Interim Policy on 
Compounding Using Bulk 
Drug Substances Under 
Section 503A of the Federal 
Food, Drug, and Cosmetic Act 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 30 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061. All comments should be identified with the docket number listed in the 
notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Office of Compounding Quality 
and Compliance at 301-796-3100. 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2023 
Compounding and Related Documents 
Revision 2 
55678425dft.docx 
12/5/2023   
Interim Policy on Compounding 
Using Bulk Drug Substances 
Under Section 503A of the 
Federal Food, Drug, and 
Cosmetic Act 
Guidance for Industry 
 
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 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2023 
Compounding and Related Documents 
Revision 2 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION AND SCOPE ..................................................................................... 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  Compounding From Bulk Drug Substances Under Section 503A of the Act ........................... 2 
B.  Efforts to Develop the List of Bulk Drug Substances Under Section 503A .............................. 4 
1. Section 503A Bulks List  Early History ........................................................................................ 4 
2. Current Nominations for the 503A Bulks List .................................................................................. 5 
3. Process for Developing the 503A List.............................................................................................. 8 
C.  Categorization Under FDAs Interim Policy ............................................................................... 9 
III.  POLICY ........................................................................................................................... 12 
A.  Compounding From Bulk Drug Substances Nominated for the 503A Bulks List ................. 12 
B.  Substances Not Nominated, Nominated Without Adequate Support, or Nominated On or 
After the Date of Publication of This Guidance ........................................................................ 13 
C.  Comments About Nominated Bulk Drug Substances ............................................................... 14 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Interim Policy on Compounding Using Bulk Drug Substances 
2  Under Section 503A of the Federal Food, Drug, and Cosmetic Act 
3  Guidance for Industry1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION AND SCOPE 
16   
17  This guidance sets forth the Food and Drug Administrations (FDA or Agency) interim 
18  regulatory policy concerning compounding using bulk drug substances under section 503A of the 
19  Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 353a).  Section 503A of the 
20  FD&C Act includes certain restrictions on the bulk drug substances that can be used in 
21  compounding and directs FDA to develop a list of bulk drug substances that can be used in 
22  compounding under that section.  FDA is developing this list of bulk drug substances (the 503A 
23  bulks list), and this guidance describes FDAs interim regulatory policy for licensed pharmacists 
24  in State-licensed pharmacies and Federal facilities and for licensed physicians that compound 
25  human drug products using bulk drug substances while the list is being developed.2,3  
26   
27  This draft guidance, when finalized, will revise FDAs current interim policy.  The revision 
28  would not change FDAs policy with respect to bulk drug substances that are nominated for 
29  inclusion on the 503A bulks list before the draft guidance is finalized. In contrast, bulk drug 
30  substances that are nominated on or after the date of publication of the final guidance would not 
31  be within the scope of the policy described in Section III.A of this guidance.  FDA intends to 
32  continue to receive and evaluate new nominations of bulk drug substances for inclusion on the 
 
1 This guidance has been prepared by multiple offices in the Center for Drug Evaluation and Research (CDER), in 
consultation with the Office of Regulatory Affairs at the Food and Drug Administration. 
 
2 Drugs compounded from bulk drug substances for use in animals are not within the scope of this guidance.  For 
policies pertaining to compounding drug products from bulk drug substances for use in animals, see the Center for 
Veterinary Medicine guidance for industry #256 Compounding Animal Drugs From Bulk Drug Substances (August 
2022).  We update guidances periodically. To make sure you have the most recent version of a guidance, check the 
FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
 
3 FDA is developing a separate list of bulk drug substances that can be used in compounding under section 503B of 
the FD&C Act.  Because section 503B contains different criteria for that list and provides for a different process for 
its development, the section 503B bulks list is discussed in a separate guidance (see the guidance for industry, 
Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and 
Cosmetic Act (January 2017)). 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
33  503A bulks list consistent with the process and criteria established in the FD&C Act and FDA 
34  regulations. 
35   
36  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
37  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
38  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
39  the word should in Agency guidances means that something is suggested or recommended, but 
40  not required.  
41   
42   
43  II.  BACKGROUND 
44   
45  A.  Compounding From Bulk Drug Substances Under Section 503A of the Act 
46   
47  Section 503A of the FD&C Act describes the conditions that must be satisfied for human drug 
48  products compounded by a licensed pharmacist in a State-licensed pharmacy or Federal facility, 
49  or by a licensed physician, to be exempt from the following three sections of the FD&C Act: 
50  section 505 (concerning the approval of drugs under new drug applications or abbreviated new 
51  drug applications); section 502(f)(1) (concerning the labeling of drugs with adequate directions 
52  for use); and section 501(a)(2)(B) (concerning current good manufacturing practice 
53  requirements).   
54   
55  One of the conditions that must be met for a compounded drug product to qualify for these 
56  exemptions is that a licensed pharmacist, or licensed physician compounds the drug product 
57  using bulk drug substances that:  
58   
59  (1) Comply with the standards of an applicable United States Pharmacopeia (USP) or 
60  National Formulary (NF) monograph, if a monograph exists, and the USP chapter on 
61  pharmacy compounding;  
62   
63  (2) If such a monograph does not exist, are drug substances that are components of drugs 
64  approved by the Secretary; or  
65   
66  (3) If such a monograph does not exist and the drug substance is not a component of a drug 
67  approved by the Secretary, appears on a list developed by the Secretary through 
68  regulations issued by the Secretary under subsection (c) of section 503A.4  
69   
70  A bulk drug substance is defined as meaning the same as active pharmaceutical ingredient as 
71  defined in 21 CFR 207.1. See 21 CFR 207.3. Active pharmaceutical ingredient is defined as 
72  any substance that is intended for incorporation into a finished drug product and is intended to 
73  furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, 
74  treatment, or prevention of disease, or to affect the structure or any function of the body, but the 
75  term does not include intermediates used in the synthesis of the substance (see section 
 
