
[Federal Register Volume 81, Number 132 (Monday, July 11, 2016)]
[Notices]
[Pages 44876-44878]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-16360]



[[Page 44876]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-N-0242]


Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Comment Request; Current Good 
Manufacturing Practice for Positron Emission Tomography Drugs

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that a 
proposed collection of information has been submitted to the Office of 
Management and Budget (OMB) for review and clearance under the 
Paperwork Reduction Act of 1995.

DATES: Fax written comments on the collection of information by August 
10, 2016.

ADDRESSES: To ensure that comments on the information collection are 
received, OMB recommends that written comments be faxed to the Office 
of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, 
FAX: 202-395-7285, or emailed to oira_submission@omb.eop.gov. All 
comments should be identified with the OMB control number 0910-0667 and 
title ``Current Good Manufacturing Practice for Positron Emission 
Tomography Drugs.'' Also include the FDA docket number found in 
brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: FDA PRA Staff, Office of Operations, 
Food and Drug Administration, Three White Flint North 10A63, 11601 
Landsdown St., North Bethesda, MD 20852, PRAStaff@fda.hhs.gov.

SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

Current Good Manufacturing Practice for Positron Emission Tomography 
Drugs OMB Control Number 0910-0667--Extension

    Positron emission tomography is a medical imaging modality 
involving the use of a unique type of radiopharmaceutical drug product. 
FDA's Current Good Manufacturing Practice (CGMP) regulations at 21 CFR 
part 212 are intended to ensure that positron emission tomography (PET) 
drug products meet the requirements of the Federal Food, Drug, and 
Cosmetic Act (the FD&C Act) regarding safety, identity, strength, 
quality, and purity. The CGMP requirements for PET drugs are issued 
under the provisions of the Food and Drug Administration Modernization 
Act of 1997 (the Modernization Act). These 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 CGMP regulations are intended to ensure that approved PET drugs 
meet the requirements of the FD&C 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 
and a third-party disclosure requirement for the production of PET 
drugs. In making our estimates of the time spent in complying with 
these information collection requirements, we relied on informal 
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.
    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 and the estimated annual burden for 
recordkeeping and third party disclosure. In response to the notice, 
FDA received several comments. The comments raised a number of issues 
that are discussed as follows.
    (Comment 1) The comment disagreed with FDA's estimate that 129 PET 
drug production facilities are required to comply with part 212. Based 
on its records, the comment said that approximately 150 facilities are 
subject to the PET CGMP requirements.
    (Response) We have revised the burden estimates to account for 150 
PET drug production facilities.
    (Comment 2) The comment disagreed with FDA's statement in section I 
of the December 29, 2015, Federal Register notice, ``Investigational 
and Research PET Drugs.'' The comment said that PET facilities devote 
resources to comply with USP 32 Chapter 823, and that FDA should 
estimate the recordkeeping burden under USP 32 Chapter 823.
    (Response) FDA agrees with the comment that facilities incur a 
burden to comply with USP 32 Chapter 823. However, compliance with USP 
provisions is beyond the scope of this information collection, which 
only pertains to the requirements under part 212.
    (Comment 3) The comment said FDA ``averages'' the burden across 
different categories of respondents and responses, and that this 
approach results in lower burden estimates. For example, the comment 
said that most recordkeeping will continue to be with a paper-based 
system and not an electronic system, and that the costs are different 
for each system. In addition, there are differences between the costs 
incurred by commercial and academic facilities.
    (Response) All commercial PET drug facilities are currently 
utilizing electronic records for recordkeeping as well as paper-based 
records. Commercial PET drug manufacturers comprise approximately 90 
percent of the manufacturing sites. Many academic PET facilities still 
use paper-based records. However, academic PET sites produce fewer 
batches for clinical use compared to commercial sites, and have fewer 
records. Sufficient resources and personnel are needed to perform the 
PET drug production activities, and academic PET drug sites limited in 
personnel and resources do bear more of the regulatory burden. After a 
firm's recordkeeping process is established, the burdens are generally 
the same for entering records into an electronic system or a paper-
based system. We question whether it is worthwhile to prepare separate 
estimates for commercial versus academic sites because academic sites 
are a small percentage of the total. Also, providing an average 
estimate is consistent with PRA requirements and, based on our 
calculations, the number of academic sites that apply for drug 
applications represents a small percentage.
    (Comment 4) The comment questioned FDA's methodology for 
determining the burden estimates, especially in table 2 where the 
actual burden may be underestimated ``by a factor of 10 to 100.''
    (Response) In estimating the time to comply with these information 
collection requirements, we relied on

