[Federal Register Volume 87, Number 72 (Thursday, April 14, 2022)]
[Notices]
[Pages 22222-22225]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-08018]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-4626]


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; Request for Nominations

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; request for nominations.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
announcing updated information for interested parties to nominate bulk 
drug substances or renominate bulk drug substances that were previously 
nominated without adequate supporting information, 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 the guidance for industry #256 entitled ``Compounding 
Animal Drugs from Bulk Drug Substances.'' Individuals may also comment 
on bulk drug substances that have been reviewed by FDA and added to 
these lists, or nominations that are currently under FDA review.

DATES: You may submit either electronic or written nominations and 
comments at any time.

ADDRESSES: You may submit nominations and comments by any of the 
following methods.

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 in the following ways:
     Mail/Hand Delivery/Courier (for 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-N-4626 for ``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.'' 
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.
     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

[[Page 22223]]

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 
nominations and comments received, go to https://www.regulations.gov 
and insert the docket number, found in brackets in the heading of this 
document, into the ``Search'' box and follow the prompts and/or go to 
the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, 
MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Cindy Burnsteel, Office of 
Surveillance and Compliance (HFV-200), Food and Drug Administration, 
7519 Standish Pl., Rockville, Rockville, MD 20855, 240-402-7011, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    Except with respect to the limited exemption provided by the 
Federal Food, Drug, and Cosmetic Act (FD&C Act) described in the 
following paragraph, statutory provisions applicable to manufactured 
animal drugs under the FD&C Act also apply to animal drugs compounded 
from bulk drug substances (also known as active pharmaceutical 
ingredients (APIs)).\1\
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    \1\ FDA regulations define ``bulk drug substance'' and ``active 
pharmaceutical ingredient'' as ``any substance that is intended for 
incorporation into a finished drug product and is intended to 
furnish pharmacological activity or other direct effect in the 
diagnosis, cure, mitigation, treatment, or prevention of disease, or 
to affect the structure or any function of the body.'' The terms do 
not include intermediates used in the synthesis of the substance. 21 
CFR 207.1. ``Active ingredient'' is defined as ``any component that 
is intended to furnish pharmacological activity or other direct 
effect in the diagnosis, cure, mitigation, treatment, or prevention 
of disease, or to affect the structure or any function of the body 
of man or other animals. The term includes those components that may 
undergo chemical change in the manufacture of the drug product and 
be present in the drug product in a modified form intended to 
furnish the specified activity or effect.'' 21 CFR 210.3(b)(7). Any 
component other than an active ingredient is an ``inactive 
ingredient.'' 21 CFR 210.3(b)(8). Inactive ingredients used in 
compounded drug products commonly include flavorings, dyes, 
diluents, or other excipients.
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    Sections 512(a)(4) and (5) of the FD&C Act (21 U.S.C. 360b(a)(4) 
and (5)) provide a limited exemption from certain requirements for 
compounded animal drugs made from already FDA-approved animal or human 
drugs. Such use is considered an extralabel use. The FD&C Act provides 
that a compounded drug is exempt from the approval requirements in 
section 512(a) of the FD&C Act and requirements for adequate directions 
for use in section 502(f)(1) of the FD&C Act (21 U.S.C. 352(f)(1)) if 
it meets the conditions set out in the statute and the extralabel use 
regulations at 21 CFR part 530.
    Elsewhere in this issue of the Federal Register, FDA is announcing 
the availability of guidance for industry #256 entitled ``Compounding 
Animal Drugs from Bulk Drug Substances'' (GFI #256).\2\ Animal drugs 
compounded from bulk drug substances by pharmacists and veterinarians 
violate the FD&C Act because they do not meet the requirements for 
approval, current good manufacturing practice (CGMP) requirements, or 
adequate directions for use. The guidance 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 512(a), 
502(f), and 501(a)(2)(B) and (a)(5) (21 U.S.C 351(a)(2)(B) and (a)(5)) 
of the FD&C Act under the circumstances described in GFI #256.
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    \2\ https://www.fda.gov/media/132567/download.
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II. Nominating Bulk Drug Substances

    In a Federal Register notice published November 19, 2019, FDA 
established a public docket (FDA-2018-N-4626) so that interested 
parties could nominate bulk drug substances to a list of bulk drug 
substances for compounding office stock drugs for use in nonfood-
producing animals or antidotes for food-producing animals (the List) 
and comment on nominated and evaluated bulk drug substances (the 2019 
request for nominations notice).
    In conjunction with finalizing GFI #256, FDA is expanding 
nominations to include drugs compounded for use as sedatives or 
anesthetics for free-ranging wildlife species. We are also reorganizing 
the List into two separate Lists:

1. The List of Bulk Drug Substances for Compounding Office Stock Drugs 
for Use in Nonfood-Producing Animals \3\ and
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    \3\ Available at https://www.fda.gov/animal-veterinary/animal-drug-compounding/list-bulk-drug-substances-compounding-office-stock-drugs-use-nonfood-producing-animals.
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2. The List of Bulk Drug Substances for Compounding Drugs for Use in 
Food-Producing Animals or Free-Ranging Wildlife Species \4\
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    \4\ Available at https://www.fda.gov/animal-veterinary/animal-drug-compounding/list-bulk-drug-substances-compounding-drugs-use-food-producing-animals-or-free-ranging-wildlife.

