Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Human Drug Compounding, Repackaging, and Related Activities Regarding Sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act, 47113-47117 [2021-17996]
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Federal Register / Vol. 86, No. 160 / Monday, August 23, 2021 / Notices
on May 20, 2021 (86 FR 27447). This
notice announces draft product-specific
guidances, either new or revised, that
are posted on FDA’s website.
II. Drug Products for Which New Draft
Product-Specific Guidances Are
Available
FDA is announcing the availability of
new draft product-specific guidances for
industry for drug products containing
the following active ingredients:
TABLE 2—REVISED DRAFT PRODUCT- DEPARTMENT OF HEALTH AND
SPECIFIC GUIDANCES FOR DRUG HUMAN SERVICES
PRODUCTS—Continued
Food and Drug Administration
Active ingredient(s)
[Docket No. FDA–2021–N–0359]
Sodium zirconium cyclosilicate
Tazarotene
For a complete history of previously
published Federal Register notices
related to product-specific guidances, go
TABLE 1—NEW DRAFT PRODUCT-SPE- to https://www.regulations.gov and
enter Docket No. FDA–2007–D–0369.
CIFIC GUIDANCES FOR DRUG PRODThese draft guidances are being
UCTS
issued consistent with FDA’s good
guidance practices regulation (21 CFR
Active ingredient(s)
10.115). These draft guidances, when
Acyclovir
finalized, will represent the current
Albuterol sulfate; Ipratropium bromide
thinking of FDA on, among other things,
Amisulpride
the product-specific design of BE
Avapritinib
studies to support ANDAs. They do not
Carbinoxamine maleate
Cefiderocol sulfate tosylate
establish any rights for any person and
Copper dotatate Cu-64
are not binding on FDA or the public.
Esomeprazole magnesium
You can use an alternative approach if
Estradiol
it satisfies the requirements of the
Ethinyl estradiol; Levonorgestrel
applicable statutes and regulations.
Fostemsavir tromethamine
Indomethacin
Ipratropium bromide
Lasmiditan succinate
Leuprolide acetate
Loteprednol etabonate
Olodaterol hydrochloride
Osilodrostat phosphate
Ozanimod hydrochloride
Paliperidone palmitate
Semaglutide
Sufentanil citrate
Tazemetostat hydrobromide
IV. Paperwork Reduction Act of 1995
FDA tentatively concludes that these
draft guidances contain no collection of
information. Therefore, clearance by the
Office of Management and Budget under
the Paperwork Reduction Act of 1995 is
not required.
V. Electronic Access
III. Drug Products for Which Revised
Draft Product-Specific Guidances Are
Available
FDA is announcing the availability of
revised draft product-specific guidances
for industry for drug products
containing the following active
ingredients:
TABLE 2—REVISED DRAFT PRODUCTSPECIFIC GUIDANCES FOR DRUG
PRODUCTS
jbell on DSKJLSW7X2PROD with NOTICES
Persons with access to the internet
may obtain the draft guidances at either
https://www.fda.gov/drugs/guidancecompliance-regulatory-information/
guidances-drugs, https://www.fda.gov/
regulatory-information/search-fdaguidance-documents, or https://
www.regulations.gov.
Dated: August 18, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for
Policy.
[FR Doc. 2021–18072 Filed 8–20–21; 8:45 am]
BILLING CODE 4164–01–P
Active ingredient(s)
Bexarotene
Budesonide
Eltrombopaq olamine (multiple referenced
listed drugs)
Ferric citrate
Letrozole
Leuprolide acetate (multiple referenced listed
drugs)
Liothyronine sodium
Loteprednol etabonate
Nystatin
Orlistat
Paclitaxel
Podofilox
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18:11 Aug 20, 2021
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47113
PO 00000
Agency Information Collection
Activities; Submission for Office of
Management and Budget Review;
Comment Request; Human Drug
Compounding, Repackaging, and
Related Activities Regarding Sections
503A and 503B of the Federal Food,
Drug, and Cosmetic Act
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice.
The Food and Drug
Administration (FDA) is announcing
that a proposed collection of
information has been submitted to the
Office of Management and Budget
(OMB) for review and clearance under
the Paperwork Reduction Act of 1995.
DATES: Submit written comments
(including recommendations) on the
collection of information by September
22, 2021.
ADDRESSES: To ensure that comments on
the information collection are received,
OMB recommends that written
comments be submitted to https://
www.reginfo.gov/public/do/PRAMain.
Find this particular information
collection by selecting ‘‘Currently under
Review—Open for Public Comments’’ or
by using the search function. The OMB
control number for this information
collection is 0910–0858. Also include
the FDA docket number found in
brackets in the heading of this
document.
SUMMARY:
FOR FURTHER INFORMATION CONTACT:
Domini Bean, Office of Operations,
Food and Drug Administration, Three
White Flint North, 10A–12M, 11601
Landsdown St., North Bethesda, MD
20852, 301–796–5733, PRAStaff@
fda.hhs.gov.
In
compliance with 44 U.S.C. 3507, FDA
has submitted the following proposed
collection of information to OMB for
review and clearance.
SUPPLEMENTARY INFORMATION:
Human Drug Compounding,
Repackaging, and Related Activities
Regarding Sections 503A and 503B of
the Federal Food, Drug, and Cosmetic
Act
OMB Control Number 0910–0858—
Revision
This information collection supports
implementation of sections 503A and
503B of the Federal Food, Drug, and
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Federal Register / Vol. 86, No. 160 / Monday, August 23, 2021 / Notices
Cosmetic Act (FD&C Act) (21 U.S.C.
353a and 21 U.S.C. 353b), which govern
compounding by pharmacies,
outsourcing facilities, and other entities.
