[Federal Register Volume 88, Number 160 (Monday, August 21, 2023)]
[Notices]
[Pages 56837-56843]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-17881]


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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) 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 two bulk drug substances that FDA has considered 
and is not including on the list at this time: ephedrine sulfate and 
hydroxychloroquine sulfate. 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 August 21, 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, 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 set forth 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

[[Page 56838]]

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 an 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 two 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), November 23, 2022 (87 
FR 71642), and April 6, 2023 (88 FR 20531). 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 
each of 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.'' 21 CFR 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 U.S. 
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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    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 the 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.\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 FDA's evaluation 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. We update guidances 
periodically. For the most recent version of a guidance, check the 
FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
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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

[[Page 56839]]

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.\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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    Both bulk drug substances addressed in this notice, ephedrine 
sulfate and hydroxychloroquine sulfate, are components of FDA-approved 
drug products. FDA therefore began its evaluation by asking one or 
both, as applicable, of the following questions:
    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 two 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.

III. FDA's Determinations Regarding Substances Proposed for the 503B 
Bulks List

    The two 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 ephedrine sulfate 
(Refs. 1 and 2) and hydroxychloroquine sulfate (Ref. 3).
    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).\15\ In the present notice, after review of the comments 
submitted to the docket for the September 2019 notice, FDA is making 
its final determination not to include ephedrine sulfate on the 503B 
Bulks List. At this time, FDA is not making a final determination 
regarding famotidine, hydralazine HCl, sodium tetradecyl sulfate, 
trypan blue, and vecuronium bromide.\16\ These substances remain under 
consideration by FDA.
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    \15\ See 84 FR 46014.
    \16\ FDA made a final determination not to include dipyridamole 
on the 503B Bulks List (see 87 FR 4240). FDA made a final 
determination not to include methacholine chloride and sodium 
bicarbonate on the 503B Bulks List (see 88 FR 20531).
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    In March 2021, the Agency issued a Federal Register notice in which 
it evaluated five nominated bulk drug substances under the section 503B 
statutory standard (the March 2021 notice).\17\ FDA proposed to include 
quinacrine hydrochloride (for oral use only) on the 503B Bulks List. 
FDA proposed not to include bromfenac sodium, mitomycin-C, nepafenac, 
and hydroxychloroquine sulfate on the 503B Bulks List. In April 2023, 
after review of comments submitted to the March 2021 docket, the Agency 
issued a Federal Register notice, making its final determination to 
include quinacrine hydrochloride on the 503B Bulks List to compound 
drug products for oral use only.\18\ In the present notice, after 
review of the comments submitted to the docket for the March 2021 
notice, FDA is making its final determination

[[Page 56840]]

not to include hydroxychloroquine sulfate on the 503B Bulks List. At 
this time, FDA is not making a final determination regarding bromfenac 
sodium, mitomycin-C, and nepafenac. These substances remain under 
consideration by FDA.
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    \17\ 86 FR 15673.
    \18\ 88 FR 20531.
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    Because both ephedrine sulfate and hydroxychloroquine sulfate 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.

