
[Federal Register Volume 78, Number 138 (Thursday, July 18, 2013)]
[Notices]
[Pages 42960-42963]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-17213]



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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 
19, 2013.

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. 
Also include the FDA docket number found in brackets in the heading of 
this document.

FOR FURTHER INFORMATION CONTACT: Ila S. Mizrachi, Office of Information 
Management, Food and Drug Administration, 1350 Piccard Dr., PI50-400B, 
Rockville, MD 20850, 301-796-7726, Ila.Mizrachi@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 (PET) 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 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 (FDAMA). 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 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. The estimated annual recordkeeping and third-
party disclosure burden is based on there being approximately 129 PET 
drug production facilities. Table 1 provides an estimate of the annual 
recordkeeping burdens. Table 2 provides an estimate of the annual 
third-party disclosure burdens associated with this collection.

A. Investigational and Research PET Drugs

    Section 212.5(b) 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 
United States Pharmacopoeia (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 FDAMA), and accordingly, 
we do not estimate any recordkeeping burden for this provision.

B. 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 221 PET drugs 
produced, with a total recordkeeping burden of approximately 4,420 
hours. We estimate that it would take a PET production facility an 
average of 1 hour to complete a batch record for each of approximately 
501 batches. Our estimated burden for completing batch records is 
approximately 64,629 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 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 1,935 
hours. We estimate that recording maintenance and cleaning information 
would take approximately 5 minutes a day for each piece of equipment, 
with a total recordkeeping burden of approximately 40,237 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 approximately 259 hours. We estimate that each 
facility would receive approximately 36 shipments annually and would 
spend approximately 30 minutes per shipment entering records. The 
annual burden for maintaining these records would be approximately 
2,322 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

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occurrence, and we do not estimate any recordkeeping burden for 
documenting process verification.

F. 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 3,225 
hours, and the annual burden for recording laboratory test results is 
approximately 10,728 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 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 email 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 
Paperwork Reduction Act (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.

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 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 4,644 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 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.

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 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 16,157 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 
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 dealt 
with.
    In the Federal Register of March 20, 2013 (78 FR 17215), FDA 
published a 60-day notice requesting public comment on the proposed 
collection of information. We received 2 comments, each raising several 
issues.
    (Comment 1) One comment said that the two tables in the Federal 
Register notice were unclear because only the part 212 section was 
cited and not the records pertaining to that section.
    (Response) FDA appreciates the comment and we have revised the 
tables accordingly.
    (Comment 2) One comment said that the collection of information 
will not have any practical utility unless the reason for the proposed 
collection is to provide better FDA understanding of the PET drug 
production industry, to facilitate upcoming inspections, and to work 
with PET facilities in meeting areas of compliance under part 212. 
Another comment said that FDA has not adequately explained the purpose 
of these regulations.
    (Response) FDA's CGMP regulations in part 212 are useful and 
necessary because they help ensure that PET drug products meet the 
requirements of the FD&C Act regarding safety, identity, strength, 
quality, and purity. The requirements are specifically designed to take 
into account the unique characteristics of PET FDA 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. As mentioned by the comment, the collection of 
information also provides FDA with a better understanding of the PET 
production industry.
    (Comment 3) One comment said that the number of PET drug production 
facilities estimated by FDA is not reflective of the current number of 
registered PET production facilities operating in the United States, 
and that the burden estimates are based on 129 PET drug production 
facilities surveyed. The comment said that the actual number of PET 
producers is over 150. The comment said that FDA did not divide the PET 
drug production facilities into commercial sites and academic sites, 
and questioned whether the data are a fair representation of both. The 
comment also said that commercial facilities are able to hire a team of 
personnel dedicated to regulatory compliance, whereas the individual 
sites, like the academic labs, must perform the same functions with a 
much smaller staff. The comment said that FDA's burden estimates for 
academic labs are too low and unrealistic.
    (Response) The 129 PET drug production facilities are based on 
facilities listed in new drug applications (NDAs) and abbreviated new 
drug applications (ANDAs) submitted to FDA. These 129 sites are 
producing PET drugs and are seeking approval from FDA for commercial 
distribution for clinical use (not for investigational or research 
use). It is unclear from the comment if the 150 sites include sites 
producing PET drugs for investigational

