Section 503A Bulks List
Final Rule  
Questions and Answers 
 
Guidance for Industry 
 
 
(Small Entity Compliance Guide) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
May 2019 
 
Compounding
   
 
Section 503A Bulks List
Final Rule  
Questions and Answers 
 
Guidance for Industry 
 
 
(Small Entity Compliance Guide) 
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
May 2019 
 
Compounding 
 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  QUESTIONS AND ANSWERS ....................................................................................... 2 
i 
  Contains Nonbinding Recommendations 
 
Section 503A Bulks List Final Rule 
Questions and Answers 
Guidance for Industry1 
 
(Small Entity Compliance Guide) 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to help small businesses better understand and comply with the final 
rule establishing the list of bulk drug substances2 that can be used in compounding under section 
503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 353a) (final rule or 
503A Bulks List Final Rule).  On February 19, 2019 (84 FR 4696), FDA published a final rule 
that establishes FDAs criteria for evaluating bulk drug substances for inclusion on the list of 
bulk drug substances that may be used to compound drug products under section 503A of the 
FD&C Act (the 503A Bulks List or the list) and that places six substances on the list.  The final 
rule, entitled List of Bulk Drug Substances That Can Be Used To Compound Drug Products in 
Accordance With Section 503A of the Federal Food, Drug, and Cosmetic Act, also identifies 
four substances that were considered for and not included on the list. 
 
The 503A Bulks List Final Rule is effective March 21, 2019.  FDA has prepared this guidance in 
accordance with section 212 of the Small Business Regulatory Enforcement Fairness Act (Public 
Law 104-121, as amended by Public Law 110-28)3 to assist small businesses in complying with 
the 503A Bulks List Final Rule.  
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required. 
  
                                                 
1 This guidance has been prepared by the Office of Regulatory Policy and the Office of Unapproved Drug Labeling 
Compliance in the Center for Drug Evaluation and Research at the Food and Drug Administration.  
2 FDA is evaluating bulk drug substances nominated for the 503A Bulks List on a rolling basis and intends to 
address additional substances in future rulemaking.  
3 5 U.S.C. 601. 
  1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
 
Section 503A of the FD&C Act describes the conditions under which a compounded drug 
product qualifies for exemptions from certain requirements of the FD&C Act related to FDA 
approval prior to marketing, current good manufacturing practice requirements, and labeling 
with adequate directions for use.  One of the conditions that must be met for a compounded drug 
product to qualify for these exemptions is that a licensed pharmacist in a State-licensed 
pharmacy or Federal facility or a licensed physician compounds the drug product using bulk drug 
substances that (1) comply with the standards of an applicable United States Pharmacopeia 
(USP) or National Formulary monograph, if a monograph exists, and the USP chapter on 
pharmacy compounding; (2) if such a monograph does not exist, are drug substances that are 
components of drugs approved by FDA; or (3) if such a monograph does not exist and the drug 
substance is not a component of a drug approved by FDA, appear on a list of bulk drug 
substances developed by FDA through regulation.4   
 
As noted above, the 503A Bulks List Final Rule establishes criteria for evaluating bulk drug 
substances for inclusion on the 503A Bulks List, identifies six bulk drug substances FDA is 
placing on the list, and identifies four other bulk drug substances that were considered and are 
not being included on the 503A Bulks List.   
 
III.  QUESTIONS AND ANSWERS     
 
Q1.  What active ingredients are subject to this final rule? 
 
The 503A Bulks List Final Rule addresses only 10 of the substances nominated for the 503A 
Bulks List.  The final rule identifies six bulk drug substances FDA is placing on the list: Brilliant 
Blue G, also known as Coomassie Brilliant Blue G-250; cantharidin (for topical use only); 
diphenylcyclopropenone (for topical use only); N-acetyl-D-glucosamine (NAG) (for topical use 
only); squaric acid dibutyl ester (for topical use only); and thymol iodide (for topical use only).  
The final rule also identifies four other bulk drug substances that are not being included on the 
list: oxitriptan, piracetam, silver protein mild, and tranilast. 
 
Although only the 10 substances listed above are specifically addressed in the final rule, the 
criteria for evaluation identified in the final rule will be applied to all bulk drug substances that 
are considered for the 503A Bulks List. 
 
Q2.  Can substances that have been considered and not placed on the 503A Bulks 
List through a final rule be used in compounding under 503A?   
 
No.  As stated above, section 503A provides compounded drug products with exemptions from 
certain requirements of the FD&C Act, including premarket approval, but only when those 
compounded drug products meet the conditions of section 503A.  A compounded drug product 
that includes one of the four bulk drug substances that are not being placed on the list would not 
meet those conditions and therefore would not qualify for the exemptions from the FD&C Act.  
                                                 
4 See section 503A(b)(1)(A)(i) of the FD&C Act (21 U.S.C. 353a(b)(1)(A)(i)). 
  2  Contains Nonbinding Recommendations 
 
In addition, as described in the Interim Policy on Compounding Using Bulk Drug Substances 
Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry,5 
substances that have been evaluated and not placed on the 503A Bulks List no longer qualify for 
the interim policy concerning compounding with bulk drug substances. 
 
