4240 Federal Register / Vol. 87, No. 18 / Thursday, January 27, 2022 / Notices 

1High-risk entities include, for example, financial 

institutions within the FTC’s jurisdiction and 

utilities, motor vehicle dealerships, 

telecommunications firms, colleges and 

universities, and hospitals. 

2Low-risk entities include, for example, public 

warehouse and storage firms, nursing and 

residential care facilities, automotive equipment 

rental and leasing firms, office supplies and 

stationery stores, fuel dealers, and financial 

transaction processing firms. 

3FTC staff estimates that the Rule affects as many 

as 18,356 card issuers within the FTC’s jurisdiction. 

This includes, for example, state credit unions, 

general retail merchandise stores, colleges and 

universities, and telecoms. 

Title: Red Flags Rule, 16 CFR 681.1; 

Card Issuers Rule, 16 CFR 681.2; 

Address Discrepancy Rule, 16 CFR part 

641. 

OMB Control Number: 3084–0137. 

Type of Review: Extension of 

currently approved collection. 

Abstract: The Red Flags Rule requires 

financial institutions and certain 

creditors to develop and implement 

written Identity Theft Prevention 

Programs. The Card Issuers Rule 

requires credit and debit card issuers to 

assess the validity of notifications of 

address changes under certain 

circumstances. The Address 

Discrepancy Rule provides guidance on 

what covered users of consumer reports 

must do when they receive a notice of 

address discrepancy from a nationwide 

consumer reporting agency. 

Collectively, these three anti-identity 

theft provisions are intended to prevent 

impostors from misusing another 

person’s personal information for a 

fraudulent purpose. 

The Rules implement sections 114 

and 315 of the Fair Credit Reporting Act 

(‘‘FCRA’’), 15 U.S.C. 1681 et seq. 

Estimated Annual Burden: (397,298 

hours; $20,103,752 in labor costs). 

A. Section 114: Red Flags and Card 

Issuers Rules: 

(1) Red Flags: 

(a) Estimated Number of Respondents: 

164,591 

(i) High-Risk Entities: 99,830 1

(ii) Low-Risk Entities: 64,761 2

(b) Estimated Hours Burden: 

(i) High-Risk Entities: 342,900 hours 

(ii) Low-Risk Entities: 16,523 hours 

(2) Card Issuers Rule: 

(a) Estimated Number of Respondents: 

18,894 3

(b) Estimated Hours Burden: 20,508 

hours 

(3) Combined Labor Cost Burden: 

$19,756,412 

B. Section 315—Address Discrepancy 

Rule: 

(1) Estimated Number of 

Respondents: 44,000 

(2) Estimated Hours Burden: 17,367 

hours 

(3) Estimated Labor Cost Burden: 

$347,340 

C. Capital/Non-Labor Costs for Sections 

114 and 315 

FTC staff believes that the Rules 

impose negligible capital or other nonlabor costs, as the affected entities are 

likely to have the necessary supplies 

and/or equipment already (e.g., offices 

and computers) for the information 

collections described herein. 

Request for Comment 

On October 15, 2021, the FTC sought 

public comment on the information 

collection requirements associated with 

the Rule. 86 FR 57425. The Commission 

received no germane comments. 

Pursuant to the OMB regulations, 5 CFR 

part 1320, that implement the PRA, 44 

U.S.C. 3501 et seq., the FTC is providing 

this second opportunity for public 

comment while seeking OMB approval 

to renew the pre-existing clearance for 

the Rules. 

Your comment—including your name 

and your state—will be placed on the 

public record of this proceeding. 

Because your comment will be made 

public, you are solely responsible for 

making sure that your comment does 

not include any sensitive personal 

information, such as anyone’s Social 

Security number; date of birth; driver’s 

license number or other state 

identification number, or foreign 

country equivalent; passport number; 

financial account number; or credit or 

debit card number. You are also solely 

responsible for making sure that your 

comment does not include any sensitive 

health information, such as medical 

records or other individually 

identifiable health information. In 

addition, your comment should not 

include any ‘‘trade secret or any 

commercial or financial information 

which . . . is privileged or 

confidential’’ —as provided by Section 

6(f) of the FTC Act, 15 U.S.C. 46(f), and 

FTC Rule 4.10(a)(2), 16 CFR 4.10(a)(2)— 

including in particular competitively 

sensitive information such as costs, 

sales statistics, inventories, formulas, 

patterns, devices, manufacturing 

processes, or customer names. 

Josephine Liu, 

Assistant General Counsel for Legal Counsel. 

[FR Doc. 2022–01539 Filed 1–26–22; 8:45 am] 

BILLING CODE 6750–01–P 

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. 

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 (i.e., 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 four bulk 

drug substances that FDA has 

considered and is including on the list 

at this time: Diphenylcyclopropenone 

(DPCP) for topical use only, glycolic 

acid for topical use only in 

concentrations up to 70 percent, squaric 

acid dibutyl ester (SADBE) for topical 

use only, and trichloroacetic acid (TCA) 

for topical use only. This notice also 

identifies eight bulk drug substances 

that FDA has considered and is not 

including on the list at this time: 

diazepam, dipyridamole, dobutamine 

hydrochloride (HCl), dopamine HCl, 

edetate calcium disodium, folic acid, 

glycopyrrolate, and sodium thiosulfate 

(except for topical administration). 

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 

January 27, 2022. 

ADDRESSES: For access to the docket to 

read background documents or 

comments received, go to https://

www.regulations.gov and insert the 

docket number found in brackets in the 

heading of this notice 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: 

Kemi Asante, Center for Drug 

Evaluation and Research, Food and 

Drug Administration, 10903 New 


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Federal Register / Vol. 87, No. 18 / Thursday, January 27, 2022 / Notices 4241 

1Section 503B(a) of the FD&C Act. 

2Compare 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). 

3Section 503B(b)(4) and (5) of the FD&C Act. 

4Section 503B(d)(4)(C) of the FD&C Act. 

5Section 503B(a)(2)(A) of the FD&C Act. 

6Section 503B(a)(2)(A)(i)(I) to (III) of the FD&C 

Act. 

7 21 CFR 207.3. 

8Section 503B(a)(2) of the FD&C Act and 21 CFR 

207.1. 

9 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. 

10See 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), 

and March 24, 2021 (86 FR 15673). 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. In this notice, FDA is reaching a final 

determination on whether certain substances 

evaluated in the September 2019 and July 2020 

notices will be included on the 503B Bulks List. 

The substances considered in the September 2019 

and July 2020 notices that are not addressed in this 

notice remain under consideration by the Agency. 

In addition, bumetanide, which was considered in 

the August 2018 notice remains under 

consideration by the Agency. 

11This 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. 

12Section 503B of the FD&C Act does not require 

FDA to consult the PCAC before developing the 

503B Bulks List. 

Hampshire Ave., Bldg. 51, Rm. 2247, 

Silver Spring, MD 20993, 301–796– 

3110. 

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

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 riskbased 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

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

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

For purposes of section 503B of the 

FD&C Act, bulk drug substance means 

an active pharmaceutical ingredient as 

defined in 21 CFR 207.1.7 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.8 9

FDA has published a series of Federal 

Register notices addressing bulk drug 

substances nominated for inclusion on 

the 503B Bulks List.10 This notice 

identifies four bulk drug substances that 

FDA has considered and is including on 

the 503B Bulks List and eight bulk drug 

substances that FDA has considered and 

is not including on the 503B Bulks List. 

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. In the 

Federal Register of 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. 

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 


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4242 Federal Register / Vol. 87, No. 18 / Thursday, January 27, 2022 / Notices 

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. 

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. 

15Specifically, diazepam, dipyridamole, 

dobutamine HCl, dopamine HCl, edetate calcium 

disodium, folic acid, glycopyrrolate, and sodium 

thiosulfate. 

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

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 

determinations regarding the substances 

set forth in this notice, FDA is 

interpreting 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 is not interpreting 

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 bulk drug 

substances 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, we are not 

considering cost of the compounded 

drug product as compared with an FDAapproved drug product when assessing 

‘‘clinical need.’’ 

