.3  [Amended]

0
4. Amend Sec.  210.3 in paragraphs (a) and (b) introductory text by
removing the phrase ``211 through 226'' and adding in its place the
phrase ``211, 225, and 226''.

PART 211--CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED
PHARMACEUTICALS

0
5. The authority citation for 21 CFR part 211 continues to read as
follows:

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

0
6. Amend Sec.  211.1 by revising paragraph (a) to read as follows:

Sec.  211.1   Scope.

    (a) The regulations in this part contain the minimum current good
manufacturing practice for preparation of drug products (excluding
positron emission tomography drugs) for administration to humans or
animals.
* * * * *

0
7. Add part 212 to read as follows:

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

Subpart A--General Provisions

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

Subpart B--Personnel and Resources

212.10 What personnel and resources must I have?

Subpart C--Quality Assurance

212.20 What activities must I perform to ensure drug quality?

Subpart D--Facilities and Equipment

212.30 What requirements must my facilities and equipment meet?

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

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

Subpart F--Production and Process Controls

212.50 What production and process controls must I have?

Subpart G--Laboratory Controls

212.60 What requirements apply to the laboratories where I test
components, in-

process materials, and finished PET drug products?
212.61 What must I do to ensure the stability of my PET drug
products through expiry?

Subpart H--Finished Drug Product Controls and Acceptance Criteria

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

Subpart I--Packaging and Labeling

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

Subpart J--Distribution

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

Subpart K--Complaint Handling

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

Subpart L--Records

212.110 How must I maintain records of my production of PET drugs?

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

Subpart A--General Provisions

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

    The following definitions apply to words and phrases as they are
used in this part. Other definitions of these words may apply when they
are used in other parts of this chapter.
    Acceptance criteria means numerical limits, ranges, or other
criteria for tests that are used for or in making a decision to accept
or reject a unit, lot, or batch of a PET drug product.
    Act means the Federal Food, Drug, and Cosmetic Act, as amended (21
U.S.C. 321 et seq.).
    Active pharmaceutical ingredient means a substance that is intended
for incorporation into a finished PET drug product and is intended to
furnish pharmacological activity or other direct effect in the
diagnosis or monitoring of a disease or a manifestation of a disease in
humans, but does not include intermediates used in the synthesis of
such substance.
    Batch means a specific quantity of PET drug intended to have
uniform character and quality, within specified limits, that is
produced according to a single production order during the same cycle
of production.
    Batch production and control record means a unique record that
references an accepted master production and control record and
documents specific details on production, labeling, and quality control
for a single batch of a PET drug.
    Component means any ingredient intended for use in the production
of a PET drug, including any ingredients that may not appear in the
final PET drug product.
    Conditional final release means a final release made prior to
completion of a required finished-product test because of a malfunction
involving analytical equipment.
    Final release means the authoritative decision by a responsible
person in a PET production facility to permit the use of a batch of a
PET drug in humans.
    Inactive ingredient means any intended component of the PET drug
other than the active pharmaceutical ingredient.
    In-process material means any material fabricated, compounded,
blended, or derived by chemical reaction that is produced for, and is
used in, the preparation of a PET drug.
    Lot means a batch, or a specifically identified portion of a batch,
having uniform character and quality within specified limits. In the
case of a PET drug produced by continuous process, a lot is a
specifically identified amount produced in a unit of time or quantity
in a manner that ensures its having uniform character and quality
within specified limits.
    Lot number, control number, or batch number means any distinctive
combination of letters, numbers, or symbols from which the complete
history of the production, processing, packing, holding, and
distribution of a batch or lot of a PET drug can be determined.
    Master production and control record means a compilation of
instructions containing the procedures and specifications for the
production of a PET drug.
    Material release means the authoritative decision by a responsible
person in a PET production facility to permit the use of a component,
container and closure, in-process material, packaging material, or
labeling in the production of a PET drug.
    PET means positron emission tomography.
    PET drug means a radioactive drug that exhibits spontaneous
disintegration of unstable nuclei by the emission of positrons and is
used for providing dual photon positron emission tomographic diagnostic
images. The definition includes any nonradioactive reagent, reagent
kit, ingredient, nuclide generator, accelerator, target material,
electronic synthesizer, or other apparatus or computer program to be
used in the preparation of a PET drug. ``PET drug'' includes a ``PET
drug product'' as defined in this section.
    PET drug product means a finished dosage form of a PET drug,
whether or not in association with one or more other ingredients.
    PET drug production facility means a facility that is engaged in
the production of a PET drug.
    Production means the manufacturing, compounding, processing,
packaging, labeling, reprocessing, repacking, relabeling, and testing
of a PET drug.
    Quality assurance means a system for ensuring the quality of active
ingredients, PET drugs, intermediates, components that yield an active
pharmaceutical ingredient, analytical supplies, and other components,
including container-closure systems and in-process materials, through
procedures, tests, analytical methods, and acceptance criteria.
    Receiving facility means any hospital, institution, nuclear
pharmacy, imaging facility, or other entity or part of an entity that
accepts a PET drug product that has been given final release, but does
not include a common or contract carrier that transports a PET drug
product from a PET production facility to a receiving facility.
    Specifications means the tests, analytical procedures, and
appropriate acceptance criteria to which a PET drug, PET drug product,
component, container-closure system, in-process material, or other
material used in PET drug production must conform to be considered
acceptable for its intended use. Conformance to specifications means
that a PET drug, PET drug product, component, container-closure system,
in-process material, or other material used in PET drug production,
when tested according to the described analytical procedures, meets the
listed acceptance criteria.
    Strength means the concentration of the active pharmaceutical
ingredient (radioactivity amount per volume or weight at the time of
calibration).
    Sub-batch means a quantity of PET drug having uniform character and
quality, within specified limits, that is produced during one
succession of multiple irradiations, using a given synthesis and/or
purification operation.
    Verification means confirmation that an established method,
process, or system meets predetermined acceptance criteria.

