[Federal Register Volume 87, Number 67 (Thursday, April 7, 2022)]
[Notices]
[Pages 20420-20429]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-07392]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

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


Agency Information Collection Activities; Proposed Collection; 
Comment Request; Current Good Manufacturing Practices for Positron 
Emission Tomography Drugs

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
an opportunity for public comment on the proposed collection of certain 
information by the Agency. Under the Paperwork Reduction Act of 1995 
(PRA), Federal Agencies are required to publish notice in the Federal 
Register concerning each proposed collection of information, including 
each proposed extension of an existing collection of information, and 
to allow 60 days for public comment in response to the notice. This 
notice solicits comments on collection of information under FDA's 
current good manufacturing practice (CGMP) regulations for positron 
emission tomography (PET) drugs. PET is a medical imaging modality 
involving the use of a unique type of radiopharmaceutical drug product.

DATES: Submit either electronic or written comments on the collection 
of information by June 6, 2022.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. Electronic comments 
must be submitted on or before June 6, 2022. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of June 6, 2022. Comments received 
by mail/hand delivery/courier (for written/paper submissions) will be 
considered timely if they are postmarked or the delivery service 
acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your

[[Page 20421]]

comment does not include any confidential information that you or a 
third party may not wish to be posted, such as medical information, 
your or anyone else's Social Security number, or confidential business 
information, such as a manufacturing process. Please note that if you 
include your name, contact information, or other information that 
identifies you in the body of your comments, that information will be 
posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include Docket No. FDA-
2013-N-0242 for ``Agency Information Collection Activities; Proposed 
Collection; Comment Request; Current Good Manufacturing Practices for 
Positron Emission Tomography Drugs.'' Received comments, those filed in 
a timely manner (see ADDRESSES), will be placed in the docket and, 
except for those submitted as ``Confidential Submissions,'' publicly 
viewable at https://www.regulations.gov or at the Dockets Management 
Staff between 9 a.m. and 4 p.m. Eastern Time, Monday through Friday, 
240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Amber Sanford, Office of Operations, 
Food and Drug Administration, Three White Flint North, 10A-12M, 11601 
Landsdown St., North Bethesda, MD 20852, 301-796-8867, 
[email protected].

SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3521), Federal 
Agencies must obtain approval from the Office of Management and Budget 
(OMB) for each collection of information they conduct or sponsor. 
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR 
1320.3(c) and includes Agency requests or requirements that members of 
the public submit reports, keep records, or provide information to a 
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A)) 
requires Federal Agencies to provide a 60-day notice in the Federal 
Register concerning each proposed collection of information, including 
each proposed extension of an existing collection of information, 
before submitting the collection to OMB for approval. To comply with 
this requirement, FDA is publishing notice of the proposed collection 
of information set forth in this document.
    With respect to the following collection of information, FDA 
invites comments on these topics: (1) Whether the proposed collection 
of information is necessary for the proper performance of FDA's 
functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.

Current Good Manufacturing Practices for Positron Emission Tomography 
Drugs--21 CFR Part 212

OMB Control Number 0910-0667--Revision

    FDA CGMP regulations in part 212 (21 CFR part 212) are intended to 
ensure that PET drug products meet the requirements of the Federal 
Food, Drug, and Cosmetic Act (FD&C Act) regarding safety, identity, 
strength, quality, and purity and are issued under the provisions of 
the Food and Drug Administration Modernization Act of 1997 (FDAMA) 
(Pub. L. 105-115). These CGMP requirements are designed according to 
the unique characteristics of PET drugs, including their short half-
lives and because most PET drugs are produced at locations close to the 
patients to whom the drugs are administered.

I. Investigational and Research PET Drugs

    Section 212.5(b) (21 CFR 212.5(b)) provides that for 
investigational PET drugs produced under an investigational new drug 
application (IND) and research PET drugs produced with approval of a 
Radioactive Drug Research Committee (RDRC), PET producers must meet the 
requirement (FD&C Act) to follow CGMP by complying with the regulations 
under part 212 or complying with United States Pharmacopeia (USP) 32 
Chapter 823. We believe that PET production facilities producing drugs 
under INDs and RDRCs are already substantially complying with the 
recordkeeping requirements of USP 32 Chapter 823 (see section 121(b) of 
FDAMA). Some IND and RDRC PET facilities also produce PET drugs 
approved under abbreviated new drug applications (ANDAs) or new drug 
applications (NDAs), and our estimates include these facilities. The 
facilities described above are included under academia or small firms. 
The corporate sites that also produce IND PET drugs are included in the 
estimated 91 individual corporate sites.
    To estimate the amount of time that respondents have spent 
complying with

[[Page 20422]]

CGMP requirements, we relied on the following:
     Informal communications with PET producers.
     FDA staff visits to PET production facilities.
     Our experience with PET drug applications, including 
amendment and supplement submissions.
     Our general knowledge of pharmaceutical manufacturing 
practices.
     Various CGMP compliance reports FDA received from 2019 to 
2021.