A. Ephedrine Sulfate

    Ephedrine sulfate was nominated for inclusion on the 503B Bulks 
List to compound drug products to treat acute bronchospasm, drug 
induced hypotension due to anesthesia, and nasal congestion.\19\ The 
proposed route of administration is intravenous, the proposed dosage 
form is a preservative-free solution, and the proposed strengths are 5 
mg/mL and 10 mg/mL.\20\ During the comment period for the September 
2019 notice, a commenter proposed that there was a clinical need to 
compound higher concentration ephedrine sulfate drug products to treat 
priapism. The proposed route of administration for this new proposed 
use is intracorporeal, the proposed dosage form is a solution, and the 
proposed strength is 100 mg/mL.\21\ Because additional references were 
provided supporting this proposed use and route of administration, FDA 
considered this use and this route of administration before reaching a 
final clinical need determination (Ref. 2).
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    \19\ See Docket No. FDA-2013-N-1524, document nos. FDA-2013-N-
1524-2292 and FDA-2013-N-1524-2298.
    \20\ Nominator(s) proposed to compound a preservative-free 
solution. However, they failed to acknowledge that there is a 
preservative-free formulation of ephedrine sulfate that is marketed 
or explain why that formulation would be medically unsuitable for 
certain patients. Additionally, since the September 2019 notice, 
ephedrine sulfate has been FDA-approved as a preservative-free, 25 
mg/5mL (5 mg/mL) single dose, premixed, labeled syringe (not for 
dilution) (See NDA 213407 labeling available as of the date of this 
notice at https://www.accessdata.fda.gov/spl/data/3155f177-4aff-4560-9f7c-f77649d065d9/3155f177-4aff-4560-9f7c-f77649d065d9.xml) and 
a preservative-free, 50 mg/10mL (5 mg/mL) single dose, premixed vial 
(See NDA 213407 labeling available as of the date of this notice at 
https://www.accessdata.fda.gov/spl/data/54276f21-7800-44f4-ae51-0060fb1c43ad/54276f21-7800-44f4-ae51-0060fb1c43ad.xml).
    \21\ See Docket No. FDA-2018-N-3240, document no. FDA-2018-N-
3240-0047. Other commenters proposed additional uses and routes of 
administration: intramuscular administration of a higher 
concentration of ephedrine sulfate for postoperative nausea and 
vomiting refractory to traditional antiemetics; intravenous or 
intrathecal administration of ephedrine sulfate for hypotension in 
patients that received a certain type of anesthesia or received an 
overdose of a drug that can lower blood pressure; and continuous 
(intravenous) infusion to prevent hypotension secondary to spinal 
anesthesia during cesarean section. These other uses will not be 
considered further because the commenters either proposed uses or 
routes of administration already evaluated in the September 2019 
notice and the literature provided in the comments did not contain 
any new information that would support FDA's reconsideration of its 
proposal on the substance, or the commenters proposed new uses or 
routes of administration but did not provide sufficient information, 
including citations to relevant literature, supporting a clinical 
need.
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    As noted above, ephedrine sulfate is a component of FDA-approved 
drug products (e.g., NDAs 208943 and 208289). FDA-approved ephedrine 
sulfate is available as a 1 mL single-dose drug product that contains 
50 mg/mL (50 mg/mL) ephedrine sulfate, preservative-free, for 
intravenous administration, and as a 10 mL multi-dose vial that 
contains 500 mg/10 mL (50 mg/mL) ephedrine sulfate, with preservative, 
for intravenous administration.\22\ These ephedrine sulfate drug 
products must be diluted before administration to achieve the desired 
concentration for their labeled indications. Ephedrine sulfate is also 
available as a 5 mL single dose, prefilled syringe that contains 25 mg/
5 mL (5 mg/mL) ephedrine sulfate, preservative-free, for intravenous 
administration, and as a 10 mL single dose, prefilled syringe that 
contains 50 mg/10 mL (5 mg/mL) ephedrine sulfate, preservative-free, 
for intravenous administration.\23\ The products available as prefilled 
syringes are premixed formulations and do not require dilution prior to 
administration for their labeled indications.
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    \22\ See, e.g., NDAs 208943 and 208289.
    \23\ See, e.g., NDAs 208289 and NDA 213407.
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1. Suitability of FDA-Approved Drug Product
    In its proposal to not include ephedrine sulfate on the 503B Bulks 
List, FDA explained that the nominations did not identify an attribute 
of the FDA-approved drug products that make them medically unsuitable 
to treat certain patients and that the proposed compounded drug 
products are intended to address. Several comments received agreed with 
FDA's proposal not to include ephedrine sulfate on the 503B Bulks 
List.\24\ Several comments were not supportive. However, none of the 
comments received on FDA's proposal provided information that led FDA 
to change its position on this question. A commenter stated that there 
is a clinical need for an intracorporeal, single-ingredient, higher 
concentration ephedrine sulfate compounded drug product for use to 
treat priapism.\25\ However, the commenter failed to identify an 
attribute of the FDA-approved drug products, including the intravenous 
formulations of ephedrine sulfate 50 mg/mL solution for dilution (e.g., 
NDA 208943), that is medically unsuitable for patients with priapism or 
identify an attribute of the FDA-approved products that the proposed 
compounded drug product is intended to address. The FDA-approved 
products are available in the concentration of 50 mg/mL (undiluted) and 
can be administered in a sufficient volume or in multiple doses to 
achieve the proposed dose of 100 mg for the treatment of 
priapism.26 27 A commenter also stated that the FDA-approved 
ephedrine sulfate products are not compatible with new technology such 
as syringe-robotics and vial docking technology to easily make stock

