0667 SS Part A 2016

Current Good Manufacturing Practice for
Positron Emission Tomography (PET) Drugs
OMB Control No. 0910-0667
SUPPORTING STATEMENT Part A
A. Justification
1. Circumstances Making the Collection of Information Necessary
This information collection is intended to ensure that Positron Emission Tomography (PET) drug
products meet the requirements of the Federal Food, Drug, and Cosmetic Act (the act) regarding
safety, identity, strength, quality, and purity. Positron emission tomography is a medical
imaging modality involving the use of a unique type of radiopharmaceutical drug product. The
majority of PET drug products are injected intravenously into patients for diagnostic purposes.
Most PET drugs are produced using cyclotrons and other production equipment at locations that
are close to the patients to whom the drugs are administered (for example, in hospitals or
academic institutions). Due to their short half-lives, PET drugs usually are administered to
patients within a few minutes or hours of production.
Under section 501(a)(2)(B) of the act, a drug is adulterated if the methods used in, or the
facilities or controls used for, its manufacture, processing, packing, or holding do not conform to
or are not operated or administered in conformity with Current Good Manufacturing Practice
(CGMP) regulations to ensure that such drug meets the requirements of the act as to safety and
has the identity and strength, and meets the quality and purity characteristics, which it purports
or is represented to possess. FDA has the authority under section 701(a) of the act to issue
regulations for the efficient enforcement of the act regarding CGMP procedures for
manufacturing, processing, and holding drugs and drug products. Our CGMP requirements for
non-PET drug products are set forth in 21 CFR parts 210 and 211. The CGMP regulations help
ensure that drug products meet the statutory requirements for safety and have their purported or
represented identity, strength, quality, and purity characteristics. The recordkeeping
requirements in the CGMP regulations provide FDA with the necessary information to perform
its duty to protect public health and safety. CGMP requirements establish accountability in the
manufacturing and processing of drug products, provide for meaningful FDA inspections, and
enable manufacturers to improve the quality of drug products over time. The CGMP
recordkeeping requirements also serve preventive and remedial purposes and provide crucial
information if it is necessary to recall a drug product.
2. Purpose and Use of the Information Collection
Respondents to the collection are manufacturers of PET drugs. The information collection is
used to ensure compliance with CGMP regulatory requirements applicable to PET drugs
including: Batch Production and Control Records; Equipment and Facilities Records; Records
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of Components, Containers, and Closures; Process Verification; Laboratory Testing Records;
Sterility Test Failure Notices; Conditional Final Releases; Out-of-Specification Investigations;
Reprocessing Procedures; Distribution Records; and Complaints.
3. Use of Improved Information Technology and Burden Reduction
Generally, recordkeeping required by CGMP regulations are developed and maintained by the
respondents. Because the CGMP regulations provide great latitude on how these requirements
are to be implemented, manufacturers may establish their own methods of recordkeeping. FDA
accepts any recordkeeping method which meets the objectives of 21 CFR parts 210, 211, and
212. For example, drug manufacturing establishments may use automatic, mechanical, or
electronic equipment or other types of equipment, including computers, or related systems that
will perform a function satisfactorily, to comply with these recordkeeping requirements.
4. Efforts to Identify Duplication and Use of Similar Information
We are unaware of any other information collection which may be duplicative.
5. Impact on Small Businesses or Other Small Entities
While the information collection applies to small and large businesses alike, FDA provides small
business and industry assistance to respondents on its website and through its Center for Drug
Evaluation and Research (CDER).
6. Consequences of Collecting the Information Less Frequently
FDA believes that the information collection schedule is consistent with its statutory mandate to
ensure compliance with CGMP regulations applicable to PET drugs.
7. Special Circumstances Relating to the Guidelines in 5 CFR 1320.5
There are no special circumstances associated with this collection of information.
8. Comments in Response to the Federal Register Notice and Efforts to Consult Outside the
Agency
In the Federal Register of December 29, 2015 (80 FR 81332), FDA published a 60-day notice
requesting public comment on the proposed collection of information. Two comments were
received in response to the notice, considered by the agency, and are discussed in the Federal
Register of July 11, 2016 (81 FR 44876). In response to specific comment regarding the number
of production facilities, the agency increased its estimated number of respondents from 129 to
150 as discussed more fully under Number 12a. below.