Eight of the bulk drug substances that 

we are addressing in this notice are 

components of FDA-approved drug 

products,15 and we evaluated them by 

asking one or both 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 

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 approved 

drug product, there are certain benefits 

of doing so over starting with a bulk 

drug substance, including that 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 or compounding starting 

with an approved drug product. FDA 

did not answer ‘‘yes’’ to both of the 

threshold questions for the eight bulk 

drug substances that are components of 

approved drug products that we are 

addressing in this notice. Accordingly, 

as explained further 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 four bulk drug 

substances we are addressing in this 

notice that are not components of FDAapproved drug products, DPCP, glycolic 

acid, SADBE, and TCA, we conducted a 

balancing test with four factors, 

considered each factor in the context of 

the others, and balanced them to 

determine whether the statutory 

‘‘clinical need’’ standard was 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 


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Federal Register / Vol. 87, No. 18 / Thursday, January 27, 2022 / Notices 4243 

16See 84 FR 46014. 

17See 85 FR 46126. 

18As explained in the July notice, the Agency 

considered data and information from its earlier 

evaluations regarding the use of these bulk drug 

substances for the list of bulk drug substances that 

can be used in compounding under section 503A 

of the FD&C Act (the 503A Evaluations) in addition 

to the nominations for the 50B Bulks List. 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. 

19See Docket No. FDA–2013–N–1524, document 

no. FDA–2013–N–1524–1363. 

references in peer-reviewed medical 

literature. 

The discussion below reflects FDA’s 

consideration of these four factors 

where they are applicable and describes 

how they were applied to develop 

FDA’s decision to include four bulk 

drug substances on the 503B Bulks List. 

C. Inclusion of a Bulk Drug Substance 

on the 503B Bulks List or Exclusion 

From the List 

In evaluating a substance for the 503B 

Bulks List, FDA considered whether the 

clinical need for the bulk drug 

substance in the compounded drug 

product is limited, by, for example, 

route of administration or dosage form. 

As appropriate, and as explained further 

below, the Agency tailored its entries on 

the 503B Bulks List to reflect its 

findings related to clinical need for 

these bulk substances. Specifically, the 

listings for DCPC, glycolic acid, SADBE, 

and TCA are limited to the use of these 

bulk drug substances to compound drug 

products for topical use only. 

In the Federal Register notice of July 

31, 2020, which proposed updates to the 

503B Bulks List, FDA solicited comment 

on whether: (1) To allow compounding 

of drug products containing only the 

listed bulk drug substance and no other 

active ingredients or (2) to allow 

compounding of drug products that 

contain the listed bulk drug substance 

without limits on compounding a drug 

product that contains other active 

ingredients (85 FR 46126). FDA received 

a comment supporting the first option 

and stating that ‘‘FDA should restrict 

the use of any bulk drug substance on 

the 503B Bulks List in combination with 

one or more other active ingredients, 

unless there is specific clinical need for 

the combination product, as determined 

through FDA evaluation.’’ In addition, 

the comment stated that this approach 

is important to limit safety risks to 

patients, particularly given the higher 

complexity of combination 

formulations. 

FDA has 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 active 

pharmaceutical ingredients unless those 

active pharmaceutical ingredients have 

been listed in combination on the 503B 

Bulks List. 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 (active 

pharmaceutical ingredients). The use of 

certain active pharmaceutical 

ingredients in combination with other 

active pharmaceutical ingredients 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. 

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).16 In 

this notice, after review of the 

comments submitted to the docket for 

the September 2019 notice, FDA is 

making its final determination with 

regard to dipyridamole. At this time, 

FDA is not making a final determination 

regarding ephedrine sulfate, famotidine, 

hydralazine HCl, methacholine 

chloride, sodium bicarbonate, sodium 

tetradecyl sulfate, trypan blue, and 

vecuronium bromide. These substances 

remain under consideration by FDA. 

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).17 FDA proposed to include 

DPCP, glycolic acid, SADBE, and 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 for DPCP, glycolic 

acid, SADBE, TCA, diazepam, 

dobutamine HCl, dopamine HCl, edetate 

calcium disodium, folic acid, 

glycopyrrolate, and sodium thiosulfate. 

At this time, FDA is not making a final 

determination regarding hydroxyzine 

HCl, ketorolac tromethamine, labetalol 

HCl, mannitol, metoclopramide HCl, 

moxifloxacin HCl, nalbuphine HCl, 

polidocanol, potassium acetate, 

procainamide HCl, sodium 

nitroprusside, and verapamil HCl. These 

substances remain under consideration 

by FDA. Additional bulk drug 

substances nominated by the public for 

inclusion on this list are currently under 

consideration and may be the subject of 

future notices. 

A. Substances Evaluated and Included 

on the 503B Bulks List 

Because the substances in this section 

are not components of FDA-approved 

drug products, FDA applied the 

balancing test described above. The four 

bulk drug substances that FDA 

evaluated, proposed to include on the 

503B Bulks List in a July 2020 Federal 

Register notice, and is now placing on 

the 503B Bulks List are: DPCP, glycolic 

acid, SADBE, and TCA. The reasons for 

FDA’s proposals are included below 

(Refs. 3–6).18 Having received no 

adverse comment, and for the same 

reasons set forth in those proposals, 

FDA is now placing these four bulk drug 

substances on the 503B Bulks List. 

1. Diphenylcyclopropenone (DPCP) 

DPCP was nominated as a bulk drug 

substance for the 503B Bulks List to 

compound drug products for topical use 

at variable concentrations, usually 2 

percent, in the treatment of alopecia 

areata.19 The nominated bulk drug 

substance is not a component of an 

FDA-approved drug product. We 

evaluated DPCP for potential inclusion 

on the 503B Bulks List under the 

clinical need standard in section 503B 

of the FD&C Act, considering data and 

information regarding the physical and 

chemical characterization of DPCP, 

safety issues raised by use of this 

substance in compounding, available 

evidence of effectiveness or lack of 


lotter on DSK11XQN23PROD with NOTICES1
4244 Federal Register / Vol. 87, No. 18 / Thursday, January 27, 2022 / Notices 

20See Docket No. FDA–2015–N–3469, document 

nos. FDA–2015–N–3469–0035 and FDA–2015–N– 

3469–0123. One of the nominations also states that 

prescribers may want glycolic acid compounds in 

other formulations to treat other conditions, but 

does not identify the conditions or formulations. It 

also refers to the use of glycolic acid in combination 

with other ingredients and, in particular, to 

compounding a formulation containing 

hydroquinone 6 percent and tretinoin 0.1 percent. 

Information submitted with this nomination 

relevant to compounding with glycolic acid for the 

treatment of hyperpigmentation disorders and 

photodamaged skin was considered. FDA’s 

evaluation in this notice does not consider whether 

there is a clinical need for outsourcing facilities to 

compound drug products containing glycolic acid 

and hydroquinone or tretinoin, or other bulk drug 

substances, which may be the subject of future 

Federal Register notices. 

21See Docket No. FDA–2013–N–1524, document 

no. FDA–2013–N–1524–1363. 

22See Docket No. FDA–2018–D–1067, document 

no. FDA–2018–D–1067–0005. 

effectiveness, and historical and current 

use in compounding (Ref. 3). 

DPCP is well characterized, but there 

are concerns about stability and 

consistency in product quality. 

Although there are still gaps in the 

evidence for DPCP’s safety and 

effectiveness, including a lack of longterm safety data, substantial human 

safety data have been collected and 

clinicians worldwide have gained 

experience in the use of DPCP to treat 

alopecia areata. DPCP has been used for 

several decades to compound drug 

products for dermatologists to treat 

alopecia areata and continues to be used 

for this purpose. The reported adverse 

effects are related to DPCP’s mechanism 

of therapeutic action as a sensitizer, 

causing allergic contact dermatitis in 

treated patients. Alopecia areata may 

not respond adequately to available 

treatments. DPCP can be a potentially 

effective agent for patients who have 

failed FDA-approved and other 

therapies for this condition. 

