Interim Policy on Compounding 
Using Bulk Drug Substances 
Under Section 503B 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DRAFT GUIDANCE 
 
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft guidance.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, Rockville, 
MD  20852.  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 
55679316dft.docx 
12/4/2023   
Interim Policy on Compounding 
Using Bulk Drug Substances 
Under Section 503B 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Draft  Not for Implementation 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 503B ............................................. 2 
B.  Section 503B Bulks List ................................................................................................................. 3 
1. Section 503B Bulks List History ...................................................................................................... 3 
2. Nominations for the 503B Bulks List ............................................................................................... 3 
3. Process for Developing the 503B Bulks List .................................................................................... 6 
C.  Categorization Under FDAs Interim Policy ............................................................................... 8 
III.  POLICY ........................................................................................................................... 10 
A.  Compounding From Bulk Drug Substances Nominated for the 503B Bulks List ................. 11 
B.  Substances Not Nominated, Nominated Without Adequate Support, or Nominated On or 
After the Date This Guidance Is Finalized ................................................................................ 12 
C.  Comments About Nominated Bulk Drug Substances ............................................................... 13 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Interim Policy on Compounding Using Bulk Drug Substances Under  
2  Section 503B 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 the Agency) interim 
18  regulatory policy concerning compounding by outsourcing facilities registered under section 
19  503B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) 2 using bulk drug substances.  
20  Section 503B of the FD&C Act (21 U.S.C. 353b) includes certain restrictions on the bulk drug 
21  substances that outsourcing facilities can use in compounding and directs FDA to develop a list 
22  of bulk drug substances that can be used in compounding under that section.  FDA is developing 
23  that list of bulk drug substances (the 503B bulks list), and this guidance describes FDAs interim 
24  regulatory policy regarding outsourcing facilities that compound human drug products using 
25  bulk drug substances while the list is being developed.3,4  
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 503B bulks list before the draft guidance is finalized.  In contrast, bulk drug 
 
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 Outsourcing facility refers to a facility that meets the definition of an outsourcing facility under section 503B(d)(4) 
of the FD&C Act.  
 
3 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.  
 
4 FDA is also developing a separate list of bulk drug substances that can be used in compounding under section 
503A of the FD&C Act.  Because section 503A contains different criteria for that list and provides for a different 
process for its development, the section 503A bulks list is covered under a separate guidance (see the guidance for 
industry Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, 
Drug, and Cosmetic Act (January 2017)).  
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
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 
33  503B bulks list consistent with the process and clinical need standard established in the FD&C 
34  Act. 
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 503B 
46   
47  Section 503B of the FD&C Act describes the conditions that must be satisfied for human drug 
48  products compounded by an outsourcing facility to be exempt from the following three sections 
49  of the FD&C Act: section 505 (concerning the approval of drugs under new drug applications or 
50  abbreviated new drug applications); section 502(f)(1) (concerning the labeling of drugs with 
51  adequate directions for use); and section 582 (concerning drug supply chain security 
52  requirements).  
53   
54  One of the conditions that must be met for a drug product compounded by an outsourcing facility 
55  to qualify for these exemptions is that the outsourcing facility does not compound drug products 
56  using a bulk drug substance unless (a) it appears on a list established by the Secretary of Health 
57  and Human Services identifying bulk drug substances for which there is a clinical need, or (b) 
58  the drug compounded from such bulk drug substances appears on the drug shortage list in effect 
59  under section 506E of the FD&C Act at the time of compounding, distribution, and dispensing 
60  (section 503B(a)(2)(A) of the FD&C Act).  
61   
62  A bulk drug substance is defined as meaning the same as active pharmaceutical ingredient as 
63  defined in 21 CFR 207.1.  See 21 CFR 207.3.  Active pharmaceutical ingredient is defined as 
64  any substance that is intended for incorporation into a finished drug product and is intended to 
65  furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, 
66  treatment, or prevention of disease, or to affect the structure or any function of the body, but the 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
67  term does not include intermediates used in the synthesis of the substance (see section 
68  503B(a)(2) and 21 CFR 207.3).5,6    
69   
70  Bulk drug substances used in compounding under section 503B must also meet certain other 
71  requirements, including: (1) if an applicable monograph exists under the United States 
72  Pharmacopeia (USP), National Formulary (NF), or another compendium or pharmacopeia 
73  recognized by the Secretary for purposes of this paragraph, the bulk drug substance complies 
74  with the monograph; (2) the bulk drug substance must be manufactured by an establishment that 
75  is registered under section 510 of the FD&C Act; and (3) the bulk drug substance must be 
76  accompanied by a valid certificate of analysis (COA) (section 503B(a)(2) of the FD&C Act).    
77   
78  B.  Section 503B Bulks List  
79   
80  1.  Section 503B Bulks List History 
81   
82  Section 503B, added to the FD&C Act by the Drug Quality and Security Act in 2013, requires 
83  that FDA create a list of bulk drug substances for which there is a clinical need by publishing a 
84  notice in the Federal Register proposing bulk drug substances for inclusion on the list, providing 
85  a public comment period of 60 calendar days, and then publishing a notice in the Federal 
86  Register designating bulk drug substances for inclusion on the list.  See section 503B(a)(2)(A)(i) 
87  of the FD&C Act.  In the December 4, 2013, Federal Register (78 FR 72838), FDA published a 
88  notice inviting all interested persons to nominate bulk drug substances for inclusion on a list of 
89  bulk drug substances that can be used for compounding under section 503B of the FD&C Act.    
90   
91  2.  Nominations for the 503B Bulks List 
92   
93  In response to the December 2013 Federal Register notice, over 2,000 substances were 
94  nominated for the 503B bulks list. However, many of the nominations for the 503B bulks list 
95  were not for substances used in compounding as active ingredients, or they did not include 
96  sufficient information to allow FDA to evaluate the nominated substances for placement on the 
97  list. To improve the efficiency of the process for developing the 503B bulks list, FDA reopened 
98  the nomination process in July 2014 (79 FR 37750) and provided more detailed information on 
99  what it needs to evaluate nominations for the list.  FDA stated that bulk drug substances that 
100  were previously nominated would not be further considered unless they were renominated, and 
 
