[Federal Register Volume 87, Number 72 (Thursday, April 14, 2022)]
[Notices]
[Pages 22212-22215]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-08092]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-D-4533]


Compounding Animal Drugs From Bulk Drug Substances; Guidance for 
Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is 
announcing the availability of a final guidance for industry (GFI) #256 
entitled ``Compounding Animal Drugs from Bulk Drug Substances.'' This 
guidance describes FDA's current thinking about compounding animal 
drugs from bulk drug substances, identifies our enforcement priorities 
with respect to drugs compounded from bulk drug substances, and 
describes circumstances under which FDA generally does not intend to 
take action against veterinarians or pharmacists in either State-
licensed pharmacies or Federal facilities, who compound animal drugs 
from bulk drug substances. We are also 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 (PRA).

DATES: The announcement of the guidance is published in the Federal 
Register on April 14, 2022. Submit written comments (including 
recommendations) on the collection of information by May 16, 2022.

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-NEW. Also include the FDA docket 
number found in brackets in the heading of this document.
    You may submit either electronic or written comments on Agency 
guidances 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-2018-D-4533 for ``Compounding Animal Drugs from Bulk Drug 
Substances.'' Received comments will be placed in the docket and, 
except for those submitted as ``Confidential Submissions,'' publicly 
viewable at https://www.regulations.gov or at the Dockets Management 
Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.

[[Page 22213]]

     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of the guidance to the 
Policy and Regulations Staff (HFV-6), Center for Veterinary Medicine, 
Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855. 
Send one self-addressed adhesive label to assist that office in 
processing your requests. See the SUPPLEMENTARY INFORMATION section for 
electronic access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Cindy Burnsteel, Office of 
Surveillance and Compliance (HFV-200), Food and Drug Administration, 
7519 Standish Pl., Rockville, MD 20855, 240-402-7011.
    Regarding the proposed collection of information: 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:

I. Background

    In the Federal Register of November 20, 2019 (84 FR 64085), FDA 
published the notice of availability for draft GFI #256 entitled 
``Compounding Animal Drugs from Bulk Drug Substances'' with a 90-day 
comment period. In response to requests from interested parties, we 
extended the comment period to July 17, 2020, and then to October 15, 
2020. We requested comments on the draft guidance with respect to 
animal drug compounding from bulk drug substances under certain 
circumstances when no other medically appropriate treatment option 
exists. This final GFI #256 describes FDA's current thinking about 
compounding animal drugs from bulk drug substances, identifies our 
enforcement priorities with respect to drugs compounded from bulk drug 
substances, and describes circumstances under which FDA generally does 
not intend to take action against veterinarians or pharmacists in 
either State-licensed pharmacies or Federal facilities, who compound 
animal drugs from bulk drug substances. FDA does not intend to take 
action under sections 501(a)(2)(B) and (a)(5), 502(f), and 512(a) of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 351(a)(2)(B) and 
(a)(5), 352(f), and 360(b)) under the circumstances described in GFI 
#256.
    FDA received numerous comments on the draft guidance, which were 
considered as the guidance was finalized. Changes made in response to 
comments include identifying compliance with relevant State and local 
laws as the standard for compounding methods and eliminating references 
to United States Pharmacopeia and National Formulary Chapters <795> 
``Pharmaceutical Compounding--Nonsterile Preparations'' and <797> 
``Pharmaceutical Compounding--Sterile Preparations.'' We also revised 
the recommended label statement regarding reporting of adverse events 
to include reporting to the pharmacy as well as FDA.
    We also made a number of changes related to recommendations for 
copies of approved products. We simplified the definition of ``copy'' 
used in the guidance and clarified that ``clinical difference'' 
includes issues affecting patient compliance and the safety of these 
who administer the drug, but excludes cost differences between approved 
and compounded products. The final guidance includes examples of how to 
briefly describe the medical rationale for making a copy, such as the 
compounding pharmacist contacting the prescribing veterinarian to 
obtain the rationale and noting it in the compounding records as an 
alternative to the veterinarian noting the rationale on the 
prescription. It also provides examples of rationales to explain why an 
approved drug cannot be used in a legal extralabel manner to compound a 
drug with the same active moiety.
    We also made changes to lists of bulk drug substances for 
compounding office stock for nonfood-producing animals or antidotes for 
food-producing animals. As outlined in the Appendix to the final 
guidance,\1\ we streamlined the nomination process for these bulk drug 
substances, reducing the information requested by FDA to support a 
nomination. The list of bulk substances to compound drugs for use in 
food-producing animals has been expanded to encompass nominations of 
sedatives or anesthetics for free-ranging wildlife species.
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    \1\ Elsewhere in this issue of the Federal Register, FDA is 
requesting nominations or renominations for bulk drug substances to 
be included on the ``Lists of Bulk Drug Substances for Compounding 
Office Stock Drugs for Use in Nonfood-Producing Animals or Drugs for 
Use in Food-Producing Animals or Free-Ranging Wildlife Species'' for 
inclusion on a list of bulk drug substances for compounding certain 
animal drugs without a patient specific prescription (i.e., office 
stock) for use in nonfood-producing animals or for inclusion on a 
list of compounded drugs for use as antidotes for food-producing 
animals or for use as sedatives or anesthetics for free-ranging 
wildlife species as described in GFI #256. That Federal Register 
notice describes information requested by FDA to evaluate 
nominations and explains when FDA will include bulk drug substances 
on a list. Such nominations will be collected in a separate docket.
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    In addition, editorial changes were made to improve clarity in the 
final guidance. The guidance announced in this notice finalizes the 
draft guidance dated November 2019. However, as explained in section II 
of this notice, the information collection recommendations footnoted 
with an asterisk are subject to OMB review and approval and are not for 
current implementation.
    This level 1 guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The guidance represents 
the current thinking of FDA on compounding animal drugs from bulk drug 
substances. It does not establish any rights for any person and is not 
binding on FDA or the public. You can use an alternative approach if it 
satisfies the requirements of the applicable statutes and regulations.