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solutions to produce onsite.\28\ However, FDA is not aware of issues 
with using the FDA-approved product when the compounding process and 
equipment are appropriately selected. Additionally, these arguments do 
not take into account the approval by FDA of two ephedrine sulfate drug 
products that are pre-diluted and thus would not need additional 
manipulation at the bedside by a medical provider before use for their 
labeled indications.\29\ Commenters also made various arguments 
addressing supply issues, convenience, and cost.\30\ However, as 
explained above, FDA does not consider supply issues, convenience, and 
costs to be within the meaning of ``clinical need'' for compounding 
with a bulk drug substance under section 503B of the FD&C Act. 
Accordingly, with respect to the ephedrine sulfate drug products 
proposed to be compounded, FDA finds no basis to conclude that an 
attribute of the FDA-approved product makes it medically unsuitable to 
treat certain patients for a condition that FDA has identified for 
evaluation.
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    \24\ See Docket No. FDA-2018-N-3240, document nos. FDA-2018-N-
3240-0043, FDA-2018-N-3240-0045, FDA-2018-N-3240-0050, FDA-2018-N-
3240-0052.
    \25\ See Docket No. FDA-2018-N-3240, document no. FDA-2018-N-
3240-0047.
    \26\ In noting this issue, we do not mean to suggest or imply 
that the approved drug products, or products prepared from them, are 
approved for the use proposed by the commenter. For the Part 1.a. 
analysis we asked a limited, threshold question to determine whether 
there might be clinical need for a compounded drug product, by 
asking what attributes of the FDA-approved drug the proposed 
compounded drug would change, and why. Because this proposed product 
did not pass through Part 1.a. (for the reasons described in the 
memo) we did not reach Part 2 and therefore did not consider the 
Part 2 factors, including the available evidence of effectiveness or 
lack of effectiveness of a drug product compounded with ephedrine 
sulfate. FDA-approved ephedrine sulfate 50 mg/mL solution for 
dilution has not been shown to be safe and effective for 
intracorporal administration to treat priapism.
    \27\ The commenter proposes that in order to achieve a 100 mg/mL 
dose, more than one vial of FDA-approved ephedrine sulfate is 
needed. While there is a 50 mg/mL formulation that is available in 1 
mL vials, there is also an FDA-approved formulation of intravenous 
ephedrine sulfate solution that is available as a 500 mg/10 mL vial 
(dilution required). In order to achieve the 100 mg/mL dose, 2 mL of 
ephedrine sulfate could be used.
    \28\ See Docket No. FDA-2018-N-3240, document no. FDA-2018-N-
3240-0047.
    \29\ See footnote 20 above.
    \30\ See Docket No. FDA-2018-N-3240, document nos. FDA-2018-N-
3240-0053, FDA-2018-N-3240-0049, and FDA-2018-N-3240-0047.
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2. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    The nominations do not provide support for the position that drug 
products containing ephedrine sulfate must be compounded from bulk drug 
substances rather than the approved drug product. No further 
information was supplied during the comment period that supports the 
need for compounding ephedrine sulfate drug products from bulk drug 
substances. Because there is no basis to conclude that an attribute of 
the FDA-approved ephedrine sulfate products makes them medically 
unsuitable for some patients; however, FDA has not considered whether 
there is a basis to conclude that the proposed compounded products must 
be made from a bulk drug substance rather than from an FDA-approved 
product.