Compounding is generally a practice in
which a licensed pharmacist, a licensed
physician, or, in the case of an
outsourcing facility, a person under the
supervision of a licensed pharmacist,
combines, mixes, or alters ingredients of
a drug to create a medication tailored to
the needs of an individual patient.
Although compounded drugs can serve
an important medical need for certain
patients, they also present risks to
patients. Our compounding program
aims to protect patients from unsafe,
ineffective, and poor quality
compounded drugs, while preserving
access to lawfully-marketed
compounded drugs for patients who
have a medical need for them.
Respondents to the information
collection are pharmacies, outsourcing
facilities, and other entities.
To assist respondents in complying
with statutory requirements, we have
issued the following topic-specific
guidance documents:
TABLE 1—PUBLISHED GUIDANCE DOCUMENTS REGARDING SECTIONS 503A AND 503B OF THE FD&C ACT
Title
Notice of availability
publication date
Compounding and Repackaging of Radiopharmaceuticals by State-Licensed Nuclear Pharmacies, Federal Facilities, and Certain Other Entities (‘‘Radiopharmaceutical Compounding and Repackaging Guidance’’).
Compounding and Repackaging of Radiopharmaceuticals by Outsourcing Facilities (‘‘Radiopharmaceutical Outsourcing Repackaging Guidance’’).
Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities (‘‘Repackaging Guidance’’).
Mixing, Diluting, or Repackaging Biological Products Outside the Scope of an Approved Biologics License Application (‘‘Biologics Guidance’’).
September 26, 2018 (83 FR
48633).
September 26, 2018 (83 FR
48630).
January 13, 2017 (82 FR
4343).
January 19, 2018 (83 FR
2787).
These guidance documents were
issued consistent with our Good
Guidance Practice regulations in 21 CFR
part 10.115 which provide for public
comment at any time. The guidance
documents communicate our current
thinking on the respective topics and
include information collection that may
result in expenditures of time and effort
by respondents. In our notices of
availability we also solicited public
comment under the PRA on the
information collection provisions. FDA
has developed and maintains a
searchable guidance database available
at: https://www.fda.gov/regulatoryinformation/search-fda-guidancedocuments. Guidance documents
covered by this information collection
may be found by choosing ‘‘Center for
Drug Evaluation and Research’’ from
among the FDA Organizations, and by
selecting the term ‘‘Compounding’’ from
among the possible ‘‘Topic’’ filters.1 For
efficiency of operations we are
consolidating the related information
collections.
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Compounding and Repackaging of
Radiopharmaceuticals by StateLicensed Nuclear Pharmacies, Federal
Facilities, and Certain Other Entities
Because Congress explicitly excluded
radiopharmaceuticals from section 503A
of the FD&C Act (see section
503A(d)(2)), compounded
radiopharmaceuticals are not eligible for
1 Guidance documents applicable to animal drug
compounding regulated by our Center for
Veterinary Medicine would also be returned if no
FDA Organization is selected; this information
collection covers only those Compounding
documents issued by the Center for Drug Evaluation
and Research.
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the exemptions under section 503A
from section 505 of the FD&C Act (21
U.S.C. 355) (concerning new drug
approval requirements), section
502(f)(1) of the FD&C Act (21 U.S.C.
352(f)(1)) (concerning labeling with
adequate directions for use), and section
501(a)(2)(B) of the FD&C Act (21 U.S.C.
351(a)(2)B)) (concerning current good
manufacturing practice (CGMP)
requirements). In addition, the FD&C
Act does not provide an exemption for
repackaged radiopharmaceuticals. This
guidance document describes the
conditions under which FDA does not
intend to take action for violations of
sections 505, 502(f)(1), and 501(a)(2)(B)
of the FD&C Act when a state-licensed
nuclear pharmacy, Federal facility, or
other facility that is not an outsourcing
facility and that holds a radioactive
materials license for medical use issued
by the Nuclear Regulatory Commission
or by an Agreement State compounds or
repackages radiopharmaceuticals for
human use. The guidance explains that
one condition is that the compounded
radiopharmaceutical is not essentially a
copy of an approved
radiopharmaceutical. As described in
the guidance, FDA does not intend to
consider a compounded
radiopharmaceutical to be essentially a
copy if, among other reasons, there is a
change between the compounded
radiopharmaceutical and the approved
radiopharmaceutical that produces a
clinical difference for an identified
individual patient, as determined by the
prescribing practitioner and
documented in writing on the
prescription or order. In addition, FDA
does not intend to consider a
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compounded radiopharmaceutical to be
essentially a copy if the FDA-approved
radiopharmaceutical is on FDA’s drug
shortage list (see section 506E of the
FD&C Act (21 U.S.C. 356e)) at the time
of compounding and distribution. If the
facility compounded a drug that is
identical or nearly identical to an
approved drug product that appeared on
FDA’s drug shortage list, the facility
should maintain documentation (e.g., a
notation on the order for the
compounded drug) regarding the status
of the drug on FDA’s drug shortage list
at the time of compounding,
distribution, and dispensing.
Radiopharmaceutical Outsourcing
Repackaging Guidance
In contrast to section 503A, section
503B of the FD&C Act does not exclude
radiopharmaceuticals. Therefore, FDA’s
overall policies regarding section 503B
apply to the compounding of
radiopharmaceutical drug products.
However, we have developed specific
policies that apply only to the
compounding of radiopharmaceuticals
by outsourcing facilities using bulk drug
substances and to the compounding of
radiopharmaceuticals by outsourcing
facilities that are essentially copies of
approved drugs when such
compounding is limited to minor
deviations, as that term is defined in the
guidance. FDA issued this guidance in
part to describe the conditions under
which the Agency does not generally
intend to take action for violations of
sections 505 and 502(f)(1) of the FD&C
Act when an outsourcing facility
repackages radiopharmaceuticals for
human use.