II. Recordkeeping Burden

A. One-Time Recordkeeping Burden for Corporate Firms

    We estimate that corporate firms will have to employ one-time and 
annual recordkeeping. We estimate that, for some major PET 
manufacturing corporations, most of the quality, manufacturing, and 
testing procedures are developed at the corporate level and issued to 
the individual production and testing sites located in various States 
across the country. It is estimated that a total of 91 of these 
individual corporate sites are controlled among 4 major corporations. 
Thus, we have calculated the burden for 4 recordkeeping activities as a 
one-time effort for creating standard operating procedures (SOPs) and 
master batch records (MBRs) instead of 91 recordkeeping activities for 
individual corporate sites.
    Each corporate firm is estimated to expend approximately 8 hours to 
create 1 MBR per PET drug. We estimate that 4 corporate firms will each 
create and maintain 10 MBRs associated with production and quality 
control (QC) testing procedures (a total of 40 records), which results 
in a total recordkeeping burden of approximately 320 hours.
    Sections 212.20(c), 212.30(b), 212.50(d), and 212.60(f) (21 CFR 
212.20(c), 212.30(b), 212.50(d), and 212.60(f) contain written SOP 
provisions for equipment operation, maintenance, and cleaning, 
including maintenance of physical facilities. We estimate that 4 
corporate firms will expend approximately 5 hours each to establish and 
maintain 13 procedures for equipment and facility maintenance (a total 
of 52 procedures), which results in a total recordkeeping burden of 
approximately 260 hours.
    Sections 212.20(b) and 212.40(a) and (b) contain requirements on 
SOPs regarding receiving, testing, and accepting components. We 
estimate that 4 corporate firms will expend approximately 8 hours each 
to create 1 procedure for acceptance of raw materials and components (a 
total of 4 procedures), which results in a total recordkeeping burden 
of approximately 32 hours.
    We estimate that approximately 4 corporate firms will expend 2 
hours each to create 25 specification data sheets for components (a 
total of 100 specification data sheets), which results in a total 
recordkeeping burden of approximately 200 hours.
    Section 212.71(a) and (b) requires that PET drug firms establish 
procedures for rejecting PET drug batches that do not conform to 
established specifications and requires that PET drug firms establish 
procedures for investigating deviations and out-of-specifications (OOS) 
failures of products during manufacturing and testing. Section 
212.50(a) also requires that firms establish 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. We estimate that 4 corporate firms will expend 
approximately 8 hours each to establish 1 procedure (a total of 4 
procedures), which results in a total recordkeeping burden of 
approximately 32 hours.
    Section 212.90(a) requires the establishment and maintenance of 
written procedures for the distribution of PET drug products. We 
estimate that 4 corporate firms will each expend approximately 8 hours 
to establish and maintain 1 written procedure regarding the 
distribution of PET drugs (a total of 4 records), which results in a 
total recordkeeping burden of approximately 32 hours.
    Sections 212.20(e) and 212.100(a), (b), and (c) require that PET 
drug firms establish and maintain written procedures for handling 
complaints and establish and maintain procedures for field alert 
reports (FARs). We estimate that 4 corporate firms will each establish 
3 written procedures (a total of 12 procedures) and that each corporate 
firm will expend approximately 8 hours for each procedure. Establishing 
and maintaining written procedures results in a total recordkeeping 
burden of approximately 96 hours.

B. One-Time Recordkeeping Burden for Academia, Small Firms, and High-
Risk Component Manufacturers

    A total of 63 combined sites represent academia and small 
commercial firms, including some IND and RDRC sites manufacturing ANDA-
approved and NDA-approved PET drugs, and high-risk component 
manufacturers. Of the 63 combined sites (herein and the other sections 
of this document referred to as ``entities''), 14 producers of starting 
materials, precursors, generators, and sterile component material 
manufacturing for kits are also required to comply with selected 
regulations in part 212, according to the PET drug definition in 
section 121(a) of FDAMA and codified in section 201(ii)(1)(A) of the 
FD&C Act (21 U.S.C. 321(ii)(1)(A)). We refer to such producers as high-
risk component manufacturers in tables 2 and 5.
    The 63 entities will expend approximately 8 hours each to create 
MBRs and manufacturing and quality procedures. We estimate that the 
entities will each maintain 8 records (a total of approximately 504 
records), which results in a total recordkeeping burden of 4,032 hours.
    Each of the entities will expend approximately 8 hours to create 
equipment-related and facility-related procedures (consistent with 
corporate firms discussed in section II.A above). A total of 63 
entities will each maintain an estimated 12 records (a total of 756 
records), which results in a total recordkeeping burden of 
approximately 6,048 hours.
    The estimated burden for the 63 entities to each create and 
maintain 12 procedures for acceptance of raw materials and components 
(a total of 126 procedures) is approximately 8 hours per procedure. The 
creation and maintenance of these procedures results in a total 
recordkeeping burden of approximately 1,008 hours.
    We estimate that the 63 entities will each expend approximately 30 
minutes to create and maintain 21 specification data sheets (a total of 
1,323). The creation and maintenance of specification data sheets 
results in a total recordkeeping burden of approximately 662 hours.
    We estimate that approximately 63 entities will each create 1 
procedure relating to deviations and OOS investigations and 1 procedure 
relating to the distribution of finished products (2 procedures for a 
total of 126). Each of these entities will expend 8 hours per 
procedure, which results in a total recordkeeping burden of 1,008 
hours--504 hours for each procedure.
    We estimate that each of the 63 entities will create approximately 
3 procedures relating to customer complaints, returned products, and 
FAR (a total of 189 records). Each of these entities will expend 8 
hours per record, which results in a total recordkeeping burden of 
1,512 hours.

