[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.

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

DATES: 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
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                                                  Notice of availability
                      Title                          publication date
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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'').
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    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
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                                                              Radiopharmaceutical Guidance
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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.
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                                                Radiopharmaceutical Outsourcing And Repackaging Guidance
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Designing, testing, and producing each label on                        2               5              10  0.5 (30 minutes)..............               5
 immediate containers, packages and/or outer containers.
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                                                                  Repackaging Guidance
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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.).
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                                                                   Biologics Guidance
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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.
                                                         -----------------------------------------------------------------------------------------------
    Total...............................................  ..............  ..............           2,123  ..............................           967.5
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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