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Federal Register / Vol. 86, No. 160 / Monday, August 23, 2021 / Notices
As discussed in the guidance, one
condition is that if a
radiopharmaceutical is repackaged by
an outsourcing facility, the label on the
immediate container (primary
packaging, e.g., the syringe) of the
repackaged product includes certain
information. The guidance also provides
that the label on the container from
which the individual units are removed
for administration (secondary
packaging, e.g., the bag, box, or other
package in which the repackaged
products are distributed) includes: (1)
The active and inactive ingredients, if
the immediate product label is too small
to include this information, and
directions for use, including (as
appropriate) dosage and administration
and (2) the following information to
facilitate adverse event reporting: and
1–800–FDA–1088.
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Repackaging Guidance
This guidance describes the
conditions under which FDA does not
intend to take action for violations of
sections 505 (concerning new drug
applications), 502(f)(1) (concerning
labeling with adequate directions for
use), 582 ((21 U.S.C. 360eee–1)
concerning drug supply chain security
requirements), and (where specified in
the guidance) section 501(a)(2)(B) of the
FD&C Act (concerning CGMPs), when a
state-licensed pharmacy, Federal
facility, or outsourcing facility
repackages certain prescription drug
products. One condition discussed in
the guidance is that if a drug is
repackaged by an outsourcing facility,
the label on the immediate container
(primary packaging, e.g., the syringe) of
the repackaged product includes certain
information described in the guidance.
Another condition discussed in the
guidance is that the label on the
container from which the individual
units are removed for administration
(secondary packaging, e.g., the bag, box,
or other package in which the
repackaged products are distributed)
includes: (1) The active and inactive
ingredients, if the immediate product
label is too small to include this
information, and directions for use,
including (as appropriate) dosage and
administration, (2) directions for use,
including, as appropriate, dosage and
administration, and (3) the following
information to facilitate adverse event
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reporting: https://www.fda.gov/
medwatch and 1–800–FDA–1088.
Biologics Guidance
Certain licensed biological products
may sometimes be mixed, diluted, or
repackaged in a way not described in
the approved labeling for the product to
meet the needs of a specific patient. As
described in the guidance, biological
products subject to licensure under
section 351 of the Public Health Service
(PHS) Act (42 U.S.C. 262) are not
eligible for the statutory exemptions
available to certain compounded drugs
under sections 503A and 503B of the
FD&C Act. In addition, a biological
product that is mixed, diluted, or
repackaged outside the scope of an
approved Biologics License Application
(BLA) is considered an unlicensed
biological product under section 351 of
the PHS Act.
This guidance document describes
several conditions under which FDA
does not intend to take action for
violations of section 351 of the PHS Act
and sections 502(f)(1), 582, and (where
specified) 501(a)(2)(B) of the FD&C Act,
when a State-licensed pharmacy, a
Federal facility, or an outsourcing
facility dilutes, mixes, or repackages
certain biological products outside the
scope of an approved BLA.
One condition discussed in the
guidance is that if the labeling for the
licensed biological product includes
storage instructions, handling
instructions, or both (for example,
protect from light, do not freeze, keep at
specified storage temperature), the
labeling for the biological product that
is mixed, diluted, or repackaged
specifies the same storage conditions.
Another condition described in the
guidance is that, if the biological
product is mixed, diluted, or repackaged
by an outsourcing facility, the label on
the immediate container (primary
packaging, for example, the syringe) of
the mixed, diluted, or repackaged
product includes certain information
described in the guidance. In addition,
the guidance communicates that as a
condition for biological products mixed,
diluted, or repackaged by an
outsourcing facility that, if the
immediate product label is too small to
bear the active and inactive ingredients,
such information is included on the
label of the container from which the
individual units are removed for
administration (secondary packaging,
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47115
for example, the bag, box, or other
package in which the mixed, diluted, or
repackaged biological products are
distributed).
The guidance also communicates our
thinking about the condition for
biological products mixed, diluted, or
repackaged by an outsourcing facility
that the label on the container from
which the individual units are removed
for administration include directions for
use. These directions include, as
appropriate, the dosage and
administration and the following
information to facilitate adverse event
reporting: https://www.fda.gov/
medwatch and 1–800–FDA–1088.
Finally, another condition described
in the guidance is that outsourcing
facilities maintain records of the testing
performed in accordance with
‘‘Appendix A—Assigning a BUD for
Repackaged Biological Products Based
On Stability Testing’’ of the guidance for
biological products repackaged by
outsourcing facilities for which the
beyond use date (BUD) is established
based on a stability program conducted
in accordance with Appendix A.
Section III.C of the guidance,
‘‘Licensed Allergenic Extracts for
Subcutaneous Immunotherapy,’’
discusses the preparation of
prescription sets (that is, licensed
allergenic extracts that are mixed and
diluted to provide subcutaneous
immunotherapy to an individual
patient) by a physician, a State-licensed
pharmacy, a Federal facility, or an
outsourcing facility. Another condition
described in the guidance is that if the
prescription set is prepared by an
outsourcing facility, the label of the
container from which the individual
units of the prescription set are removed
for administration (secondary
packaging) includes the following
information to facilitate adverse event
reporting: https://www.fda.gov/
medwatch and 1–800–FDA–1088. Each
prescription set prepared by an
outsourcing facility is also accompanied
by instructions for use.
In the Federal Register of April 29,
2021 (86 FR 22674), we published a 60day notice requesting public comment
on the proposed collection of
information. No comments were
received.
We estimate the burden of the
information collection as follows:
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Federal Register / Vol. 86, No. 160 / Monday, August 23, 2021 / Notices
TABLE 2—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1
Number of
disclosures
per
respondent
Number of
respondents
Activity
Total annual
disclosures
Average
burden per
disclosure
Total hours
Radiopharmaceutical Guidance
Consultation between the compounder and prescriber and
the notation on the prescription or order documenting
the prescriber’s determination of clinical difference.