[[Page 20423]]

C. Annual Recordkeeping Burden for Corporate Firms

    As discussed in section II.A, we estimate that there are a total of 
91 individual corporate sites controlled under 4 major corporations. 
The information collection discussed in this section relates to 
individual PET drugs manufactured at each of the sites located across 
the country.
    We estimate that the 91 corporate sites will each expend 
approximately 30 minutes to fill 240 batches (approximately 20 batches 
each month and a total of 21,840 batches for all 91 sites), which 
results in a total recordkeeping burden of 10,920 hours. We further 
estimate that, annually, corporate firms may have to create some new 
batch records or quality records for newly introduced or existing 
drugs.
    We estimate that the 4 major corporations will each expend 
approximately 8 hours to create 9 new quality procedure and MBRs (a 
total of 36 records), which results in a total recordkeeping burden of 
288 hours.
    We estimate that approximately 91 individual corporate sites will 
each expend approximately 15 minutes to create 480 records for 
equipment maintenance, cleaning, calibration, and facilities 
maintenance (a total of 43,680 records), which results in a total 
recordkeeping burden of 10,920 hours.
    Sections 212.20(b) and (c) and 212.40(a) and (b) set forth 
requirements for acceptance of raw materials and component shipments 
received at the centrally controlled, corporate quality assurance (QA) 
facilities annually. We estimate that the 4 corporate QA sites, 
internally located within corporate administrative sites, will create 
48 records for incoming raw material acceptance (a total of 192 
records) for approximately 4 bulk shipments per month (12 x 4) on 
behalf of the individual corporate sites. Corporate QA sites will 
expend approximately 2 hours to create records, which results in a 
total recordkeeping burden of 384 hours.
    Sections 212.60(g), 212.61(b), and 212.70(d)(2) and (d)(3) set 
forth requirements for documenting laboratory testing results obtained 
from each PET drug manufactured and referred to in laboratory testing, 
including final release testing. Each of the 91 individual corporate 
firms must maintain records of different tests for each of their 
products. We estimate that approximately 91 individual corporate sites 
will each expend 30 minutes to document 240 records of cumulative QC 
test results (1 record that includes 5 to 6 tests and a total of 21,840 
records), which results in a total recordkeeping burden of 
approximately 10,920 hours.
    We estimate approximately 2 hours for each of the 91 individual 
corporate sites to record OOS events and perform investigations for 
each incident. We also estimate that the individual corporate sites 
will each conduct an average of 2 OOS investigations per site (a total 
of 182 records for OOS investigations), which results in a total 
recordkeeping burden of 364 hours. This estimate includes reprocessing 
or conditional release events, which are very rare.
    Section 212.100(b) and (c) requires that PET drug firms document 
how they handle each complaint that they receive. We estimate that each 
of the 4 corporate QA sites will expend approximately 2 hours to 
document and investigate 1 complaint. Because complaints are usually 
investigated at the corporate firm level, we estimate that each 
corporate QA site will receive and handle 5 complaints annually (a 
total of 20 complaints for documentation), which results in a total 
recordkeeping burden of 40 hours.
    Our estimate for PET drug firms-performing QA and release of 
manufactured PET drugs from the 91 individual corporate sites is 
approximately 5,460 hours from 21,840 released batches (15 minutes per 
batch for each of the 240 released batches).
    Section 212.90(b) requires that corporate firms maintain 
distribution records. We estimate that each of the 91 corporate firms 
will expend approximately 5,460 hours to release 21,840 batches (15 
minutes per batch for each of the 240 released batches).