B. Hydroxychloroquine Sulfate

    Hydroxychloroquine sulfate was nominated for inclusion on the 503B 
Bulks List to compound drug products to treat rheumatoid arthritis and 
juvenile arthritis (also known as juvenile idiopathic arthritis).\31\ 
The proposed route of administration is oral, the proposed dosage forms 
are a capsule or suspension, and the proposed doses or concentrations 
are 200 to 500 mg capsules and 100 to 200 mg/mL suspension. The 
nominated bulk drug substance is a component of FDA-approved drug 
products (e.g., NDA 009768, ANDA 040104, and ANDA 
213342).32 33 34
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    \31\ See Docket No. FDA-2015-N-3469, document no. FDA-2015-N-
3469-0165.
    \32\ See, e.g., NDA 009768 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf.
    \33\ See, e.g., ANDA 040104 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/e5375cf7-9423-40a4-bd33-ce5812da4a73/e5375cf7-9423-40a4-bd33-ce5812da4a73.xml.
    \34\ See, e.g., ANDA 213342 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/spl/data/a594d892-e496-38f5-e053-2a95a90a9da8/a594d892-e496-38f5-e053-2a95a90a9da8.xml.
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    FDA-approved hydroxychloroquine sulfate is available as 200 mg 
(equivalent to 155 mg of hydroxychloroquine base), film-coated tablets 
for oral administration.\35\
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    \35\ See, e.g., NDA 009768 labeling available as of the date of 
this notice at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009768s037s045s047lbl.pdf.
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1. Suitability of FDA-Approved Drug Product(s)
    As described in FDA's preliminary Federal Register notice 
addressing this substance, there is a basis to conclude that an 
attribute of the approved hydroxychloroquine sulfate tablets for oral 
administration makes them medically unsuitable for the treatment of 
some patients with rheumatoid arthritis and juvenile arthritis.\36\ The 
nomination suggested that the FDA-approved oral tablets, a solid oral 
dosage form, are medically unsuitable in pediatric patients who are 
unable to swallow tablets. We agree that there may be certain patients 
for whom the approved oral tablets are medically unsuitable, and this 
would depend on a patient's clinical presentation and age, among other 
considerations. As a general matter, the drug product proposed to be 
compounded appears to address the potential unsuitability of a solid 
oral dosage form because the nominator proposes to compound a 
suspension of hydroxychloroquine sulfate for oral administration.
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    \36\ In noting this issue, we do not mean to suggest or imply 
that the approved drug products, or products prepared from them, are 
approved for all of the uses proposed by the nomination. For the 
question 1 analysis we asked 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 the 
proposed compounded drug would change, and why. Because this 
nomination did not pass through question 2, we did not reach the 
balancing test and therefore did not consider the four factors, 
including the available evidence of effectiveness or lack of 
effectiveness of a drug product compounded with hydroxychloroquine 
sulfate. The safety and efficacy of chronic use of 
hydroxychloroquine sulfate have not been established for juvenile 
idiopathic arthritis.
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    The nomination further states that ``pediatric dosing is not 
standardized but weight-based, making getting the correct dose 
difficult with tablets.'' We agree that an oral suspension could allow 
for more flexible dosing when compared to the approved tablets when 
following weight-based dosing recommendations, and that this also 
supports the proposition that the approved product may be unsuitable 
for certain patients.\37\
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    \37\ We note that the nominator's proposed concentration of 100 
to 200 mg/mL would offer little benefit in the younger aged 
pediatric population because a suspension at this strength would 
likely require administration of small volumes (e.g., <=1 mL). We 
are aware of several published pharmacy compounding formulations for 
hydroxychloroquine sulfate 25 mg/mL suspensions (Refs. 4 to 6), 
which may be more suitable for the younger pediatric population.
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    In addition to the proposed suspension, the nomination also 
proposes that there is a clinical need to compound hydroxychloroquine 
sulfate 200 to 500 mg capsules for oral administration. The nomination 
does not explain how the proposed compounded capsule products are 
intended to address the medical unsuitability of the approved product. 
Similar to tablets, capsules are less flexible in dosing and would be 
difficult for patients to take if they are unable to swallow tablets. 
In addition, the nomination does not identify any data or information 
as to the need for compounded products with a higher concentration than 
the approved product. No further information was supplied on this point 
during the comment period.
    The nomination also claims that some patients are ``unable to 
tolerate excipients'' in the approved product, but the nomination does 
not identify which excipients they are referring to, nor do they 
provide any data or information supporting how the proposed drug 
products will address that particular attribute. No further information 
was supplied on this point during the comment period.
2. Whether the Drug Product Must Be Compounded From a Bulk Drug 
Substance
    Because there is a basis to conclude that an attribute of the 
approved hydroxychloroquine sulfate tablets makes them medically 
unsuitable for some patients, and the proposed compounded oral 
suspension is intended to address that attribute, FDA

