[Federal Register Volume 88, Number 66 (Thursday, April 6, 2023)]
[Notices]
[Pages 20531-20542]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-07237]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-3240]


List of Bulk Drug Substances for Which There Is a Clinical Need 
Under Section 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, the Agency, or we) is 
evaluating substances that have been nominated for inclusion on a list 
of bulk drug substances (active pharmaceutical ingredients (APIs)) for 
which there is a clinical need (the 503B Bulks List). Drug products 
that outsourcing facilities compound using bulk drug substances on the 
503B Bulks List can qualify for certain exemptions from the Federal 
Food, Drug, and Cosmetic Act (FD&C Act) provided certain conditions are 
met. This notice identifies one bulk drug substance that FDA has 
considered and is including on the list at this time: quinacrine 
hydrochloride (HCl) to compound drug products for oral use only. This 
notice also identifies 10 bulk drug substances that FDA has considered 
and is not including on the list at this time: hydroxyzine HCl, 
mannitol, methacholine chloride, metoclopramide HCl, nalbuphine HCl, 
potassium acetate, procainamide HCl, sodium bicarbonate, sodium 
nitroprusside, and verapamil HCl. Additional bulk drug substances 
nominated by the public for inclusion on this list are currently under 
consideration and will be the subject of future notices.

DATES: The announcement of the notice is published in the Federal 
Register on April 6, 2023.

ADDRESSES: 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,

[[Page 20532]]

and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, 
Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Tracy Rupp, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 51, Silver Spring, MD 20993, 301-796-3100.

SUPPLEMENTARY INFORMATION: 

I. Background

    Section 503B of the FD&C Act (21 U.S.C. 353b) describes the 
conditions that must be satisfied for drug products compounded in an 
outsourcing facility to be exempt from section 505 (21 U.S.C. 355) 
(concerning the approval of drugs under new drug applications (NDAs) or 
abbreviated new drug applications (ANDAs)), section 502(f)(1) (21 
U.S.C. 352(f)(1)) (concerning the labeling of drugs with adequate 
directions for use), and section 582 of the FD&C Act (21 U.S.C. 360eee-
1) (concerning drug supply chain security requirements).\1\
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    \1\ Section 503B(a) of the FD&C Act.
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    Compounded drug products that meet the conditions in section 503B 
are not exempt from current good manufacturing practice (CGMP) 
requirements in section 501(a)(2)(B) of the FD&C Act (21 U.S.C. 
351(a)(2)(B)).\2\ Outsourcing facilities are also subject to FDA 
inspections according to a risk-based schedule, adverse event reporting 
requirements, and other conditions that help to mitigate the risks of 
the drug products they compound.\3\ Outsourcing facilities may or may 
not obtain prescriptions for identified individual patients and can, 
therefore, distribute compounded drugs to healthcare practitioners for 
``office stock,'' to hold in their offices in advance of patient 
need.\4\
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    \2\ Compare section 503A(a) of the FD&C Act (21 U.S.C. 353a(a) 
(exempting drugs compounded in accordance with that section)) with 
section 503B(a) of the FD&C Act (not providing the exemption from 
CGMP requirements).
    \3\ Section 503B(b)(4) and (5) of the FD&C Act.
    \4\ Section 503B(d)(4)(C) of the FD&C Act.
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    One of the conditions that must be met for a drug product 
compounded by an outsourcing facility to qualify for the exemptions 
under section 503B of the FD&C Act is that the outsourcing facility may 
not compound a drug using a bulk drug substance unless: (1) the bulk 
drug substance appears on a list established by the Secretary of Health 
and Human Services (the Secretary) identifying bulk drug substances for 
which there is a clinical need (the 503B Bulks List) or (2) the drug 
compounded from the bulk drug substance appears on the drug shortage 
list in effect under section 506E of the FD&C Act (21 U.S.C. 356e) at 
the time of compounding, distribution, and dispensing.\5\
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    \5\ Section 503B(a)(2)(A) of the FD&C Act.
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    Section 503B of the FD&C Act directs FDA to establish the 503B 
Bulks List by: (1) publishing a notice in the Federal Register 
proposing bulk drug substances to be included on the list, including 
the rationale for such proposal; (2) providing a period of not less 
than 60 calendar days for comment on the notice; and (3) publishing a 
notice in the Federal Register designating bulk drug substances for 
inclusion on the list.\6\
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    \6\ Section 503B(a)(2)(A)(i)(I) to (III) of the FD&C Act.
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    FDA has published a series of Federal Register notices addressing 
bulk drug substances nominated for inclusion on the 503B Bulks List.\7\ 
This notice identifies one bulk drug substance that FDA has considered 
and is including on the 503B Bulks List and 10 bulk drug substances 
that FDA has considered and is not including on the 503B Bulks List.
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    \7\ See Federal Register of August 28, 2018 (83 FR 43877), March 
4, 2019 (84 FR 7383), September 3, 2019 (84 FR 46014), July 31, 2020 
(85 FR 46126), March 24, 2021 (86 FR 15673), and November 23, 2022 
(87 FR 71642). The comment period for the July 2020 notice was 
reopened for 30 days on January 8, 2021 (86 FR 1515), to allow 
interested parties an additional opportunity to comment. FDA has not 
yet reached a final determination on whether the substances 
evaluated in the September 2019, July 2020, or March 2021 notices 
will be added to the 503B Bulks List. In addition, bumetanide, which 
was considered in the August 2018 notice, remains under 
consideration by the Agency.
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    For purposes of section 503B of the FD&C Act, bulk drug substance 
means an active pharmaceutical ingredient as defined in 21 CFR 
207.1.\8\ Active pharmaceutical ingredient means 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, but the term does not 
include intermediates used in the synthesis of the 
substance.9 10
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    \8\ See section 503B(a)(2) of the FD&C Act, which defines bulk 
drug substances used in compounding under section 503B according to 
21 CFR 207.3(a)(4) ``or any successor regulation.'' Section 207.1 is 
the successor regulation.
    \9\ Section 503B(a)(2) of the FD&C Act and 21 CFR 207.1.
    \10\ Inactive ingredients are not subject to section 503B(a)(2) 
of the FD&C Act and will not be included in the 503B Bulks List 
because they are not included within the definition of a bulk drug 
substance. Pursuant to section 503B(a)(3), inactive ingredients used 
in compounding must comply with the standards of an applicable 
United States Pharmacopeia (USP) or National Formulary (NF) 
monograph, if a monograph exists.
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II. Methodology for Developing the 503B Bulks List

A. Process for Developing the List

    FDA requested nominations for specific bulk drug substances for the 
Agency to consider for inclusion on the 503B Bulks List in the Federal 
Register of December 4, 2013 (78 FR 72838). FDA reopened the nomination 
process in the Federal Register of July 2, 2014 (79 FR 37747), and 
provided more detailed information on what FDA needs to evaluate 
nominations for the list. On October 27, 2015 (80 FR 65770), the Agency 
opened a new docket, FDA-2015-N-3469, to provide an opportunity for 
interested persons to submit new nominations of bulk drug substances, 
renominate substances with sufficient information, or submit comments 
on nominated substances.
    As FDA evaluates bulk drug substances, it intends to publish 
notices for public comment in the Federal Register that describe its 
proposed position on each substance along with the rationale for that 
position.\11\ After considering any comments on FDA's proposals 
regarding whether to include nominated substances on the 503B Bulks 
List, FDA intends to consider whether input from the Pharmacy 
Compounding Advisory Committee (PCAC) on the nominations would be 
helpful to the Agency in making its determination, and if so, it will 
seek PCAC input.\12\ Depending on its review of the docket comments and 
other relevant information before the Agency, FDA may finalize its 
proposed determination without change, or it may finalize a 
modification to its proposal to reflect new evidence or analysis 
regarding clinical need. FDA will then publish in the Federal Register 
a final determination identifying the bulk drug substances for which it 
has determined there is a clinical need and FDA's rationale in making 
that final determination. FDA will also publish in the Federal Register 
a final determination regarding those substances it considered but 
found that there is no clinical need to use in compounding and FDA's 
rationale in making this decision.
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    \11\ This is consistent with procedures set forth in section 
503B(a)(2)(A)(i) of the FD&C Act. Although the statute only directs 
FDA to issue a Federal Register notice and seek public comment when 
it proposes to include bulk drug substances on the 503B Bulks List, 
we intend to seek comment when the Agency has evaluated a nominated 
substance and proposes either to include or not to include the 
substance on the list.
    \12\ Section 503B of the FD&C Act does not require FDA to 
consult the PCAC before developing the 503B Bulks List.