D. Annual Recordkeeping Burden for Academia and Small Firms

    We assume that each academia and small firm will expend the same 
amount of time to perform the same information collection activities as 
corporate firms (discussed in section II.A above).
    Approximately 49 academia and small firms will each expend 
approximately 30 minutes to fill 96 batch and production records (a 
total of 4,704 records), which results in a total recordkeeping burden 
of 2,352 hours.
    For the 49 academia and small firms to create new MBRs or quality 
records, we estimate they will expend 8 hours per record (147 total 
records (3 per site)), which results in a total recordkeeping burden of 
1,176 hours.
    We estimate that approximately 49 academia and small firms will 
maintain 23,520 calibration and cleaning records (480 records per 
site), such as logbooks for each piece of equipment and documentation 
of calibration records in each PET production firm. The calibration 
efforts for academia and small firms is twice per year per equipment 
(10 pieces of equipment per site). In addition, we estimate that 
academic and small firms will each expend 30 minutes to maintain 
records, which results in a total recordkeeping burden of 11,760 hours.
    Under Sec. Sec.  212.20(b) and (c) and 212.40(a) and (b), academia 
and firms will maintain a total of approximately 588 raw material and 
component acceptance records (12 shipments per year). We estimate that 
they will expend 30 minutes to create records, which results in a total 
recordkeeping burden of 294 hours.
    We estimate that approximately 49 academia and small firms will 
each expend 30 minutes to document a total of 4,704 laboratory QC test 
records (96 records per site), which results in a total recordkeeping 
burden of approximately 2,352 hours.
    We estimate that approximately 49 academic and small firms will 
each maintain records of OOS and customer-complaint events and perform 
investigations and that they will expend approximately 2 hours annually 
for these activities. We also estimate an average of 2 OOS events and 2 
customer complaints and investigations per firm, with a total of 392 
hours for each category (196 for each site). This estimate includes any 
reprocessing or special batch release events, which have been rarely 
observed.
    We estimate that approximately 49 academia and small firms will 
each perform QA and release of manufactured PET drugs and that they 
will expend 15 minutes per batch (96 batches per site), which results 
in a total recordkeeping burden of 1,176 hours for 4,704 batches.
    Section 212.90(b) requires that academia and small firms maintain 
distribution records. We estimate that it will take approximately 15 
minutes per batch (96 batches per site) to create a distribution record 
for each batch of PET drug product, with a total recordkeeping burden 
of approximately 1,176 hours for 4,704 batches per site.

E. Annual Recordkeeping Burden for High-Risk Component Manufacturers 
(Producers of Starting Materials, Precursors, Generators, and Sterile 
Raw Materials)

    According to section 121(a) of FDAMA, the PET drug definition 
includes any non-radioactive or radioactive reagents, kits, nuclidic 
generators, target materials, synthesizers, or other apparatus or 
computer program to be used in preparation of PET drug. FDA performs

[[Page 20424]]

risk assessments of each manufacturer and inspects such manufacturers. 
Producers of sterile kit components, precursors, and generators are 
included in this category, including producers of sterile raw 
materials. We have estimated that 14 such facilities be included in 
this category based on inspections and have included them in this 
section. These manufacturers must comply with selected sections of part 
212 since they are not producing the final PET drug products to be 
administered to patients. As stated in section II.B, we refer to such 
producers as high-risk component manufacturers in tables 2 and 5.
    We estimate that approximately 14 high-risk component manufacturers 
will expend 30 minutes to complete each manufacturing batch record (24 
batches per site) and that there will be a total of 336 records, which 
results in a total recordkeeping burden of approximately 168 hours.
    We also estimate that the 14 high-risk component manufacturers will 
each expend approximately 30 minutes to create and file equipment 
calibration and cleaning and facility maintenance-related records (130 
records each and a total of 1,820), which results in a total 
recordkeeping burden of 910 hours.
    We estimate that the 14 such manufacturers will each expend 30 
minutes to document 24 records for components, containers, and closures 
for incoming acceptance tests (a total of 336 batches), which results 
in a total recordkeeping burden of approximately 168 hours from all 
sites.
    We estimate that the 14 such manufacturers will expend 30 minutes 
to document 24 laboratory testing records for 336 batches, which 
results in a total burden of approximately 168 hours. These 
manufacturers will also document OOS investigations for any laboratory 
test failures (1 record for each site), which results in a total 
recordkeeping burden of 14 hours.
    We also estimate that such manufacturers will perform QA and 
release manufactured PET drugs for a total of 336 batches (24 each) 
released annually. In addition, we estimate that such manufacturers 
will expend approximately 15 minutes per batch, which results in a 
total recordkeeping burden of 84 hours.
    We estimate that such manufacturers will each expend approximately 
15 minutes to create and maintain distribution records that will result 
in 336 records (24 each). The total recordkeeping burden hours will 
result in 84 hours.