4 See section 503A(b)(1)(A)(i) of the FD&C Act. 
 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
76  503A(b)(1)(A) and 21 CFR 207.3).5,6  FDA has interpreted an applicable USP or NF 
77  monograph to mean an official USP or NF drug substance monograph.7 Accordingly, FDA 
78  does not consider USP monographs for dietary supplements to be applicable USP or NF 
79  monographs within the meaning of section 503A(b)(1)(A)(i)(I).     
80   
81  Under section 503A(c)(1), before developing this list through regulation, FDA must convene and 
82  consult an advisory committee on compounding unless FDA determines that the issuance of such 
83  regulation before consultation with the advisory committee is necessary to protect the public 
84  health.  FDA must also consult with USP when promulgating the regulations.8  The criteria for 
85  determining which bulk drug substances should appear on the section 503A bulks list shall 
86  include historical use, reports in peer-reviewed medical literature, or other criteria the Secretary 
87  may identify.9   
88   
89  Bulk drug substances used in compounding under section 503A must also meet certain other 
90  requirements, including: (1) the bulk drug substance must be manufactured by an establishment 
91  registered under section 510 of the FD&C Act and (2) the bulk drug substance must be 
92  accompanied by a valid certificate of analysis (COA).10 
93   
94  In July 2014, FDA issued a guidance, Pharmacy Compounding of Human Drug Products Under 
95  Section 503A of the Federal Food, Drug, and Cosmetic Act, that stated: 
96   
97  Until a bulk drug substances list is published in the Federal Register as a final rule, 
98  human drug products should be compounded using only bulk drug substances that are 
99  components of drugs approved under section 505 of the FD&C Act, or are the subject of 
100  USP or NF monographs.11 
 
5 Section 503A references the definition of bulk drug substances in FDAs drug establishment registration and 
listing regulations, which was codified at 21 CFR 207.3(a)(4) when section 503A was enacted. On Aug 31, 2016, 
FDA published a final rule in the Federal Register to update its registration and listing regulations in Part 207, which 
made minor changes to the definition of bulk drug substance and moved the definition to 21 CFR 207.3.  See 81 FR 
169 (Aug 31, 2016). Under the previous definition, bulk drug substance was defined to mean any substance that is 
represented for use in a drug and that, when used in the manufacturing, processing, or packaging of a drug, becomes 
an active ingredient or a finished dosage form of the drug, but the term does not include intermediates used in the 
synthesis of such substances. 
 
6 Inactive ingredients are not subject to section 503A(b)(1)(A)(i) or the policies described in this guidance because 
they are not included within the definition of a bulk drug substance. See 21 CFR 207.3. Pursuant to section 
503A(b)(1)(B), inactive ingredients used in compounding must comply with the standards of an applicable USP or 
NF monograph, if a monograph exists, and the USP chapter on pharmacy compounding. 
 