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

    Current good manufacturing practice for PET drugs is the minimum
requirements for the methods to be used

in, and the facilities and controls used for, the production, quality
assurance, holding, or distribution of PET drugs intended for human
use. Current good manufacturing practice is intended to ensure that
each PET drug meets the requirements of the act as to safety and has
the identity and strength, and meets the quality and purity
characteristics, that it is supposed to have.

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

    (a) Application solely to PET drugs. The regulations in this part
apply only to the production, quality assurance, holding, and
distribution of PET drugs. Any human drug that does not meet the
definition of a PET drug must be manufactured in accordance with the
current good manufacturing practice requirements in parts 210 and 211
of this chapter.
    (b) Investigational and research PET drugs. For investigational PET
drugs for human use produced under an investigational new drug
application in accordance with part 312 of this chapter, and PET drugs
produced with the approval of a Radioactive Drug Research Committee in
accordance with part 361 of this chapter, the requirement under the act
to follow current good manufacturing practice is met by complying with
the regulations in this part or by producing PET drugs in accordance
with Chapter 823, ``Radiopharmaceuticals for Positron Emission
Tomography--Compounding,'' May 1, 2009, pp. 365-369, 32d ed. of the
United States Pharmacopeia (USP) National Formulary (NF) (USP 32/NF 27)
(2009). The Director of the Federal Register approves this
incorporation by reference in accordance with 5 U.S.C. 552(a) and 1 CFR
part 51. You may obtain a copy from the United States Pharmacopeial
Convention, Inc., 12601 Twinbrook Pkwy., Rockville, MD 20852, Geeta M.
Tirumalai,<PHONE_NUMBER>, e-mail<EMAIL_ADDRESS>Internet address: http://
www.usp.org/USPNF/notices. You may inspect a copy at the Food and Drug
Administration Biosciences Library, 10903 New Hampshire Ave., Silver
Spring, MD, 20993-0002,<PHONE_NUMBER>, or at the National Archives and
Records Administration (NARA). For information on the availability of
this material at NARA, call<PHONE_NUMBER>, or go to http://
www.archives.gov/federal_register/code_of_federal_regulations/ibr_
locations.html.

Subpart B--Personnel and Resources

Sec.  212.10   What personnel and resources must I have?

    You must have a sufficient number of personnel with the necessary
education, background, training, and experience to perform their
assigned functions. You must have adequate resources, including
facilities and equipment, to enable your personnel to perform their
functions.