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[[Page 20533]]

    FDA intends to maintain a list of all bulk drug substances it has 
evaluated on its website, and separately identify bulk drug substances 
it has placed on the 503B Bulks List and those it has decided not to 
place on the 503B Bulks List. This list is available at https://www.fda.gov/media/120692/download. FDA will only place a bulk drug 
substance on the 503B Bulks List when it has determined there is a 
clinical need for outsourcing facilities to compound drug products 
using the bulk drug substance. If a clinical need to compound drug 
products using the bulk drug substance has not been demonstrated, based 
on the information submitted by the nominator and any other information 
considered by the Agency, FDA will not place a bulk drug substance on 
the 503B Bulks List.
    FDA is evaluating bulk drug substances nominated for the 503B Bulks 
List on a rolling basis. FDA intends to evaluate and publish in the 
Federal Register its proposed and final determinations in groups of 
bulk drug substances until all nominated substances that were 
sufficiently supported have been evaluated and either placed on the 
503B Bulks List or identified as bulk drug substances that were 
considered but determined not to be appropriate for inclusion on the 
503B Bulks List (Ref. 1).\13\
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    \13\ In January 2017, FDA announced the availability of a 
revised final guidance for industry that provides additional 
information regarding FDA's policies for bulk drug substances 
nominated for the 503B Bulks List pending our review of nominated 
substances under the ``clinical need'' standard entitled ``Interim 
Policy on Compounding Using Bulk Drug Substances Under Section 503B 
of the Federal Food, Drug, and Cosmetic Act'' (the ``Interim 
Policy''), available at https://www.fda.gov/media/94402/download.
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B. Analysis of Substances Nominated for the List

    As noted above, the 503B Bulks List will include bulk drug 
substances for which there is a clinical need. The Agency is evaluating 
bulk drug substances that were nominated for inclusion on the 503B 
Bulks List, proceeding case by case, under the standard provided by the 
statute (Ref. 2).\14\ In applying this standard to make its 
determinations regarding the substances set forth in this notice, FDA 
interprets the phrase ``bulk drug substances for which there is a 
clinical need'' to mean that the 503B Bulks List may include a bulk 
drug substance if: (1) there is a clinical need for an outsourcing 
facility to compound the drug product and (2) the drug product must be 
compounded using the bulk drug substance. FDA does not interpret supply 
issues, such as backorders, to be within the meaning of ``clinical 
need'' for compounding with a bulk drug substance. Section 503B of the 
FD&C Act separately provides for compounding from a bulk drug substance 
under the exemptions from the FD&C Act discussed above if the drug 
product compounded from the bulk drug substance is on the FDA drug 
shortage list at the time of compounding, distribution, and dispensing. 
Additionally, FDA does not consider convenience in administering a 
particular compounded drug product (e.g., a ready-to-use form) or the 
cost of the compounded drug product as compared with an FDA-approved 
drug product when assessing ``clinical need.''
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    \14\ In March 2019, FDA announced the availability of a final 
guidance entitled ``Evaluation of Bulk Drug Substances Nominated for 
Use in Compounding Under Section 503B of the Federal Food, Drug, and 
Cosmetic Act'' (the ``Clinical Need Guidance''), available at 
https://www.fda.gov/media/121315/download. This guidance describes 
FDA policies for developing the 503B Bulks List and the Agency's 
interpretation of the phrase ``bulk drug substances for which there 
is a clinical need'' as it is used in section 503B. The analysis 
under the statutory ``clinical need'' standard described in this 
notice is consistent with the approach described in FDA's guidance.
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    All of the bulk drug substances addressed in this notice, with the 
exception of quinacrine HCl, are components of FDA-approved drug 
products.\15\ FDA began its evaluation of the bulk drug substances that 
are components of FDA-approved drug products by asking one or both, as 
applicable, of the following questions:
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    \15\ Specifically, hydroxyzine HCl, mannitol, methacholine 
chloride, metoclopramide HCl, nalbuphine HCl, potassium acetate, 
procainamide HCl, sodium bicarbonate, sodium nitroprusside, and 
verapamil HCl.
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    1. Is there a basis to conclude, for each FDA-approved product that 
includes the nominated bulk drug substance, that (a) an attribute of 
the FDA-approved drug product makes it medically unsuitable to treat 
certain patients for a condition that FDA has identified for 
evaluation, and (b) the drug product proposed to be compounded is 
intended to address that attribute?
    2. Is there a basis to conclude that the drug product proposed to 
be compounded must be produced from a bulk drug substance rather than 
from an FDA-approved drug product?
    The reason for question 1 is that unless an attribute of the FDA-
approved drug is medically unsuitable for certain patients, and a drug 
product to be compounded using a bulk drug substance that is a 
component of the FDA-approved drug is intended to address that 
attribute, there is no clinical need to compound a drug product using 
that bulk drug substance. Rather, such compounding would unnecessarily 
expose patients to the risks associated with drug products that do not 
meet the standards applicable to FDA-approved drug products for safety, 
effectiveness, quality, and labeling and would undermine the drug 
approval process. The reason for question 2 is that to place a bulk 
drug substance on the 503B Bulks List, FDA must determine that there is 
a clinical need for outsourcing facilities to compound a drug product 
using the bulk drug substance rather than starting with an FDA-approved 
drug product. When it is feasible to compound a drug product by 
starting with an FDA-approved drug product, there are certain benefits 
of doing so over starting with a bulk drug substance, including that 
FDA-approved drugs have undergone premarket review for safety, 
effectiveness, and quality, and are manufactured by a facility that is 
subject to premarket assessment, including site inspection, as well as 
routine post-approval risk-based inspections. In contrast, FDA does not 
conduct a premarket review of the quality standards, specifications, 
and controls for bulk drug substances used in compounding and does not 
conduct a premarket assessment of the manufacturer of the bulk drug 
substance.
    If the answer to both of the above questions is ``yes,'' there may 
be a clinical need for outsourcing facilities to compound using the 
bulk drug substance, and we would evaluate the substance further, 
applying the factors described below. If the answer to either of these 
questions is ``no,'' we generally would not include the bulk drug 
substance on the 503B Bulks List, because there would not be a basis to 
conclude that there may be a clinical need to compound drug products 
using the bulk drug substance instead of administering an FDA-approved 
drug or compounding starting with an FDA-approved drug product. FDA did 
not answer ``yes'' to both of the threshold questions for the 10 bulk 
drug substances that are components of FDA-approved drug products that 
we are addressing in this notice. Accordingly, as explained below, we 
did not proceed further in our evaluation of these substances and have 
decided not to include them on the 503B Bulks List.
    With respect to the bulk drug substance addressed in this notice 
that is not a component of an FDA-approved drug, quinacrine HCl, we 
conducted a balancing test using four factors. Specifically, we 
considered available data relevant to each factor in the context of the 
other factors and balanced all four factors to determine whether the

[[Page 20534]]

statutory ``clinical need'' standard has been met. The balancing test 
includes the following factors:
     The physical and chemical characterization of the 
substance;
     any safety issues raised by the use of the substance in 
compounding;
     the available evidence of effectiveness or lack of 
effectiveness of a drug product compounded with the substance, if any 
such evidence exists; and
     current and historical use of the substance in compounded 
drug products, including information about the medical condition(s) 
that the substance has been used to treat and any references in peer-
reviewed medical literature.
    The discussion below reflects FDA's consideration of these four 
factors and describes how they were applied to develop FDA's decision 
to include quinacrine HCl for oral use on the 503B Bulks List.

C. Inclusion of a Bulk Drug Substance on the 503B Bulks List

    In evaluating a bulk drug substance for the 503B Bulks List, FDA 
has considered whether the clinical need for the bulk drug substance in 
the proposed compounded drug product is limited, by, for example, route 
of administration or dosage form. In the Federal Register notice of 
July 31, 2020 (85 FR 46126), FDA requested comments on the proposal to 
limit listings in this manner. On January 8, 2021 (86 FR 1515), the 
comment period for the July 2020 notice was reopened for 30 days to 
allow interested parties an additional opportunity to comment before 
FDA began to develop its final determinations. After considering the 
comments submitted regarding the proposal, in the Federal Register 
notice of January 27, 2022 (87 FR 4240), FDA listed three bulk drug 
substances to compound drug products for topical use only, consistent 
with its findings related to clinical need for those bulk drug 
substances.
    FDA has also determined that to be eligible for the statutory 
exemptions under section 503B, drug products compounded using a bulk 
drug substance that appears on the 503B Bulks List cannot contain other 
APIs unless those APIs have been listed in combination on the 503B 
Bulks List (87 FR 4240). FDA's assessment of the clinical need for 
compounding with a particular bulk drug substance or combination of 
bulk drug substances could be affected if a bulk drug substance is 
commonly used in compounded drug products that contain multiple bulk 
drug substances (APIs). The use of certain APIs in combination with 
other APIs in a compounded drug product could also pose a safety risk 
or affect the compounded drug product's effectiveness. These 
considerations of the composition of a nominated compounded 
combination, the history of its use in compounding, and evidence of 
safety or effectiveness would be included in FDA's clinical need 
evaluation.
    In accordance with these considerations and the clinical need 
analysis set forth below, FDA is adding one bulk drug substance--
quinacrine HCl--to the 503B Bulks List to compound single-ingredient 
drug products for oral use only.\16\
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    \16\ In this notice, ``single-ingredient'' refers to a drug 
product containing one active ingredient. The drug product may also 
contain excipients.
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III. FDA's Determinations Regarding Substances Proposed for the 503B 
Bulks List