10
25
250
.05 (3 minutes).
12.5
5
10
0.5 (30 minutes).
6
21
126
1 ....................
126
3
4
12
3 ....................
24
Radiopharmaceutical Outsourcing And Repackaging Guidance
Designing, testing, and producing each label on immediate
containers, packages and/or outer containers.
2
5
Repackaging Guidance
Designing, testing, and producing each label on immediate
containers, packages, and/or outer containers.
Biannual product reports identifying drug products repackaged by the outsourcing facility during the previous 6month period (Guidance Section III.A.).
Biologics Guidance
Designing, testing, and producing the label, container,
packages, and/or outer containers for each mixed, diluted, or repackaged biological product.
Designing, testing, and producing each label on immediate
containers, packages and/or outer containers for each licensed allergenic extract.
Maintaining records of testing performed in accordance
with Biologics Guidance Appendix A.
15
5
75
0.5 (30 minutes).
37.5
5
300
1,500
0.5 (30 minutes).
750
5
30
150
0.083 (5 minutes).
12.5
Total ...............................................................................
........................
........................
2,123
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1 There
.......................
967.5
are no capital costs or operating and maintenance costs associated with this collection of information.
As defined in 44 U.S.C. 3502(13), the
term ‘‘recordkeeping requirement’’
means a requirement imposed on
respondents to maintain specified
records, as well as a requirement to
‘‘retain such records; notify third
parties, the Federal Government, or the
public of the existence of such records;
disclose such records to third parties,
the Federal Government, or the public;
or report to third parties, the Federal
Government, or the public regarding
such records.’’ For purposes of our
analysis, therefore, we have
characterized the burden associated
with the time and effort expended on
the information collection
recommendations discussed in the
respective guidance documents as
recordkeeping activities. At the same
time, our findings show that compliance
with recordkeeping requirements
applicable to compounded and
repackaged drug products is standard
practice in the compounding and selling
of these drug products under States’
pharmacy laws and other State laws
governing recordkeeping by healthcare
professionals and healthcare facilities.
We have therefore excluded from our
estimate recordkeeping practices
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discussed in the respective guidance
documents we consider usual and
customary. We invite comment on this
assumption.
Radiopharmaceutical Compounding
and Repackaging Guidance
We estimate 10 compounders
annually will consult a prescriber to
determine whether a compounded
radiopharmaceutical has a change that
produces a clinical difference for an
identified individual patient as
compared to the comparable approved
radiopharmaceutical. We estimate that
those compounders will document this
determination on 250 prescriptions or
orders for compounded
radiopharmaceuticals. We assume
consultation between the compounder
and the prescriber and noting this
determination on each prescription or
order that does not already document
this determination will take 3 minutes
(0.05 hours) per prescription or order,
for a total of approximately 12.5 hours.
Radiopharmaceutical Outsourcing and
Repackaging Guidance
We estimate a total of 2 outsourcing
facilities annually will each design, test,
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and produce an average of 5 different
labels for a total of 10 labels, as
described in the guidance (including
directions for use). We assume that
designing, testing, and producing each
label will take 30 minutes (0.5 hours) for
each repackaged radiopharmaceutical,
for a total of 5 hours. We consider that
the provision to include ‘‘https://
www.fda.gov/medwatch’’ and ‘‘1–800–
FDA–1088’’ is not a collection of
information as defined in 5 CFR
1320.3(c)(2) and is therefore exempt
from OMB review and approval under
the PRA.
Repackaging Guidance
Based on current data for outsourcing
facilities, we estimate 6 outsourcing
facilities annually will submit an initial
report identifying all drugs repackaged
in the facility in the previous year. For
the purposes of this estimate, each
product’s structured product labeling
(SPL) submission is considered a
separate response and therefore each
facility’s product report will include
multiple responses. Taking into account
that a particular product that is
repackaged may come in different
strengths and can be reported in a single
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SPL response, we estimate that each
facility will average approximately 6
products.
Similarly, we estimate that 6
outsourcing facilities will submit an
initial report identifying all drugs
repackaged in the facility in the past
year. Taking into account that a
particular product that is repackaged
may come in different strengths and can
be reported in a single SPL response, we
assume that each facility will average 6
products. Our estimate is based on
current product reporting data. We
expect that each product report will
consist of multiple SPL responses per
facility and assume preparing and
electronically submitting this
information will take up to 2 hours for
each initial SPL response.
We also estimate 3 registered
outsourcing facilities will submit a
report twice each year (June and
December) that identifies all drugs
repackaged at the facility in the
previous 6 months. We also estimate
that an average of 3 facilities will
prepare and submit 3 SPL responses and
assume that preparing and submitting
this information electronically could
also take up to 2 hours per response. If
a product was not repackaged during a
particular reporting period, outsourcing
facilities do not need to send an SPL
response for that product during that
reporting period. Our figures reflect
what we believe to be the average
burden among respondents. We expect
to receive no waiver requests from the
electronic submission process for initial
product reports and semiannual reports.
Biologics Guidance
We estimate 15 outsourcing facilities
annually who mix, dilute, or repackage
biological products will each design,
test, and produce 5 different labels, for
a total of 75 labels that include the
information set forth in section III.B—
‘‘Mixing, Diluting, or Repackaging
Licensed Biological Products’’ of the
guidance (including directions for use)
as well as inclusion of storage
instructions, handling instructions, or
both. We assume that designing, testing,
and producing each label will take 30
minutes (0.5 hours). We consider that
the provision to include ‘‘https://
www.fda.gov/medwatch’’ and ‘‘1–800–
FDA–1088’’ is not a collection of
information as defined in 5 CFR
1320.3(c)(2) and is therefore exempt
from OMB review and approval under
the PRA.