7 See 84 FR 4696, 4705 (2019). 
 
8 See section 503A(c)(2) of the FD&C Act. 
 
9 See section 503A(c)(2) of the FD&C Act. 
 
10 See section 503A(b)(1)(A) of the FD&C Act. 
 
11 See page 5 of the 2014 guidance Pharmacy Compounding of Human Drug Products Under Section 503A of the 
Federal Food, Drug, and Cosmetic Act, available at https://www.regulations.gov/docket/FDA-2013-D-
1444/document.   
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
101   
102  FDA has received comments that this policy could be causing unnecessary and inappropriate 
103  disruptions in patient care because there are patients receiving drugs compounded with bulk drug 
104  substances that are not components of FDA-approved drugs, or the subject of an applicable USP 
105  or NF monograph, but that may ultimately be included on the 503A bulks list, and those patients 
106  care should not be disrupted while the list is under development.  After considering this issue, 
107  FDA has decided to use this guidance to describe its interim policy concerning compounding 
108  with bulk drug substances while the 503A bulks list is being developed.  FDA revised the July 
109  2014 guidance to state: 
110   
111  FDAs interim policy concerning bulk drug substances that are not components of drugs 
112  approved under section 505 of the FD&C Act or that are not the subject of applicable 
113  USP or NF monographs can be found in the guidance, Interim Policy on Compounding 
114  Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug and 
115  Cosmetic Act.12  
116   
117  FDA seeks to avoid unnecessary disruption to patient treatment while the Agency considers the 
118  bulk drug substances that were nominated with sufficient support to permit FDA to evaluate 
119  them and promulgates the regulations required under section 503A.  Therefore, as described 
120  further below, FDA is issuing this interim guidance stating that it does not intend to take 
121  regulatory action for compounding drug products under section 503A using a bulk drug 
122  substance  when an applicable USP or NF monograph for the substance does not exist and the 
123  substance is not a component of an FDA-approved product if, among other conditions, the bulk 
124  drug substance appears on Category 1 on FDAs website, as described below.     
125   
126  B.  Efforts to Develop the List of Bulk Drug Substances Under Section 503A 
127   
128  1.  Section 503A Bulks List  Early History  
129   
130  Section 503A was enacted in 1997 as part of the Food and Drug Administration Modernization 
131  Act.  In the Federal Register of April 7, 1998 (63 FR 17011), FDA invited all interested persons 
132  to nominate bulk drug substances for inclusion on the list of bulk drug substances that can be 
133  used in compounding under section 503A and received nominations for 41 different drug 
134  substances.  In November 1998, FDA published a guidance for industry, Enforcement Policy 
135  During Implementation of Section 503A of the Federal Food, Drug, and Cosmetic Act.  In this 
136  guidance, FDA announced that it would not normally take regulatory action relating to a drug 
137  product that had been compounded with a bulk drug substance that had been nominated for 
138  inclusion on the bulk drug substances list on or before November 21, 1999, while the substance 
139  was being evaluated, as long as the compounding complied with the other effective requirements 
140  in section 503A and did not appear to present a significant safety risk.13 
141   
 
12 See the guidance Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, 
Drug, and Cosmetic Act (June 2016) at section III.B.2.   
 
13 The 1998 guidance was withdrawn in the Federal Register notice announcing the availability of the draft guidance 
Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic 
Act.  See 78 FR 72901 (Dec. 4, 2013).  The final guidance was published in July 2014.   
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
142  In January 1999, after evaluating the nominated drug substances and consulting with the 
143  Pharmacy Compounding Advisory Committee (PCAC) as required by section 503A, FDA 
144  published a proposed rule listing 20 drug substances on the section 503A bulks list (64 FR 996, 
145  January 7, 1999). The preamble to the proposed rule indicated that 10 of the 41 nominated drug 
146  substances were the subject of a USP or NF monograph, or components of FDA-approved drugs 
147  and did not need to be considered for inclusion on the list.14  The proposed rule also described 10 
148  nominated drug substances that were still under consideration for the bulk drug substances list 
149  and stated that one of the substances was withdrawn by its nominator at the first meeting of the 
150  PCAC.  The PCAC reconvened in May 1999 to discuss bulk drug substances included in the 
151  proposed rule, in addition to other bulk drug substances (64 FR 19791; April 22, 1999). 
152   
153  However, after a 2002 U.S. Supreme Court decision holding that certain provisions of section 
154  503A were unconstitutional,15 FDA suspended its efforts to develop the bulk drugs list under 
155  section 503A.  
156   
157  Because of the amount of time that had passed between the publication of the proposed rule and 
158  the enactment of the 2013 Drug Quality and Security Act, which removed the provisions of the 
159  FD&C Act that the U.S. Supreme Court held to be unconstitutional in 2002, FDA felt it was 
160  necessary to begin again to develop the section 503A bulk drug substance list.  In the December 
161  4, 2013, Federal Register (78 FR 72841), FDA published a notice withdrawing the 1999 
162  proposed rule and inviting all interested persons to nominate bulk drug substances for inclusion 
163  on a list of bulk drug substances that can be used for compounding under section 503A of the 
164  FD&C Act. 
165   
166  2.  Current Nominations for the 503A Bulks List  
167   
168  In response to the December 2013, Federal Register notice, over 2,000 substances were 
169  nominated for the 503A bulks list.  However, many of the substances nominated for the 503A list 
170  were for substances that can be compounded without being on the list because they are the 
171  subject of an applicable USP or NF monograph or are a component of an FDA-approved drug.  
172  In addition, many of the nominations were not for bulk drug substances used in compounding as 
173  active ingredients or did not include sufficient information for FDA to evaluate the nominated 
174  substances for inclusion on the list. To improve the efficiency of the process for developing the 
175  503A bulks list, FDA reopened the nomination process in July 2014 (79 FR 37747) and provided 
176  more detailed information on what it needs to evaluate nominations for the 503A bulks list (July 
177  2014 docket).  FDA stated that bulk drug substances that were previously nominated would not 
178  be considered further unless they were re-nominated with adequate support to permit a 
179  meaningful evaluation.  Substances that were already eligible for use in compounding or that 
180  were not adequately supported would not be evaluated for placement on the 503A bulks list.  
181   
182  In the Federal Register of October 27, 2015, FDA established a docket (October 2015 docket) 
183  where new nominations for these substances can be submitted with sufficient supporting 
 