[[Page 22214]]

II. Paperwork Reduction Act of 1995

    In compliance with 44 U.S.C. 3507, FDA has submitted the following 
proposed collection of information to OMB for review and clearance. FDA 
is issuing this guidance as final, footnoting with an asterisk 
recommendation that include information collection subject to review 
and approval by OMB under the PRA. FDA will implement the information 
collection recommendations if OMB approves them. At that time, FDA will 
announce OMB approval in the Federal Register and update the guidance 
to reflect this approval.
    Title: Compounding Animal Drugs from Bulk Drug Substances (OMB 
Control Number 0910-NEW).
    Description of Respondents: The respondents to the information 
collection are pharmacists in either State-licensed pharmacies or 
Federal facilities, or veterinarians who compound animal drugs from 
bulk drug substances.
    Description: The Center for Veterinary Medicine has developed GFI 
#256 to address a need for Agency guidance in its work with the animal 
health industry. The guidance describes FDA's current thinking, based 
on our current understanding of the risks of animal drugs compounded 
from bulk drug substances, and describes the circumstances under which 
FDA generally does not intend to take enforcement action against 
pharmacists and veterinarians who compound animal drugs from bulk drug 
substances.
    In the Federal Register of November 20, 2019 (84 FR 64085), we 
published a notice of availability announcing draft guidance GFI #256, 
including an analysis under the PRA, and solicited public comment on 
the proposed collection of information. Comments regarding the 
information collection included concerns that the guidance document 
will impose requirements not placed on other prescribers. In any other 
setting, the comments suggested, the prescription itself serves as 
documentation of the veterinarian's determination of clinical need. We 
disagree with these comments suggesting that a prescription serves the 
same purpose as the medical rationale documentation recommended in GFI 
#256. The documentation of the medical rationale by the compounding 
pharmacist is recommended for copies of approved products because a 
prescription demonstrates an animal's need for a prescription drug but 
does not explain why an approved product could not be used legally to 
treat the animal. The medical rationale addresses the clinical need for 
an animal drug compounded from a bulk drug substance when there is an 
approved product available.
    Our exercise of discretion is dependent upon our ability to assess 
whether the circumstances under which FDA intends to exercise such 
discretion, as described in the guidance, exist. FDA staff may use 
pharmacy and veterinary records, among other things, to determine the 
circumstances surrounding the compounding activity. Except with regard 
to the recommendations that compounders document rationales for 
prescribing a compounded product from a bulk drug substance, routine 
business records kept by pharmacists who compound animal drugs from 
bulk drug substances and veterinarians who compound animal drugs from 
bulk drug substances, as well as veterinarians prescribing compounded 
animal drugs within a valid veterinarian-client-patient relationship, 
should be adequate to demonstrate that the circumstances described in 
the guidance exist. While we believe it is usual and customary business 
practice for veterinarians to document medical rationales for 
prescribing a compounded product as recommended in the guidance, we 
acknowledge that documenting this information by the pharmacist 
compounder, as well as documenting the rationale for using a bulk drug 
substance as the source of the active ingredient by the veterinarian/
pharmacist compounder, may not be usual and customary practice. We have 
therefore included an estimate for recordkeeping to account for burden 
beyond that which may be usual and customary for respondents who follow 
the recommended documentation of rationales for compounding the drug 
product from bulk drug substance as discussed in the guidance.
    We estimate the burden of the information collection as follows:

                                                   Table 1--Estimated Annual Recordkeeping Burden \1\
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                                                                   Number of
                                                   Number of      records per    Total annual
                   Activity                      recordkeepers   recordkeeper       records         Average burden per recordkeeping        Total hours
                                                                      \2\
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Documenting rationales by licensed                       7,500           1,134       8,505,000  0.017 (1 minute)........................         144,585
 veterinarian/pharmacist compounder.
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\ Rounded to the nearest whole number.