On balance, the physical and 

chemical characterization, safety, 

effectiveness, and historical and current 

use of DPCP weigh in favor of including 

this substance on the 503B Bulks List. 

No commenters disagreed with FDA’s 

proposal to include DPCP for topical use 

only on the 503B Bulks List. 

Accordingly, we are adding DPCP to the 

503B Bulks List for topical use only. 

2. Glycolic Acid 

Glycolic acid was nominated as a bulk 

drug substance for the 503B Bulks List 

to compound drug products for topical 

use at concentrations ranging from 0.08 

to 70 percent for the treatment of 

hyperpigmentation and photodamaged 

skin.20 The nominated bulk drug 

substance is not a component of an 

FDA-approved drug product. We 

evaluated glycolic acid for potential 

inclusion on the 503B Bulks List under 

the clinical need standard in section 

503B of the FD&C Act, considering data 

and information regarding the physical 

and chemical characterization of 

glycolic acid, 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. 4). 

Glycolic acid, also known as 

hydroxyacetic acid, is physically and 

chemically well characterized. When 

used in high concentrations, glycolic 

acid causes local effects that are typical 

of a strong acid, such as dermal and eye 

irritation. Reported adverse reactions 

were generally limited in duration and 

readily manageable. There is no 

information available on long-term 

outcomes. The available data on shortterm outcomes do not raise major safety 

concerns associated with the topical use 

of glycolic acid. 

Data from controlled clinical trials 

have shown consistently positive results 

in the treatment of epidermal melasma 

or other forms of hyperpigmentation. 

The available evidence suggests that 

there is a role for glycolic acid in the 

treatment of melasma, typically as a 

second line treatment. There is also 

some evidence indicating that glycolic 

acid may be effective for the mitigation 

of manifestations of photodamaged skin. 

Glycolic acid has been used for several 

decades to compound drug products for 

dermatologists and continues to be used 

for this purpose. Conclusions regarding 

each of these factors are for use at 

concentrations up to 70 percent; data 

and evidence regarding use of higher 

concentrations are very limited. 

On balance, the physical and 

chemical characterization, safety, 

effectiveness, and historical and current 

use of glycolic acid weigh in favor of 

including this substance on the 503B 

Bulks List at concentrations up to 70 

percent. No commenters disagreed with 

FDA’s proposal to include glycolic acid 

on the 503B Bulks List. Accordingly, we 

are adding glycolic acid to the 503B 

Bulks List for topical use only in 

concentrations up to 70 percent. 

3. Squaric Acid Dibutyl Ester (SADBE) 

SADBE was nominated as a bulk drug 

substance for the 503B Bulks List to 

compound drug products for topical use 

at variable concentrations, ranging from 

2 percent initially to 0.0001 percent to 

0.001 percent for maintenance, for the 

treatment of alopecia areata and warts.21

The nominated bulk drug substance is 

not a component of an FDA-approved 

drug product. We evaluated SADBE for 

potential inclusion on the 503B Bulks 

List under the clinical need standard in 

section 503B of the FD&C Act, 

considering data and information 

regarding the physical and chemical 

characterization of SADBE, 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. 5). 

SADBE is well-characterized, but 

there are concerns about stability and 

consistency in product quality. There is 

a lack of adequate nonclinical data, 

long-term safety data, and safety 

information about use in specific 

populations such as pregnant and 

lactating women. Despite these data 

gaps, considerable human safety data 

have accumulated over the past 40 years 

from its use in compounding drug 

products for dermatologists to treat 

alopecia areata and resistant non-genital 

warts and from reports of its use 

internationally. The reported adverse 

effects are related to SADBE’s 

mechanism of therapeutic action as a 

sensitizer causing allergic contact 

dermatitis in treated patients. 

In addition, both alopecia areata and 

warts may not respond adequately to 

available treatments. SADBE can be a 

potentially effective agent for patients 

who have failed FDA-approved and 

other therapies for these conditions. We 

recognize that treatment with SADBE 

requires initial sensitization and typical 

protocols involve a SADBE 

concentration of 2 percent, but lower 

concentrations may be used in other 

patients. 

On balance, the physical and 

chemical characterization, safety, 

effectiveness, and historical and current 

use of SADBE weigh in favor of 

including this substance on the 503B 

Bulks List. No commenters disagreed 

with FDA’s proposal to include SADBE 

on the 503B Bulks List. Accordingly, we 

are adding SADBE to the 503B Bulks 

List for topical use only. 

4. Trichloroacetic Acid (TCA) 

TCA was nominated as a bulk drug 

substance for the 503B Bulks List to 

compound drug products for topical use 

at concentrations ranging from 6 percent 

to 20 percent as a chemical skin peeling 

agent for the treatment of acne and 

melasma.22 The nominated bulk drug 

substance is not a component of an 

FDA-approved drug product. We 

evaluated TCA for potential inclusion 

on the 503B Bulks List under the 

clinical need standard in section 503B 

of the FD&C Act, considering data and 

information regarding the physical and 

chemical characterization of TCA, safety 


lotter on DSK11XQN23PROD with NOTICES1
Federal Register / Vol. 87, No. 18 / Thursday, January 27, 2022 / Notices 4245 

23See Docket No. FDA–2013–N–1524, document 

nos. FDA–2013–N–1524–2292 and FDA–2013–N– 

1524–2298. 

24See, e.g., ANDA 072079 labeling available as of 

the date of this notice at https://www.accessdata.

fda.gov/spl/data/4e800d0d-2181-49b1-a2c8- 

4c6c49edd83a/4e800d0d-2181-49b1-a2c8- 

4c6c49edd83a.xml. 

25Per the label for ANDA 072079, each mL 

contains 5 mg diazepam, 40 percent propylene 

glycol, 10 percent alcohol, 5 percent sodium 

benzoate and benzoic acid added as buffers, and 1.5 

percent benzyl alcohol added as a preservative. 

26 Diazepam is also approved as an oral tablet, 

oral concentrate, oral solution, and rectal gel. 

27See Docket No. FDA–2015–N–3469, document 

no. FDA–2015–N–3469–0031. 

28See, e.g., ANDA 074521 labeling available as of 

the date of this notice at https://www.accessdata.

fda.gov/spl/data/baa2cb6d-2b97-4ad3-a5fcbad3b8bc6175/baa2cb6d-2b97-4ad3-a5fcbad3b8bc6175.xml. 

29 Dipyridamole is also approved as an oral tablet 

and in combination with aspirin as an extended 

release capsule. 

30According to the label for ANDA 074521, 

dipyridamole injection should be diluted in at least 

a 1:2 ratio with sodium chloride injection 0.45%, 

sodium chloride injection 0.9% or dextrose 

injection 5% for a total volume of approximately 20 

to 50 mL. 

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. 6). 

TCA is well characterized in its 

physical and chemical properties. 

Nonclinical evidence suggests that 

topical use of TCA does not raise 

serious safety issues for humans. 

Although there have been no clinical 

trials specifically designed to address 

the safety of TCA, safety assessments 

were among the study procedures in 

several clinical trials and reports of 

adverse reactions have included 

burning, pain, erythema, 

hyperpigmentation, and 

hypopigmentation. More serious 

adverse reactions reported were 

ulcerations, scarring, and pustules. 

Adverse events were reported more 

frequently with higher concentrations. 

Several studies indicate that TCA may 

be effective as a chemical peel for the 

treatment of acne (Ref. 7) and melasma 

(Ref. 8), but there is a lack of evidence 

comparing TCA to FDA-approved drug 

products for those uses. TCA has been 

used, in the United States and 

worldwide, for dermatologic conditions 

for over 40 years and for at least 20 

years in pharmacy compounding. 

On balance, the physical and 

chemical characterization, safety, 

effectiveness, and historical and current 

use of TCA weigh in favor of including 

this substance on the 503B Bulks List. 

No commenters disagreed with FDA’s 

proposal to include TCA on the 503B 

Bulks List. Accordingly, we are adding 

TCA to the 503B Bulks List for topical 

use only. 