Subpart C--Quality Assurance

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

    (a) Production operations. You must oversee production operations
to ensure that each PET drug meets the requirements of the act as to
safety and has the identity and strength, and meets the quality and
purity characteristics, that it is supposed to have.
    (b) Materials. You must examine and approve or reject components,
containers, closures, in-process materials, packaging materials,
labeling, and finished dosage forms to ensure compliance with
procedures and specifications affecting the identity, strength,
quality, or purity of a PET drug.
    (c) Specifications and processes. You must approve or reject,
before implementation, any initial specifications, methods, processes,
or procedures, and any proposed changes to existing specifications,
methods, processes, or procedures, to ensure that they maintain the
identity, strength, quality, and purity of a PET drug. You must
demonstrate that any change does not adversely affect the identity,
strength, quality, or purity of any PET drug.
    (d) Production records. You must review production records to
determine whether errors have occurred. If errors have occurred, or a
production batch or any component of the batch fails to meet any of its
specifications, you must determine the need for an investigation,
conduct investigations when necessary, and take appropriate corrective
actions.
    (e) Quality assurance. You must establish and follow written
quality assurance procedures.

Subpart D--Facilities and Equipment

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

    (a) Facilities. You must provide adequate facilities to ensure the
orderly handling of materials and equipment, the prevention of mix-ups,
and the prevention of contamination of equipment or product by
substances, personnel, or environmental conditions that could
reasonably be expected to have an adverse effect on product quality.
    (b) Equipment procedures. You must implement procedures to ensure
that all equipment that could reasonably be expected to adversely
affect the identity, strength, quality, or purity of a PET drug, or
give erroneous or invalid test results when improperly used or
maintained, is clean, suitable for its intended purposes, properly
installed, maintained, and capable of repeatedly producing valid
results. You must document your activities in accordance with these
procedures.
    (c) Equipment construction and maintenance. Equipment must be
constructed and maintained so that surfaces that contact components,
in-process materials, or PET drugs are not reactive, additive, or
absorptive so as to alter the quality of PET drugs.

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

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

    (a) Written procedures. You must establish, maintain, and follow
written procedures describing the receipt, login, identification,
storage, handling, testing, and acceptance and/or rejection of
components and drug product containers and closures. The procedures
must be adequate to ensure that the components, containers, and
closures are suitable for their intended use.
    (b) Written specifications. You must establish appropriate written
specifications for the identity, quality, and purity of components and
for the identity and quality of drug product containers and closures.
    (c) Examination and testing. Upon receipt, each lot of components
and containers and closures must be uniquely identified and tested or
examined to determine whether the lot complies with your
specifications. You must not use in PET drug production any lot that
does not meet its specifications, including any expiration date if
applicable, or that has not yet received its material release. Any
incoming lot must be appropriately designated as quarantined, accepted,
or rejected. You must use a reliable supplier as a source of each lot
of each component, container, and closure.
    (1)(i) If you conduct finished-product testing of a PET drug
product that includes testing to ensure that the correct components
have been used, you must determine that each lot of incoming components
used in that PET

drug product complies with written specifications by examining a
certificate of analysis provided by the supplier. You are not required
to perform a specific identity test on any of those components.
    (ii) If you do not conduct finished-product testing of a PET drug
product that ensures that the correct components have been used, you
must conduct identity testing on each lot of a component that yields an
active ingredient and each lot of an inactive ingredient used in that
PET drug product. This testing must be conducted using tests that are
specific to each component that yields an active ingredient and each
inactive ingredient. For any other component, such as a solvent or
reagent, that is not the subject of finished-product testing, you must
determine that each lot complies with written specifications by
examining a certificate of analysis provided by the supplier; if you
use such a component to prepare an inactive ingredient on site, you
must perform an identity test on the components used to make the
inactive ingredient before the components are released for use.
However, if you use as an inactive ingredient a product that is
approved under section 505 of the act (21 U.S.C. 355) and is marketed
as a finished drug product intended for intravenous administration, you
need not perform a specific identity test on that ingredient.
    (2) You must examine a representative sample of each lot of
containers and closures for conformity to its written specifications.
You must perform at least a visual identification of each lot of
containers and closures.
    (d) Handling and storage. You must handle and store components,
containers, and closures in a manner that prevents contamination, mix-
ups, and deterioration and ensures that they are and remain suitable
for their intended use.
    (e) Records. You must keep a record for each shipment of each lot
of components, containers, and closures that you receive. The record
must include the identity and quantity of each shipment, the supplier's
name and lot number, the date of receipt, the results of any testing
performed, the disposition of rejected material, and the expiration
date (where applicable).