F. One-Time and Annual Recordkeeping for External Control Testing 
Laboratories

    We have included a new category of facilities--external control 
testing laboratories--in this information collection. These testing 
laboratories perform chemical, microbiological, or sterility testing 
functions to support manufacturing and release of final PET drug 
products. Assignment and inspection of control testing laboratories may 
be determined through risk-based assessments. We have estimated that 23 
such facilities be included in this category, based on inspections and 
NDA and ANDA applications that FDA has received. These testing 
laboratories must comply with selected sections of part 212 (and 
compliance with 21 CFR part 211 is acceptable) since they are not 
producing the final PET drugs to be administered to patients. In this 
section, we refer to these testing laboratories as external testing 
facilities in general; however, in table 6, we refer to them as 
external control testing laboratories.
    We estimate that approximately 23 external testing facilities will 
each expend 9 hours to complete testing SOP and validation of test 
methods and assays (6 records each and a total of 138), which results 
in a total recordkeeping burden of approximately 1,242 hours.
    We estimate that 23 external testing facilities will expend 
approximately 30 minutes each to perform incoming acceptance test for 
testing materials and to create test result records, which results in a 
total recordkeeping burden of 368 hours. For incoming acceptance tests, 
sites will expend 276 hours (24 records for a total of 552), and for 
testing records, sites will expend 92 hours (8 records for a total of 
184).
    We estimate that 23 external testing facilities will each document 
2,254 equipment cleaning and calibration records, 184 QA release 
records, and 23 OOS investigation records, which results in a total 
recordkeeping burden of approximately 564, 23, and 46 hours, 
respectively (see table 6).

III. Process Verification

    Section 212.50(f)(2) requires the recordkeeping of any process 
verification activities and results. PET drug producers usually perform 
process verification as a one-time activity before a product is 
approved or if any major manufacturing process or equipment changes are 
made. We have estimated that PET drug producers will conduct process 
verification under one-time batch creation for existing products; 
annual new creation of MBRs; and manufacturing and quality procedures 
for ongoing activities, including media fills (see tables 1 and 2).

IV. Conditional Final Releases

    Section 212.70(f) requires that PET drug producers document any 
conditional final releases of a product. We believe that conditional 
final releases will be uncommon, and we have included them in the 
burden estimates under annual OOS investigations and final QA release 
efforts for each manufactured batch in tables 3 and 4.

V. Reprocessing Procedures

    Sections 212.20(c) and 212.71(d) require that PET drug producers 
establish and document procedures for reprocessing PET drugs. We have 
rarely received reprocessing options for application of such drugs and, 
if reprocessing occurs, we have included such rare events in the burden 
estimates under annual QA release efforts in tables 3 and 4.

VI. Third-Party Disclosure Burden for Sterility Test Failure Notices

    Section 212.70(e) requires that PET drug producers notify all 
receiving facilities if a batch fails sterility tests. FDA receives 
FARs based on confirmed sterility failures of released PET drugs. Based 
on the last 3 years' sterility failure reports, we estimate that all 
140 sites (91 individual corporate sites and 49 academia and small 
firms) will send notifications to the affected clinical or receiving 
facilities of approximately 7 failures. Therefore, we estimate that 7 
PET drug producers will submit 2 reports to FDA and send 1 notification 
(a total of 3 reports) to FDA and the affected clinical or receiving 
site per year. PET drug producers would submit the notice to the 
receiving site by email or Fax and submit the FAR notice to FDA 
electronically and would expend 2.5 hours per incident, which results 
in a total burden of 53 hours.
    FDA estimates the burden of this collection of information as 
follows:

[[Page 20425]]



                    Table 1--Estimated One-Time Recordkeeping Burden for Corporate Firms \1\
----------------------------------------------------------------------------------------------------------------
                                                                                      Average
Information collection activity;     Number of       Number of     Total annual     burden per      Total hours
         21 CFR section            recordkeepers    records per       records      recordkeeper         \2\
                                                   recordkeeper                     (in hours)
----------------------------------------------------------------------------------------------------------------
                                 Subparts C and F; Sec.  Sec.   212.20 to 212.50
----------------------------------------------------------------------------------------------------------------
Master Batch Production and                    4              10              40               8             320
 Quality Control Procedures
 (Sec.  Sec.   212.20(c) and (e)
 and 212.50(a) and (b)).........
----------------------------------------------------------------------------------------------------------------
                             Subparts C, D, F, and G; Sec.  Sec.   212.20 to 212.60
----------------------------------------------------------------------------------------------------------------
Equipment and Facilities Records               4              13              52               5             260
 (SOP) (Sec.  Sec.   212.20(c),
 212.30(b), 212.50(d), and
 212.60(f)).....................
----------------------------------------------------------------------------------------------------------------
                                 Subparts C and E; Sec.  Sec.   212.20 to 212.40
----------------------------------------------------------------------------------------------------------------
Records of Components,                         4               1               4               8              32
 Containers, and Closures (SOP)
 (Sec.  Sec.   212.20(b) and
 212.40(a) and (b)).............
Records of Components,                         4              25             100               2             200
 Containers, and Closures
 (specification data sheets)
 (Sec.  Sec.   212.20(b) and (c)
 and 212.40(a) and (b)).........
----------------------------------------------------------------------------------------------------------------
                                            Subpart H; Sec.   212.71
----------------------------------------------------------------------------------------------------------------
OOS Investigations (SOP) (Sec.                 4               1               4               8              32
 212.71(a) and (b)).............
----------------------------------------------------------------------------------------------------------------
                                            Subpart J; Sec.   212.90
----------------------------------------------------------------------------------------------------------------
Distribution Records (SOP) (Sec.               4               1               4               8              32
   212.90(a))...................
----------------------------------------------------------------------------------------------------------------
                                Subparts C and K; Sec.  Sec.   212.20 to 212.100
----------------------------------------------------------------------------------------------------------------
Complaints and Returned Product                4               3              12               8              96
 (Sec.  Sec.   212.20(e) and
 212.100(a), (b), and (c))......
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............             216  ..............             972
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ Totals have been rounded to the nearest whole number.