We estimate that annually a total of 5
outsourcing facilities that prepare
prescription sets will each include on
the labels, packages, and/or containers
of approximately 300 prescription sets
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the information set forth in section III.C
‘‘Licensed Allergenic Extracts for
Subcutaneous Immunotherapy’’ of the
draft guidance (including directions for
use), for a total of 1,500 disclosures. We
assume the initial process of designing,
testing, and producing labeling and
attaching to each prescription set each
label, package, and/or container will
take approximately 30 minutes (0.5
hours), for a total of approximately 750
hours.
Finally, we estimate that annually five
outsourcing facilities who repackage
biological products and establish a BUD
in accordance with Appendix A—
‘‘Assigning a BUD for Repackaged
Biological Products Based On Stability
Testing’’ will maintain 150 records of
the testing, as described in Appendix A
of the guidance. We assume maintaining
the records will take 5 minutes per
record, for a total of 12.5 hours.
Our estimated burden for the
information collection reflects program
changes and adjustments. We are
changing the scope of the information
collection to include burden attendant
to provisions found in the Agency
guidance documents discussed in this
notice and have adjusted our estimate to
reflect a resulting increase of 955 hours
and 1,873 responses annually.
Dated: August 5, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for
Policy.
[FR Doc. 2021–17996 Filed 8–20–21; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2013–D–1464]
Bioequivalence Studies With
Pharmacokinetic Endpoints for Drugs
Submitted Under an Abbreviated New
Drug Application; Draft Guidance for
Industry; Availability
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice of availability.
The Food and Drug
Administration (FDA or Agency) is
announcing the availability of a revised
draft guidance for industry entitled
‘‘Bioequivalence Studies With
Pharmacokinetic Endpoints for Drugs
Submitted Under an ANDA.’’ This
revised draft supersedes the draft
guidance entitled ‘‘Bioequivalence
Studies With Pharmacokinetic
Endpoints for Drug Products Submitted
Under an ANDA,’’ which was
SUMMARY:
PO 00000
Frm 00068
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47117
announced in the Federal Register on
December 5, 2013. This revised draft
guidance provides recommendations to
applicants planning to include
bioequivalence (BE) information in
abbreviated new drug applications
(ANDAs) and ANDA supplements. In
addition, this guidance describes how to
meet the BE requirements set forth in
the Federal Food, Drug, and Cosmetic
Act (FD&C Act) and FDA regulations.
DATES: Submit either electronic or
written comments on the draft guidance
by October 22, 2021 to ensure that the
Agency considers your comment on this
draft guidance before it begins work on
the final version of the guidance.
ADDRESSES: You may submit comments
on any guidance at any time as follows:
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
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 the Docket No. FDA–
E:\FR\FM\23AUN1.SGM
23AUN1
]]>Agencies
[Federal Register Volume 86, Number 160 (Monday, August 23, 2021)]
[Notices]
[Pages 47113-47117]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-17996]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2021-N-0359]
Agency Information Collection Activities; Submission for Office
of Management and Budget Review; Comment Request; Human Drug
Compounding, Repackaging, and Related Activities Regarding Sections
503A and 503B of the Federal Food, Drug, and Cosmetic Act
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is announcing that a
proposed collection of information has been submitted to the Office of
Management and Budget (OMB) for review and clearance under the
Paperwork Reduction Act of 1995.
DATES: Submit written comments (including recommendations) on the
collection of information by September 22, 2021.
ADDRESSES: To ensure that comments on the information collection are
received, OMB recommends that written comments be submitted to https://www.reginfo.gov/public/do/PRAMain. Find this particular information
collection by selecting ``Currently under Review--Open for Public
Comments'' or by using the search function. The OMB control number for
this information collection is 0910-0858. Also include the FDA docket
number found in brackets in the heading of this document.
FOR FURTHER INFORMATION CONTACT: Domini Bean, Office of Operations,
Food and Drug Administration, Three White Flint North, 10A-12M, 11601
Landsdown St., North Bethesda, MD 20852, 301-796-5733,
[email protected].
SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has
submitted the following proposed collection of information to OMB for
review and clearance.
Human Drug Compounding, Repackaging, and Related Activities Regarding
Sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act
OMB Control Number 0910-0858--Revision
This information collection supports implementation of sections
503A and 503B of the Federal Food, Drug, and
[[Page 47114]]
Cosmetic Act (FD&C Act) (21 U.S.C. 353a and 21 U.S.C. 353b), which
govern compounding by pharmacies, outsourcing facilities, and other
entities. Compounding is generally a practice in which a licensed
pharmacist, a licensed physician, or, in the case of an outsourcing
facility, a person under the supervision of a licensed pharmacist,
combines, mixes, or alters ingredients of a drug to create a medication
tailored to the needs of an individual patient. Although compounded
drugs can serve an important medical need for certain patients, they
also present risks to patients. Our compounding program aims to protect
patients from unsafe, ineffective, and poor quality compounded drugs,
while preserving access to lawfully-marketed compounded drugs for
patients who have a medical need for them. Respondents to the
information collection are pharmacies, outsourcing facilities, and
other entities.
To assist respondents in complying with statutory requirements, we
have issued the following topic-specific guidance documents:
Table 1--Published Guidance Documents Regarding Sections 503A and 503B
of the FD&C Act
------------------------------------------------------------------------
Notice of availability
Title publication date
------------------------------------------------------------------------
Compounding and Repackaging of September 26, 2018 (83
Radiopharmaceuticals by State-Licensed Nuclear FR 48633).
Pharmacies, Federal Facilities, and Certain
Other Entities (``Radiopharmaceutical
Compounding and Repackaging Guidance'').
