[Federal Register Volume 84, Number 224 (Wednesday, November 20, 2019)]
[Notices]
[Pages 64080-64083]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-25140]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

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


List of Bulk Drug Substances for Compounding Office Stock Drugs 
for Use in Nonfood-Producing Animals or Antidotes for Food-Producing 
Animals; Request for Nominations

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; request for nominations.

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[[Page 64081]]

SUMMARY: FDA is establishing a public docket 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 as antidotes for food-
producing animals, as described in the draft guidance for industry 
#256, ``Compounding Animal Drugs from Bulk Drug Substances,'' when that 
guidance is finalized. Individuals may also comment on bulk drug 
substances that have been reviewed by FDA and added to this list, 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 ``List of Bulk Drug Substances for Compounding 
Office Stock Drugs for Use in Nonfood-Producing Animals or Antidotes 
for Food-Producing Animals.'' 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.
     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.gpo.gov/fdsys/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.

FOR FURTHER INFORMATION CONTACT: Eric Nelson, Division of Compliance 
(HFV-230), Center for Veterinary Medicine, Food and Drug 
Administration, 7519 Standish Pl., Rockville, MD 20855, 240-402-7001, 
cvmcompliance@fda.hhs.gov.

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.
    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 draft guidance for industry #256 entitled 
``Compounding Animal Drugs from Bulk Drug Substances'' (GFI #256).\1\ 
The draft guidance describes circumstances under which FDA, based on 
our current understanding of the risks of animal drugs compounded from 
bulk drug substances, does not intend to take action against 
pharmacists in either State-licensed pharmacies or Federal facilities, 
or veterinarians, who compound animal drugs from bulk drug substances. 
If the draft guidance is finalized, FDA would not intend to take action 
under sections 512(a), 501(a)(5), 502(f), and 501(a)(2)(B) of the FD&C 
Act so long as such compounding is done under the approach described in 
draft GFI #256.
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    \1\ Draft GFI #256 can be found at https://www.fda.gov/animal-veterinary/guidance-industry/guidance-number.
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II. Nominating Bulk Drug Substances

    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

[[Page 64082]]

Drugs from Bulk Drug Substances'' (announced in the same issue of the 
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 evaluating whether to include a bulk drug 
substance on the list described in the 2015 request for nominations 
notice is substantially the same as the approach below for including a 
bulk drug substance on the 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 antidotes for 
food-producing animals in accordance with FDA's draft guidance for 
industry #256 (the List). As a result, CVM intends to include on the 
List the eight bulk drug substances that FDA previously determined met 
the approach set out in the now withdrawn 2015 draft guidance. To the 
extent these substances and conditions of use meet the approach of the 
final guidance, FDA intends to include them on the List when the draft 
guidance is finalized.
     Apomorphine hydrochloride--Indication: For the induction 
of emesis in dogs. Dosage form: 6.25 mg subconjunctival tablets, 3.125-
6.25 milligrams/milliliters (mg/ml) subconjunctival solution, and 2.5 
mg/ml injectable solution.
     Cisapride--Indication: For the management of 
gastrointestinal motility disorders in cats. Dosage form: 2.5 & 5 mg 
oral tablets, 2.5 & 5 mg oral capsules, 5-10 mg/ml oral suspension.
     Dipyrone--Indication: For the treatment of severe, acute 
fever in dogs suffering from Shar-Pei Fever. Dosage form: 250 mg/ml and 
500 mg/ml injectable solution.
     Guaifenesin--Indication: For muscle relaxation in the 
horse during anesthetic induction and/or surgery. Dosage form: 50 g 
soluble powder to be reconstituted into a solution for IV infusion with 
the addition of 500 ml (10%) or 1000 ml (5%) sterile diluent.
     Miconazole nitrate--Indication: For the treatment of 
fungal keratitis in horses. Dosage form: 1% or 2% miconazole nitrate 
ophthalmic solution or ophthalmic ointment.
     Potassium bromide--Indication: For initiation of treatment 
for seizures in dogs. Dosage form: 250 mg/ml oral solution.
     Tacrolimus--Indication: For treatment of dogs with 
keratoconjunctivitis sicca that is non-responsive to cyclosporine. 
Dosage form: 0.01-0.03% tacrolimus ophthalmic drops.
     Metronidazole benzoate--Indication: For the treatment of 
feline inflammatory bowel disease in cats. Dosage form: 80 mg/ml oral 
suspension.
    The docket used to collect the previous nominations is now closed 
for comment. However, FDA is establishing a new public docket so that 
interested parties can nominate bulk drug substances, re-nominate bulk 
drug substances with adequate supporting information that were 
previously nominated without adequate supporting information, or 
comment on the eight previously nominated bulk drug substances that FDA 
intends to add to the List when the draft guidance is finalized. This 
docket will remain open indefinitely so that individuals may nominate 
and comment on bulk drug substances at any time.