14 See 64 FR 996, at 997 (Jan 7, 1999). 
 
15 For additional legal history of section 503A, see the guidance Pharmacy Compounding of Human Drug Products 
Under Section 503A of the Federal Food, Drug, and Cosmetic Act.    
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
184  information or where nominations for substances that were not previously nominated can be 
185  submitted. 
186   
187  In response to this request for nominations, as of publication of the June 2016 guidance, 
188  approximately 740 unique substances were nominated.  Of those nominated substances: 
189   
190    Approximately 315 substances are already eligible for use in compounding under section 
191  503A.   
192   
193  These are the subject of an applicable USP or NF monograph or components of an FDA-
194  approved drug product, which can be used in compounding pursuant to sections 
195  503A(b)(1)(A)(i)(I) and (II) and, therefore, can be compounded without being included 
196  on the 503A bulks list.  To determine if a bulk drug substance is the subject of an 
197  applicable USP or NF monograph, see the USP-NF available at https://www.uspnf.com.  
198  To determine if a bulk drug substance is a component of an FDA-approved drug, see the 
199  FDAs Orange Book: Approved Drug Products with Therapeutic Equivalence 
200  Evaluations, available at http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm.16 
201   
202    At least one17 of the nominated substances is not a bulk drug substance.   
203   
204  This is a finished drug product that was nominated by its brand name.  Finished drug 
205  products are not eligible for the 503A bulks list because they do not meet the definition of 
206  a bulk drug substance in 21 CFR 207.3.   
207   
208    At least four of the nominated substances appear on the list published by FDA of 
209  substances that have been withdrawn or removed from the market because such drug 
210  products or components of such drug products have been found to be unsafe or not 
211  effective (withdrawn or removed list).18   
212   
213  Such substances cannot be used in compounding under section 503A of the FD&C Act 
214  and, therefore, are not eligible for inclusion on the 503A bulks list.   
215   
216    One of the nominated substances has no currently accepted medical use and is included 
217  on Schedule I of the Controlled Substances Act (CSA) (21 U.S.C. 812(c)).19   
 
16 Biological products subject to approval in a biologics license application (BLA) under section 351 of the Public 
Health Service (PHS) Act are not eligible for the exemptions in section 503A of the FD&C Act (21 USC 
353a).  Biological products subject to approval in a BLA under section 351 of the PHS Act will not be considered 
for the 503A bulks list.  See the guidance for industry Mixing, Diluting, or Repackaging Biological Products 
Outside the Scope of an Approved Biologics License Application (January 2018) for FDAs policies regarding State-
licensed pharmacies, Federal facilities, and outsourcing facilities that mix, dilute, or repackage biological products 
outside the scope of an approved BLA.   
 
17 The nonprescription finished drug product Maalox was nominated.  Maalox is not a bulk drug substance. 
 
18 See section 503A(b)(1)(C) of the FD&C Act.  See also 21 CFR 216.24.  The four substances are: chloroform 
reagent, cobalt chloride hexahydrate, cobalt gluconate, and phenacetin. 
19 An extract of cannabidiol (CBD) and tetrahydrocannabinol (THC) derived from marijuana (marihuana) was 
nominated.  This is a Schedule I substance. 
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
218   
219  The CSA does not allow possession or distribution of Schedule I substances (21 USC 
220  841(a)(1) and 829), except for research purposes (21 U.S.C. 823(f)), and these substances 
221  will not be considered for the 503A bulk drug substances list at this time.  Those desiring 
222  to do research on a Schedule I substance can apply to do so under an investigational new 
223  drug application (IND). 
224   
225    Of the substances that are not components of an approved drug or the subject of an 
226  applicable USP or NF monograph, that are not included on Schedule I of the CSA, and do 
227  not appear on the withdrawn or removed list, approximately 350 substances were 
228  nominated without sufficient supporting evidence for FDA to evaluate them. 
229   
230    The remaining substances may be eligible for inclusion on the 503A list and were 
231  nominated with sufficient supporting information for FDA to evaluate them.  However, 
232  FDA has identified significant safety risks relating to the use of some of these bulk drug 
233  substances in compounded drug products.   
234   
235  FDAs website identifies the following categories of substances nominated for the 503A bulks 
236  list:20   
237   
238  503A Category 1  Substances Nominated for the Bulks List Currently Under 
239  Evaluation:  These substances may be eligible for inclusion on the 503A bulks list, were 
240  nominated with sufficient supporting information for FDA to evaluate them, and do not 
241  appear on any other list.  
242   
243  503A Category 2  Substances Nominated for the Bulks List That Raise Significant 
244  Safety Risks:  These substances were nominated with sufficient supporting information to 
245  permit FDA to evaluate them, and they may be eligible for inclusion on the 503A bulks list.  
246  However, FDA has identified significant safety risks relating to the use of these substances in 
247  compounding pending further evaluation, and therefore does not intend to adopt the policy 
248  described for the substances in Category 1.  If FDA adds a substance to Category 2, it will 
249  publish a public communication (e.g., a safety alert) describing the safety risks and will post 
 