    Interested parties can nominate bulk drug substances to either 
List, renominate bulk drug substances with adequate supporting 
information that were previously nominated without adequate supporting 
information, or comment on previously nominated bulk drug substances 
that have been added to a List. This docket will remain open 
indefinitely so that individuals may nominate and comment on bulk drug 
substances at any time.

A. When will FDA include a bulk drug substance on either of the Lists?

    FDA intends to include a bulk drug substance on either of the Lists 
when:
    1. There is no marketed FDA-approved, conditionally approved, or 
indexed animal drug(s) that can be used as labeled to treat the 
condition;
    2. There is no marketed FDA-approved, conditionally approved, or 
indexed animal or human drug(s) with the same active ingredient(s) that 
could be used in an extralabel manner to treat the condition; and
    3. FDA has not identified a significant safety concern specific to 
the use of the bulk drug substance in animals.
    For bulk drug substances used to compound drugs intended as office 
stock for nonfood-producing animals, in addition to 1 to 3 above:
    4. Urgent treatment with the compounded drug is necessary to avoid 
animal suffering or death, or to protect public safety.
    For bulk drug substances used to compound drugs intended for use as 
antidotes in food-producing animals or for use as sedatives or 
anesthetics for free-ranging wildlife species, in addition to 1 to 3 
above:
    5. There is sufficient scientific information for the prescribing 
veterinarian to determine appropriate withdrawal, withholding, or 
discard time(s) for meat, milk, eggs, or any food that might be derived 
from the treated animal(s).

[[Page 22224]]

B. How do I submit a nomination for one of the Lists?

    You may submit nominations and comments to the docket through 
https://www.regulations.gov. The information to support nominations can 
be uploaded as attachments to your comment. The docket number is FDA-
2018-N-4626.
    You may submit written submissions to the Dockets Management Staff 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, 
Rockville, MD 20852. All submissions must include the Docket No. FDA-
2018-N-4626 for ``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.''

C. What information should I submit with the nomination?

    You may nominate specific bulk drug substances for inclusion on 
either of the Lists. Each bulk drug substance should be submitted to 
the docket as its own, separate nomination. Submissions to the docket 
containing more than one bulk drug substance will not be considered an 
adequate nomination and will not be reviewed. Nominated substances that 
do not meet the definition of a bulk drug substance will not be 
evaluated for inclusion on a List.
    For FDA to evaluate a bulk drug substance for inclusion on a List, 
you should submit the following information about the bulk drug 
substance and the compounded animal drug in the nomination:
    1. Description of the Bulk Drug Substance:
    (a) Chemical name(s);
    (b) common name(s);
    2. Description of the Animal Drugs That Will be Compounded with the 
Nominated Bulk Drug Substance:
    (a) Dosage form(s) into which the bulk drug substance will be 
compounded (e.g., capsule, tablet, suspension);
    (b) strength(s) of the compounded drug(s); and
    (c) intended route(s) of administration of the compounded drug(s) 
(e.g., oral, topical, injection, etc.).
    3. Information Requested for FDA to Evaluate Bulk Drug Substances 
for Inclusion on a List:
    (a) The species the drug to be compounded with the nominated bulk 
drug substance is intended to treat;
    (b) The disease or condition(s) the drug to be compounded with the 
nominated bulk drug substance is intended to treat;
    (c) If there is a marketed FDA-approved, conditionally approved, or 
indexed animal drug(s) that addresses the same condition(s) in the same 
species, an explanation of why a compounded drug is necessary (e.g., 
why FDA-approved, conditionally approved, or indexed animal drug(s) is 
not suitable for a particular animal population);
    (d) Confirmation that there is no marketed FDA-approved, 
conditionally approved, or indexed drug(s) that could be prescribed to 
treat the condition in the species that the drug compounded with the 
nominated substance is intended to address;
    (e) If known by the nominator, if the bulk drug substance is an 
active ingredient in a marketed FDA-approved, conditionally approved, 
or indexed animal or human drug(s), an explanation of why the animal 
drug cannot be compounded from the marketed FDA-approved, conditionally 
approved, or indexed animal or human drug(s).
    (f) If known by the nominator, a description of any human user or 
animal safety concerns associated with use of the nominated bulk drug 
substance or finished compounded drug for the condition(s) in the 
species that the compounded drug is intended to address. If there are 
concerns, an explanation of why the concerns should not preclude 
inclusion of that bulk drug substance on the List;
    (g) For compounded drugs intended as office stock for nonfood-
producing animals, an explanation of why the animal drug to be 
compounded with the nominated bulk drug substance is important to be 
available to the veterinarian for urgent treatment to avoid animal 
suffering or death, e.g., why animal suffering or death will result if 
treatment is delayed until a compounded animal drug can be obtained 
pursuant to a prescription for an individually identified animal; and
    (h) For compounded drugs intended for use as antidotes to treat 
toxicoses in food-producing animals, or as sedatives or anesthetics for 
free-ranging wildlife species, relevant scientific literature or other 
evidence that demonstrates that the prescribing veterinarian has a 
basis for determining appropriate withdrawal, withholding, or discard 
time(s) for meat, milk, eggs, or any food which might be derived from 
the treated animal(s).
    4. Contact information for FDA should there be followup questions 
regarding the nomination.