Compounding and Repackaging of September 26, 2018 (83
Radiopharmaceuticals by Outsourcing Facilities FR 48630).
(``Radiopharmaceutical Outsourcing Repackaging
Guidance'').
Repackaging of Certain Human Drug Products by January 13, 2017 (82
Pharmacies and Outsourcing Facilities FR 4343).
(``Repackaging Guidance'').
Mixing, Diluting, or Repackaging Biological January 19, 2018 (83
Products Outside the Scope of an Approved FR 2787).
Biologics License Application (``Biologics
Guidance'').
------------------------------------------------------------------------
These guidance documents were issued consistent with our Good
Guidance Practice regulations in 21 CFR part 10.115 which provide for
public comment at any time. The guidance documents communicate our
current thinking on the respective topics and include information
collection that may result in expenditures of time and effort by
respondents. In our notices of availability we also solicited public
comment under the PRA on the information collection provisions. FDA has
developed and maintains a searchable guidance database available at:
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. Guidance documents covered by this information collection
may be found by choosing ``Center for Drug Evaluation and Research''
from among the FDA Organizations, and by selecting the term
``Compounding'' from among the possible ``Topic'' filters.\1\ For
efficiency of operations we are consolidating the related information
collections.
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\1\ Guidance documents applicable to animal drug compounding
regulated by our Center for Veterinary Medicine would also be
returned if no FDA Organization is selected; this information
collection covers only those Compounding documents issued by the
Center for Drug Evaluation and Research.
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Compounding and Repackaging of Radiopharmaceuticals by State-Licensed
Nuclear Pharmacies, Federal Facilities, and Certain Other Entities
Because Congress explicitly excluded radiopharmaceuticals from
section 503A of the FD&C Act (see section 503A(d)(2)), compounded
radiopharmaceuticals are not eligible for the exemptions under section
503A from section 505 of the FD&C Act (21 U.S.C. 355) (concerning new
drug approval requirements), section 502(f)(1) of the FD&C Act (21
U.S.C. 352(f)(1)) (concerning labeling with adequate directions for
use), and section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 351(a)(2)B))
(concerning current good manufacturing practice (CGMP) requirements).
In addition, the FD&C Act does not provide an exemption for repackaged
radiopharmaceuticals. This guidance document describes the conditions
under which FDA does not intend to take action for violations of
sections 505, 502(f)(1), and 501(a)(2)(B) of the FD&C Act when a state-
licensed nuclear pharmacy, Federal facility, or other facility that is
not an outsourcing facility and that holds a radioactive materials
license for medical use issued by the Nuclear Regulatory Commission or
by an Agreement State compounds or repackages radiopharmaceuticals for
human use. The guidance explains that one condition is that the
compounded radiopharmaceutical is not essentially a copy of an approved
radiopharmaceutical. As described in the guidance, FDA does not intend
to consider a compounded radiopharmaceutical to be essentially a copy
if, among other reasons, there is a change between the compounded
radiopharmaceutical and the approved radiopharmaceutical that produces
a clinical difference for an identified individual patient, as
determined by the prescribing practitioner and documented in writing on
the prescription or order. In addition, FDA does not intend to consider
a compounded radiopharmaceutical to be essentially a copy if the FDA-
approved radiopharmaceutical is on FDA's drug shortage list (see
section 506E of the FD&C Act (21 U.S.C. 356e)) at the time of
compounding and distribution. If the facility compounded a drug that is
identical or nearly identical to an approved drug product that appeared
on FDA's drug shortage list, the facility should maintain documentation
(e.g., a notation on the order for the compounded drug) regarding the
status of the drug on FDA's drug shortage list at the time of
compounding, distribution, and dispensing.
Radiopharmaceutical Outsourcing Repackaging Guidance
In contrast to section 503A, section 503B of the FD&C Act does not
exclude radiopharmaceuticals. Therefore, FDA's overall policies
regarding section 503B apply to the compounding of radiopharmaceutical
drug products. However, we have developed specific policies that apply
only to the compounding of radiopharmaceuticals by outsourcing
facilities using bulk drug substances and to the compounding of
radiopharmaceuticals by outsourcing facilities that are essentially
copies of approved drugs when such compounding is limited to minor
deviations, as that term is defined in the guidance. FDA issued this
guidance in part to describe the conditions under which the Agency does
not generally intend to take action for violations of sections 505 and
502(f)(1) of the FD&C Act when an outsourcing facility repackages
radiopharmaceuticals for human use.
[[Page 47115]]
As discussed in the guidance, one condition is that if a
radiopharmaceutical is repackaged by an outsourcing facility, the label
on the immediate container (primary packaging, e.g., the syringe) of
the repackaged product includes certain information. The guidance also
provides that the label on the container from which the individual
units are removed for administration (secondary packaging, e.g., the
bag, box, or other package in which the repackaged products are
distributed) includes: (1) The active and inactive ingredients, if the
immediate product label is too small to include this information, and
directions for use, including (as appropriate) dosage and
administration and (2) the following information to facilitate adverse
event reporting: and 1-800-FDA-1088.
Repackaging Guidance
This guidance describes the conditions under which FDA does not
intend to take action for violations of sections 505 (concerning new
drug applications), 502(f)(1) (concerning labeling with adequate
directions for use), 582 ((21 U.S.C. 360eee-1) concerning drug supply
chain security requirements), and (where specified in the guidance)
section 501(a)(2)(B) of the FD&C Act (concerning CGMPs), when a state-
licensed pharmacy, Federal facility, or outsourcing facility repackages
certain prescription drug products. One condition discussed in the
guidance is that if a drug is repackaged by an outsourcing facility,
the label on the immediate container (primary packaging, e.g., the
syringe) of the repackaged product includes certain information
described in the guidance.