20 See https://www.fda.gov/media/94155/download.  As discussed in the July 2014 Federal Register notice 
requesting nominations for the 503A bulks list (79 FR 37742), nominators were to confirm that all substances 
nominated for the list are active ingredients that meet the definition of a bulk drug substance. Inclusion of a 
substance in any of these categories does not reflect a determination by FDA that the substance is a bulk drug 
substance.  Whether a substance is a bulk drug substance subject to the conditions in section 503A(b)(1)(A) depends 
on whether it meets the definition of a bulk drug substance in 21 CFR 207.3.  If the substance is used in a 
compounded drug as an inactive ingredient, then it does not meet the definition of a bulk drug substance in 21 CFR 
207.3, is not subject to the conditions in section 503A(b)(1)(A), and need not appear on the 503A bulks list to be 
eligible for use in compounding.  Instead, when used as an inactive ingredient, the substance is subject to the 
conditions in section 503A(b)(1)(B), which applies to ingredients other than bulk drug substances used in 
compounded drugs. 
 
7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
250  the communication on FDAs human drug compounding website,21 advising that the 
251  substance has been added to Category 2 and, is no longer within the scope of the policies 
252  regarding substances in Category 1. 
253   
254  503A Category 3  Substances Nominated for the Bulks List Without Adequate 
255  Support:  These substances may be eligible for inclusion on the 503A bulks list but were 
256  nominated with insufficient supporting information for FDA to evaluate them.  These 
257  substances can be re-nominated with sufficient supporting information through a docket that 
258  FDA has established, as discussed below in section III.B. 
259   
260  3.  Process for Developing the 503A List 
261   
262  FDA is currently evaluating the substances that were nominated for the 503A bulks list with 
263  sufficient information to permit evaluation.  FDA is considering a number of factors in 
264  prioritizing the order in which it reviews the nominated bulk drug substances, including but not 
265  limited to the following:   
266   
267    Safety concerns about use of the bulk drug substance in compounding 
268   
269    Whether the bulk drug substance was nominated by multiple parties or identified as 
270  necessary by medical professional organizations 
271   
272    The efficiency with which the evaluation can be completed, based on ease of acquiring 
273  the necessary information to conduct the review, available resources, and other logistical 
274  issues 
275   
276  FDA may also group some nominated drug substances to facilitate efficient review and 
277  discussion.  These include drugs that raise similar issues (e.g., vitamins or botanicals) or have 
278  been nominated for the treatment of the same condition (e.g., warts).   
279   
280  In conducting its evaluations, FDA reviews the information provided in support of the 
281  nomination and other available information to assess each bulk drug substance according to the 
282  following four criteria:22 
283   
284    The physical and chemical characterization of the substance   
285   
286    Any safety issues raised by the use of the substance in compounded drug products  
287   
 
21 See https://www.fda.gov/drugs/guidance-compliance-regulatory-information/human-drug-compounding.  FDA 
also encourages compounding facilities to subscribe to FDAs list serve to receive updates at: 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/human-drug-compounding#subscribe.  
22 See 21 CFR 216.23(c). 
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288    Historical use of the substance in compounded drug products, including information 
289  about the medical condition(s) the substance has been used to treat and any references in 
290  peer-reviewed medical literature  
291   
292    The available evidence of effectiveness or lack of effectiveness of a drug product 
293  compounded with the substance, if any such evidence exists   
294   
295  In evaluating candidates for the 503A bulks list under these criteria, FDA is using a balancing 
296  test.  No single one of these criteria is dispositive; rather, FDA is considering each criterion in 
297  the context of the others and balancing them, on a substance-by-substance basis, to evaluate 
298  whether a particular substance is appropriate for inclusion on the list.  
299   
300  Once the evaluation of a substance is complete, FDA will present the results of its review to the 
301  PCAC to obtain its advice on whether to include the substance on the list.23   
302   
303  Section 503A requires that FDA create the 503A bulks list by regulation in consultation with the 
304  USP.  To this end, FDA has been periodically meeting with USP and discussing the list.  FDA 
305  will publish a notice of proposed rulemaking (NPRM) that identifies substances FDA proposes 
306  for placement on the 503A bulks list and the substances FDA has evaluated but is not proposing 
307  to include on the 503A bulks list.  After publication of the NPRM, the public will have an 
308  opportunity to comment on the proposed rule.  After considering the comments submitted to the 
309  docket, FDA will publish a final rule that establishes the 503A bulks list and identifies the 
310  substances that were considered and will not be placed on the list.  FDA does not intend to 
311  evaluate all of the sufficiently supported nominations before publishing the first NPRM.  Instead, 
312  after FDA has made a decision on whether to propose a group of substances (e.g., 10 substances) 
313  it intends to publish an NPRM with respect to that group of substances and continue to prepare 
314  the list on a rolling basis.   
315   
316  A final rule will list the substances that FDA has determined can be used in compounding under 
317  section 503A and those substances that have been evaluated and not placed on the section 503A 
318  bulks list, if any.   
319   
320  After a final rule is published, drug products compounded using the substances on the 503A 
321  bulks list will be eligible for the section 503A exemptions provided the drug product is 
322  compounded in compliance with the other conditions of section 503A.  Those substances that 
323  have been evaluated and not placed on the 503A bulks list will no longer be within the scope of 
324  policies described in this guidance. 
325   
326  C.  Categorization Under FDAs Interim Policy 
327   
328  Section 503A of the FD&C Act directs FDA to establish a list of bulk drug substances that can 
329  be used in compounding under that section.  After enactment of the Drug Quality and Security 
330  Act (DQSA) in 2013, FDA engaged in renewed efforts to implement section 503A, including the 
331  condition concerning bulk drug substances.  However, because FDA had not yet promulgated 
332  regulations to develop the 503A bulks list, compounded drug products containing such bulk drug 
 