[[Page 56842]]

next considers whether there is a basis to conclude that the proposed 
oral suspension must be made from a bulk drug substance rather than 
from an FDA-approved product. The approved hydroxychloroquine sulfate 
drug products are 200 mg immediate release tablets with film 
coating.\38\
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    \38\ The tablet is not scored. The approved product labeling 
states that the ``film-coated tablets cannot be divided, therefore 
they should not be used to treat patients who weigh less than 31 
kg.''
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    As described in FDA's preliminary Federal Register notice 
addressing this substance, although the approved products are film-
coated, the coating is not intended to change/control the release 
profile. FDA is not aware of issues with using the FDA-approved product 
when the compounding process and equipment are appropriately selected. 
No further information was supplied on this point during the comment 
period. We also note that there is a draft USP monograph for the 
compounded suspension that uses an FDA-approved film-coated tablet as 
the starting material (Ref. 6).\39\ As with all suspensions, the 
particle size of the powder should be carefully controlled and the 
density of suspension vehicle should be selected appropriately in order 
to make the oral suspension uniform and stable, which can affect the 
dose administrated to the patients.
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    \39\ We note that the product labeling for hydroxychloroquine 
sulfate film-coated tablets (e.g., NDA 009768, ANDA 213342) states, 
``Do not crush or divide hydroxychloroquine sulfate film-coated 
tablets.'' However, this does not change our view that the product 
can be compounded starting with the approved drug product.
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    One commenter supported FDA's proposal not to include 
hydroxychloroquine sulfate on the 503B Bulks List. Commenters provided 
no new information supporting the clinical need for compounding from 
the bulk drug substance hydroxychloroquine sulfate. Because we do not 
find a basis to conclude that a bulk drug substance is needed to 
compound the proposed compounded hydroxychloroquine sulfate oral 
suspension, rather than starting with the FDA-approved product, we do 
not find a clinical need to include hydroxychloroquine sulfate on the 
503B Bulks List under question 2.