    In September 2019, the Agency issued a Federal Register notice in 
which it evaluated nine nominated bulk drug substances under the 
section 503B statutory standard--dipyridamole, ephedrine sulfate, 
famotidine, hydralazine HCl, methacholine chloride, sodium bicarbonate, 
sodium tetradecyl sulfate, trypan blue, and vecuronium bromide--and 
proposed not to include them on the 503B Bulks List (the September 2019 
notice).\17\ In this notice, after review of the comments submitted to 
the docket for the September 2019 notice, FDA is making its final 
determination not to include methacholine chloride and sodium 
bicarbonate on the 503B Bulks List. At this time, FDA is not making a 
final determination regarding ephedrine sulfate, famotidine, 
hydralazine HCl, sodium tetradecyl sulfate, trypan blue, and vecuronium 
bromide.\18\ These substances remain under consideration by FDA.
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    \17\ See 84 FR 46014.
    \18\ FDA made a final determination not to include dipyridamole 
on the 503B Bulks List (see 87 FR 4240).
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    In July 2020, the Agency issued a Federal Register notice in which 
it evaluated 23 nominated bulk drug substances under the section 503B 
statutory standard (the July 2020 notice).\19\ FDA proposed to include 
diphenylcyclopropenone (DPCP), glycolic acid, squaric acid dibutyl 
ester (SADBE), and trichloroacetic acid (TCA) on the 503B Bulks List. 
FDA proposed not to include diazepam, dobutamine HCl, dopamine HCl, 
edetate calcium disodium, folic acid, glycopyrrolate, hydroxyzine HCl, 
ketorolac tromethamine, labetalol HCl, mannitol, metoclopramide HCl, 
moxifloxacin HCl, nalbuphine HCl, polidocanol, potassium acetate, 
procainamide HCl, sodium nitroprusside, sodium thiosulfate, and 
verapamil HCl on the 503B Bulks List. In this notice, after review of 
the comments submitted to the docket for the July 2020 notice, FDA is 
making its final determination not to include hydroxyzine HCl, 
mannitol, metoclopramide HCl, nalbuphine HCl, potassium acetate, 
procainamide HCl, sodium nitroprusside, and verapamil HCl on the 503B 
Bulks List. FDA has previously made final determinations for DPCP, 
glycolic acid, SADBE, TCA, diazepam, dobutamine HCl, dopamine HCl, 
edetate calcium disodium, folic acid, glycopyrrolate, and sodium 
thiosulfate (except the topical route of administration) (87 FR 4240). 
At this time, FDA is not making a final determination regarding 
ketorolac tromethamine, labetalol HCl, moxifloxacin HCl, and 
polidocanol. These substances remain under consideration by FDA.
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    \19\ 85 FR 46126.
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    In March 2021, the Agency issued a Federal Register notice in which 
it evaluated five bulk drug substances under the section 503B statutory 
standard (the March 2021 notice).\20\ FDA proposed to include 
quinacrine HCl on the 503B Bulks List to compound drug products for 
oral use only. FDA proposed not to include bromfenac sodium, mitomycin-
C, nepafenac, and hydroxychloroquine sulfate on the 503B Bulks List. In 
this notice, after review of the comments submitted to the docket for 
the March 2021 notice, FDA is making its final determination to include 
quinacrine HCl on the 503B Bulks List to compound drug products for 
oral use only. At this time, FDA is not making a final determination 
regarding bromfenac sodium, mitomycin-C, nepafenac, and 
hydroxychloroquine sulfate. These substances remain under consideration 
by FDA. Additional bulk drug substances nominated by the public for 
inclusion on the 503B Bulks List are currently under consideration and 
may be the subject of future notices.
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    \20\ 86 FR 15673.
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A. Substance Evaluated and Included on the 503B Bulks List

    FDA is placing quinacrine HCl on the 503B Bulks List. FDA evaluated 
quinacrine HCl and proposed to include it on the 503B Bulks List in the 
March 2021 notice. The reasons for FDA's proposal to place quinacrine 
HCl for oral use on the 503B Bulks List are

[[Page 20535]]

included below (Ref. 3).\21\ For the reasons set forth in the proposal, 
FDA is now placing quinacrine HCl on the 503B Bulks List for oral use 
only.
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    \21\ In addition to FDA's evaluation of the quinacrine HCl 
nomination for the 503B Bulks List, the Agency considered data and 
information from its earlier evaluation regarding the use of this 
bulk drug substance for the list of bulk drug substances that can be 
used in compounding under section 503A of the FD&C Act (the 503A 
Evaluation) (see appendices A-D in ``FDA Memo to File, Clinical Need 
for Quinacrine Hydrochloride in Compounding Under Section 503B of 
the FD&C Act'' (Ref. 3)). FDA also considered a report provided by 
the University of Maryland Center of Excellence in Regulatory 
Science and Innovation and conducted a search for relevant 
scientific literature and safety information, focusing on materials 
published or submitted to FDA since the 503A Evaluations (see 
appendix H in Ref. 3).
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Quinacrine HCl
    FDA considered the bulk drug substance quinacrine HCl for inclusion 
on the 503B Bulks List to compound drug products in oral dosage forms 
at strengths of 25-100 milligrams (mg) for the treatment of cutaneous 
lupus erythematosus (CLE), as described in the Agency's nomination and 
evaluation.\22\
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    \22\ See appendix G in Ref. 3.
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    Quinacrine HCl is not a component of an FDA-approved drug product. 
The Agency therefore evaluated quinacrine HCl for potential inclusion 
on the 503B Bulks List under the clinical need standard in section 503B 
of the FD&C Act using the balancing test described above. FDA 
considered data and information regarding the physical and chemical 
characterization of quinacrine HCl, safety issues raised by use of this 
substance in compounding, available evidence of effectiveness or lack 
of effectiveness, and historical and current use in compounding (Ref. 
3).
    Quinacrine HCl is well-characterized physically and chemically. 
Although there are concerns about its safety profile in certain patient 
populations, FDA believes these risks are well known within the 
rheumatology and dermatology specialties that most often treat CLE, and 
the known risks could be controlled with appropriate dosing and 
monitoring. Quinacrine HCl has been used for several decades to treat 
systemic lupus erythematosus and CLE, and there is a significant body 
of experience, documented in the scientific literature, that quinacrine 
HCl may be effective in the treatment of patients with cutaneous lupus, 
and patients who are not fully clinically responsive to, or are 
intolerant of, treatment with FDA-approved products alone. These 
patients may respond to the addition of quinacrine HCl to their 
existing therapy, or to the use of quinacrine HCl alone. On balance, 
the physical and chemical characterization, safety, effectiveness, and 
historical and current use of quinacrine HCl weigh in favor of 
including this substance on the 503B Bulks List. Two commenters 
supported FDA's proposal to include quinacrine HCl on the 503B Bulks 
List, although one of them disagreed with FDA's proposal to limit the 
entry to oral use only. No commenters opposed adding quinacrine HCl to 
the 503B Bulks List. Several commenters objected generally to FDA's 
proposals, and these overarching concerns are addressed in section IV 
of this notice. Accordingly, FDA is adding quinacrine HCl to the 503B 
Bulks List for oral use only. The entry on the 503B Bulks List is 
limited in this way because, as discussed above, FDA's evaluation only 
revealed a clinical need for outsourcing facilities to compound drug 
products containing the bulk drug substance quinacrine HCl for the oral 
route of administration.
    Due to the safety risks referred to above, FDA is making safety 
information about the use of quinacrine HCl available to prescribers, 
pharmacists, outsourcing facilities, and the public through a safety 
guide on FDA's website, available at https://www.fda.gov/drugs/human-drug-compounding/consumer-and-health-care-professional-information.