       Table 2--Estimated One-Time Recordkeeping Burden for Academia, Small Firms, and High-Risk Component
                                                Manufacturers \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                        Average
Information collection activity;     Number of      records per    Total annual     burden per      Total hours
         21 CFR section            recordkeepers   recordkeeper       records      recordkeeper         \2\
                                                        \2\                         (in hours)
----------------------------------------------------------------------------------------------------------------
                                 Subparts C and F; Sec.  Sec.   212.20 to 212.50
----------------------------------------------------------------------------------------------------------------
Batch Production and Control                  63               8             504               8           4,032
 Records (Sec.  Sec.   212.20(c)
 and 212.50(a) and (b)).........
----------------------------------------------------------------------------------------------------------------
                             Subparts C, D, F, and G; Sec.  Sec.   212.20 to 212.60
----------------------------------------------------------------------------------------------------------------
Equipment and Facilities Records              63              12             756               8           6,048
 (SOP) (Sec.  Sec.   212.20(c),
 212.30(b), 212.50(d), and
 212.60(f)).....................
----------------------------------------------------------------------------------------------------------------
                                 Subparts C and E; Sec.  Sec.   212.20 to 212.40
----------------------------------------------------------------------------------------------------------------
Records of Components,                        63               2             126               8           1,008
 Containers, and Closures (SOP)
 (Sec.  Sec.   212.20(b) and
 212.40(a) and (b)).............
Records of Components,                        63              21           1,323             0.5             662
 Containers, and Closures
 (specification data sheets)
 (Sec.  Sec.   212.20(b) and (c)
 and 212.40(a) and (b)).........
----------------------------------------------------------------------------------------------------------------
                                 Subparts C and H; Sec.  Sec.   212.20 to 212.71
----------------------------------------------------------------------------------------------------------------
OOS Investigations (SOP) (Sec.                63               1              63               8             504
 Sec.   212.20(c) and 212.71(a)
 and (b)).......................
----------------------------------------------------------------------------------------------------------------

[[Page 20426]]

 
                                            Subpart J; Sec.   212.90
----------------------------------------------------------------------------------------------------------------
Distribution Records (SOP) (Sec.              63               1              63               8             504
   212.90(a))...................
----------------------------------------------------------------------------------------------------------------
                                Subparts C and K; Sec.  Sec.   212.20 to 212.100
----------------------------------------------------------------------------------------------------------------
Complaints and Returned Product               63               3             189               8           1,512
 (Sec.  Sec.   212.20(e) and
 212.100(a), (b), and (c))......
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............           3,024  ..............          14,270
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ Totals have been rounded to the nearest whole number.


                     Table 3--Estimated Annual Recordkeeping Burden for Corporate Firms \1\
----------------------------------------------------------------------------------------------------------------
                                                                                      Average
Information collection activity;     Number of       Number of     Total annual     burden per      Total hours
         21 CFR section            recordkeepers    records per       records      recordkeeper         \2\
                                                   recordkeeper                     (in hours)
----------------------------------------------------------------------------------------------------------------
                                 Subparts C and F; Sec.  Sec.   212.20 to 212.50
----------------------------------------------------------------------------------------------------------------
Batch Production Records (create              91             240          21,840             0.5          10,920
 batch-related records per year)
 (Sec.  Sec.   212.20(c) and (e)
 and 212.50(a) and (b)).........
Creating Any New Batch Records                 4               9              36               8             288
 and Quality Records for New or
 Existing Drugs (Sec.  Sec.
 212.20(c) and (e) and 212.50(a)
 and (b)).......................
----------------------------------------------------------------------------------------------------------------
                               Subparts D, F, and G; Sec.  Sec.   212.30 to 212.60
----------------------------------------------------------------------------------------------------------------
Equipment and Facilities Records              91             480          43,680            0.25          10,920
 (calibration and cleaning
 records systems) (Sec.  Sec.
 212.30(b), 212.50(d), and
 212.60(f)).....................
----------------------------------------------------------------------------------------------------------------
                                 Subparts C and E; Sec.  Sec.   212.20 to 212.40
----------------------------------------------------------------------------------------------------------------
Records of Components,                         4              48             192               2             384
 Containers, and Closures for
 incoming inspection (Sec.  Sec.
   212.20(b) and (c) and
 212.40(a) and (b)).............
----------------------------------------------------------------------------------------------------------------
                                 Subparts G and H; Sec.  Sec.   212.60 to 212.70
----------------------------------------------------------------------------------------------------------------
Laboratory Testing Records                    91             240          21,840             0.5          10,920
 (record laboratory test
 results) Sec.  Sec.
 212.60(g), 212.61(b), and
 212.70(d)(2) and (d)(3)........
----------------------------------------------------------------------------------------------------------------
                                            Subpart H; Sec.   212.71
----------------------------------------------------------------------------------------------------------------
Out-of-Specification                          91               2             182               2             364
 Investigations (record events
 and investigations) (Sec.
 212.71(b)).....................
----------------------------------------------------------------------------------------------------------------
                                Subparts H and K; Sec.  Sec.   212.70 to 212.100
----------------------------------------------------------------------------------------------------------------
Complaints (Sec.   212.100(b)                  4               5              20               2              40
 and (c)).......................
QA and Release of Batches (Sec.               91             240          21,840            0.25           5,460
  212.70).......................
----------------------------------------------------------------------------------------------------------------
                                            Subpart J; Sec.   212.90
----------------------------------------------------------------------------------------------------------------
Distribution Records (Sec.                    91             240          21,840            0.25           5,460
 212.90(b)).....................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............         131,470  ..............          44,756
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ Totals have been rounded to the nearest whole number.