When will FDA include a bulk drug substance on the list of bulk drug 
substances for compounding office stock drugs for use in nonfood-
producing animals or antidotes for food-producing animals?

    FDA intends to include a bulk drug substance on the List when:
    1. There is no marketed FDA-approved, conditionally approved, or 
indexed animal drug that can be used as labeled to treat the condition;
    2. There is no marketed FDA-approved animal or human drug that 
could be used in an extralabel manner under section 512(a)(4) or (a)(5) 
of the FD&C Act and part 530 to treat the condition;
    3. The drug cannot be compounded from a legally marketed FDA-
approved, conditionally approved, or indexed animal or human drug;
    4. Immediate treatment with the compounded drug is necessary to 
avoid animal suffering or death; and
    5. FDA has not identified a significant safety concern specific to 
the use of the bulk drug substance to compound animal drugs (under the 
listed conditions and limitations).
    For bulk drug substances for compounding drugs intended for use as 
antidotes in food-producing animals in addition to the above:
    6. There is sufficient scientific information for the veterinarian 
to determine appropriate withdrawal, withholding, or discard time(s) 
for meat, milk, eggs, or any food which might be derived from the 
treated animal(s).

How do I submit a nomination for the list?

    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 ``List of Bulk Drug Substances for Compounding Office 
Stock Drugs for Use in Nonfood-Producing Animals or Antidotes for Food-
Producing Animals.''

What information should I submit with the nomination?

    You may nominate specific bulk drug substances for inclusion on the 
List. 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. In addition, nominations will only 
be evaluated if they are for specific substances that meet the 
definition of a bulk drug substance.\2\ Nominated substances that do 
not meet this definition will not be evaluated for inclusion on the 
List.
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    \2\ 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. In addition, for purposes of 
evaluating nominations, FDA considers bulk chemicals used to make 
antidotes intended to treat toxicoses in animals to be bulk drug 
substances.
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    For FDA to evaluate a bulk drug substance for inclusion on the 
List, you should submit the following information about the bulk drug 
substance and the compounded animal drug in the nomination:
    1. Confirmation That the Nominated Substance is a Bulk Drug 
Substance: A

[[Page 64083]]

statement that the nominated substance meets the definition of bulk 
drug substance.
    2. Description of the Bulk Drug Substance:
    (a) Chemical name(s);
    (b) common name(s);
    (c) chemical grade (e.g., USP-NF, ACS, etc.);
    (d) description of the strength, stability, purity; and
    (e) how the bulk drug substance is supplied (e.g., powder, liquid).
    3. Description of the Animal Drugs That Will be Compounded With the 
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).
    4. Information Requested for FDA to Evaluate Bulk Drug Substances 
for Inclusion on the List:
    (a) the species and condition(s) that the drug to be compounded 
with the nominated bulk drug substance is intended to treat;
    (b) a bibliography of scientific literature containing safety and 
effectiveness data for the drug compounded using the nominated 
substance;
    (c) a list of animal drugs, if any, that are FDA-approved, 
conditionally approved, or indexed for the condition(s) in the species 
that the drug compounded with the nominated substance is intended to 
address;
    (d) if there are marketed FDA-approved, conditionally approved, or 
indexed drugs that address the same condition(s) in the same species, 
an explanation, supported by relevant scientific literature or other 
evidence, of why a compounded drug is necessary (e.g., why the FDA-
approved, conditionally approved, or indexed drug is not suitable for a 
particular animal population);
    (e) confirmation, using supporting evidence, that there are no 
marketed FDA-approved animal or human drugs that could be prescribed in 
an extralabel manner under section 512(a)(4) and (a)(5) of the FD&C Act 
and 21 CFR part 530 to treat the condition(s) in the species that the 
drug compounded with the nominated substance is intended to address;
    (f) If the bulk drug substance is an active ingredient in a 
marketed FDA-approved, conditionally approved, or indexed animal or 
human drug, an explanation, supported by appropriate scientific data or 
information, of why the animal drug cannot be compounded from the 
marketed FDA-approved, conditionally approved, or indexed animal or 
human drug.
    (g) An explanation, supported by relevant scientific literature or 
other evidence, of why the animal drug to be compounded with the 
nominated bulk drug substance must be available to the veterinarian for 
immediate treatment to avoid animal suffering or death. Nominations 
should include specific information documenting that 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) 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, 
supported by scientific literature or other evidence, of why the 
concerns should not preclude inclusion of that bulk drug substance on 
the List.
    (i) For compounded drugs intended for use as antidotes to treat 
toxicoses in food-producing animals, 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).

    Dated: November 14, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-25140 Filed 11-19-19; 8:45 am]
 BILLING CODE 4164-01-P