B. Substances Evaluated and Not Included on the 503B Bulks List

    The 10 bulk drug substances that FDA has evaluated, proposed not to 
include on the 503B Bulks List in a Federal Register notice, and has 
now decided not to place on the 503B Bulks List are: hydroxyzine HCl, 
mannitol, methacholine chloride, metoclopramide HCl, nalbuphine HCl, 
potassium acetate, procainamide HCl, sodium bicarbonate, sodium 
nitroprusside, and verapamil HCl.
    Because the substances discussed in this section are components of 
FDA-approved drug products, FDA considered one or both of the following 
questions: (1) is there a basis to conclude that an attribute of each 
FDA-approved drug product containing the bulk drug substance makes each 
one medically unsuitable to treat certain patients for a condition that 
FDA has identified for evaluation, and the drug product(s) proposed to 
be compounded is intended to address that attribute in each FDA-
approved drug product, and (2) is there a basis to conclude that the 
drug product(s) proposed to be compounded must be compounded using a 
bulk drug substance. FDA considered comments to the docket submitted 
within the public comment period, but as explained below, none of the 
comments received on these bulk drug substances provided information 
that led FDA to change its determination.
1. Hydroxyzine HCl
    Hydroxyzine HCl has been nominated for inclusion on the 503B Bulks 
List to compound drug products that treat alcohol withdrawal syndrome, 
analgesia in labor, pre- and postpartum reduction of narcotic use, and 
relief of anxiety, among other conditions.\23\ The proposed route of 
administration is intramuscular, the proposed dosage form is a 
solution, and the proposed concentration is 50 milligrams/milliliters 
(mg/mL). The nominators proposed to compound a preserved solution. 
However, they failed to acknowledge that there is a preserved 
formulation of hydroxyzine HCl that is FDA-approved or identify an 
attribute of that formulation that makes it medically unsuitable for 
certain patients. The nominations state that hydroxyzine HCl might also 
be used to compound other drug products but do not identify those 
products. The nominated bulk drug substance is a component of FDA-
approved drug products (e.g., ANDA 087408). FDA-approved hydroxyzine 
HCl is marketed as a preserved 50 mg/mL solution for intramuscular 
administration.24 25 26
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    \23\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \24\ See, e.g., ANDA 087408 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/e711ee73-c054-4f3f-a189-bb3c01c7aecc/e711ee73-c054-4f3f-a189-bb3c01c7aecc.xml.
    \25\ Per the label for ANDA 087408, each mL contains hydroxyzine 
HCl 25 mg or 50 mg, benzyl alcohol 0.9 percent, and water for 
injection q.s. pH is adjusted with sodium hydroxide and/or 
hydrochloric acid.
    \26\ Hydroxyzine HCl is also FDA-approved as an oral tablet and 
as an oral syrup.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
    The nominations do not identify an attribute of the FDA-approved 
preserved 50 mg/mL hydroxyzine HCl solution for intramuscular 
administration that makes it medically unsuitable for certain patients 
or identify an attribute of the FDA-approved drug products that the 
proposed compounded drug product is intended to address. Two commenters 
supported FDA's proposal not to include hydroxyzine HCl on the 503B 
Bulks List. No new information supporting the clinical need for 
compounding from the bulk drug substance hydroxyzine HCl was provided 
by the commenters.
    Accordingly, FDA finds no basis to conclude that there is an 
attribute of the

[[Page 20536]]

FDA-approved products that makes them medically unsuitable to treat 
certain patients for a condition that FDA has identified for evaluation 
and that a proposed compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    Because the nominations do not identify specific differences 
between drug products that would be compounded using hydroxyzine HCl 
and the FDA-approved drug product containing hydroxyzine HCl, there is 
nothing for FDA to evaluate under question 2. No further information 
was supplied on this point during the comment period. Therefore, FDA 
finds no basis to conclude that the drug product proposed to be 
compounded must be prepared using a bulk drug substance rather than an 
FDA-approved drug product.
2. Mannitol
    Mannitol has been nominated for inclusion on the 503B Bulks List to 
compound drug products for treatment of acute renal failure, inhalation 
bronchial challenge testing, and irrigation of the urinary bladder, 
among other conditions.\27\ The proposed route of administration is 
intravenous, the proposed dosage form is a solution, and the proposed 
concentration is 25 percent. The nominators proposed to compound a 
preservative-free solution. However, they failed to acknowledge that 
there is a preservative-free formulation of mannitol that is FDA-
approved or identify an attribute of that formulation that makes it 
medically unsuitable for certain patients. The nominations state that 
mannitol might also be used to compound other drug products but do not 
identify those products. The nominated bulk drug substance is a 
component of FDA-approved drug products (e.g., NDA 016269). FDA-
approved mannitol is marketed as a preservative-free solution in water 
for injection in various concentrations, including a 25 percent 
concentration in a flip-top vial for administration by intravenous 
infusion only.28 29 30
---------------------------------------------------------------------------

    \27\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \28\ See, e.g., NDA 016269 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/016269s056lbl.pdf.
    \29\ Per the label for NDA 016269, the solutions contain no 
bacteriostat, antimicrobial agent, or added buffer (except for pH 
adjustment) and each is intended only as a single-dose injection.
    \30\ Mannitol is also FDA-approved as a single ingredient as a 
solution for irrigation and as a powder for inhalation.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
    The nominations do not identify an attribute of each of the FDA-
approved 25 percent preservative-free solution products that makes them 
medically unsuitable for certain patients or identify an attribute of 
the FDA-approved drug products that the proposed compounded drug 
product is intended to address. Two commenters supported FDA's proposal 
not to include mannitol on the 503B Bulks List. The commenters provided 
no new information supporting the clinical need for compounding from 
the bulk drug substance mannitol.
    Accordingly, FDA finds no basis to conclude that there is an 
attribute of the FDA-approved products that makes them medically 
unsuitable to treat certain patients for a condition that FDA has 
identified for evaluation and that a proposed compounded product is 
intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    Because the nominations do not identify specific differences 
between drug products that would be compounded using mannitol and FDA-
approved drug products containing mannitol, there is nothing for FDA to 
evaluate under question 2. No further information was supplied on this 
point during the comment period. Therefore, FDA finds no basis to 
conclude that drug products must be compounded using a bulk drug 
substance rather than an FDA-approved drug product.
3. Methacholine Chloride
    Methacholine chloride has been nominated for inclusion on the 503B 
Bulks List to compound drug products that aid in the diagnosis of 
bronchial airway hyperactivity.\31\ The proposed route of 
administration is inhalation tapering dose kits, the proposed dosage 
form is an inhalant, and the proposed strengths are as follows: 8 
dilutions (0.125 mg/mL, 0.25 mg/mL, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 4 mg/
mL, 8 mg/mL, 16 mg/mL) and 10 dilutions (0.031 mg/mL, 0.0625 mg/mL, 
0.125 mg/mL, 0.25 mg/mL, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 4 mg/mL, 8 mg/mL, 
16 mg/mL). The nominated bulk drug substance is a component of an FDA-
approved drug product (NDA 019193). FDA-approved methacholine chloride 
is marketed as a 100 mg/vial powder for solution to be administered 
only by inhalation.\32\ Per its labeling, methacholine chloride is 
reconstituted and diluted to the following concentrations with 0.9 
percent sodium chloride injection or 0.9 percent sodium chloride 
injection containing 0.4 percent phenol (pH 7.0): 0.025 mg/mL, 0.25 mg/
mL, 2.5 mg/mL, 10 mg/mL, and 25 mg/mL.
---------------------------------------------------------------------------

    \31\ See Docket No. FDA-2013-N-1524, document no. FDA-2013-N-
1524-2292.
    \32\ See, e.g., NDA 208943 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/7f538d73-80e2-4c00-911a-df2637e5a4d1/7f538d73-80e2-4c00-911a-df2637e5a4d1.xml.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product
    The nomination does not identify an attribute of the FDA-approved 
drug product that makes it medically unsuitable to treat certain 
patients and that the proposed compounded drug products are intended to 
address. Specifically, the nomination does not identify an attribute of 
the FDA-approved 100 mg/vial powder for solution (for reconstitution) 
that makes it medically unsuitable for certain patients. The commenters 
propose to compound a ready-to-use product from a bulk drug substance 
to seek improved efficiency for prescribers or healthcare providers, or 
to address the possibility that the FDA-approved drug might be 
mishandled by a medical professional, neither of which falls within the 
meaning of clinical need to compound a drug product using a bulk drug 
substance.\33\ Several commenters supported FDA's proposal not to 
include methacholine chloride on the 503B Bulks List. The commenters 
provided no additional information supporting the clinical need for 
compounding from the bulk drug substance methacholine chloride.
---------------------------------------------------------------------------

    \33\ See, e.g., ``List of Bulk Drug Substances for Which There 
Is a Clinical Need Under Section 503B of the Federal Food, Drug, and 
Cosmetic Act,'' 87 FR 4240 at 4248.
---------------------------------------------------------------------------

    Accordingly, FDA finds no basis to conclude that there is an 
attribute of the FDA-approved product that makes it medically 
unsuitable to treat certain patients for a condition that FDA has 
identified for evaluation and that a proposed compounded product is 
intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nomination does not provide support for the position that drug 
products containing methacholine chloride must be compounded from a 
bulk drug substance rather than by diluting the FDA-approved drug