5 Section 503B references the definition of bulk drug substance in FDAs drug establishment registration and listing 
regulations, which was codified at 21 CFR 207.3(a)(4) at the time section 503B was enacted.  On Aug 31, 2016, 
FDA published a final rule in the Federal Register to update its registration and listing regulations in 21 CFR part 
207, which made minor changes to the definition of bulk drug substance and moved the definition to 21 CFR 207.3.  
The definition is also found in 21 CFR 207.1.  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 503B(a)(2) 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 503B(a)(3), 
inactive ingredients used in compounding must comply with the standards of an applicable United States 
Pharmacopeia or National Formulary monograph, if a monograph exists.    
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
101  those nominations were adequately supported. Substances that were not adequately supported 
102  would not be evaluated by FDA to be placed on the 503B bulks list.  The notice stated that the 
103  following information about clinical need is necessary to provide adequate support for 
104  nominations to the 503B bulks list:  
105   
106    A statement describing the medical condition(s) that the drug product to be compounded 
107  with the nominated bulk drug substances is intended to treat;  
108   
109    A list of FDA-approved drug products, if any, that address the same medical condition;  
110   
111    If there are any FDA-approved drug products that address the same medical condition, an 
112  explanation of why a compounded drug product is necessary;  
113   
114    If the approved drug product is not suitable for a particular patient population, an 
115  estimate of the size of the population that would need a compounded drug product;  
116   
117    A bibliography of safety and efficacy data for the drug product compounded using the 
118  nominated substance, if available, including any relevant peer-reviewed medical 
119  literature; and  
120   
121    If there is an FDA-approved drug product that includes the bulk drug substance 
122  nominated, an explanation of why the drug product proposed to be compounded must be 
123  compounded from bulk rather than with the FDA-approved drug product.  
124   
125  In the Federal Register of October 27, 2015 (80 FR 65770), FDA established a docket (October 
126  2015 docket) where new nominations for these substances can be submitted with sufficient 
127  supporting information or where nominations for substances that were not previously nominated 
128  can be submitted. 
129   
130  In response to this request for nominations, as of publication of the June 2016 guidance 
131  approximately 2,590 unique substances were nominated.  Of those nominated substances:  
132   
133    Approximately 1,740 are biological products (these are individual allergenic extracts) 
134  subject to approval in a biologics license application (BLA) under section 351 of the 
135  Public Health Service (PHS) Act (42 U.S.C. 262).   
136   
137  These products are not eligible for the 503B bulks list because biological products subject 
138  to approval in a BLA under section 351 of the PHS Act are not eligible for the 
139  exemptions in section 503B.7  No biological products subject to approval in a BLA will 
140  be considered for the 503B bulks list.  
141   
 
