Notice2022-07392
Agency Information Collection Activities; Proposed Collection; Comment Request; Current Good Manufacturing Practices for Positron Emission Tomography Drugs
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Published
April 7, 2022
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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.
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<title>Federal Register, Volume 87 Issue 67 (Thursday, April 7, 2022)</title>
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[Federal Register Volume 87, Number 67 (Thursday, April 7, 2022)]
[Notices]
[Pages 20420-20429]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management
Staff between 9 a.m. and 4 p.m. Eastern Time, Monday through Friday,
240-402-7500.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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,
<a href="/cdn-cgi/l/email-protection#0b5b594a587f6a6d6d4b6d6f6a25636378256c647d"><span class="__cf_email__" data-cfemail="134341524067727575537577723d7b7b603d747c65">[email protected]</span></a>.
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:
<bullet> Informal communications with PET producers.
<bullet> FDA staff visits to PET production facilities.
<bullet> Our experience with PET drug applications, including
amendment and supplement submissions.
<bullet> Our general knowledge of pharmaceutical manufacturing
practices.
<bullet> 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
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