Q3.  What should I do if I am a pharmacist and I receive a prescription for a 
compounded drug product that includes one of the four bulk drug substances that is 
not being placed on the 503A Bulks List as part of this final rule? 
 
A drug product compounded using a bulk drug substance that is identified in a final rule as not 
being placed on the 503A Bulks List does not qualify for the exemptions under section 503A of 
the FD&C Act.  Compounding with any of the four substances identified in the 503A Bulks List 
Final Rule, or with substances identified in any other final rule as not being placed on the 503A 
Bulks List, may subject the compounder to regulatory action. 
 
Q4.  When and how do compounders have to comply with this final rule? 
 
The 503A Bulks List Final Rule is effective March 21, 2019.  As of that date, drug products 
compounded using any of the four bulk drug substances that are identified as not being included 
on the list do not qualify for the exemptions under 503A of the FD&C Act.  Drug products 
compounded using one of the six bulk drug substances that are on the list will qualify for the 
exemptions under section 503A of the FD&C Act provided the drug products are compounded in 
compliance with the other conditions of section 503A of the FD&C Act. 
 
Q5.  Going forward, how will FDA decide whether to place a bulk drug substance 
on the 503A Bulks List? 
 
As described in the final rule, FDA is evaluating nominated bulk drug substances using four 
criteria: the physical and chemical characteristics of the substance, the safety of the substance in 
compounded drug products, evidence of effectiveness, and historical use of the substance in 
compounded drug products.  As required by section 503A of the FD&C Act, FDA is consulting 
with the Pharmacy Compounding Advisory Committee (PCAC) and USP regarding the 503A 
Bulks List and is developing the list through notice and comment rulemaking. 
 
Q6.  Why did FDA find the four substances it is not placing on the 503A Bulks 
List to be inappropriate for use in compounding drug products under section 503A 
of the FD&C Act? 
 
For reasons described at length in the proposed rule that published on December 16, 2016 (81 FR 
91071), entitled List of Bulk Drug Substances That Can Be Used To Compound Drug Products 
in Accordance With Section 503A of the Federal Food, Drug, and Cosmetic Act, and in the 
briefing materials presented to the PCAC, applying the four criteria identified in Question 5 
above, FDA determined that these four substances are not appropriate for use in compounding 
drug products under section 503A of the FD&C Act. 
                                                 
5 We update guidances periodically. To make sure you have the most recent version of a guidance, be sure to check 
the Agencys guidance website at http://www.fda.gov/ForIndustry/FDABasicsforIndustry/ucm234622.htm.  
  3  Contains Nonbinding Recommendations 
 
 
Q7.  What information did FDA rely on to make its determinations for the bulk 
drug substances that are addressed in the final rule? 
 
As stated in the December 16, 2016 proposed rule, FDA considered information obtained from 
publicly available sources, including peer-reviewed medical literature.  Some of this information 
was referenced in the nominations, and the remainder FDA gathered through independent 
searches of medical and pharmaceutical databases.  FDA did not review raw data.  The nature, 
quantity, and quality of the information FDA assessed varied considerably from substance to 
substance.  In some cases, there were very little data.  For other substances, reports in the 
literature were more plentiful and sometimes comprised hundreds or thousands of articles.  In 
those cases, generally, the Agency limited its review to a sample of the best literature sources 
available (e.g., review articles in widely known, peer-reviewed journals; meta-analyses; reports 
of randomized controlled trials).   
 
Q8.  What should I do if I want to use one of the four bulk drug substances that 
has been identified in the final rule as not being placed on the list to compound a 
route of administration or dosage form different than what the bulk drug substance 
was nominated and considered for when it was determined that it would not be 
placed on the list (e.g., the bulk drug substance was considered in the context of 
compounding an injectable drug product, but I want to use it to compound a 
tablet)? 
 
If you would like to compound a drug product using a bulk drug substance identified as not 
placed on the list, you may submit a citizen petition under 21 CFR 10.30.  The petition should 
ask FDA to consider revising the rule to include the bulk drug substance.  The petition should 
explain any differences in how you propose to use the bulk drug substance as compared with 
how it was previously nominated and evaluated for inclusion on the list. 
 
Q9.  Does FDA plan to add additional substances to the 503A Bulks List going 
forward? 
 
Many substances have been nominated for the 503A Bulks List, and FDA has been evaluating 
them on a rolling basis.  FDA intends to publish additional notice and comment rulemaking to 
address whether these substances should be included on the list. 
 
Q10.  Where can I get more information, if needed? 
 
Questions regarding compliance with the 503A Bulks List Final Rule should be directed to 
Compounding@fda.hhs.gov.   
  4