IV. Other Issues Raised in Nominations and Comments

    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.\40\ In addition, there was also concern expressed about 
whether FDA is evaluating bulk drug substances for clinical need 
pursuant to a non-binding guidance document.
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    \40\ See 84 FR 7390, 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.\41\ 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, there have 
been many opportunities for nominators and interested members of the 
public 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 March 2021 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.
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    \41\ 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.
---------------------------------------------------------------------------

    Another issue raised was whether 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.\42\ 
The Agency is fulfilling its statutory mandate of regulating 
outsourcing facilities' 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 [FD&C Act] . . . and . . . 
does not intrude on the practice of medicine.'' \43\
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    \42\ See United States v. Evers, 643 F.2d 1043, 1048 (5th Cir. 
1981) (``[W]hile the [FD&C Act] 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 FD&C Act ``regulate[s] the 
distribution of drugs by licensed physicians''); Gonzales v. Raich, 
545 U.S. 1, 28 (2005) (``[T]he dispensing of new drugs, even when 
doctors approve their use must await federal approval.'').
    \43\ Athenex Inc. v. Azar, 397 F. Supp. 3d 56, 72 (D.D.C. 2019).
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    Another concern was the possibility that FDA is promoting the off-
label use of FDA-approved drug products. FDA disagrees that it is 
promoting the off-label use of FDA-approved drug products. 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.
    Regarding FDA's decision to evaluate clinical need in the context 
of the specific drug products proposed to be compounded in the 
nomination, a concern was raised 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 and 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.\44\ Section 503B of the FD&C Act 
includes this limitation, among others,

[[Page 56843]]

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 
\45\ and without conditions on interstate distribution that are 
applicable to other compounded drugs.\46\ 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.\47\ 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.'' \48\ 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.\49\ 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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    \44\ Section 503B(a)(2(A)(i) and (ii) of the FD&C Act.
    \45\ 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).
    \46\ 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). See also 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).
    \47\ 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 chapter on pharmacy compounding; or if 
such a monograph does not exist, are drug substances that are 
components of drugs approved by the Secretary).
    \48\ Athenex Inc., 397 F. Supp. 3d at 65.
    \49\ Id.
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    Finally, changes to the Interim Policy were requested. 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 no clinical 
need for outsourcing facilities to compound using the bulk drug 
substances ephedrine sulfate and hydroxychloroquine sulfate, and 
therefore we are not including these bulk drug substances on the 503B 
Bulks List.

VI. References

    The following references marked with an asterisk (*) 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. References without asterisks are not on public 
display at https://www.regulations.gov because they have copyright 
restriction. Some may be available at the website address, if listed. 
References without asterisks are available for viewing only at the 
Dockets Management Staff. 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 Memorandum to File, ``Clinical Need for Ephedrine 
Sulfate in Compounding Under Section 503B of the FD&C Act,'' March 
2021.
    *2. FDA Memorandum to File, ``Clinical Need Supplemental 
Memorandum for Ephedrine Sulfate in Compounding Under Section 503B 
of the FD&C Act,'' August 2023.
    *3. FDA Memorandum to File, ``Clinical Need for 
Hydroxychloroquine Sulfate in Compounding Under Section 503B of the 
FD&C Act,'' March 2021.
    4. McHenry, A.R., M.F. Wempe, and P.J. Rice, (2017) ``Stability 
of Extemporaneously Prepared Hydroxychloroquine Sulfate 25-mg/mL 
Suspensions in Plastic Bottles and Syringes,'' International Journal 
of Pharmaceutical Compounding, 21(3), 251-254 (APA). Retrieved from 
https://ijpc.com/Abstracts/Abstract.cfm?ABS=4322.
    5. American Society of Hospital Pharmacists (ASHP 2020), 
``Hydroxychloroquine Sulfate Suspension 25 mg/mL.'' Retrieved from 
www.ashp.org.
    6. USP 2020, ``USP Draft Compounded Preparation Monograph for 
Hydroxychloroquine Sulfate Compounded Oral Suspension.'' Published 
for public comment in Pharmacopeial Forum 46(2). Retrieved from 
https://go.usp.org/l/323321/2020-04-08/33wcg6.

    Dated: August 15, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-17881 Filed 8-18-23; 8:45 am]
BILLING CODE 4164-01-P