B. Substances Evaluated and Not 

Included on the 503B Bulks List 

Because the substances 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 proposed to be 

compounded is intended to address that 

attribute and (2) is there a basis to 

conclude that the drug product 

proposed to be compounded must be 

compounded using a bulk drug 

substance. 

The eight 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: Diazepam, dipyridamole, 

dobutamine HCl, dopamine HCl, edetate 

calcium disodium, folic acid, 

glycopyrrolate, and sodium thiosulfate 

(except for topical administration). 

1. Diazepam 

Diazepam was nominated for 

inclusion on the 503B Bulks List to 

compound drug products that are used 

for alcohol withdrawal syndrome, 

anxiety, and as premedication before 

surgery, endoscopic procedures, and 

cardioversion, among other 

conditions.23 The proposed route of 

administration is intravenous or 

intramuscular, the proposed dosage 

form is a preserved solution, and the 

proposed concentration is 5 milligrams 

per milliliter (mg/mL). The nominators 

propose to compound a preserved 

solution. However, they fail to 

acknowledge that there is an FDAapproved formulation of diazepam that 

is preserved and do not explain why 

that formulation would be medically 

unsuitable for certain patients. The 

nominations state that diazepam might 

also be used to compound other drug 

products, but do not identify those 

products. The nominated bulk drug 

substance is a component of FDAapproved drug products (e.g., ANDA 

072079). FDA-approved diazepam is 

available as a preserved 10 mg/2 mL (5 

mg/mL) and 50 mg/10 mL (5 mg/mL) 

solution for intravenous or 

intramuscular administration.24 25 26

a. Suitability of FDA-Approved Drug 

Product(s) 

The nominations do not explain why 

an attribute of each of the FDAapproved preserved 5 mg/mL solution 

products is medically unsuitable for 

certain patients or identify an attribute 

of the approved drug products that the 

proposed compounded drug product 

(also a preserved 5 mg/mL solution) is 

intended to address. 

Two commenters agreed with FDA’s 

proposal not to include diazepam on the 

503B Bulks List. Several commenters 

objected generally to FDA’s proposals in 

the July 2020 notice and these 

overarching concerns are addressed in 

section IV. No new information 

supporting the clinical need for 

compounding from the bulk drug 

substance diazepam was provided by 

the commenters. 

Accordingly, FDA finds no basis to 

conclude that an attribute of the FDAapproved products 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 nominations do not identify 

specific differences between drug 

products that would be compounded 

using diazepam and approved drug 

products containing diazepam, and 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. 

2. Dipyridamole 

Dipyridamole was nominated for 

inclusion on the 503B Bulks List to 

compound drug products that are used 

for thallium myocardial perfusion 

imaging for the evaluation of coronary 

artery disease in patients who cannot 

exercise adequately.27 The proposed 

route of administration is intravenous, 

the proposed dosage form is an 

injection, and the proposed strength is 

1 milligram per milliliter (mg/mL) in a 

50 mL and 60 mL syringe. The 

nominated bulk drug substance is a 

component of FDA-approved drug 

products (e.g., ANDAs 074521 and 

074939). FDA-approved dipyridamole is 

available as a 5 mg/mL injection for 

intravenous administration.28 29 Per its 

labeling, it should be diluted to a final 

concentration of less than or equal to 2.5 

mg/mL.30


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4246 Federal Register / Vol. 87, No. 18 / Thursday, January 27, 2022 / Notices 

31See Docket No. FDA–2015–N–3469, document 

no. FDA–2015–N–3469–0032. 

32See, e.g., ANDA 074086 labeling available as of 

the date of this notice at https://www.accessdata.

fda.gov/spl/data/7b9ea626-7073-2e77-e053- 

2a91aa0a9215/7b9ea626-7073-2e77-e053-

2a91aa0a9215.xml. 

33See, e.g., NDA 020201 (ready-to-use version) 

labeling available as the date of this notice at 

https://www.accessdata.fda.gov/spl/data/d1873a74- 

56e6-4a01-8e4d-875789e5e344/d1873a74-56e6- 

4a01-8e4d-875789e5e344.xml. 

34See Docket No. FDA–2013–N–1524, document 

nos. FDA–2013–N–1524–2292 and FDA–2013–N– 

1524–2298. 

35See, e.g., ANDA 207707 labeling available as of 

the date of this notice at https://www.accessdata.

fda.gov/spl/data/d2927591-5fe5-4704-9091- 

82ab08bb792b/d2927591-5fe5-4704-9091-

82ab08bb792b.xml. 

36According to the label for ANDA 207707, each 

mL contains metabisulfite 9 mg added as an 

antioxidant, citric acid, anhydrous 10 mg, sodium 

citrate, and dihydrate 5 mg added as a buffer. May 

contain additional citric acid and/or sodium citrate 

for pH adjustment. 

a. Suitability of FDA-Approved Drug 

Product 

The nomination does not identify an 

attribute of the FDA-approved drug 

products that makes them medically 

unsuitable to treat certain patients and 

that the proposed compounded drug 

products are intended to address. 

Specifically, the nomination does not 

explain why the 5 mg/mL injection (for 

dilution) is medically unsuitable for 

certain patients. 

Several commenters agreed with 

FDA’s proposal not to include 

dipyridamole on the 503B Bulks List. 

One commenter objected generally to 

FDA’s proposals in the September 2019 

notice asserting that FDA was 

inappropriately engaging in the practice 

of medicine. This overarching concern 

is addressed in section IV. No new 

information supporting the clinical need 

for compounding from the bulk drug 

substance dipyridamole was provided 

by commenters. Accordingly, FDA finds 

no basis to conclude that an attribute of 

the FDA-approved products 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 take the 

position or provide support for the 

position that drug products containing 

dipyridamole must be compounded 

from bulk drug substances rather than 

by diluting the approved drug product, 

and no further information was 

supplied on this point during the 

comment period. Therefore, FDA finds 

no basis to conclude that the 

dipyridamole drug products proposed 

in the nominations must be 

compounded using a bulk drug 

substance rather than an approved drug 

product. 

3. Dobutamine HCl 

Dobutamine HCl was nominated for 

inclusion on the 503B Bulks List to 

compound drug products for ionotropic 

support in the short-term treatment of 

adults with cardiac decompensation due 

to depressed contractility resulting 

either from organic heart disease or from 

cardiac surgical procedures.31 The 

proposed route of administration is 

intravenous, the proposed dosage form 

is an injection, and the proposed 

concentrations are 1 mg/mL, 2 mg/mL, 

and 4 mg/mL in various volumes of 

intravenous infusions (large volume 

parenterals). The nominated bulk drug 

substance is a component of FDAapproved drug products (e.g., ANDA 

074086 and NDA 020201). FDA has 

approved dobutamine HCl drug 

products as equivalent (EQ) 50 mg base/ 

100 mL (EQ 0.5 mg base/mL), EQ 100 

mg base/100 mL (EQ 1 mg base/mL), EQ 

200 mg base/100 mL (EQ 2 mg base/ 

mL), and EQ 400 mg base/100 mL (EQ 

4 mg base/mL) ready-to-administer 

forms (no further dilution needed) for 

intravenous administration and as an 

EQ 12.5mg base/mL single-dose vial that 

must be diluted prior to infusion.32 33

a. Suitability of FDA-Approved Drug 

Product(s) 

The nomination does not explain why 

an attribute of each of the FDAapproved EQ 12.5 mg base/mL solution 

for dilution for intravenous 

administration products and each of the 

approved EQ 1 mg base/mL, EQ 2 mg 

base/mL, and EQ 4 mg base/mL readyto-administer forms is 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 agreed with FDA’s 

proposal not to include dobutamine HCl 

on the 503B Bulks List. Several 

commenters objected generally to FDA’s 

proposals in the July 2020 notice and 

these overarching concerns are 

addressed in section IV. No new 

information supporting the clinical need 

for compounding from the bulk drug 

substance dobutamine HCl was 

provided by the commenters. 