[[Page 20537]]

product. None of the commenters provided support for such a position 
during the comment period. Some commenters stated that there could be a 
benefit from using a bulk drug substance to compound drug products to 
avoid the manipulations that the FDA-approved drug products that 
contain methacholine chloride require before they can be administered 
(e.g., dilution). Commenters also contended that outsourcing 
facilities, as opposed to hospitals, are better able to prepare 
methacholine in the sterile environment that is necessary for the 
sterility of an injectable drug product. This is essentially an 
argument that the approved drug might be mishandled by a medical 
professional, which, as discussed above, does not fall within the 
meaning of clinical need to compound a drug product using a bulk drug 
substance. The commenters also did not establish that drug products in 
the relevant concentrations, including ready-to-use products, cannot be 
prepared from the FDA-approved drug products, which are labeled for 
dilution.
    Having considered these arguments, and because no further 
information was supplied regarding the clinical need for compounding 
from the bulk drug substance, FDA finds no basis to conclude that the 
methacholine chloride drug products proposed to be compounded must be 
prepared using a bulk drug substance rather than the FDA-approved drug 
product.
4. Metoclopramide HCl
    Metoclopramide HCl has been nominated for inclusion on the 503B 
Bulks List to compound drug products that treat chemotherapy-induced 
nausea and vomiting, diabetic gastroparesis, gastroesophageal reflux 
disease, and postoperative nausea and vomiting, among other 
conditions.\34\ The proposed routes of administration are intravenous 
and intramuscular, the proposed dosage form is a suspension, and the 
proposed concentration is 5 mg/mL. The nominators proposed to compound 
both preservative-free and preserved suspensions. However, they failed 
to acknowledge that there is a preservative-free formulation of 
metoclopramide HCl that is FDA-approved or identify an attribute of 
that formulation that would be medically unsuitable for certain 
patients. The nominations state that metoclopramide HCl might also be 
used to compound other drug products but do not identify those 
products. The nominated bulk drug substance is a component of FDA-
approved drug products (e.g., ANDA 073118). FDA-approved metoclopramide 
HCl is marketed as a preservative-free 10 mg/2 mL (5 mg/mL) solution 
for intravenous or intramuscular administration.35 36 37
---------------------------------------------------------------------------

    \34\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \35\ See, e.g., ANDA 073118 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/d693380f-94fa-46df-ad37-4ecf3c59b8b8/d693380f-94fa-46df-ad37-4ecf3c59b8b8.xml.
    \36\ Per the label for ANDA 073118, the solution is 
preservative-free and is intended for intravenous or intramuscular 
administration.
    \37\ Metoclopramide is also FDA-approved as an oral solution, 
metered nasal spray, and tablet.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
    The nominations do not identify an attribute of each of the FDA-
approved preservative-free 10 mg/2 mL (5 mg/mL) solution products for 
intravenous or intramuscular administration that makes them medically 
unsuitable for certain patients or identify an attribute of the FDA-
approved drug products that the proposed compounded drug product is 
intended to address. In particular, the nominations do not identify any 
data or information indicating that there are some patients who need a 
preserved product rather than the FDA-approved preservative-free 
products. In addition, the nominations do not identify any data or 
information indicating that there are some patients who need a 
suspension rather than a solution for intravenous and intramuscular 
administration. Two commenters supported FDA's proposal not to include 
metoclopramide HCl on the 503B Bulks List. Commenters provided no new 
information supporting the clinical need for compounding from the bulk 
substance metoclopramide HCl.
    Accordingly, FDA finds no basis to conclude that there is an 
attribute of the FDA-approved products that makes them medically 
unsuitable to treat certain patients for a condition that FDA has 
identified for evaluation and that a proposed compounded product is 
intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    Because the nominations have not identified an attribute of the 
FDA-approved drug product that makes it medically unsuitable for 
certain patients, FDA has not evaluated whether the proposed drug 
products containing metoclopramide HCl must be compounded from bulk 
drug substances rather than using the FDA-approved drug product. No 
further information was supplied on this point during the comment 
period. Therefore, FDA finds no basis to conclude that the drug 
products proposed to be compounded must be prepared using a bulk drug 
substance rather than an FDA-approved drug product.
5. Nalbuphine HCl
    Nalbuphine HCl has been nominated for inclusion on the 503B Bulks 
List to compound drug products that are used for general anesthesia and 
to treat moderate to severe pain as a preoperative, postoperative, and 
obstetrical analgesia.\38\ The proposed routes of administration are 
intravenous, intramuscular, and subcutaneous, the proposed dosage form 
is a solution, and the proposed concentrations are 10 mg/mL and 20 mg/
mL. The nominators proposed to compound a preservative-free solution 
and a preserved solution. However, they failed to acknowledge that 
there are both a preservative-free solution formulation and a preserved 
solution formulation of nalbuphine HCl that are FDA-approved or 
identify an attribute of those formulations that makes them medically 
unsuitable for certain patients. The nominations state that nalbuphine 
HCl might also be used to compound other drug products but do not 
identify those products. The nominated bulk drug substance is a 
component of FDA-approved drug products (e.g., ANDAs 070914 and 
070918). FDA-approved nalbuphine HCl is marketed as both preservative-
free and as preserved 10 mg/mL and 20 mg/mL solutions for intravenous, 
intramuscular, and subcutaneous administration.39 40
---------------------------------------------------------------------------

    \38\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2298 and FDA-2013-N-1524-2292.
    \39\ See, e.g., ANDA 070914 and 070918 labeling available as of 
the date of this notice at https://www.accessdata.fda.gov/spl/data/f118d0a9-270f-4ced-ba4c-c62e32e0d635/f118d0a9-270f-4ced-ba4c-c62e32e0d635.xml and https://www.accessdata.fda.gov/spl/data/0e1346b6-7c47-4957-b0be-849a84b18a89/0e1346b6-7c47-4957-b0be-849a84b18a89.xml, respectively.
    \40\ Per the labels for ANDA 070914 and 070918, single-dose 
products contain no bacteriostat or antimicrobial agent and unused 
portions must be discarded.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
    The nominations do not identify an attribute of each of the FDA-
approved 10 mg/mL and 20 mg/mL nalbuphine HCl solutions for 
intravenous, intramuscular, and subcutaneous administration that makes 
them medically unsuitable for certain patients or identify an attribute 
of the approved drug products that the proposed compounded drug 
products are

[[Page 20538]]

intended to address. Two commenters supported FDA's proposal not to 
include nalbuphine HCl on the 503B Bulks List. The commenters provided 
no new information supporting the clinical need for compounding from 
the bulk substance nalbuphine HCl.
    Accordingly, FDA finds no basis to conclude that there is an 
attribute of the FDA-approved products that makes them medically 
unsuitable to treat certain patients for a condition that FDA has 
identified for evaluation and that a proposed compounded product is 
intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    Because the nominations do not identify specific differences 
between drug products that would be compounded using nalbuphine HCl and 
approved drug products containing nalbuphine HCl, there is nothing for 
FDA to evaluate under question 2. No further information was supplied 
on this point during the comment period. Therefore, FDA finds no basis 
to conclude that the drug products proposed to be compounded must be 
prepared using a bulk drug substance rather than an FDA-approved drug 
product.
6. Potassium Acetate
    Potassium acetate has been nominated for inclusion on the 503B 
Bulks List to compound drug products that facilitate electrolyte 
management.\41\ The proposed route of administration is intravenous, 
the proposed dosage form is a solution, and the proposed concentration 
is 2 milliequivalents per milliliter (mEq/mL). The nominators proposed 
to compound a preservative-free solution. However, they failed to 
acknowledge that there is a preservative-free formulation of potassium 
acetate that is FDA-approved or identify an attribute of that 
formulation that makes it medically unsuitable for certain patients. 
The nominations state that potassium acetate might also be used to 
compound other drug products but do not identify those products. The 
nominated bulk drug substance is a component of FDA-approved drug 
products (e.g., NDA 018896). FDA-approved potassium acetate is marketed 
as a 40 mEq/20 mL (2 mEq/mL) preservative-free solution for intravenous 
administration.42 43
---------------------------------------------------------------------------