23 See section 503A(c)(1) of the FD&C Act. 
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333  substances were not eligible for the exemptions in section 503A.  Stakeholders advised FDA that 
334  some of these compounded drug products, which patients may have received prior to the 
335  DQSAs enactment, were important for patient care.  In 2016, FDA issued a guidance setting 
336  forth its interim policy on compounding using bulk drug substances by State-licensed 
337  pharmacies, Federal facilities, and physicians (not registered as outsourcing facilities).  The 
338  guidance explained that the purpose of the interim policy was to avoid unnecessary disruption 
339  to patient treatment while the Agency considers the bulk drug substances that were nominated 
340  with sufficient support to permit FDA to evaluate them.24  As described in the guidance, FDA 
341  categorized bulk drug substances that had been nominated by a certain date and explained an 
342  interim policy under which the Agency did not intend to take action against a State-licensed 
343  pharmacy, Federal facility, or licensed physician for compounding drug products using those 
344  bulk drug substances if certain conditions were met.   However, stakeholders advised FDA that, 
345  less than 3 years after DQSA was enacted, certain compounded drug products containing bulk 
346  drug substances that had not yet been nominated were important for patient care.  Accordingly, 
347  in 2017, FDA published a guidance revision (guidance for industry Interim Policy on 
348  Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and 
349  Cosmetic Act (January 2017) (2017 503A Interim Policy Guidance)) to provide for ongoing 
350  categorization of newly nominated bulk drug substances. 
351   
352  As discussed further below, since FDA developed the 2017 503A Interim Policy Guidance, 
353  stakeholders have had substantial opportunity to nominate new bulk drug substances for 
354  categorization.  As reflected in the updated policy described in section III below, FDA has 
355  determined that ongoing categorization of newly nominated substances, as described in the 2017 
356  503A Interim Policy Guidance, no longer serves the interim policys stated objective of avoiding 
357  unnecessary disruption to patient treatment and does not otherwise benefit public health.  
358  Categorizing substances nominated on or after the date of finalization of this guidance would 
359  unnecessarily expose patients to the risks associated with drugs compounded from such bulk 
360  drug substances. 
361   
362  Drug products compounded from bulk drug substances nominated for inclusion on the 503A 
363  bulks list may present particular risks when FDA has not yet completed the process to conclude 
364  whether they will be placed on the 503A bulks list, and because they are not the subject of an 
365  applicable USP or NF monograph or components of an FDA-approved drug.  When FDA 
366  evaluates bulk drug substances nominated for the list, Agency medical and scientific experts 
367  examine the physical and chemical characterization of the substance; any safety issues raised by 
368  the use of the substance in compounded drug products; historical use of the substance in 
369  compounded drug products; and available evidence of effectiveness or lack of effectiveness of a 
370  drug product compounded with the substance, if any such evidence exists.  FDA considers 
371  whether these criteria, on balance, weigh in favor or against inclusion of the bulk drug substance 
372  on the 503A bulks list.  An advisory committee and the USP provide expert advice, and FDA 
373  engages in notice-and-comment rulemaking, taking into consideration any public comments 
374  received.  Although FDAs evaluation of a substance for the 503A bulks list is, necessarily, far 
375  less rigorous and less comprehensive than the Agencys review of drugs as part of the new drug 
 