[[Page 20427]]


                 Table 4--Estimated Annual Recordkeeping Burden for Academia and Small Firms \1\
----------------------------------------------------------------------------------------------------------------
                                                                                      Average
Information collection activity;     Number of       Number of     Total annual     burden per      Total hours
         21 CFR section            recordkeepers    records per       records      recordkeeper         \2\
                                                   recordkeeper                     (in hours)
----------------------------------------------------------------------------------------------------------------
                                 Subparts C and F; Sec.  Sec.   212.20 to 212.50
----------------------------------------------------------------------------------------------------------------
Batch Production Records                      49              96           4,704             0.5           2,352
 (filling batch-related records
 per year) (Sec.  Sec.
 212.20(c) and (e) and 212.50(a)
 and (b)).......................
Creating Any New Batch Records                49               3             147               8           1,176
 and Procedures for New Drugs
 (Sec.  Sec.   212.20(c) and (e)
 and 212.50(a) and (b)).........
----------------------------------------------------------------------------------------------------------------
                               Subparts D, F, and G; Sec.  Sec.   212.30 to 212.60
----------------------------------------------------------------------------------------------------------------
Equipment and Facilities Records              49             480          23,520             0.5          11,760
 (calibration and cleaning
 records) (Sec.  Sec.
 212.30(b), 212.50(d), and
 212.60(f)).....................
----------------------------------------------------------------------------------------------------------------
                                 Subparts C and E; Sec.  Sec.   212.20 to 212.40
----------------------------------------------------------------------------------------------------------------
Records of Components,                        49              12             588             0.5             294
 Containers, and Closures
 (incoming acceptance tests)
 (Sec.  Sec.   212.20(b) and (c)
 and 212.40(a) and (b)).........
----------------------------------------------------------------------------------------------------------------
                                 Subparts G and H; Sec.  Sec.   212.60 to 212.70
----------------------------------------------------------------------------------------------------------------
Laboratory Testing Records (QC                49              96           4,704             0.5           2,352
 test results) Sec.  Sec.
 212.60(g), 212.61(b), and
 212.70(d)(2) and (d)(3)........
----------------------------------------------------------------------------------------------------------------
                                            Subpart H; Sec.   212.71
----------------------------------------------------------------------------------------------------------------
Out-of-Specification                          49               2              98               2             196
 Investigations (record events
 and investigations) (Sec.
 212.71(b)).....................
----------------------------------------------------------------------------------------------------------------
                                Subparts H and K; Sec.  Sec.   212.70 to 212.100
----------------------------------------------------------------------------------------------------------------
Complaints (Record events and                 49               2              98               2             196
 investigations) (Sec.
 212.100(b) and (c))............
QA and Release of Batches (Sec.               49              96           4,704            0.25           1,176
  212.70).......................
----------------------------------------------------------------------------------------------------------------
                                            Subpart J; Sec.   212.90
----------------------------------------------------------------------------------------------------------------
Distribution Records (Sec.                    49              96           4,704            0.25           1,176
 212.90(b)).....................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............          43,267  ..............          20,678
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ Totals have been rounded to the nearest whole number.


            Table 5--Estimated Annual Recordkeeping Burden for High-Risk Component Manufacturers \1\
----------------------------------------------------------------------------------------------------------------
                                                                                      Average
Information collection activity;     Number of       Number of     Total annual     burden per      Total hours
         21 CFR section            recordkeepers    records per       records      recordkeeper         \2\
                                                   recordkeeper                     (in hours)
----------------------------------------------------------------------------------------------------------------
                                 Subparts C and F; Sec.  Sec.   212.20 to 212.50
----------------------------------------------------------------------------------------------------------------
Batch Production (creating                    14              24             336             0.5             168
 manufacturing records and batch-
 related records per year) (Sec.
  Sec.   212.20(c) and (e) and
 212.50(a) and (b)).............
----------------------------------------------------------------------------------------------------------------
                         Subparts D, F, and G; Sec.  Sec.   212.30 to 212.60 and 212.90
----------------------------------------------------------------------------------------------------------------
Equipment and Facilities Records              14             130           1,820             0.5             910
 (calibration and cleaning
 records systems) (Sec.  Sec.
 212.30(b), 212.50(d), and
 212.60(f)).....................
----------------------------------------------------------------------------------------------------------------
                                 Subparts C and E; Sec.  Sec.   212.20 to 212.40
----------------------------------------------------------------------------------------------------------------
Records of Components,                        14              24             336             0.5             168
 Containers, and Closures
 (incoming acceptance test)
 (Sec.  Sec.   212.20(c) and
 212.40(a) and (b)).............
----------------------------------------------------------------------------------------------------------------