    We have revised figures from our 60-day notice to reflect a more 
recent review of our experience with the information collection.
    Sections III.A.5 and III.A.6 of the guidance describe circumstances 
under which FDA recommends veterinarian and pharmacist compounders 
document the prescribing veterinarian's medical rationale and the 
reason that a bulk drug substance is being used as the source of the 
active ingredient. Based on our evaluation, we believe it is usual and 
customary business practice for veterinarians to document the medical 
rationale, as recommended in the guidance. However, we believe 
pharmacist compounders may not document the information recommended in 
the guidance as a usual and customary business practice. According to 
the American Pharmacists Association, of the approximately 56,000 
community-based pharmacies in the United States, about 7,500 pharmacies 
specialize in compounding services.\2\ We assume 11,339,400 
prescriptions will be written for compounded animal drugs annually. 
Based on our experience with the regulation of compounded animal drugs, 
we assume 50 to 75 percent of these prescriptions will result in 
documenting rationales as discussed in the guidance. Using the upper-
bound estimate of 75 percent, approximately 8,504,550 prescriptions 
(0.75 x

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11,339,400 prescriptions) will necessitate documenting rationales. 
Averaging this figure equally among 7,500 compounding pharmacies, 1,134 
(rounded to the nearest whole number) rationales will be documented 
annually, for a total of 8,505,000 records. We estimate it will take 1 
minute (0.017 hours) to document the rationales described in the 
guidance, for a total of 144,585 hours, as reported in table 1.
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    \2\ American Pharmacists Association, ``Frequently Asked 
Questions About Pharmaceutical Compounding,'' n.d., https://www.pharmacist.com/Practice/Patient-Care-Services/Compounding/Compounding-FAQs (accessed September 15, 2021). We currently have no 
data on the number of veterinarians who compound drugs for 
individual patients, specifically, compound drugs from bulk drug 
substances for individual patients; therefore, we are including this 
class of respondents in our burden estimate.
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    Under 5 CFR 1320.3(b)(2), the time, effort, and financial resources 
necessary to comply with a collection of information are excluded from 
the burden estimate if the reporting, recordkeeping, or disclosure 
activities needed to comply are usual and customary because they would 
occur in the normal course of activities. If the compounded drug is 
compounded for use as an antidote for food-producing animals or for use 
as a sedative or anesthetic for free-ranging wildlife species, section 
III.C.3 of the guidance recommends that the veterinarian establishes 
and documents a scientifically based withdrawal time that ensures 
residues of the: (1) Antidote and the underlying toxin or (2) sedative 
or anesthetic are not present in the animal at the time of slaughter or 
harvest or the veterinarian ensures the animal does not enter the food 
supply. We believe that it is usual and customary for veterinarians to 
establish and document a scientifically based withdrawal time as a 
matter of maintaining an adequate medical record in routine practice 
and, therefore, estimate no burden for the time it would take for a 
veterinarian to make this record. See 5 CFR 1320.3(b)(2).
    In addition, the guidance makes a number of recommendations 
regarding the labeling of animal drugs compounded from bulk drug 
substances. In sections III.A.8, III.B.6, and III.C.6, the guidance 
recommends basic information that pharmacists and veterinarians should 
include on the label of the compounded drug, such as the name and 
strength of the drug and the name, address, and contact information for 
the compounding pharmacy or compounding veterinarian. We believe that 
it is usual and customary for pharmacists and veterinarians to include 
such information on the labels of compounded animal drugs in the normal 
course of their activities, and therefore, estimate no burden for the 
time it would take to prepare such labeling. See 5 CFR 1320.3(b)(2). 
Sections III.A.8, III.B.6, and III.C.6 of the guidance also recommend 
compounders (pharmacists and veterinarians) include several specific 
statements on the label of animal drugs compounded from bulk drug 
substances (e.g., ``This is a compounded drug. Not an FDA approved or 
indexed drug.''). Because these recommended labeling statements are 
public disclosure of information originally supplied by the Federal 
Government to the recipient for the purpose of disclosure to the public 
(5 CFR 1320.3(c)(2)), they are exempt from OMB review and approval 
under the PRA.

III. Electronic Access

    Persons with access to the internet may obtain the guidance at 
https://www.fda.gov/animal-veterinary/guidance-regulations/guidance-industry, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.

    Dated: April 11, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-08092 Filed 4-13-22; 8:45 am]
BILLING CODE 4164-01-P