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use. FDA requests that the commenter provide any updated data on the 
number of PET drug sites. In addition, FDA believes it is fair to make 
a general estimate across academic and commercial sites because the 
number of academic sites that apply for drug applications is a 
relatively small percentage.
    (Comment 4) One comment said that the burden hour estimates are not 
accurate because each facility will compile their records differently 
and will use either a paper-based method or an electronic method. The 
comment said that FDA did not specify how many PET drug facilities are 
using paper-based records compared with electronic-based records, and 
that the burden hours for those using paper-based records would be 
higher than those using electronic recordkeeping. The comment said that 
the burden hour estimate is not a fair representation of the time 
needed for all PET facilities to comply with the recordkeeping 
requirements.
    (Response) All commercial PET drug manufacturers 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 
choose to 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 we do not agree that academic 
PET drug sites limited in personnel and resources 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. In addition, 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.
    (Comment 5) One comment said that the estimate of 30 minutes per 
batch production and control record should be increased to 90 minutes 
because of the following responsibilities: Recording the identification 
number, tracking number, and lot number of each equipment item, 
component, or reagent utilized in the production of the PET drug; 
reviewing and recording daily sterility data for 14 days after release 
and inoculation; and quality assurance review of all batch record 
entries.
    (Response) FDA agrees that some of the responsibilities may take 
additional time, and we have increased the burden estimate to 1 hour.
    (Comment 6) One comment said that the recordkeeping estimate of 10 
minutes for components, containers, and closures should be increased to 
60 minutes because of the following responsibilities: To document the 
receipt, quarantine, and release of each component at separate and 
distinctly timed intervals; to recover certificates of analysis; 
contacting vendors; requesting documents; receiving and printing 
documents and maintaining files for documents; and acceptance, which 
requires performing and recording lab results. For media, this includes 
completing packaging and shipping documents for offsite testing as well 
as specifying testing parameters to the contract lab.
    (Response) To log in each incoming component may take 10 minutes, 
but the time needed to perform all procedures as described by the 
commenter, including verifying that the component meets the firm's 
internal specifications, will take longer. Therefore, we have we have 
increased the burden estimate to 30 minutes.
    (Comment 7) One comment said that the estimate of 36 out-of-
specification investigations per year should be increased to 120 
investigations because FDA requires an investigation of not only those 
that are most serious but also every incident involving an unexpected 
result.
    (Response) FDA disagrees that 36 out-of-specification 
investigations per year are too low based on the information from our 
field alert reporting system. Out-of-specification investigations 
pertain to those products not meeting one or more of its release 
specifications. On the other hand, certain deviations in manufacturing 
also warrant investigations in order to prevent future recurrence. It 
is unlikely that a firm could have 120 total investigations per 
facility.
    (Comment 8) One comment said that the use of automated collection 
techniques and other forms of information technology increase costs to 
producers: Software solutions with necessary validation costs could 
cost $100,000; support and maintenance could cost $20,000 per year; and 
applications training and implementing the electronic methods require 
several months of effort.
    (Response) There will be initial costs to establish an electronic 
recordkeeping system, but once the system is set up, the annual costs 
will be minimal. FDA requires electronic records (i.e., batch records 
and analytical test records) to comply with the basic electronic 
records requirements at 21 CFR part 11, namely, record security and an 
audit trail. Those sites that are under corporate management can apply 
their electronic recordkeeping system to all sites within the same 
corporation.
    (Comment 9) One comment asked to see the list of questions from the 
survey that was used to determine the time spent to comply with the 
recordkeeping requirements.
    (Response) In making our estimates of the time spent in complying 
with these information collection 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. There was no formal survey to 
industry.
    (Comment 10) One comment suggested that FDA establish an ``on-line 
database'' requiring a username and password for access to minimize the 
burden of the collection of information on respondents.
    (Response) FDA believes the information collection burden is 
reasonable at this time, and we have no plans to implement an online 
database.

                               Table 1--Estimated Annual Recordkeeping Burden \1\
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                                                   Number of
        21 CFR Section             Number of      records per    Total  annual   Average burden    Total  hours
                                 recordkeepers   recordkeeper       records     per recordkeeper
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Batch Production and Control               129            1.71             221  20..............           4,420
 Records 212.20(c) and (e);
 212.50(a) and (b).
Batch Production and Control               129             501          64,629  1...............          64,629
 Records 212.20(d) and (e);
 212.50(c); 212.80(c).

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Equipment and Facilities                   129              15           1,935  1...............           1,935
 Records 212.20(c); 212.30(b);
 212.50(d); 212.60(f).
Equipment and Facilities                   129           3,758         484,782  .08 (5 minutes).          40,237
 Records 212.30(b); 212.50(d);
 212.60(f).
Records of Components,                     129               2             258  1...............             258
 Containers, and Closures
 212.20(c); 212.40(a) and (b).
Records of Components,                     129              36           4,644  .5 (30 minutes).           2,322
 Containers, and Closures
 212.40(e).
Laboratory Testing Records                 129              25           3,225  1...............           3,225
 212.20(c); 212.60(a) and (b);
 212.61(a); 212.70(a), (b),
 and (d).
Laboratory Testing Records                 129             501          64,629  .16 (10 min.)...          10,728
 212.60(g); 212.61(b);
 212.70(d)(2) and (d)(3).
Conditional Final Releases                 129               1             129  1...............             129
 212.70(f).
Out-of-Specification                       129              36           4,644  1...............           4,644
 Investigations 212.20(c);
 212.71(a).
Out-of-Specification                       129               1             129  1...............             129
 Investigations 212.71(b).
Reprocessing Procedures                    129               1             129  1...............             129
 212.20(c); 212.71(d).
Distribution Records                       129               1             129  1...............             129
 212.20(c); 212.90(a).
Distribution Records 212.90(b)             129             501          64,629  .25 (15 min.)...          16,157
Complaints 212.20(c);                      129               1             129  1...............             129
 212.100(a).
Complaints 212.100(b) and (c).             129               1             129  .5 (30 min.)....              65
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    Total.....................  ..............  ..............  ..............  ................         149,266
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


                                               Table 2--Estimated Annual Third-Party Disclosure Burden \1\
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                                                                                         Number of
                           21 CFR Section                               Number of       disclosures      Total annual   Average  burden    Total hours
                                                                       respondents    per  respondent    disclosures    per  disclosure
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Sterility Test Failure Notices 212.70(e)...........................             129              .25               32                1               32
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\1\ There are no capital costs or operating and maintenance costs associated with this information collection.


    Dated: July 12, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-17213 Filed 7-17-13; 8:45 am]
BILLING CODE 4160-01-P