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9. Explanation of Any Payment or Gift to Respondents
No payment or gift is provided to respondents.
10. Assurance of Confidentiality Provided to Respondents
Certain data and information collected during an inspection of a drug manufacturing
establishment for the purpose of enforcing compliance with the CGMP regulations are
considered confidential and not releasable to the public. Confidentiality is maintained for trade
secret or confidential, commercial, or financial information under 21 CFR 20.61 and
investigatory records under 21 CFR 20.64. In addition, certain sections of 21 CFR 314.430
provide confidentiality of information contained in NDAs and ANDAs.
11. Justification for Sensitive Questions
This information collection does not involve questions that are of a personally sensitive nature.
12. Estimates of Annualized Hour Burden and Costs
12a. Annualized Hour Burden Estimate
We estimate the annual burden of this collection of information as follows:
Table 1.--Estimated Annual Recordkeeping Burden1
Activity;
21 CFR Section

Batch Production and Control
Records - 212.20(c), 212.20(e);
212.50(a), 212.50(b)
Batch Production and Control
Records - 212.20(d) and (e);
212.50(c); 212.80(c)
Equipment and Facilities
Records - 212.20(c); 212.30(b);
212.50(d), 212.60(f)
Equipment and Facilities
Records - 212.30(b), 212.50(d);
212.60(f)
Records of Components,
Containers, and Closures 212.20(c); 212.40(a), 212.40(b)
Records of Components,
Containers, and Closures 212.40(e)

No. of
Recordkeepers

150

No. of
Records per
Recordkeeper
1.71

Total
Annual
Records
256.5

Avg. Burden
per
Recordkeeper
20

150

501

75,150

0.50

37,575

150

15

2,250

1

2,250

150

3,758

563,700

0.08

45,096

150

2

300

1

300

150

36

5,400

0.17

918

3

Total
Hours2

5,130

Activity;
21 CFR Section

No. of
Recordkeepers

Laboratory Testing Records 212.20(c); 212.60(a), 212.60(b),
212.61(a); 212.70(a), 212.70(b),
212.70(d)
Laboratory Testing Records
212.60(g); 212.61(b);
212.70(d)(2), 212.70(d)(3)
Conditional Final Releases 212.70(f)
Out-of-Specification
Investigations - 212.20(c);
212.71(a); 212.71(b)
Reprocessing Procedures 212.20(c); 212.71(d)
Distribution Records - 212.20(c);
212.90(a); 212.90(b)
Complaints - 212.20(c);
212.100(a)
Complaints - 212.100(b),
212.100(c)
TOTAL

150

No. of
Records per
Recordkeeper
25

Total
Annual
Records
3,750

Avg. Burden
per
Recordkeeper
1

Total
Hours2

150

501

75,150

0.17

12,776

150

1

150

1

150

150

36

5,400

1

5,400

150

1

150

1

150

150

501

75,150

0.25

18,788

150

1

150

1

150

150

1

150

0.50

75

3,750

807,106.5

132,508

1

There are no capital costs or operating and maintenance costs associated with this collection of information.
2
Number rounded to the nearest whole number.

Table 2. Estimated Annual Third-Party Disclosure Burden1
21 CFR Section

Sterility Test Failure Notices
- 212.70(e)
1
2

No. of
Respondents

150

No. of
Disclosures per
Respondent
.25

Total
Annual
Disclosures
37.5

Avg.
Burden per
Disclosure
1

Total
Hours2

38

There are no capital costs or operating and maintenance costs associated with this information collection.
Number rounded to the nearest whole number.

Investigational and Research PET Drugs
Section 212.5(b)(2) provides that for investigational PET drugs produced under an
investigational new drug (IND) and research PET drugs produced with approval of a Radioactive
Drug Research Committee (RDRC), the requirement under the FD&C Act to follow current good
manufacturing practice is met by complying with the regulations in 21 CFR 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 do not estimate
any recordkeeping burden for this provision.