    \41\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \42\ See, e.g., NDA 018896 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/28f98aef-8865-4faf-b491-a77b56513d5d/28f98aef-8865-4faf-b491-a77b56513d5d.xml.
    \43\ Per the label for NDA 018896, the potassium acetate 
solution contains no bacteriostat, antimicrobial agent, or added 
buffer but may contain acetic acid for pH adjustment.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s)
    The nominations do not identify an attribute of each of the FDA-
approved 2 mEq/mL preservative-free solution products that makes them 
medically unsuitable for certain patients or identify an attribute of 
the approved drug products that the proposed compounded drug product is 
intended to address. Two commenters supported FDA's proposal not to 
include potassium acetate on the 503B Bulks List. The commenters 
provided no new information supporting the clinical need for 
compounding from the bulk substance potassium acetate. Accordingly, FDA 
finds no basis to conclude that there is an attribute of the FDA-
approved products that makes them medically unsuitable to treat certain 
patients for a condition that FDA has identified for evaluation and 
that a proposed compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    Because the nominations do not identify specific differences 
between drug products that would be compounded using potassium acetate 
and approved drug products containing potassium acetate, there is 
nothing for FDA to evaluate under question 2. No further information 
was supplied on this point during the comment period. Therefore, FDA 
finds no basis to conclude that the drug products proposed to be 
compounded must be prepared using a bulk drug substance rather than an 
FDA-approved drug product.
7. Procainamide HCl
    Procainamide HCl has been nominated for inclusion on the 503B Bulks 
List to compound drug products that treat ventricular arrhythmia.\44\ 
The proposed routes of administration are intramuscular and 
intravenous, the proposed dosage form is a solution, and the proposed 
concentrations are 100 mg/mL and 500 mg/mL. The nominators proposed to 
compound a preserved solution. However, they failed to acknowledge that 
there is a preserved formulation of procainamide HCl that is FDA-
approved or identify an attribute of that formulation that makes it 
medically unsuitable for certain patients. The nominations state that 
procainamide HCl might also be used to compound other drug products but 
do not identify those products. The nominated bulk drug substance is a 
component of FDA-approved drug products (e.g., ANDA 089069). FDA-
approved procainamide HCl is marketed as 100 mg/mL and 500 mg/mL 
preserved solutions for intramuscular and intravenous 
administration.45 46
---------------------------------------------------------------------------

    \44\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \45\ See, e.g., ANDA 089069 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/6918f728-6c39-4be9-b0f6-6eb5f12bbcaf/6918f728-6c39-4be9-b0f6-6eb5f12bbcaf.xml.
    \46\ Per the label for ANDA 089069, each milliliter of the 2 mL 
vial contains procainamide hydrochloride 500 mg, methylparaben 1 mg, 
and sodium metabisulfite 1.8 mg added in water for injection, and 
may contain hydrochloric acid and/or sodium hydroxide for pH 
adjustment.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product(s).
    The nominations do not identify an attribute of each of the FDA-
approved 100 mg/mL and 500 mg/mL preserved solutions that makes them 
medically unsuitable for certain patients or identify an attribute of 
the approved drug products that the proposed compounded drug products 
are intended to address. Two commenters supported FDA's proposal not to 
include procainamide HCl on the 503B Bulks List. Commenters provided no 
new information supporting the clinical need for compounding from the 
bulk drug substance procainamide HCl. Accordingly, FDA finds no basis 
to conclude that there is an attribute of the FDA-approved products 
that makes them medically unsuitable to treat certain patients for a 
condition that FDA has identified for evaluation and that a proposed 
compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    Because the nominations do not identify specific differences 
between drug products that would be compounded using procainamide HCl 
and approved drug products containing procainamide HCl, there is 
nothing for FDA to evaluate under question 2. No further information 
was supplied on this point during the comment period. Therefore, FDA 
finds no basis to conclude that the drug products proposed to be 
compounded must be prepared using a bulk drug substance rather than an 
FDA-approved drug product.

[[Page 20539]]

8. Sodium Bicarbonate
    Sodium bicarbonate has been nominated for inclusion on the 503B 
Bulks List to compound drug products that treat various conditions, 
including metabolic acidosis, certain drug intoxications, severe 
diarrhea, and indigestion.\47\ The proposed route of administration is 
intravenous, the proposed dosage forms are an injectable solution and 
injection solutions, and the proposed strengths range from 4.2 percent 
to 8.4 percent. The nominators proposed to compound a preservative-free 
solution. However, they failed to acknowledge that there is an FDA-
approved preservative-free formulation of sodium bicarbonate or 
identify an attribute of that formulation that makes it medically 
unsuitable for certain patients. The nominations state that sodium 
bicarbonate might also be used to compound other drug products but do 
not identify those products. The nominated bulk drug substance is a 
component of FDA-approved drug products (e.g., ANDAs 203449 and 
202494). FDA-approved sodium bicarbonate is a single-dose, 
preservative-free 1 mEq/mL (8.4 percent) solution for intravenous 
administration. 48 49 50 
---------------------------------------------------------------------------

    \47\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298; see also Docket No. FDA-2015-N-
3469, document no. FDA-2015-N-3469-0095.
    \48\ See, e.g., ANDA 203449 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/0e955d36-928c-4f09-9b34-0cc954e5b1f4/0e955d36-928c-4f09-9b34-0cc954e5b1f4.xml.
    \49\ Per the label for ANDA 203449, the solutions contain no 
bacteriostat, antimicrobial agent, or added buffer and are intended 
only for use as a single-dose injection.
    \50\ Sodium bicarbonate is also FDA-approved in combination with 
other ingredients as an injectable, solution for irrigation, and 
various oral formulations.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Product
    The nominations do not identify an attribute of the FDA-approved 
drug products, including the single-dose, preservative-free 1 mEq/mL 
(8.4 percent) solution, that makes them medically unsuitable to treat 
certain patients and that the proposed compounded drug products are 
intended to address. Two commenters supported FDA's proposal not to 
include sodium bicarbonate on the 503B Bulks List. Commenters provided 
no new information supporting the clinical need for compounding from 
the bulk drug substance sodium bicarbonate. Accordingly, FDA finds no 
basis to conclude that there is an attribute of the FDA-approved 
product that makes it medically unsuitable to treat certain patients 
for a condition that FDA has identified for evaluation and that the 
proposed compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nominations do not provide support for the position that the 
proposed sodium bicarbonate products with concentrations at or below 
8.4 percent (1 mEq/mL) must be compounded from bulk drug substances 
rather than by diluting the FDA-approved drug product. Because no data 
or information was submitted supporting the need for a higher 
concentration, we have not considered whether a bulk drug substance 
must be used to compound a sodium bicarbonate drug product at 
concentrations higher than 8.4 percent. No comments provided support 
for the position that the proposed sodium bicarbonate products with 
concentrations at or below 8.4 percent (1 mEq/mL) must be compounded 
from bulk drug substances rather than by diluting the FDA-approved drug 
product. Several commenters stated that the ability to compound sodium 
bicarbonate using a bulk drug substance was crucial to address 
persistent drug shortages. However, as explained above, section 503B of 
the FD&C Act already provides for compounding from a bulk drug 
substance if the drug product compounded from such bulk drug substance 
is on the FDA drug shortage list at the time of compounding, 
distribution, and dispensing. The Agency does not interpret supply 
issues, such as shortages and backorders, to be within the meaning of 
``clinical need'' for compounding with a bulk drug substance.\51\ Other 
commenters asserted that there could be a benefit from using the bulk 
drug substance sodium bicarbonate to compound drug products to avoid 
the manipulations that the FDA-approved drug products that contain 
sodium bicarbonate require before they can be administered (e.g., 
dilution or drawing the drug into a syringe before administration). One 
commenter proposes to compound ready-to-use products from bulk drug 
substances to seek improved efficiency for prescribers or healthcare 
providers and to address the possibility that the approved drug might 
be mishandled by a medical professional, neither of which falls within 
the meaning of clinical need to compound a drug product using a bulk 
drug substance.
---------------------------------------------------------------------------

    \51\ See, e.g., ``List of Bulk Drug Substances for Which There 
Is a Clinical Need Under Section 503B of the Federal Food, Drug, and 
Cosmetic Act,'' 87 FR 4240 at 4248.
---------------------------------------------------------------------------

    Having considered these arguments, and because no further 
information was supplied regarding the clinical need for compounding 
from the bulk drug substance, FDA finds no basis to conclude that the 
drug products proposed to be compounded must be prepared using a bulk 
drug substance rather than an FDA-approved drug product.
9. Sodium Nitroprusside
    Sodium nitroprusside has been nominated for inclusion on the 503B 
Bulks List to compound drug products to treat acute decompensated heart 
failure and acute hypertension.\52\ The proposed route of 
administration is an injection, the proposed dosage form is a solution, 
and the proposed concentration is 12.5 mg/mL. The nomination states 
that sodium nitroprusside might also be used to compound other drug 
products but does not identify those products. The nominated bulk drug 
substance is a component of FDA-approved drug products (e.g., ANDA 
209493). FDA-approved sodium nitroprusside is marketed as a 50 mg/2 mL 
(25 mg/mL) solution that must be diluted prior to injection. 
53 54 
---------------------------------------------------------------------------