Accordingly, FDA finds no basis to 

conclude that an attribute of the FDAapproved products 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 identify 

specific differences between drug 

products that would be compounded 

using dobutamine HCl and approved 

drug products containing dobutamine 

HCl, and 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. 

4. Dopamine HCl 

Dopamine HCl has been nominated 

for inclusion on the 503B Bulks List to 

compound drug products that treat 

cardiogenic shock, congestive heart 

failure, decreased cardiac output, and 

renal failure, among other conditions.34

The proposed route of administration is 

intravenous, the proposed dosage form 

is a preservative-free solution, and the 

proposed concentration is 80 mg/mL. 

The nominators proposed to compound 

a preservative-free solution. However, 

they did not acknowledge that there is 

a preservative-free formulation of 

dopamine HCl available that is FDAapproved or explain why that 

formulation would be medically 

unsuitable for certain patients. The 

nominations state that dopamine 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 FDAapproved drug products (e.g., ANDA 

207707). FDA-approved dopamine HCl 

is available as a single-dose, 

preservative-free 40 mg/mL or 80 mg/ 

mL solution for intravenous 

administration.35 36

a. Suitability of FDA-Approved Drug 

Product(s) 

The nominations do not explain why 

an attribute of each of the FDAapproved preservative-free 80 mg/mL 

solution products is 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 agreed with FDA’s 

proposal not to include dopamine HCl 

on the 503B Bulks List. Several 

commenters objected generally to FDA’s 

proposals in the July 2020 notice and 

these overarching concerns are 


lotter on DSK11XQN23PROD with NOTICES1
Federal Register / Vol. 87, No. 18 / Thursday, January 27, 2022 / Notices 4247 

37See Docket No. FDA–2013–N–1524, document 

nos. FDA–2013–N–1524–2302, FDA–2013–N– 

1524–2301, FDA–2013–N–1525–0225, FDA–2013– 

N–1524–2305, and FDA–2013–N–1524–2297. 38 In the nominations, the name of the nominated 

substance is listed as ‘‘edetate calcium disodium 

dihydrate.’’ Since the nominated dosage form is an 

injection, ‘‘edetate calcium disodium’’ and ‘‘edetate 

calcium disodium dihydrate’’ result in the same 

entity when in solution. 

39See NDA 008922 labeling available as of the 

date of this notice at https://www.accessdata.

fda.gov/spl/data/143830d7-46a5-49a3-b8b2-

457a59533008/143830d7-46a5-49a3-b8b2-

457a59533008.xml. 

40Per the label for NDA 008922, edetate calcium 

disodium dihydrate is available in a preservativefree ampule. Each 5 ml ampule contains 1,000 mg 

of edetate calcium disodium (equivalent to 200 mg/ 

ml) in water for injection. 

41See fn. 40. 

42See drug products on NDA 008922 available at 

https://www.accessdata.fda.gov/scripts/cder/daf/ 

index.cfm?event=overview.process&ApplNo=

008922. 

43See Docket No. FDA–2013–N–1524, document 

no. FDA–2013–N–1524–2292. 

44See, e.g., ANDA 089202 labeling available as of 

the date of this notice at https://www.accessdata.

fda.gov/spl/data/d1a4f664-040d-4c6d-b137-

e0a0a9e7bf26/d1a4f664-040d-4c6d-b137- 

e0a0a9e7bf26.xml. 

45Folic acid is also approved as a single-activeingredient, oral tablet. 

addressed in section IV. No new 

information supporting the clinical need 

for compounding from the bulk drug 

substance dopamine HCl was provided 

by the commenters. 

Accordingly, FDA finds no basis to 

conclude that an attribute of the FDAapproved products 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 nominations do not identify 

specific differences between drug 

products that would be compounded 

using dopamine HCl and approved drug 

products containing dopamine HCl, and 

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. 

5. Edetate Calcium Disodium 

Edetate calcium disodium dihydrate 

was nominated for inclusion on the 

503B Bulks List to compound drug 

products that treat cardiovascular 

disease, diabetes, hypercholesterolemia, 

arthritis, cancer, and chronic renal 

failure, among other conditions.37 The 

proposed route of administration is slow 

intravenous, the proposed dosage form 

is a preservative-free injection, and the 

proposed concentration is 200 mg/mL. 

The nominators proposed to compound 

a preservative-free solution. However, 

they did not acknowledge that there is 

a preservative-free formulation of 

edetate calcium disodium available that 

is FDA-approved or explain why that 

formulation would be medically 

unsuitable for certain patients. The 

nominated bulk drug substance is a 

component of an FDA-approved drug 

product (NDA 008922).38 FDA-approved 

edetate calcium disodium is available as 

a preservative-free 200 mg/mL injection 

for intravenous and intramuscular 

administration.39 40

a. Suitability of FDA-Approved Drug 

Product(s) 

The nominations do not explain why 

an attribute of the FDA-approved 

preservative-free 200 mg/mL injection is 

medically unsuitable for certain patients 

or identify an attribute of the approved 

drug product that the proposed 

compounded drug product is intended 

to address. 

Several commenters on FDA’s 

proposal not to include edetate calcium 

disodium on the 503B Bulks List assert 

that there is a clinical need for a 

compounded drug product containing 

edetate calcium disodium for 

intravenous administration for heavy 

metal chelation and conditions 

including coronary artery disease, 

neuropathy, and memory loss. However, 

the commenters do not explain why an 

attribute of the FDA-approved product 

is medically unsuitable for certain 

patients or identify an attribute of the 

approved drug product that the 

proposed compounded drug product is 

intended to address. 

Several commenters also claimed that 

FDA erroneously stated that edetate 

calcium disodium was available as an 

FDA-approved product in the July 2020 

notice when the product was 

discontinued and is not available in 

manufactured form. FDA disagrees with 

these comments. FDA correctly 

identified the nominated bulk drug 

substance as a component of an FDAapproved drug product (NDA 008922), 

which is a preservative-free 200 mg/mL 

injection for intravenous and 

intramuscular administration.41

Although a 500 mg tablet containing 

edetate calcium was approved under the 

same NDA number and was 

discontinued, this has no bearing on the 

availability of the currently marketed 

approved formulation for injection.42

The fact that the 500 mg tablet is no 

longer marketed does not affect our 

evaluation of the nomination for edetate 

calcium disodium because there is a 

currently-marketed FDA-approved drug 

product for injection that contains 

edetate calcium disodium, and the 

nominators proposed to compound a 

drug product for injection. Other 

commenters agreed with FDA’s proposal 

not to include edetate calcium disodium 

on the 503B Bulks List. 

As described above, no new 

information supporting the clinical need 

for compounding from the bulk drug 

substance edetate calcium disodium 

was provided by the commenters. 

Taking into consideration the comments 

submitted and FDA’s clinical need 

analysis, FDA finds no basis to conclude 

that an attribute of the approved drug 

product 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 nominations do not identify 

specific differences between drug 

products that would be compounded 

using edetate calcium disodium and the 

approved drug product containing 

edetate calcium disodium, and 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. 

6. Folic Acid 

Folic acid was nominated for 

inclusion on the 503B Bulks List to 

compound drug products that treat 

megaloblastic and macrocytic 

anemias.43 The proposed routes of 

administration are intravenous, 

intramuscular, and subcutaneous, the 

proposed dosage forms are injection 

solutions, and the proposed 

concentration is 5 mg/mL. The 

nomination states that folic acid might 

also be used to compound other drug 

products but does not identify those 

products. The nominated bulk drug 

substance is a component of FDAapproved drug products (e.g., ANDA 

089202). FDA-approved folic acid is 

available as a 50 mg/10 mL (5 mg/mL) 

solution for intravenous, intramuscular, 

and subcutaneous administration.44 45

a. Suitability of FDA-Approved Drug 

Product(s) 

The nomination does not explain why 

an attribute of each of the FDAapproved 5 mg/mL solution products for 


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46See, e.g., NDA 210997 and ANDA 208973 

labeling available as of the date of this notice at 

https://www.accessdata.fda.gov/spl/data/6a379327-

0f29-44a4-ba4f-54cb9379f854/6a379327-0f29-44a4- 

ba4f-54cb9379f854.xml and https://

www.accessdata.fda.gov/spl/data/fdebc248-87d3- 

4afd-a5ed-592fcaddab1c/fdebc248-87d3-4afd-a5ed592fcaddab1c.xml. 