Another condition discussed in the guidance is that the label on
the container from which the individual units are removed for
administration (secondary packaging, e.g., the bag, box, or other
package in which the repackaged products are distributed) includes: (1)
The active and inactive ingredients, if the immediate product label is
too small to include this information, and directions for use,
including (as appropriate) dosage and administration, (2) directions
for use, including, as appropriate, dosage and administration, and (3)
the following information to facilitate adverse event reporting:
https://www.fda.gov/medwatch and 1-800-FDA-1088.
Biologics Guidance
Certain licensed biological products may sometimes be mixed,
diluted, or repackaged in a way not described in the approved labeling
for the product to meet the needs of a specific patient. As described
in the guidance, biological products subject to licensure under section
351 of the Public Health Service (PHS) Act (42 U.S.C. 262) are not
eligible for the statutory exemptions available to certain compounded
drugs under sections 503A and 503B of the FD&C Act. In addition, a
biological product that is mixed, diluted, or repackaged outside the
scope of an approved Biologics License Application (BLA) is considered
an unlicensed biological product under section 351 of the PHS Act.
This guidance document describes several conditions under which FDA
does not intend to take action for violations of section 351 of the PHS
Act and sections 502(f)(1), 582, and (where specified) 501(a)(2)(B) of
the FD&C Act, when a State-licensed pharmacy, a Federal facility, or an
outsourcing facility dilutes, mixes, or repackages certain biological
products outside the scope of an approved BLA.
One condition discussed in the guidance is that if the labeling for
the licensed biological product includes storage instructions, handling
instructions, or both (for example, protect from light, do not freeze,
keep at specified storage temperature), the labeling for the biological
product that is mixed, diluted, or repackaged specifies the same
storage conditions. Another condition described in the guidance is
that, if the biological product is mixed, diluted, or repackaged by an
outsourcing facility, the label on the immediate container (primary
packaging, for example, the syringe) of the mixed, diluted, or
repackaged product includes certain information described in the
guidance. In addition, the guidance communicates that as a condition
for biological products mixed, diluted, or repackaged by an outsourcing
facility that, if the immediate product label is too small to bear the
active and inactive ingredients, such information is included on the
label of the container from which the individual units are removed for
administration (secondary packaging, for example, the bag, box, or
other package in which the mixed, diluted, or repackaged biological
products are distributed).
The guidance also communicates our thinking about the condition for
biological products mixed, diluted, or repackaged by an outsourcing
facility that the label on the container from which the individual
units are removed for administration include directions for use. These
directions include, as appropriate, the dosage and administration and
the following information to facilitate adverse event reporting:
https://www.fda.gov/medwatch and 1-800-FDA-1088.
Finally, another condition described in the guidance is that
outsourcing facilities maintain records of the testing performed in
accordance with ``Appendix A--Assigning a BUD for Repackaged Biological
Products Based On Stability Testing'' of the guidance for biological
products repackaged by outsourcing facilities for which the beyond use
date (BUD) is established based on a stability program conducted in
accordance with Appendix A.
Section III.C of the guidance, ``Licensed Allergenic Extracts for
Subcutaneous Immunotherapy,'' discusses the preparation of prescription
sets (that is, licensed allergenic extracts that are mixed and diluted
to provide subcutaneous immunotherapy to an individual patient) by a
physician, a State-licensed pharmacy, a Federal facility, or an
outsourcing facility. Another condition described in the guidance is
that if the prescription set is prepared by an outsourcing facility,
the label of the container from which the individual units of the
prescription set are removed for administration (secondary packaging)
includes the following information to facilitate adverse event
reporting: https://www.fda.gov/medwatch and 1-800-FDA-1088. Each
prescription set prepared by an outsourcing facility is also
accompanied by instructions for use.
In the Federal Register of April 29, 2021 (86 FR 22674), we
published a 60-day notice requesting public comment on the proposed
collection of information. No comments were received.
We estimate the burden of the information collection as follows:
[[Page 47116]]
Table 2--Estimated Annual Recordkeeping Burden 1
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Number of
Activity Number of disclosures Total annual Average burden per disclosure Total hours
respondents per respondent disclosures
--------------------------------------------------------------------------------------------------------------------------------------------------------
Radiopharmaceutical Guidance
--------------------------------------------------------------------------------------------------------------------------------------------------------
Consultation between the compounder and prescriber and 10 25 250 .05 (3 minutes)............... 12.5
the notation on the prescription or order documenting
the prescriber's determination of clinical difference.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Radiopharmaceutical Outsourcing And Repackaging Guidance
--------------------------------------------------------------------------------------------------------------------------------------------------------
Designing, testing, and producing each label on 2 5 10 0.5 (30 minutes).............. 5
immediate containers, packages and/or outer containers.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Repackaging Guidance
--------------------------------------------------------------------------------------------------------------------------------------------------------
Designing, testing, and producing each label on 6 21 126 1............................. 126
immediate containers, packages, and/or outer containers.
Biannual product reports identifying drug products 3 4 12 3............................. 24
repackaged by the outsourcing facility during the
previous 6-month period (Guidance Section III.A.).
--------------------------------------------------------------------------------------------------------------------------------------------------------
Biologics Guidance
--------------------------------------------------------------------------------------------------------------------------------------------------------
Designing, testing, and producing the label, container, 15 5 75 0.5 (30 minutes).............. 37.5
packages, and/or outer containers for each mixed,
diluted, or repackaged biological product.
Designing, testing, and producing each label on 5 300 1,500 0.5 (30 minutes).............. 750
immediate containers, packages and/or outer containers
for each licensed allergenic extract.
Maintaining records of testing performed in accordance 5 30 150 0.083 (5 minutes)............. 12.5
with Biologics Guidance Appendix A.