24 See the guidance for industry Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A 
of the Federal Food, Drug, and Cosmetic Act (June 2016), available at https://www.regulations.gov/docket/FDA-
2015-D-3517/document. 
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376  approval process, this evaluation process is important to reduce the risk of patient harm and the 
377  risk of patients receiving ineffective treatments. 
378   
379  In the early days of DQSA implementation, FDA recognized that patients may have a medical 
380  need for treatment with certain drugs that they may have received prior to enactment of the 
381  DQSA, but that were compounded from bulk drug substances that the Agency had not yet 
382  evaluated for inclusion on the 503A bulks list.  In developing the 2017 503A Interim Policy 
383  Guidance, FDA weighed these public health interests and concluded that, at that early stage of 
384  section 503A implementation, the potential patient benefits of such a policy outweighed the 
385  risks.  Importantly, FDA characterized the guidance as an interim policy because the Agency 
386  intended for it to be temporary.  For the reasons that follow, FDA is ending categorization of 
387  newly nominated substances because the Agency believes such a policy no longer serves the 
388  guidances stated objective of preventing unnecessary disruption to patient treatment and, 
389  therefore, the balance of public health interests supporting the policy has changed.   
390   
391  In the approximately 6x years since FDA issued the 2017 503A Interim Policy Guidance 
392  providing for ongoing categorization of bulk drug substances newly nominated to the October 
393  2015 docket, nominators have had substantial opportunity to nominate bulk drug substances with 
394  sufficient supporting information for placement in Category 1.  A substance that has not been 
395  used to compound drug products during that period cannot reasonably be considered necessary to 
396  avoid disruption to patient treatment.  Nor do we expect the policy in section III.B to adversely 
397  affect market stability because, among other reasons, FDA intends to retain the policy, described 
398  in section III.A of this guidance, for bulk drug substances already categorized.  In addition, FDA 
399  intends to continue to receive and evaluate new nominations for inclusion on the 503A bulks list 
400  consistent with the process and criteria established in the FD&C Act and FDA regulations. 
401   
402  Accordingly, the balance of public health interests relating to categorization of newly nominated 
403  bulk drug substances has changed.  As discussed above, the statutory and regulatory process for 
404  evaluating such bulk drug substances ensures that FDA, independent medical and scientific 
405  experts, and the public can carefully consider a bulk drug substance before it may appear on the 
406  503A bulks list.  During this process, FDA may, for example, uncover safety risks or 
407  effectiveness concerns, or concerns about the physical and chemical characterization of the 
408  substance, that could place patients at risk.  These concerns may not be apparent until FDA and 
409  other experts conduct an in-depth review of the substance for consideration for the 503A bulks 
410  list.25  FDA also believes that the public health is best served by FDA leveraging its limited 
411  resources to develop the 503A bulks list rather than to categorize newly nominated substances. 
412   
413  FDA does, however, recognize that certain substances that currently appear in Category 1 may 
414  be important for patient care and that the Agency has not yet made a final determination as to 
415  whether these substances will appear on the 503A bulks list.  Thus, at this time, FDA is retaining 
416  the policy outlined in section III.A of this guidance until the Agency addresses these substances 
 
25 Prior to placing an adequately supported substance in Category 1, it is FDAs practice to preliminarily assess 
whether the substance appears to present significant safety risks such that it should be placed in Category 2.  
However, some risks may not be apparent until FDA conducts the complete evaluation in accordance with the 
established criteria, consults with the advisory committee and USP, and obtains public comment. 
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417  in a final rule, or unless the Agency removes the substances from Category 1 based on, for 
418  example, information about safety risks. 
419   
420   
421  III.  POLICY 
422   
423  As discussed below, FDA does not intend to categorize bulk drug substances that the public 
424  nominates for inclusion on the 503A bulks list on or after the date this guidance is finalized.26  
425  Although the Agency intends to continue to receive and evaluate new nominations of bulk drug 
426  substances for possible inclusion on the 503A bulks list, FDA does not intend to place such bulk 
427  drug substances in categories published on FDAs website prior to evaluating them in 
428  accordance with section 503A(c). FDA is evaluating bulk drug substances nominated for the 
429  503A bulks list on a rolling basis. 
430   
431  A.  Compounding From Bulk Drug Substances Nominated for the 503A Bulks 
432  List 
433   
434  Under section 503A of the FD&C Act, a bulk drug substance that is not the subject of an 
435  applicable USP or NF monograph or is not a component of an FDA-approved drug cannot be 
436  used in compounding unless it appears on a list promulgated as a regulation pursuant to section 
437  503A(b)(1)(A)(i)(III) of the FD&C Act.  This list will be codified at 21 CFR part 216 subpart E.  
438   
439  However, until a substance has been evaluated and is identified in a final rule as being included 
440  or not included on the 503A bulks list, FDA does not intend to take action against a State-
441  licensed pharmacy, Federal facility, or licensed physician compounding a drug product using a 
442  bulk drug substance that is not a component of an FDA-approved drug product and that is not the 
443  subject of an applicable USP or NF monograph, provided that the following conditions are met: 
444   
445  (1) The bulk drug substance appears in 503A Category 1 on FDAs website at 
446  https://www.fda.gov/media/94155/download.  A Category 1 substance may be eligible 
447  for inclusion on the 503A bulks list, was nominated with sufficient supporting 
448  information for FDA to evaluate it and has not been identified by FDA as a substance that 
449  presents a significant safety risk in compounding prior to the publication of a final rule;   
450   
451  (2) The original manufacturer and all subsequent manufacturers of the bulk drug substance 
452  are establishments that are registered under section 510 (including foreign establishments 
453  that are registered under section 510(i) of the FD&C Act);  
454   
455  (3) The bulk drug substance is accompanied by a valid COA; and 
456   
 