47Per the label for NDA 210997, glycopyrrolate is 

available in a preservative-free, single-dose vial. Per 

the label for ANDA 208973, glycopyrrolate is 

available in preserved, single-dose and multipledose vials. 

48 Glycopyrrolate is also approved as an oral 

tablet, oral solution, and for inhalation as a singleactive-ingredient product. 

49See the final guidance entitled ‘‘Evaluation of 

Bulk Drug Substances Nominated for Use in 

Compounding Under Section 503B of the Federal 

Food, Drug, and Cosmetic Act’’ (84 FR 7390) (Ref. 

2) and the March 2019 Federal Register notice 

entitled ‘‘List of Bulk Drug Substances for Which 

There Is a Clinical Need Under Section 503B of the 

Federal Food, Drug, and Cosmetic Act’’ (84 FR 

7383). 

intravenous, intramuscular, and 

subcutaneous administration is 

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 agreed with FDA’s 

proposal not to include folic acid on the 

503B Bulks List. Several commenters 

objected generally to FDA’s proposals in 

the July 2020 notice and these 

overarching concerns are addressed in 

section IV. No new information 

supporting the clinical need for 

compounding from the bulk drug 

substance folic acid was provided by the 

commenters. 

Accordingly, FDA finds no basis to 

conclude that an attribute of the FDAapproved products 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 identify 

specific differences between drug 

products that would be compounded 

using folic acid and approved drug 

products containing folic acid, and 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. 

7. Glycopyrrolate 

Glycopyrrolate bromide was 

nominated for inclusion on the 503B 

Bulks List to compound drug products 

that treat cardiac dysrhythmia, 

surgically induced or drug-induced 

vagal reflex, and peptic ulcer disease, 

among other conditions. The proposed 

route of administration is intravenous, 

the proposed dosage forms are both a 

preservative-free and a preserved 

solution, and the proposed 

concentration is 0.2 mg/mL. The 

nominators proposed to compound a 

preservative-free solution. However, 

they did not acknowledge that there is 

a preservative-free formulation of 

glycopyrrolate available that is FDAapproved or explain why that 

formulation would be medically 

unsuitable for certain patients. The 

nominations state that glycopyrrolate 

might also be used to compound other 

drug products, but do not identify those 

products. The nominated bulk drug 

substance is a component of FDAapproved drug products (e.g., NDA 

210997). FDA-approved glycopyrrolate 

is available as a 0.2 mg/mL in 1 mL or 

2 mL preserved and preservative-free, 

single-dose vials for intramuscular or 

intravenous administration.46 47 48

a. Suitability of FDA-Approved Drug 

Product(s) 

The nominations do not explain why 

an attribute of the FDA-approved 0.2 

mg/mL preservative-free and the FDAapproved preserved solutions for 

intramuscular or intravenous 

administration are 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 agreed with FDA’s proposal 

not to include glycopyrrolate on the 

503B Bulks List. No new information 

supporting the clinical need for 

compounding from the bulk drug 

substance glycopyrrolate was provided 

by the commenters. 

Accordingly, FDA finds no basis to 

conclude that an attribute of the FDAapproved products 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 nominations do not identify 

specific differences between drug 

products that would be compounded 

using glycopyrrolate and approved drug 

products containing glycopyrrolate. 

One commenter submitted arguments 

regarding the need for compounding 

from the bulk drug substance. The 

commenter stated that outsourcing 

facilities supply a substantial portion of 

the market for glycopyrrolate injectable 

products and not including 

glycopyrrolate on the 503B Bulks List 

will remove substantial volume from the 

market and may create a shortage for 

that product. In addition, the 

commenter stated that glycopyrrolate 

products compounded from bulk drug 

substances are ready-to-use, an attribute 

that is essential for a medication used in 

emergency situations, and are a safer 

alternative to commercially available 

drug products. The commenter also 

stated that the additional manipulations 

required to compound a drug product 

using the FDA-approved finished 

product as a starting material would be 

costly in both labor and time. 

FDA disagrees with this comment. 

Regarding the comment’s concern about 

a shortage, as noted above, section 

503B(a)(2)(A) of the FD&C Act allows 

compounding from bulk drug 

substances if the drug product 

compounded from such bulk drug 

substance is on the drug shortage list in 

effect under section 506E of the FD&C 

Act 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.49

Regarding the concern about ready-touse drug products, the comment does 

not establish that drug products, 

including ready-to-use products, cannot 

be prepared from the approved 

glycopyrrolate drug products. Rather, 

the 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. 

Regarding the concern about starting 

from an FDA-approved drug product, 

FDA does not interpret considerations 

of cost to be within the meaning of 

‘‘clinical need.’’ Allowing outsourcing 

facilities to compound a drug product 

from a bulk drug substance that is a 

component of an FDA-approved drug 

product because of economic incentives, 

when the approved drug product, or a 

drug product compounded from the 

approved drug product, would be 

medically appropriate for the patient, 

would undermine the incentive for 

applicants to seek FDA approval of drug 

products. 

Having considered these arguments, 

and because and no further information 


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50See Docket No. FDA–2015–N–3469, document 

no. FDA–2015–N–3469–0173. 

51See, e.g., NDA 203923 labeling available as of 

the date of this notice at https://www.accessdata.

fda.gov/spl/data/29449d76-f4c7-4571-b7bb-5c2a55f

637b5/29449d76-f4c7-4571-b7bb5c2a55f637b5.xml. 

52Sodium thiosulfate is also approved for 

sequential use with sodium nitrite for intravenous 

administration. 

53Even in circumstances where it is not 

administered during dialysis, the amount of 

potassium in the approved product is small and 

potassium levels could be monitored for safety. See, 

e.g., Ref. 9 (providing, ‘‘The median dose of STS 

treatment was 25 g administered intravenously in 

100 ml of normal saline given over the last halfhour of each HD session’’) and Ref. 10 (studying 

dialysis patients on ‘‘25 grams intravenously 

diluted in 100 mL of sodium chloride 0.9 percent 

administered over 30 to 60 minutes 3 times per 

week during the last hour or after the hemodialysis 

session.’’) 

54 In making this observation, we do not suggest 

that the approved drug product, or products 

prepared from it, are approved for the use proposed 

by the nomination. Here we are asking a limited, 

threshold question to determine whether there 

might be clinical need for a compounded drug 

product, by asking what attributes of the approved 

drug the proposed compounded drug 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 drugs that 

include a needed change to an approved drug 

product rather than to produce drugs without such 

a change. Because our answer to question 1. is 

‘‘no’’, we do not evaluate the available evidence of 

effectiveness or lack of effectiveness of a drug 

product compounded with sodium thiosulfate for 

the treatment of calciphylaxis. We note that the 

references cited by the nominator appear to be 

general reviews of potassium homeostasis and 

studies in other populations showing associations 

between potassium excretion or potassium levels 

and clinical outcomes. None of these references 

address whether there is a risk posed by the amount 

of potassium in the approved product to patients 

receiving sodium thiosulfate for the treatment of 

calciphylaxis. 

was supplied regarding the clinical need 

for compounding from the bulk drug 

substance, FDA finds no basis to 

conclude that the drug product 

proposed to be compounded must be 

prepared using a bulk drug substance. 