[[Page 44877]]

informal communications we have had with PET producers, visits by our 
staff to PET facilities, our familiarity with both PET and general 
pharmaceutical manufacturing practices, and the different facilities 
listed in new drug applications (NDAs) and abbreviated new drug 
applications (ANDAs) submitted to FDA for PET drugs. FDA is willing to 
consider any specific estimates to replace the data we used in the 
tables, just as we did for the 150 facilities submitted by the comment. 
However, other than the 150 facilities, the comment has submitted no 
other specific estimates upon which we could base alternative 
estimates.
    (Comment 5) The comment said more time is needed to prepare its 
analysis of FDA's information collection burden for part 212. The 
comment also offered to work with FDA in the future to develop 
estimates that more fairly reflect the burden to comply with these 
regulations.
    (Response) As required under the Paperwork Reduction Act (PRA), FDA 
provided 60 days for respondents to submit comment in response to the 
December 29, 2015, notice. Upon submission to OMB, respondents are 
afforded 30 additional days to submit comments. Finally, because FDA 
must seek OMB approval for any information collection at least every 
three years, respondents are invited to submit comments accordingly. 
FDA considers all comments it receives and continually seeks ways to 
improve its burden estimates as well as the efficiency of its 
information collection activities, including suggestions from PET drug 
producers and facilities in estimating the burden of the information 
collection in part 212. Any specific estimates submitted by PET drug 
producers and facilities subsequent to the comment period provided for 
under the PRA will be reviewed and considered by FDA for future 
renewals of this information collection.
    We estimate the burden of this collection of information as 
follows:

                                                   Table 1--Estimated Annual Recordkeeping Burden \1\
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                                                                    Number of
            Activity; 21 CFR section                Number of      records per    Total annual       Average burden per recordkeeper        Total hours
                                                  recordkeepers   recordkeeper       records                                                    \2\
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Batch Production and Control Records--                      150            1.71           256.5  20.....................................           5,130
 212.20(c); 212.20(e); 212.50(a); 212.50(b).
Batch Production and Control Records--212.20(d)             150             501          75,150  0.50 (30 mins.)........................          37,575
 and (e); 212.50(c); 212.80(c).
Equipment and Facilities Records--212.20(c);                150              15           2,250  1......................................           2,250
 212.30(b); 212.50(d); 212.60(f).
Equipment and Facilities Records--212.30(b);                150           3,758         563,700  0.08 (5 mins.).........................          45,096
 212.50(d); 212.60(f).
Records of Components, Containers, and                      150               2             300  1......................................             300
 Closures--212.20(c); 212.40(a); 212.40(b).
Records of Components, Containers, and                      150              36           5,400  0.17 (10 mins.)........................             918
 Closures--212.40(e).
Laboratory Testing Records--212.20(c);                      150              25           3,750  1......................................           3,750
 212.60(a); 212.60(b); 212.61(a); 212.70(a);
 212.70(b); 212.70(d).
Laboratory Testing Records--212.60(g);                      150             501          75,150  0.17 (10 mins.)........................          12,776
 212.61(b); 212.70(d)(2); 212.70(d)(3).
Conditional Final Releases--212.70(f)..........             150               1             150  1......................................             150
Out-of-Specification Investigations--212.20(c);             150              36           5,400  1......................................           5,400
 212.71(a); 212.71(b).
Reprocessing Procedures--212.20(c); 212.71(d)..             150               1             150  1......................................             150
Distribution Records--212.20(c); 212.90(a);                 150             501          75,150  0.25 (15 mins.)........................          18,788
 212.90(b).
Complaints--212.20(c); 212.100(a)..............             150               1             150  1......................................             150
Complaints--212.100(b); 212.100(c).............             150               1             150  0.50 (30 mins.)........................              75
                                                --------------------------------------------------------------------------------------------------------
    Total......................................  ..............  ..............  ..............  .......................................         132,508
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\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 Burden \1\
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                                                                                         Number of
                           21 CFR section                               Number of     disclosures per    Total annual    Average burden  Total hours \2\
                                                                       respondents       respondent      disclosures     per disclosure
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Sterility Test Failure Notices--212.70(e)..........................             150              .25             37.5                1               38
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\1\ There are no capital costs or operating and maintenance costs associated with this information collection.
\2\ Number rounded to the nearest whole number.

I. 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 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.

[[Page 44878]]

II. 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.

III. 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.

IV. 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.

V. 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.

VI. Laboratory Testing Records

    Sections 212.20(c), 212.60(a), (b), and (g), 212.61(a) and (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 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.

VII. 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 notices per year to receiving facilities. The 
notice would be provided using email or fax transmission and should 
take no more than 1 hour.

VIII. 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.

IX. 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.

X. 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.

XI. 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.

XII. 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.

    Dated: July 5, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-16360 Filed 7-8-16; 8:45 am]
 BILLING CODE 4164-01-P