Subpart F--Production and Process Controls

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

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

Subpart G--Laboratory Controls

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

    (a) Testing procedures. Each laboratory used to conduct testing of

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

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

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

Subpart H--Finished Drug Product Controls and Acceptance

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

    (a) Specifications. You must establish specifications for each PET
drug product, including criteria for determining identity, strength,
quality, purity, and, if appropriate, sterility and pyrogens.
    (b) Test procedures. Before you implement a new test procedure in a
specification, you must establish and document the accuracy,
sensitivity, specificity, and reproducibility of the procedure. If you
use an established compendial test procedure in a specification, you
must first verify and document that the test works under the conditions
of actual use.
    (c) Conformance to specifications. Before final release, you must
conduct an appropriate laboratory determination to ensure that each
batch of a PET drug product conforms to specifications, except for
sterility. For a PET drug product produced in sub-batches, before final
release, you must conduct an appropriate laboratory determination to
ensure that each sub-batch conforms to specifications, except for
sterility.
    (d) Final release procedures. Except as conditional final release
is permitted in accordance with paragraph (f) of this section, you must
establish and follow procedures to ensure that each batch of a PET drug
product is not given final release until the following are done:
    (1) An appropriate laboratory determination under paragraph (c) of
this section is completed;
    (2) Associated laboratory data and documentation are reviewed and
they demonstrate that the PET drug product meets specifications, except
for sterility; and
    (3) A designated qualified individual authorizes final release by
dated signature.
    (e) Sterility testing. Sterility testing need not be completed
before final release but must be started within 30 hours after
completion of production. The 30-hour requirement may be exceeded due
to a weekend or holiday. If the sample for sterility testing is held
longer than 30 hours, you must demonstrate that the longer period does
not adversely affect the sample and the test results obtained will be
equivalent to test results that would have been obtained if the test
had been started within the 30-hour time period. Tested samples must be
from individual batches and not pooled. If the product fails to meet a
criterion for sterility, you must immediately notify all facilities
that received the product of the test results and provide any
appropriate recommendations. The notification must be documented. Upon
completion of an investigation into the failure to meet a criterion for
sterility, you must notify all facilities that received the product of
the findings from the investigation.
    (f) Conditional final release. (1) If you cannot complete one of
the required finished-product tests for a batch of a PET drug product
because of a malfunction involving analytical equipment, you may
approve the conditional final release of the product if you meet the
following conditions:
    (i) You have data documenting that preceding consecutive batches,
produced using the same methods used for the conditionally released
batch, demonstrate that the conditionally released batch will likely
meet the established specifications;
    (ii) You determine that all other acceptance criteria are met;
    (iii) You retain a reserve sample of the conditionally released
batch of drug product;
    (iv) You promptly correct the malfunction of analytical equipment,
complete the omitted test using the reserve sample after the
malfunction is corrected, and document that reasonable efforts have
been made to prevent recurrence of the malfunction;
    (v) If you obtain an out-of-specification result when testing the
reserve sample, you immediately notify the receiving facility; and
    (vi) You document all actions regarding the conditional final
release of the drug product, including the justification for the
release, all followup actions, results of completed testing, all
notifications, and corrective actions to prevent recurrence of the
malfunction involving analytical equipment.
    (2) Even if the criteria in paragraph (f)(1) of this section are
met, you may not approve the conditional final release of the product
if the malfunction involving analytical equipment prevents

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

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

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

Subpart I--Packaging and Labeling

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

    (a) A PET drug product must be suitably labeled and packaged to
protect the product from alteration, contamination, and damage during
the established conditions of shipping, distribution, handling, and
use.
    (b) Labels must be legible and applied so as to remain legible and
affixed during the established conditions of processing, storage,
handling, distribution, and use.
    (c) All information stated on each label must also be contained in
each batch production record.
    (d) Labeling and packaging operations must be controlled to prevent
labeling and product mix-ups.