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Batch Production and Control Records
Sections 212.20(c) through (e), 212.50(a) through (c), and 212.80(c) set forth requirements for
batch and production records as well as written control records. We estimate that it would take
approximately 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 approximately 256.5 PET
drugs produced, with a total recordkeeping burden of approximately 5,130 hours. We estimate
that it would take a PET production facility an average of 30 minutes to complete a batch record
for each of approximately 501 batches. Our estimated burden for completing batch records is
approximately 37,575 hours.
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 approximately 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
approximately 2,250 hours. We estimate that recording maintenance and cleaning information
would take approximately 5 minutes a day for each piece of equipment, for a total recordkeeping
burden of approximately 45,096 hours.
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 approximately 300 hours. We estimate that each
facility would receive approximately 36 shipments annually and would spend approximately 10
minutes per shipment entering records. The annual burden for maintaining these records would
be approximately 918 hours.
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 do not estimate any recordkeeping burden for documenting
process verification.
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. Each PET drug production facility
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will need to establish procedures and create forms for the different tests for each product 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 approximately 3,750 hours, and the associated annual burden
for recording laboratory test results is approximately 12,776 hours.
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
batches of PET drugs produced each year. Therefore, we have estimated in Table 2 that each
PET drug producer will need to provide approximately 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.
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 approximately 1 hour documenting the release and notifying
receiving facilities. The estimate of one conditional final release per year per facility is an
appropriate average number because many facilities may have no conditional final releases while
others might have only a few.
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 approximately 1 hour annually to record and update these
procedures for each PET production facility. We also estimate, for purposes of the PRA, that 36
out-of-specification investigations would be conducted at each facility each year and that it
would take approximately 1 hour to document the investigation, which results in an annual
burden of 5,400 hours.
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 approximately 1 hour a
year to document these procedures for each PET production facility. We do 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.

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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 approximately 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
approximately 15 minutes to create an actual distribution record for each batch of PET drug
products, with a total burden of approximately hours for all PET producers.
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 approximately 1 hour
annually for each PET production facility and that each facility will receive approximately one
complaint a year and will spend approximately 30 minutes recording how the complaint was
addressed.
12b. Annualized Cost Burden Estimates
We estimate the annual cost of this information collection as follows:
Table 3 – Estimated Annual Recordkeeping Costs
Number of
Labor (Months) Wage (Year
Cost2
1
Establishments
Salary)
RECORDS DAILY IMPLEMENTATION, AUDITS, UPDATES:
Academic PET Producers
28
2.25
$164,300
$554,512.23
Commercial PET Producers
122
1.0
$164,300
$1,519,774.26
TRAINING:
Academic PET Producers
28
.11
$164,300
$27,109.49
Commercial PET Producers
122
.11
$164,300
$167,175.17
TOTAL
$194,284.66

13. Estimates of Other Total Annual Cost Burden to Respondents and Recordkeepers
There are no capital, start-up, operating or maintenance costs associated with this information
collection.

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14. Annualized Cost to the Federal Government
FDA costs for this information collection consists of periodic inspections of PET drug
production facilities. We estimate that there are approximately 60 inspections annually at 40
hours per inspection, resulting in 5 FTEs X $145,000/FTE = $725,000 annual cost to FDA.
15. Explanation for Program Changes or Adjustments
While we have itemized individual burden by information collection provision in our Federal
Register notices and will continue to do so in the future, we have revised the list that will publish
on www.reginfo.gov. Specifically we have consolidated the 16 individual recordkeeping ICs
into one IC, but we have retained the single 3rd Party Disclosure IC. We have also adjusted the
number of respondents based on public comment from 129 to 150. This has resulted in an
overall increase to the collection of 112,743 responses. At the same time, we have reduced the
time burden per response for Batch Production and Control Records under 21 CFR Parts
212.20(d) and (e), 212.50(c), and 212.80(c) from one hour to one-half hour, which has resulted
in an overall decrease in burden hours by 14,910.
16. Plans for Tabulation and Publication and Project Time Schedule
Information collected under this requirement will not be tabulated or published.
17. Reason(s) Display of OMB Expiration Date is Inappropriate
Display of OMB Expiration would be appropriate.
18. Exceptions to Certification for Paperwork Reduction Act Submissions
There are no exceptions to the certification.

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