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Total............................................... .............. .............. 2,123 .............................. 967.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
1 There are no capital costs or operating and maintenance costs associated with this collection of information.
As defined in 44 U.S.C. 3502(13), the term ``recordkeeping
requirement'' means a requirement imposed on respondents to maintain
specified records, as well as a requirement to ``retain such records;
notify third parties, the Federal Government, or the public of the
existence of such records; disclose such records to third parties, the
Federal Government, or the public; or report to third parties, the
Federal Government, or the public regarding such records.'' For
purposes of our analysis, therefore, we have characterized the burden
associated with the time and effort expended on the information
collection recommendations discussed in the respective guidance
documents as recordkeeping activities. At the same time, our findings
show that compliance with recordkeeping requirements applicable to
compounded and repackaged drug products is standard practice in the
compounding and selling of these drug products under States' pharmacy
laws and other State laws governing recordkeeping by healthcare
professionals and healthcare facilities. We have therefore excluded
from our estimate recordkeeping practices discussed in the respective
guidance documents we consider usual and customary. We invite comment
on this assumption.
Radiopharmaceutical Compounding and Repackaging Guidance
We estimate 10 compounders annually will consult a prescriber to
determine whether a compounded radiopharmaceutical has a change that
produces a clinical difference for an identified individual patient as
compared to the comparable approved radiopharmaceutical. We estimate
that those compounders will document this determination on 250
prescriptions or orders for compounded radiopharmaceuticals. We assume
consultation between the compounder and the prescriber and noting this
determination on each prescription or order that does not already
document this determination will take 3 minutes (0.05 hours) per
prescription or order, for a total of approximately 12.5 hours.
Radiopharmaceutical Outsourcing and Repackaging Guidance
We estimate a total of 2 outsourcing facilities annually will each
design, test, and produce an average of 5 different labels for a total
of 10 labels, as described in the guidance (including directions for
use). We assume that designing, testing, and producing each label will
take 30 minutes (0.5 hours) for each repackaged radiopharmaceutical,
for a total of 5 hours. We consider that the provision to include
``https://www.fda.gov/medwatch'' and ``1-800-FDA-1088'' is not a
collection of information as defined in 5 CFR 1320.3(c)(2) and is
therefore exempt from OMB review and approval under the PRA.
Repackaging Guidance
Based on current data for outsourcing facilities, we estimate 6
outsourcing facilities annually will submit an initial report
identifying all drugs repackaged in the facility in the previous year.
For the purposes of this estimate, each product's structured product
labeling (SPL) submission is considered a separate response and
therefore each facility's product report will include multiple
responses. Taking into account that a particular product that is
repackaged may come in different strengths and can be reported in a
single
[[Page 47117]]
SPL response, we estimate that each facility will average approximately
6 products.
Similarly, we estimate that 6 outsourcing facilities will submit an
initial report identifying all drugs repackaged in the facility in the
past year. Taking into account that a particular product that is
repackaged may come in different strengths and can be reported in a
single SPL response, we assume that each facility will average 6
products. Our estimate is based on current product reporting data. We
expect that each product report will consist of multiple SPL responses
per facility and assume preparing and electronically submitting this
information will take up to 2 hours for each initial SPL response.
We also estimate 3 registered outsourcing facilities will submit a
report twice each year (June and December) that identifies all drugs
repackaged at the facility in the previous 6 months. We also estimate
that an average of 3 facilities will prepare and submit 3 SPL responses
and assume that preparing and submitting this information
electronically could also take up to 2 hours per response. If a product
was not repackaged during a particular reporting period, outsourcing
facilities do not need to send an SPL response for that product during
that reporting period. Our figures reflect what we believe to be the
average burden among respondents. We expect to receive no waiver
requests from the electronic submission process for initial product
reports and semiannual reports.
Biologics Guidance
We estimate 15 outsourcing facilities annually who mix, dilute, or
repackage biological products will each design, test, and produce 5
different labels, for a total of 75 labels that include the information
set forth in section III.B--``Mixing, Diluting, or Repackaging Licensed
Biological Products'' of the guidance (including directions for use) as
well as inclusion of storage instructions, handling instructions, or
both. We assume that designing, testing, and producing each label will
take 30 minutes (0.5 hours). We consider that the provision to include
``https://www.fda.gov/medwatch'' and ``1-800-FDA-1088'' is not a
collection of information as defined in 5 CFR 1320.3(c)(2) and is
therefore exempt from OMB review and approval under the PRA.
We estimate that annually a total of 5 outsourcing facilities that
prepare prescription sets will each include on the labels, packages,
and/or containers of approximately 300 prescription sets the
information set forth in section III.C ``Licensed Allergenic Extracts
for Subcutaneous Immunotherapy'' of the draft guidance (including
directions for use), for a total of 1,500 disclosures. We assume the
initial process of designing, testing, and producing labeling and
attaching to each prescription set each label, package, and/or
container will take approximately 30 minutes (0.5 hours), for a total
of approximately 750 hours.
Finally, we estimate that annually five outsourcing facilities who
repackage biological products and establish a BUD in accordance with
Appendix A--``Assigning a BUD for Repackaged Biological Products Based
On Stability Testing'' will maintain 150 records of the testing, as
described in Appendix A of the guidance. We assume maintaining the
records will take 5 minutes per record, for a total of 12.5 hours.
Our estimated burden for the information collection reflects
program changes and adjustments. We are changing the scope of the
information collection to include burden attendant to provisions found
in the Agency guidance documents discussed in this notice and have
adjusted our estimate to reflect a resulting increase of 955 hours and
1,873 responses annually.
Dated: August 5, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-17996 Filed 8-20-21; 8:45 am]
BILLING CODE 4164-01-P