Subpart J--Distribution

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

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

Subpart K--Complaint Handling

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

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

Subpart L--Records

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

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

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

BILLING CODE 4160-01-S


[Federal Register: October 25, 2006 (Volume 71, Number 206)]
[Notices]
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Comment Request; Pesticide Product Registration Maintenance Fee; EPA
ICR No. 1214.07, OMB Control No. 2070-0100

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: In compliance with the Paperwork Reduction Act (PRA) (44
U.S.C. 3501 et seq.), this document announces that EPA is planning to
submit a request to renew an existing approved Information Collection
Request (ICR) to the Office of Management and Budget (OMB). This

ICR, entitled: ``Pesticide Product Registration Maintenance Fee'' and
identified by EPA ICR No. 1214.07 and OMB Control No. 2070-0100, is
scheduled to expire on May 31, 2007. Before submitting the ICR to OMB
for review and approval, EPA is soliciting comments on specific aspects
of the proposed information collection.

DATES: Comments must be received on or before December 26, 2006.

ADDRESSES: Submit your comments, identified by docket identification
(ID) number EPA-HQ-OPP-2006-0660, by one of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov.

Follow the on-line instructions for submitting comments.
     Mail: Office of Pesticide Programs (OPP) Regulatory Public
Docket (7502P), Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460-0001.
     Delivery: OPP Regulatory Public Docket (7502P),
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South
Building), 2777 S. Crystal Drive, Arlington, VA. Deliveries are only
accepted during the Docket's normal hours of operation (8:30 a.m. to 4
p.m., Monday through Friday, excluding legal holidays). Special
arrangements should be made for deliveries of boxed information. The
Docket telephone number is<PHONE_NUMBER>.
    Instructions: Direct your comments to docket ID number EPA-HQ-OPP-
2006-0660. EPA's policy is that all comments received will be included
in the public docket without change and may be made available on-line
at http://www.regulations.gov, including any personal information

provided, unless the comment includes information claimed to be
Confidential Business Information (CBI) or other information whose
disclosure is restricted by statute. Do not submit information that you
consider to be CBI or otherwise protected through regulations.gov or e-
mail. The regulations.gov website is an ``anonymous access'' system,
which means EPA will not know your identity or contact information
unless you provide it in the body of your comment. If you send an e-
mail comment directly to EPA without going through regulations.gov your
e-mail address will be automatically captured and included as part of
the comment that is placed in the public docket and made available on
the Internet. If you submit an electronic comment, EPA recommends that
you include your name and other contact information in the body of your
comment and with any disk or CD ROM you submit. If EPA cannot read your
comment due to technical difficulties and cannot contact you for
clarification, EPA may not be able to consider your comment. Electronic
files should avoid the use of special characters, any form of
encryption, and be free of any defects or viruses.
    Docket: All documents in the docket are listed in the docket index.
Although listed in the index, some information is not publicly
available, e.g., CBI or other information whose disclosure is
restricted by statute. Certain other material, such as copyrighted
material, is not placed on the Internet and will be publicly available
only in hard copy form. Publicly available docket materials are
available either in the electronic docket at http://www.regulations.gov
, or, if only available in hard copy, at the OPP

Regulatory Public Docket in Rm. S-4400, One Potomac Yard (South
Building), 2777 S. Crystal Drive, Arlington, VA. The hours of operation
of this Docket Facility are from 8:30 a.m. to 4 p.m., Monday through
Friday, excluding legal holidays. The Docket telephone number is (703)
305-5805.

FOR FURTHER INFORMATION CONTACT: Joseph Hogue, Field and External
Affairs Division (7506P), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; telephone number:<PHONE_NUMBER>; fax number:<PHONE_NUMBER>; e-
mail address<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. What Information is EPA Particularly Interested In?

    Pursuant to section 3506(c)(2)(A) of the PRA, EPA specifically
solicits comments and information to enable it to:
    1. Evaluate whether the proposed collection of information is
necessary for the proper performance of the functions of the Agency,
including whether the information will have practical utility.
    2. Evaluate the accuracy of the Agency's estimates of the burden of
the proposed collection of information, including the validity of the
methodology and assumptions used.
    3. Enhance the quality, utility, and clarity of the information to
be collected.
    4. Minimize the burden of the collection of information on those
who are to respond, including through the use of appropriate automated
electronic, mechanical, or other technological collection techniques or
other forms of information technology, e.g., permitting electronic
submission of responses. In particular, EPA is requesting comments from
very small businesses (those that employ less than 25) on examples of
specific additional efforts that EPA could make to reduce the paperwork
burden for very small businesses affected by this collection.