26 FDA recognizes that some compounders and other stakeholders may currently be in the process of compiling a 
bulk drug substance nomination for submission to the Agency.  As noted above, FDA intends to categorize 
nominations of bulk drug substances received prior to the date FDA announces the availability of the final guidance.  
FDA believes that this will provide a sufficient amount of time in which to submit nominations that are currently in 
progress. 
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457  (4) The drug product compounded using the bulk drug substance is compounded in 
458  compliance with all other conditions of section 503A of the FD&C Act. 
459   
460  Original manufacturer means the entity that originally produced the bulk drug substance and not 
461  a subsequent packer, repacker, labeler, or distributor.  
462   
463  Drug products compounded using a bulk drug substance that does not meet each of the above 
464  conditions are not within the scope of the policy described in this guidance.  For example, drug 
465  products compounded from the following bulk drug substances are not within the scope of the 
466  policy: (1) substances not nominated for the 503A bulks list or that were nominated on or after 
467  the date this guidance is finalized; (2) substances that are the subject of a final rule concluding 
468  that they will be included, or not included, on the 503A bulks list;27 and (3) substances that are 
469  the subject of an applicable USP or NF monograph or a component of an FDA-approved drug.28 
470   
471  B.  Substances Not Nominated, Nominated Without Adequate Support, or 
472  Nominated On or After the Date of Publication of This Guidance 
473   
474  As stated above, one of the categories of bulk drug substances FDA has identified on its website 
475  contains nominated substances that may be eligible for inclusion on the 503A bulks list, but that 
476  FDA is unable to evaluate for inclusion on the list at this time because the substances were 
477  nominated with insufficient supporting evidence for FDA to evaluate them (503A Category 3).  
478  New nominations for these substances with sufficient supporting information or nominations for 
479  substances that were not previously nominated can be submitted to the October 2015 docket.   
480   
481  After a substance is nominated to the October 2015 docket,29  FDA will determine whether the 
482  nomination is supported with sufficient information to allow FDA to evaluate it.  
483   
484  Previously, after FDA made that determination, the nominated substance was placed in one of 
485  the three categories described in section II.B.2. above, and the categorization was published on 
486  the FDA website.  Section III.A. of this guidance sets forth a policy that addresses substances 
487  once they have been categorized.  This guidance retains the policy described in section III.A. 
488  with respect to substances that currently appear in the categories described in section II.B.2.  
489   
490  However, with respect to substances nominated on or after the date this guidance is finalized, 
491  including new nominations of substances that currently appear in Category 3,30 FDA no longer 
492  intends to place such substances into the categories described in section II.B.2.  Accordingly, 
493  substances nominated on or after the date this guidance is finalized are not within the scope of 
494  the policy described in section III.A of this guidance.  FDA intends to continue to evaluate such 
 
27 See section 503A(b)(1)(A)(i)(III) of the FD&C Act. 
 
28 These substances are eligible for use in compounding under section 503A without appearing on the 503A bulks 
list.  See section 503A(b)(1)(A)(i)(I), (II) of the FD&C Act. 
 
29 This includes new nominations of substances submitted with sufficient supporting information. 
 
30 This includes new nominations of substances in Category 3 that include sufficient supporting information to 
permit FDA evaluation for the 503A bulks list. 
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495  substances, provided they are nominated with sufficient supporting information to permit an 
496  evaluation, for inclusion on the 503A bulks list pursuant to section 503A(a)(2)(b)(1)(A)(i)(III) of 
497  the FD&C Act. 
498   
499  C.  Comments About Nominated Bulk Drug Substances 
500   
501  If you feel that a substance that you nominated prior to finalization of this guidance does not 
502  appear on the appropriate category as described in this guidance you can submit your comment 
503  to docket number FDA-2015-N-3534.  If you have additional information on a previously 
504  nominated substance that was placed in Category 3, you can submit a new nomination for the 
505  substance that includes the additional information.  Consistent with the policy described in 
506  section III.B. of this guidance, FDA does not intend to categorize the substance if the new 
507  nomination is submitted on or after the date this guidance is finalized.  However, provided the 
508  new nomination includes sufficient supporting information to permit an evaluation, FDA expects 
509  to consider the substance for inclusion on the 503A bulks list. 
510   
511  A nominator may also submit a comment to the docket requesting withdrawal of any of its 
512  nominations.  If the substance that is the subject of such nomination appears in one of the 
513  categories, and the party nominating the substance was the sole nominator, FDA will update the 
514  categories described in this guidance to reflect the withdrawn nomination.31  FDA intends to 
515  provide notice to the public before removing any nominated substances from Category 1 or 
516  Category 2. 
517   
518  Withdrawal of a nomination upon the nominators request and, if applicable, a resulting update 
519  to the categories described in this guidance, do not reflect a determination by FDA regarding the 
520  validity of the nomination or of any reasons given by the nominator for requesting withdrawal.  
521  In addition, FDA may continue to evaluate a substance at its discretion even if the nominator 
522  submits a comment requesting withdrawal of the nomination. 
 
31 If multiple parties nominated the same substance, each party that nominated the substance must withdraw its 
nomination for the nominated substance to be considered withdrawn and for the categories to be updated, if 
applicable, to reflect that withdrawal. 
14