8. Sodium Thiosulfate 

Sodium thiosulfate was nominated for 

inclusion on the 503B Bulks List for the 

treatment of calciphylaxis, cyanide 

toxicity, extravasation, Malassezia 

furfur, and nephrotoxicity 

prophylaxis.50 Sodium thiosulfate was 

nominated as a 250 mg/mL injectable, 

for intravenous, intradermal, 

intramuscular, and subcutaneous 

administration, and in a topical dosage 

form at an unknown concentration. FDA 

intends to address the topical route of 

administration in a future Federal 

Register notice because a comment 

provided additional support for FDA to 

evaluate it. FDA is not making a 

decision on sodium thiosulfate for 

topical administration at this time and 

compounded drug products that contain 

sodium thiosulfate for topical 

administration may be eligible for the 

enforcement discretion policy described 

in FDA’s Interim Policy provided the 

circumstances described in the guidance 

are present. FDA’s evaluation here 

addresses the clinical need for a 

compounded sodium thiosulfate drug 

product except for topical 

administration. The nominated bulk 

drug substance is a component of an 

FDA-approved drug product (NDA 

203923). FDA-approved sodium 

thiosulfate is available as a 12.5 g/50 mL 

(250 mg/mL) solution for intravenous 

administration.51 52

a. Suitability of FDA-Approved Drug 

Product(s) 

As relevant to the present analysis, 

sodium thiosulfate was nominated for 

injectable (intravenous, intradermal, 

intramuscular, subcutaneous) 

administration for the treatment of 

calciphylaxis, cyanide toxicity, 

extravasation, and nephrotoxicity 

prophylaxis. 

i. Calciphylaxis 

The nominator proposes to produce 

an injectable compounded sodium 

thiosulfate drug product without 

potassium chloride to be used in the 

treatment of calciphylaxis. The 

nominator asserts that the safety of the 

approved product is of concern because 

the potassium level of the product is too 

high for patients with renal disease or 

impairment. This assertion is inaccurate 

because the amount of potassium from 

the approved sodium thiosulfate 

product (440 mg of a 25 g dose) is small 

relative to the amount removed in a 

typical dialysis session (Refs. 14 and 

15).53

The nomination proposes to make a 

250 mg/mL injectable, as well as 

unspecified higher concentrations. The 

nomination states that it may be 

necessary to compound a product with 

a greater concentration than is 

commercially available, but the 

nomination does not identify specific 

higher concentrations that the 

nominator proposes to compound or 

provide any data or information 

supporting the need for a higher 

concentration. In addition, FDA is not 

aware of patients who would need 

concentrations above 250 mg/mL. The 

approved product is available as a 

concentrated solution (12.5 g/50 mL). 

Although the product is generally 

diluted in normal saline before 

administration to minimize potential 

complications associated with the 

intravenous infusion of a hypertonic 

solution, it logically follows that a 

concentrated, compounded sodium 

thiosulfate product would also need to 

be diluted before administration for the 

same reason. In addition, when used for 

the treatment of calciphylaxis in 

hemodialysis patients, the product is 

administered during dialysis, which 

allows for removal of excess fluid (Refs. 

9 to 11) (discussing how sodium 

thiosulfate is generally used to treat 

calciphylaxis). 

Commenters on FDA’s proposal not to 

include sodium thiosulfate on the 503B 

Bulks List continue to assert that there 

is a clinical need for potassium-free 

compounded sodium thiosulfate to treat 

calciphylaxis in hemodialysis patients. 

However, none of the literature 

pertaining to potassium referenced in 

the comments demonstrates that there is 

an attribute of the FDA-approved 

sodium thiosulfate drug product that 

makes it medically unsuitable to treat 

certain patients for calciphylaxis due to 

the presence of potassium in the 

approved product. None of the 

referenced literature pertaining to 

potassium provided additional 

justification or data to support the 

commenters’ assertion that the amount 

of potassium in the approved sodium 

thiosulfate injectable product is 

clinically significant and problematic 

for some calciphylaxis patients 

receiving dialysis. We disagree that the 

potassium content in the approved 

sodium thiosulfate product poses an 

increased risk of hyperkalemia when 

used off-label for the management of 

calciphylaxis during hemodialysis. 

Patients on hemodialysis are generally 

permitted to take in potassium (i.e., <3 

g or ∼70 milliequivalents (mEq/day). 

The amount of potassium being 

administered with the approved sodium 

thiosulfate product, i.e., 440 mg of 

potassium chloride or ∼ 6 mEq of 

potassium, is a fraction of the amount 

that the average dialysis patient is 

permitted per day. 

Accordingly, FDA finds no basis to 

conclude that an attribute of the FDAapproved product makes it medically 

unsuitable to treat patients with 

calciphylaxis and that the sodium 

thiosulfate drug products proposed to be 

compounded are intended to address.54

ii. Cyanide Toxicity 

The nomination also proposes to 

combine sodium thiosulfate with 

sodium nitroprusside to reduce the risk 

of cyanide toxicity during sodium 

nitroprusside administration. Sodium 

thiosulfate is FDA-approved for 

sequential use with sodium nitrite for 

treatment of acute cyanide poisoning 

that is judged to be serious or lifeVerDate Sep<11>2014 17:53 Jan 26, 2022 Jkt 256001 PO 00000 Frm 00059 Fmt 4703 Sfmt 4703 E:\FR\FM\27JAN1.SGM 27JAN1

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55While the nomination does not provide final 

product formulation information, it does include an 

article (Ref. 12), which reports on the stability of a 

1:10 sodium nitroprusside: sodium thiosulfate 

admixture stored up to 48 hours when compounded 

from the approved products. 

56See 84 FR 7383, which is available at https:// 

www.federalregister.gov/documents/2019/03/04/ 

2019-03807/evaluation-of-bulk-drug-substancesnominated-for-use-in-compounding-under-section503b-of-the. 

57See Public Law 113–54, § 102(a), (2013), which 

is available at https://www.govinfo.gov/content/pkg/ 

PLAW-113publ54/pdf/PLAW-113publ54.pdf. 

threatening. The nomination states that 

sodium thiosulfate is commonly 

administered with sodium 

nitroprusside, but the nomination does 

not identify the final product 

formulation proposed to be 

compounded (e.g., dosage form and 

strength of each ingredient).55 Sodium 

nitroprusside was also nominated 

separately (see FDA’s analysis in the 

July 2020 notice), but that nomination 

does not mention the use of sodium 

nitroprusside in combination with 

sodium thiosulfate. 

The nomination states that providing 

sodium thiosulfate and sodium 

nitroprusside in a combined 

compounded preparation would allow 

for faster administration in the clinical 

setting and fewer human manipulations, 

thus reducing the rate of error. We do 

not consider the risk that a clinician 

may mishandle the approved product to 

be an indicator of clinical need. Further, 

the approved labeling for sodium 

nitroprusside states that no other drugs 

should be administered in the same 

solution with sodium nitroprusside. The 

nomination has not identified any 

patients for whom co-administration of 

both approved drug products would not 

be medically appropriate, and for whom 

compounding a drug product with both 

active ingredients in one solution would 

address an unmet medical need. No new 

information supporting the clinical need 

for compounding from the bulk drug 

substance sodium thiosulfate to make 

drug products for the treatment of 

cyanide toxicity was provided by the 

commenters. 

Accordingly, with respect to the 

combination sodium thiosulfate and 

sodium nitroprusside drug products 

proposed to be compounded, FDA finds 

no basis to conclude that an attribute of 

the FDA-approved products makes them 

medically unsuitable to treat certain 

patients and that the proposed 

compounded drug products are 

intended to address. 

iii. Extravasation and Nephrotoxicity 

Prophylaxis 

The nomination does not identify an 

attribute of the approved products that 

makes them medically unsuitable for 

the conditions listed above and that the 

proposed compounded injectable drug 

products are intended to address. No 

new information supporting the clinical 

need for compounding from the bulk 

drug substance sodium thiosulfate to 

make drug products for these uses was 

provided by the commenters. 