II. What Should I Consider When I Prepare My Comments for EPA?

    You may find the following suggestions helpful for preparing your
comments:
    1. Explain your views as clearly as possible and provide specific
examples.
    2. Describe any assumptions that you used.
    3. Provide copies of any technical information and/or data you used
that support your views.
    4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
    5. Provide specific examples to illustrate your concerns.
    6. Offer alternative ways to improve the collection activity.
    7. Make sure to submit your comments by the deadline identified
under DATES.
    8. To ensure proper receipt by EPA, be sure to identify the docket
ID number assigned to this action in the subject line on the first page
of your response. You may also provide the name, date, and Federal
Register citation.

III. What Information Collection Activity or ICR Does This Action Apply
To?

    Affected entities: Entities potentially affected by this action are
pesticide registrants.
    Title: Pesticide Product Registration Maintenance Fee.
    ICR numbers: EPA ICR No. 1214.07, OMB Control No. 2070-0100.
    ICR status: This ICR is currently scheduled to expire on May 31,
2007. 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. The OMB control numbers for EPA's
regulations in title 40 of the CFR, after appearing in the Federal
Register when approved, are listed in 40 CFR part 9, are displayed
either by publication in the Federal Register or by other appropriate
means, such as on the related collection instrument or form, if
applicable. The display of OMB control numbers in certain EPA
regulations is consolidated in 40 CFR part 9.
    Abstract: This collection provides a practical means of
communication between the registrants and the Environmental Protection
Agency's

Office of Pesticide Programs (OPP) to collect registration maintenance
fees from pesticide registrants as required by law. Respondents
complete and submit EPA Form 8570-30 indicating the respondent's
liability for the registration maintenance fee. Each affected firm is
required to complete the filing form and submit their fee payment by
January 15 of each year. No changes in the substance or in the method
of collection are proposed in this ICR renewal request.
    Burden statement: The annual ``respondent'' (applicant) burden for
the Pesticide Product Registration Maintenance Fee program is estimated
to average 0.96 hours per form. Burden means the total time, effort, or
financial resources expended by persons to generate, maintain, retain,
or disclose or provide information to or for a Federal Agency. This
includes the time needed to review instructions; develop, acquire,
install, and utilize technology and systems for the purposes of
collecting, validating, and verifying information, processing and
maintaining information, and disclosing and providing information;
adjust the existing ways to comply with any previously applicable
instructions and requirements which have subsequently changed; train
personnel to be able to respond to a collection of information; search
data sources; complete and review the collection of information; and
transmit or otherwise disclose the information.
    The ICR provides a detailed explanation of this estimate, which is
only briefly summarized here:
    Estimated total number of potential respondents: 1,720.
    Frequency of response: Annually.
    Estimated total average number of responses for each respondent: 1.
    Estimated total annual burden hours: 1,645.
    Estimated total annual costs: $125,801. There are no capital
investment or maintenance and operational costs.

IV. Are There Changes In the Estimates From the Last Approval?

    The total annual burden for respondents associated with this
renewal is 1,645 hours. This reflects a decrease of 118 hours from the
last renewal period. The decrease represents the steady decline of the
number of pesticide registrants and, therefore, participation under
this program. In 2006, the projected estimate is 1,720 registrants.
This represents a decrease of 157 respondents from the 1,877 reported
in the last ICR renewal. The average time required to complete the
maintenance fee filing form depends upon the number of registrations
held by the registrant. In addition to fewer respondents in 2006, a
smaller percentage of registrants held a small number of registered
products. This shift to a slightly larger average number of
registrations per registrant resulted in a slight increase in the
average burden hours required to complete the form, from 0.94 hours in
the last ICR renewal, to 0.96 hours.

V. What is the Next Step In the Process for This ICR?

    EPA will consider the comments received and amend the ICR as
appropriate. The final ICR package will then be submitted to OMB for
review and approval pursuant to 5 CFR 1320.12. EPA will issue another
Federal Register notice pursuant to 5 CFR 1320.5(a)(1)(iv) to announce
the submission of the ICR to OMB and the opportunity to submit
additional comments to OMB. If you have any questions about this ICR or
the approval process, please contact the person listed under FOR
FURTHER INFORMATION CONTACT.

List of Subjects

    Environmental protection, Reporting and recordkeeping requirements.

    Dated: October 5, 2006.
James B. Gulliford,
Assistant Administrator, Office of Prevention, Pesticides and Toxic
Substances.
[FR Doc. E6-17778 Filed 10-24-06; 8:45 am]

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