    \52\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0238.
    \53\ See, e.g., ANDA 209493 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/37060217-1ad1-462b-a1d0-7271c68ed881/37060217-1ad1-462b-a1d0-7271c68ed881.xml.
    \54\ Sodium nitroprusside is also FDA-approved as a solution for 
intravenous administration.
---------------------------------------------------------------------------

a. Suitability of FDA-Approved Drug Products
    Although the nominator proposes to make a drug product that has a 
lower concentration than the approved drug product with the same API, 
the nomination does not identify an attribute of each of the FDA-
approved 50 mg/2 mL solution for dilution products that makes them 
medically unsuitable for certain patients or identify an attribute of 
the FDA-approved drug products that the proposed compounded drug 
product is intended to address. Two commenters supported FDA's proposal 
not to include sodium nitroprusside on the 503B Bulks List. Commenters 
provided no new information supporting the clinical need for 
compounding from the bulk drug substance sodium nitroprusside. 
Accordingly, FDA finds no basis to conclude that there is an attribute 
of the FDA-approved products

[[Page 20540]]

that makes them medically unsuitable to treat certain patients for a 
condition that FDA has identified for evaluation and that a proposed 
compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nomination does not provide support for the position that drug 
products containing sodium nitroprusside must be compounded from bulk 
drug substances rather than using the FDA-approved drug products. No 
further information was supplied on this point during the comment 
period. Therefore, FDA finds no basis to conclude that the drug 
products proposed to be compounded must be prepared using a bulk drug 
substance rather than an FDA-approved drug product.
10. Verapamil HCl
    Verapamil HCl has been nominated for inclusion on the 503B Bulks 
List to compound drug products that treat atrial fibrillation and 
flutter, hypertension, and paroxysmal supraventricular tachycardia, 
among other conditions.\55\ The proposed route of administration is 
intravenous, the proposed dosage form is a solution, and the proposed 
concentration is 2.5 mg/mL. The nominators proposed to compound a 
preservative-free solution. However, they failed to acknowledge that 
there is a preservative-free formulation of verapamil HCl that is FDA-
approved or identify an attribute of that formulation that makes it 
medically unsuitable for certain patients. The nominations state that 
verapamil HCl might also be used to compound other drug products but do 
not identify those products. The nominated bulk drug substance is a 
component of FDA-approved drug products (e.g., ANDA 070737). FDA-
approved verapamil HCl is marketed as a preservative-free 5 mg/2 mL 
(2.5 mg/mL) solution for intravenous administration. 
56 57 58 
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    \55\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2298 and FDA-2013-N-1524-2292.
    \56\ See, e.g., ANDA 070737 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/072b89b5-6d71-4f63-9686-d715d9256241/072b89b5-6d71-4f63-9686-d715d9256241.xml.
    \57\ Per the label for ANDA 070737, the solution contains no 
bacteriostat or antimicrobial agent, is intended for single-dose 
intravenous administration, and may contain hydrochloric acid for pH 
adjustment.
    \58\ Verapamil HCl is also FDA-approved in various oral capsule 
and tablet formulations.
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a. Suitability of FDA-Approved Drug Products
    The nominations do not identify an attribute of each of the FDA-
approved preservative-free 5 mg/2 mL (2.5 mg/mL) solution products for 
intravenous administration that makes them medically unsuitable for 
certain patients or identify an attribute of the FDA-approved drug 
products that the proposed compounded drug products are intended to 
address. Two commenters supported FDA's proposal not to include 
verapamil HCl on the 503B Bulks List. Commenters provided no new 
information supporting the clinical need for compounding from the bulk 
drug substance verapamil HCl. Accordingly, FDA finds no basis to 
conclude that there is an attribute of the FDA-approved products that 
makes them medically unsuitable to treat certain patients for a 
condition that FDA has identified for evaluation and that a proposed 
compounded product is intended to address.
b. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    Because the nominations do not identify specific differences 
between drug products that would be compounded using verapamil HCl and 
FDA-approved drug products containing verapamil HCl, there is nothing 
for FDA to evaluate under question 2. No further information was 
supplied on this point during the comment period. Therefore, FDA finds 
no basis to conclude that drug products proposed to be compounded must 
be prepared using a bulk drug substance rather than an FDA-approved 
drug product.

IV. Other Issues Raised in Nominations and Comments

    Two commenters expressed concern that nominations submitted before 
FDA issued the Clinical Need Guidance in March 2019 are disadvantaged 
in demonstrating clinical need because the nominators might not have 
fully understood FDA's thinking on clinical need when they submitted 
their nominations.\59\ In addition, one commenter expressed concern 
that FDA is evaluating bulk drug substances for clinical need pursuant 
to a non-binding guidance document.
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    \59\ See 84 FR 7383, which is available at https://www.federalregister.gov/documents/2019/03/04/2019-03807/evaluation-of-bulk-drug-substances-nominated-for-use-in-compounding-under-section-503b-of-the.
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    FDA disagrees with these comments. First, as explained in section 
II.B of this notice, FDA is evaluating bulk drug substances nominated 
for inclusion on the 503B Bulks List under the ``clinical need'' 
standard provided by the FD&C Act, as amended by the Drug Quality and 
Security Act in 2013.\60\ The analysis under the statutory ``clinical 
need'' standard described in this notice is consistent with the 
approach described in FDA's Clinical Need Guidance. Second, the 
commenters fail to note the many opportunities that nominators and 
interested members of the public had to provide information supporting 
a clinical need to compound drug products containing the bulk drug 
substances that are the subject of this notice. As explained in section 
II.A, a public docket, FDA-2015-N-3469, is available for interested 
persons to submit nominations, including updated or revised 
nominations, or comments on nominated substances. Furthermore, during 
the comment periods for the September 2019 and July 2020 Federal 
Register notices, commenters had an additional opportunity to submit 
comments to the docket associated with those notices to provide 
additional supporting information for the bulk drug substances that are 
the subject of this notice, and many did so. Moreover, in response to a 
request from a commenter, FDA reopened the comment period on the July 
2020 Federal Register notice for an additional 30 days to allow 
interested persons yet another opportunity to submit additional 
comments.
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    \60\ See Public Law 113-54, section 102(a) (2013), which is 
available at https://www.govinfo.gov/content/pkg/PLAW-113publ54/pdf/PLAW-113publ54.pdf.
---------------------------------------------------------------------------

    Three commenters on the bulk drug substances addressed in this 
notice asserted that FDA is regulating and interfering with the 
practice of medicine by not placing bulk drug substances on the 503B 
Bulks List despite some physicians wanting to prescribe drug products 
compounded from those bulk drug substances. FDA disagrees with these 
comments. The Agency's evaluation under the clinical need standard only 
regulates the ability of certain compounded drug products to reach the 
market and is well within the Agency's authorities.\61\ The Agency is 
fulfilling its statutory mandate of regulating outsourcing facilities'

[[Page 20541]]

production and distribution of compounded drug products, not 
interfering with physicians' clinical decisions regarding which drug 
products to prescribe. Indeed, a Federal court considered the very 
claim raised in these comments and determined that FDA's evaluation 
under the clinical need standard ``regulates the type of drug that 
reaches the marketplace,'' a decision that ``rests well within FDA's 
regulatory authority under the FDCA . . . and . . . does not intrude on 
the practice of medicine.'' \62\
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    \61\ See United States v. Evers, 643 F.2d 1043, 1048 (5th Cir. 
1981) (``[W]hile the [FDCA] was not intended to regulate the 
practice of medicine, it was obviously intended to control the 
availability of drugs for prescribing by physicians.''); United 
States v. Regenerative Scis., LLC, 741 F.3d 1314, 1319-20 (D.C. Cir. 
2014); (citing Evers and noting that the FDCA ``regulate[s] the 
distribution of drugs by licensed physicians''); Gonzales v. Raich, 
545 U.S. 1, 28 (2005) (``the dispensing of new drugs, even when 
doctors approve their use must await federal approval.'').
    \62\ Athenex Inc. v. Azar, 397 F. Supp. 3d 56, 72 (D.D.C. 2019).
---------------------------------------------------------------------------