D. What about drugs that have been nominated for one of the Lists and 
are still under review?

    FDA identifies those bulk drug substances that have been nominated 
and under review at ``Bulk Drug Substances Currently Under Review.'' 
\5\ At this time, FDA generally intends to refrain from taking 
enforcement action when these bulk drug substances currently under 
review are used to compound a finished drug as described in the 
nomination. Bulk drug substances will remain on ``Bulk Drug Substances 
Currently Under Review'' only during FDA's review of their nomination. 
If FDA completes its review and declines to place the bulk drug 
substance on a List based on the information provided, FDA will place 
the bulk drug substance on ``Bulk Drug Substances Reviewed and Not 
Listed''; \6\ however, FDA will continue to accept and review any 
adequate additional information submitted by any party that supports 
the previously reviewed nomination. Should adequate additional 
information be provided such that FDA can conduct further substantial 
review, the bulk drug substance will again be placed on ``Bulk Drug 
Substances Currently Under Review.''
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    \5\ Available at: https://www.fda.gov/animal-veterinary/animal-drug-compounding/bulk-drug-substances-currently-under-review.
    \6\ Available at https://www.fda.gov/animal-veterinary/animal-drug-compounding/bulk-drug-substances-reviewed-and-not-listed.
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E. What happens when FDA approves or indexes a drug made with a bulk 
substance as described on one of the Lists?

    FDA intends to remove a bulk substance from a List if a finished 
drug containing that substance in the appropriate dosage form and 
strength is approved or indexed. Please see ``Bulk Drug Substances 
Reviewed and Not Listed.''

F. What happens when FDA reviews a bulk drug substance and determines 
that it cannot be placed on a List because of insufficient information 
or because of other reasons (e.g., safety concerns)?

    Please see ``Bulk Drug Substances Reviewed and Not Listed'' for 
those bulk drug substances that have been reviewed by FDA but are not 
on either List.
    In a Federal Register notice published on May 19, 2015 (80 FR 
28622), FDA invited all interested parties to nominate bulk drug 
substances for inclusion on a list of bulk drug substances that could 
be used by outsourcing facilities registered under the FD&C Act to 
compound animal drugs under the conditions described in draft GFI #230, 
``Compounding Animal Drugs from Bulk Drug Substances'' (announced in 
the same issue of the

[[Page 22225]]

Federal Register (80 FR 28624)) (the 2015 request for nominations 
notice).
    Although that draft guidance was subsequently withdrawn in November 
2017, FDA received over 30 comments containing nominations for multiple 
bulk drug substances in response to the 2015 request for nominations 
notice. FDA's approach for determining whether to include a bulk drug 
substance on the list described in the 2015 request for nominations 
notice was substantially the same as the approach described above for 
including a bulk drug substance on the ``List of Bulk Drug Substances 
for Compounding Office Stock Drugs for Use in Nonfood-Producing 
Animals'' in accordance with GFI #256. Therefore, and in keeping with 
our intention as stated in the 2019 request for nomination notice, the 
Agency is including certain of these nominated bulk drug substances on 
this List. For other of these nominated bulk drug substances, finished 
drugs containing the bulk drug substances in the appropriate dosage 
form and strength have subsequently been approved; thus, these 
nominated bulk drug substances will not appear on the List.
    Some bulk drug substances were nominated in response to the 2015 
request for nominations notice with insufficient supporting 
information. FDA subsequently searched for additional supporting 
information for these bulk substances, conducted further review, and 
added those with sufficient supporting information to the ``List of 
Bulk Drug Substances for Compounding Office Stock Drugs for Use in 
Nonfood-Producing Animals.''
    In addition, on its own initiative, FDA has identified certain bulk 
drug substances that are used in minor species. Several have been 
evaluated and are included on the ``List of Bulk Drug Substances for 
Compounding Office Stock Drugs for Use in Nonfood-Producing Animals.'' 
Those identified bulk drug substances still under evaluation are 
included on ``Bulk Drug Substances Currently Under Review.'' As FDA 
continues to identify and evaluate bulk drug substances that are used 
in minor species, we also encourage outside nominations.

    Dated: April 11, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-08018 Filed 4-13-22; 8:45 am]
BILLING CODE 4164-01-P