[[Page 20428]]

 
                                 Subparts G and H; Sec.  Sec.   212.60 to 212.70
----------------------------------------------------------------------------------------------------------------
Laboratory Testing Records                    14              24             336             0.5             168
 (record QC test results) Sec.
 Sec.   212.60(g), 212.61(b),
 and 212.70(d)(2) and (d)(3)....
----------------------------------------------------------------------------------------------------------------
                                            Subpart H; Sec.   212.71
----------------------------------------------------------------------------------------------------------------
OOS Investigations (record                    14               1              14               1              14
 events and investigations)
 (Sec.   212.71(b)).............
QA and Release of Batches (Sec.               14              24             336            0.25              84
  212.70).......................
----------------------------------------------------------------------------------------------------------------
                                    Subpart J; Sec.  Sec.   212.90 to 212.50
----------------------------------------------------------------------------------------------------------------
Distribution Records (Sec.                    14              24             336            0.25              84
 212.90(b)).....................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............           3,514  ..............           1,596
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ Totals have been rounded to the nearest whole number.


    Table 6--Estimated One-Time and Annual Recordkeeping Burden for External Control Testing Laboratories \1\
----------------------------------------------------------------------------------------------------------------
                                                                                      Average
Information collection activity;     Number of       Number of     Total annual     burden per      Total hours
         21 CFR citation           recordkeepers    records per       records      recordkeeper         \2\
                                                   recordkeeper                     (in hours)
----------------------------------------------------------------------------------------------------------------
One-Time Recordkeeping Assay                  23               6             138               9           1,242
 Validation (creating SOP and
 performing validation).........
----------------------------------------------------------------------------------------------------------------
                          Subparts C, E, and F; Sec.  Sec.   212.20, 212.40, and 212.50
----------------------------------------------------------------------------------------------------------------
Annual Recordkeeping Incoming                 23              24             552             0.5             276
 Acceptance Tests Records (Sec.
 Sec.   212.20(c), 212.40(a) and
 (b))...........................
Annual Recordkeeping Batch                    23               8             184             0.5              92
 Testing (creating testing
 records for sterility, periodic
 quality indicator test, or any
 test) (Sec.  Sec.   212.20(c)
 and (e) and 212.50(a) and (b)).
----------------------------------------------------------------------------------------------------------------
                          Subparts D, F, and G; Sec.  Sec.   212.30, 212.50, and 212.60
----------------------------------------------------------------------------------------------------------------
Annual Recordkeeping Equipment                23              98           2,254            0.25             564
 and Facilities Records
 (calibration, cleaning, and
 maintenance records) (Sec.
 Sec.   212.30(b), 212.50(d),
 and 212.60(f)).................
----------------------------------------------------------------------------------------------------------------
                                            Subpart H; Sec.   212.71
----------------------------------------------------------------------------------------------------------------
Annual OOS Investigations                     23               1              23               1              23
 (recording events and
 investigations) (Sec.
 212.71(b)).....................
Annual QA and Release of Test                 23               8             184            0.25              46
 Results........................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............           3,335  ..............           2,243
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ Totals have been rounded to the nearest whole number.


                                   Table 7--Estimated Annual Third-Party Disclosure Burden for PET Drug Producers \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        Number of
                                                                        sterility        Number of       Total annual   Average  burden
          Information collection activity; 21 CFR section                failure        disclosures      disclosures    per  disclosure  Total hours \2\
                                                                        incidents      per respondent                      (in hours)
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                Subpart H; Sec.   212.70
--------------------------------------------------------------------------------------------------------------------------------------------------------
Sterility Test Failure Notices \3\ (Sec.   212.70(e))..............               7                3               21              2.5               53
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\ Totals have been rounded to the nearest whole number.
\3\ Two reports are sent to FDA per incident, and 1 notification is sent to the receiving site.


[[Page 20429]]

    Our estimated burden for the information collection reflects an 
overall increase of 25,425 hours and a corresponding increase of 84,703 
records. We attribute this increase to the inclusion of external 
control testing laboratories that perform only specialized chemical, 
microbiological, or sterility testing functions to support 
manufacturing and release of final PET drug products.

    Dated: March 30, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-07392 Filed 4-6-22; 8:45 am]
BILLING CODE 4164-01-P