    Several commenters expressed concern that FDA is promoting the off-
label use of FDA-approved drug products. FDA disagrees with this 
comment. In performing the clinical need evaluation, FDA asks a 
limited, threshold question to determine whether there might be a 
clinical need for a compounded drug product, by asking what attributes 
of the approved drug product the proposed compounded drug product would 
change and why. Asking this question helps ensure that if a bulk drug 
substance is included on the 503B Bulks List, it is to compound drug 
products that include a needed change to an approved drug product 
rather than to compound drug products without such a change. We do not 
suggest that the approved drug product or products prepared from it are 
approved for the use proposed by the nomination being evaluated.
    One commenter expressed concern with FDA's decision to evaluate 
clinical need in the context of the specific drug products proposed to 
be compounded in the nomination. This commenter stated that requiring 
nominators to provide information on specific drug products is 
unnecessary to determine whether there is a clinical need for the bulk 
drug substance. This commenter also asserted that FDA should not 
evaluate bulk drug substances in the context of finished dosage forms 
for drug products. FDA disagrees with these comments. As explained in 
section I of this notice, section 503B of the FD&C Act limits the bulk 
drug substances that outsourcing facilities can use in compounding to 
those that are used to compound drugs in shortage or that appear on a 
list developed by FDA of bulk drug substances for which there is a 
clinical need.\63\ Section 503B of the FD&C Act includes this 
limitation, among others, to help ensure that outsourcing facilities do 
not grow into conventional manufacturing operations making unapproved 
new drug products without complying with critical requirements, such as 
new drug approval. Outsourcing facilities, as opposed to other 
compounders, may compound and distribute drug products for ``office 
stock'' without first receiving a prescription for an individually 
identified patient \64\ and without conditions on interstate 
distribution that are applicable to other compounded drugs (Ref. 
4).\65\ Because of these differences and others, section 503B of the 
FD&C Act places different conditions on drugs compounded by outsourcing 
facilities, including limitation on the outsourcing facilities' use of 
bulk drug substances, which are more stringent than those placed on 
other compounders' use of bulk drug substances.\66\ The clinical need 
standard in section 503B of the FD&C Act requires FDA to perform a 
sorting function--to distinguish bulk drug substances for which there 
is a clinical need from those for which there is not--and this requires 
FDA to apply its expertise to consider whether there is a need for the 
finished drug product that would be compounded from the bulk drug 
substance. Indeed, a Federal court considered the very claim raised in 
these comments and determined that ``[o]nly when `clinical need' is 
assessed against the availability and suitability of an approved drug 
does the term perform the classifying function that Congress 
intended.'' In reaching this view, the court found that only when the 
clinical need evaluation ``considers the actual way in which the active 
pharmaceutical ingredient supplies a therapeutic benefit--by its 
administration as a finished drug product--does the inquiry produce the 
categorization that Congress surely envisioned'' in enacting section 
503B of the FD&C Act.\67\ FDA's clinical need assessments help limit 
patient exposure to compounded drug products that have not been 
demonstrated to be safe and effective to those situations in which the 
compounded drug product is necessary for patient treatment. In 
addition, FDA's assessments preserve the incentives for applicants to 
invest in the research and testing required to obtain FDA approval and 
continue to manufacture FDA-approved drug products, thereby helping to 
maintain a supply of high-quality, safe, and effective drugs.
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    \63\ Section 503B(a)(2(A)(i) and (ii) of the FD&C Act.
    \64\ By contrast, to qualify for the exemptions in section 503A 
of the FD&C Act, drug products compounded by licensed pharmacists in 
State-licensed pharmacies or Federal facilities, or by licensed 
physicians, must be compounded based on the receipt of a valid 
prescription for an individually identified patient. This means that 
for drug products compounded under section 503A to meet the 
conditions of that section and qualify for the exemptions in the 
statute, the pharmacist or physician compounding under section 503A 
of the FD&C Act must compound either: (1) after receiving a valid 
prescription for an identified, individual patient or (2) before 
receiving a patient-specific prescription, in limited quantities, 
based on a history of receiving valid orders generated solely within 
the context of an established relationship with the patient or 
prescriber. See FDA's final guidance for industry ``Prescription 
Requirement Under Section 503A of the Federal Food, Drug, and 
Cosmetic Act'' (December 2016).
    \65\ For drug products compounded under section 503A of the FD&C 
Act to meet the conditions of that section and qualify for the 
exemptions in the statute, drug products must be compounded in a 
State: (i) that has entered into a memorandum of understanding with 
the Secretary which addresses the distribution of inordinate amounts 
of compounded drug products interstate and provides for appropriate 
investigation by a State agency of complaints relating to compounded 
drug products distributed outside such State; or (ii) that has not 
entered into the memorandum of understanding described in clause (i) 
and the licensed pharmacist, licensed pharmacy, or licensed 
physician distributes (or causes to be distributed) compounded drug 
products out of the State in which they are compounded in quantities 
that do not exceed 5 percent of the total prescription orders 
dispensed or distributed by such pharmacy or physician (see section 
503A(b)(3)(a)(B)(i) and (ii) of the FD&C Act).
    \66\ Licensed pharmacies and physicians who compound drugs under 
the conditions of section 503A of the FD&C Act, including the 
requirement to compound drugs only pursuant to a prescription for an 
identified individual patient, may use many bulk drug substances by 
operation of the statute, without action by FDA. See section 
503A(b)(1)(A)(i)(I) and (II) of the FD&C Act (providing that a drug 
product may be compounded consistent with the exemptions in section 
503A of the FD&C Act if the licensed pharmacist or licensed 
physician compounds the drug product using bulk drug substances that 
comply with the standards of an applicable USP or NF monograph, if a 
monograph exists, and the USP chapters on pharmacy compounding; or 
if such a monograph does not exist, are drug substances that are 
components of drugs approved by the Secretary).
    \67\ Athenex Inc. at 65.
---------------------------------------------------------------------------

    Some of the bulk drug substance nominations and comments discussed 
above asserted that there could be a benefit from using a bulk drug 
substance to compound drug products to avoid the manipulations that the 
FDA-approved drug products that contain these bulk drug substances 
require before they can be administered (e.g., dilution or drawing the 
drug into a syringe before administration). As explained above, when a 
bulk drug substance is a component of an FDA-approved drug, we ask 
whether there is a basis to conclude that an attribute of each FDA-
approved drug product makes each one medically unsuitable to treat 
certain patients for their condition, an interpretation that protects 
patients and the integrity of the drug approval process. The 
nominations proposing to compound drug products in ready-to-use form 
containing bulk drug substances in one or more FDA-approved drug 
products do not show

[[Page 20542]]

that the FDA-approved drug product, when not manufactured in the ready-
to-use form, is medically unsuitable for certain patients. Nor do the 
nominations and comments establish that drug products in the relevant 
concentrations, including ready-to-use products, cannot be prepared 
from the FDA-approved drug products. Rather, they propose to compound a 
ready-to-use product from bulk drug substances to seek improved 
efficiency for prescribers or healthcare providers, or to address the 
possibility that the FDA-approved drug might be mishandled by a medical 
professional, neither of which falls within the meaning of clinical 
need to compound a drug product using a bulk drug substance.
    Two commenters requested changes to the Interim Policy. These 
comments are outside the scope of FDA's bulk drug substance evaluations 
and decisions that are the subject of this notice. FDA welcomes public 
comments on its guidance documents that address human drug compounding. 
Comments on the Interim Policy may be submitted to the docket for the 
guidance, Docket No. FDA-2015-D-3539, at any time at https://www.regulations.gov.

V. Conclusion

    For the reasons stated above, we find that there is a clinical need 
for outsourcing facilities to compound drug products using the bulk 
drug substance quinacrine HCl for oral use only, and therefore we are 
now including it on the 503B Bulks List. In addition, we find that 
there is no clinical need for outsourcing facilities to compound using 
the bulk drug substances hydroxyzine HCl, mannitol, methacholine 
chloride, metoclopramide HCl, nalbuphine HCl, potassium acetate, 
procainamide HCl, sodium bicarbonate, sodium nitroprusside, and 
verapamil HCl, and therefore we are not including these bulk drug 
substances on the 503B Bulks List.

VI. References

    The following references are on display at the Dockets Management 
Staff (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at https://www.regulations.gov. FDA has 
verified the website addresses, as of the date this document publishes 
in the Federal Register, but websites are subject to change over time.

1. FDA, Guidance for Industry, ``Interim Policy on Compounding Using 
Bulk Drug Substances Under Section 503B of the Federal Food, Drug, 
and Cosmetic Act,'' January 2017 (available at https://www.fda.gov/media/94402/download).
2. FDA, Guidance for Industry, ``Evaluation of Bulk Drug Substances 
Nominated for Use in Compounding Under Section 503B of the Federal 
Food, Drug, and Cosmetic Act,'' March 2019 (available at https://www.fda.gov/media/121315/download).
3. FDA Memorandum to File, ``Clinical Need for Quinacrine 
Hydrochloride in Compounding Under Section 503B of the FD&C Act,'' 
March 2021.
4. FDA Guidance for Industry, ``Prescription Requirement Under 
Section 503A of the Federal Food, Drug, and Cosmetic Act,'' December 
2016 (available at https://www.fda.gov/media/97347/download).

    Dated: April 3, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-07237 Filed 4-5-23; 8:45 am]
BILLING CODE 4164-01-P