Accordingly, FDA finds no basis to 

conclude that an attribute of the FDAapproved products makes them 

medically unsuitable to treat certain 

patients and that the proposed 

compounded drug products are 

intended to address. 

b. Whether the Drug Product Must Be 

Compounded From a Bulk Drug 

Substance 

Because FDA finds no basis to 

conclude that an attribute of the FDAapproved products 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, for the reasons 

described above, we do not consider 

whether there is a basis to conclude that 

the drug products proposed to be 

compounded must be prepared using a 

bulk drug substance rather than an FDAapproved drug product. 

c. Listing Determination for Sodium 

Thiosulfate (Except for Topical 

Administration) 

In addition to the comments 

discussed above, two other commenters 

agreed with FDA’s proposal not to 

include sodium thiosulfate on the 503B 

Bulks List. As discussed in more detail 

above, the information supporting the 

clinical need for compounding from the 

bulk drug substance sodium thiosulfate 

to produce drug products (except for 

topical administration) provided by the 

commenters does not alter FDA’s view 

that there is no clinical need for 

compounding from the bulk drug 

substance for these uses. FDA therefore 

finds that there is no clinical need for 

compounding from the bulk drug 

substance sodium thiosulfate to produce 

drug products (except for topical 

administration) under section 503B of 

the FD&C Act, and we have determined 

that it will not be placed on the 503B 

Bulks List. Sodium thiosulfate for 

topical administration only remains 

under consideration by the Agency at 

this time, and as noted above may be 

eligible for the enforcement discretion 

policy described in FDA’s Interim 

Policy provided the circumstances 

described in the guidance are present. 

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.56 In addition, one 

commenter expressed concern that FDA 

is evaluating bulk drug substances for 

clinical need pursuant to a non-binding 

guidance document. FDA disagrees with 

these comments. First, as explained in 

section II.B, 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 2013.57 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. 

Three commenters on the bulk drug 

substances addressed in this notice 

assert 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 


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58See 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 (DC 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.’’). 

59Athenex Inc. v. Azar, 397 F. Supp. 3d 56, 72 

(D.D.C. 2019). 

60Section 503B(a)(2(A)(i) and (ii) of the FD&C 

Act. 61By contrast, to qualify for the exemptions in 

section 503A of the FD&C Act, drug products 

compounded by licensed pharmacists in Statelicensed pharmacies or Federal facilities, or by 

licensed physicians, must be compounded be 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 patientspecific 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) (Ref. 13). 

62For 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). 

63Licensed 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). 

64Athenex Inc. at 65. 

Agency’s authorities.58 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 FDCA 

. . . and . . . does not intrude on the 

practice of medicine.’’ 59

One commenter 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. These comments 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 asserts 

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.60 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 61 and without 

conditions on interstate distribution that 

are applicable to other compounded 

drugs.62 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.63 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 the 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.64 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 FDAapproved drug products, thereby 

helping to maintain a supply of highquality, safe, and effective drugs. 

Some of the bulk drug substance 

nominations and comments assert that 

there could be a benefit gained from 

using a bulk drug substance to 

compound drug products that do not 

require the manipulations that the 

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 

approved drug, we asked whether there 


lotter on DSK11XQN23PROD with NOTICES1
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is a basis to conclude that an attribute 

of each 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-touse form containing bulk drug 

substances in one or more FDAapproved drug products do not show 

that the 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 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 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 comments 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. We 

encourage comments on the Interim 

Policy to be submitted the docket for the 

guidance, docket number FDA–2015–D– 

3539. Comments may be submitted to 

this docket at any time on https://

www.regulations.gov. 

V. Conclusion 

For the reasons stated above, we find 

that there is a clinical need for 

outsourcing facilities to compound 

using the bulk drug substances DPCP for 

topical use only, glycolic acid for 

topical use only in concentrations up to 

70 percent, SADBE for topical use only, 

and TCA for topical use only and, 

therefore, we are now including them 

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 

diazepam, dipyridamole, dobutamine 

HCl, dopamine HCl, edetate calcium 

disodium, folic acid, glycopyrrolate, and 

sodium thiosulfate (except for topical 

administration), and therefore we are 

not including these bulk drug 

substances on the 503B Bulks List. 

VII. 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, 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 Diphenylcyclopropenone (DPCP) in 

Compounding Under Section 503B of the 

FD&C Act, July 2020. 

*4. FDA Memorandum to File, Clinical Need 

for Glycolic Acid in Compounding 

Under Section 503B of the FD&C Act, 

July 2020. 

*5. FDA Memorandum to File, Clinical Need 

for Squaric Acid Dibutyl Ester (SADBE) 

in Compounding Under Section 503B of 

the FD&C Act, July 2020. 

*6. FDA Memorandum to File, ‘‘Clinical 

Need for Trichloroacetic Acid (TCA) in 

Compounding Under Section 503B of the 

FD&C Act,’’ July 2020. 

7. Leheta, T. M., A. El Tawdy, R. M. Abdel 

Hay, and S. Farid, 2011, ‘‘Percutaneous 

Collagen Induction Versus FullConcentration Trichloroacetic Acid in 

the Treatment of Atrophic Acne Scars,’’ 

Dermatologic Surgery, 37(2):207–216. 

8. Kumari, R. and D. M. Thappa, 2010, 

‘‘Comparative Study of Trichloroacetic 

Acid Versus Glycolic Acid Chemical 

Peels in the Treatment of Melasma,’’ 

Indian Journal of Dermatology, 

Venereology and Leprology, 76:447, 

available at https://ijdvl.com/ 

comparative-study-of-trichloroaceticacid-versus-glycolic-acid-chemical-peelsin-the-treatment-of-melasma/. 

9. Nigwekar, S. U., S. M. Brunelli, D. Meade, 

et al., 2013, ‘‘Sodium Thiosulfate 

Therapy for Calcific Uremic 

Arteriolopathy,’’ Clinical Journal of the 

American Society of Nephrology, 

8(7):1162–1170. 

10. Generali, J. A. and D. J. Cada, 2015, 

‘‘Sodium Thiosulfate: Calciphylaxis,’’ 

Hospital Pharmacy, 50(11):975–977. 

11. Udomkarnjananun, S., K. Kongnatthasate, 

K. Praditpornsilpa, et al., 2019, 

‘‘Treatment of Calciphylaxis in CKD: A 

Systematic Review and Meta-Analysis,’’ 

Kidney International Reports, 4(2):231– 

244. 

12. Schulz, L. T., E. J. Elder, Jr, K. J. Jones, 

et al., 2010, ‘‘Stability of Sodium 

Nitroprusside and Sodium Thiosulfate 

1:10 Intravenous Admixture,’’ Hospital 

Pharmacy, 45(10):779–784. 

*13. 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). 

14. Pun, Patrick H. and John P. Middleton, 

2017, ‘‘Dialysate Potassium, Dialysate 

Magnesium, and Hemodialysis Risk,’’ 

Journal of the American Society of 

Nephrology, 28: 3441–3451. 

15. De Nicola, L., V. Bellizzi, R. Minutolo, et 

al., 2000, ‘‘Effect of Dialysate Sodium 

Concentration on Interdialytic Increase 

of Potassium,’’ Journal of the American 

Society of Nephrology, 11:2337–2343. 

Dated: January 21, 2022. 

Lauren K. Roth, 

Associate Commissioner for Policy. 

[FR Doc. 2022–01558 Filed 1–26–22; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2022–D–0092] 

Revising Abbreviated New Drug 

Application Labeling Following 

Revision of the Reference Listed Drug 

Labeling; Draft Guidance for Industry; 

Availability 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice of availability. 

SUMMARY: The Food and Drug 

Administration (FDA or Agency) is 

announcing the availability of a draft 

guidance for industry entitled ‘‘Revising 

ANDA Labeling Following Revision of 

the RLD Labeling.’’ This guidance 

provides recommendations for updating 

labeling for abbreviated new drug 

applications (ANDAs) following 

revisions to the labeling of a reference 

listed drug (RLD), including information 

on how to identify RLD labeling updates 

and how to submit labeling updates to 

both unapproved and approved ANDAs 

to conform to RLD labeling updates. 

This draft guidance revises the guidance 

for industry entitled ‘‘Revising ANDA 

Labeling Following Revision of the RLD 

Labeling’’ issued in April 2000. 


lotter on DSK11XQN23PROD with NOTICES1