7 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.  
 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
142    At least one8 of the nominated substances is not a bulk drug substance.    
143   
144  This is a finished drug product that was nominated by its brand name.  Finished drug 
145  products are not eligible for the 503B bulks list because they do not meet the definition of 
146  a bulk drug substance in 21 CFR 207.3.    
147   
148    At least five of the nominated substances appear on the list of drugs that have been 
149  withdrawn or removed from the market because such drug products or components of 
150  such drug products have been found to be unsafe or not effective (withdrawn or removed 
151  list).     
152   
153  Such substances cannot be used in compounding under section 503B of the FD&C Act, 
154  and therefore are not eligible for inclusion on the 503B bulks list.9  
155    One of the nominated substances has no currently accepted medical use and is included 
156  on Schedule I of the Controlled Substances Act (CSA) (21 U.S.C. 812(c)).10   
157    
158  The CSA does not allow possession or distribution of Schedule I substances (see 21 
159  U.S.C. 841(a)(1) and 829), except for research purposes (21 U.S.C. 823(f)), and these 
160  substances will not be considered for the 503B bulks list at this time.  Those desiring to 
161  do research on a Schedule I substance can apply to do so under an investigational new 
162  drug application (IND).    
163   
164    Of the substances that may be eligible for use in compounding under section 503B, 
165  approximately 650 substances were nominated without sufficient supporting evidence for 
166  FDA to evaluate them.   
167   
168    The remaining substances that were nominated for inclusion on the 503B bulks list may 
169  be eligible for inclusion on the list and were nominated with sufficient supporting 
170  information for FDA to evaluate them.   However, FDA has identified significant safety 
171  risks relating to the use in compounded drug products of some of these bulk drug 
172  substances.  
173    
174  FDAs website identifies the following categories of substances nominated for the 503B bulks 
175  list:11    
 
8 The nonprescription finished drug product Maalox was nominated.  Maalox is not a bulk drug substance.  
 
9 See section 503B(a)(4) of the FD&C Act.  See also 21 CFR 216.24.  The five substances are: chloroform reagent, 
cobalt chloride hexahydrate, cobalt gluconate, methapyrilene fumarate, and phenacetin.  
10 An extract of cannabidiol (CBD) and tetrahydrocannabinol (THC) derived from marijuana (marihuana) was 
nominated.  This is a Schedule I substance.  
 
11 https://www.fda.gov/drugs/human-drug-compounding/bulk-drug-substances-used-compounding-under-section-
503b-fdc-act.  As discussed in the July 2014 Federal Register notice requesting nominations for the 503B bulks list 
(79 FR 37747), 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 
 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
176   
177  503B Category 1 Substances Nominated for the Bulks List Currently Under 
178  Evaluation:  These substances may be eligible for inclusion on the 503B bulks list, were 
179  nominated with sufficient supporting information for FDA to evaluate them, and do not 
180  appear on any other list.    
181    
182  503B Category 2 Substances Nominated for the Bulks List That Raise Significant 
183  Safety Risks:  These substances were nominated with sufficient supporting information to 
184  permit FDA to evaluate them, and they may be eligible for inclusion on the 503B bulks list.  
185  However, FDA has identified significant safety risks relating to the use of these substances in 
186  compounding pending further evaluation, and therefore does not intend to adopt the policy 
187  described for the substances in Category 1.  If FDA adds a substance to Category 2, it will 
188  publish a public communication (e.g., a safety alert) describing the safety risks and will post 
189  the communication on FDAs human drug compounding website12 advising that the 
190  substance has been added to Category 2 and, is not within the scope of the policies regarding 
191  substances in Category 1.  
192   
193  503B Category 3 Substances Nominated for the Bulks List Without Adequate 
194  Support:  These substances may be eligible for inclusion on the 503B bulks list but were 
195  nominated with insufficient supporting information for FDA to evaluate them.  These 
196  substances can be renominated with sufficient supporting information through a docket that 
197  FDA has established, as discussed below in section III.B.  
198   
199  3.  Process for Developing the 503B Bulks List 
200   
201  FDA is currently evaluating the bulk drug substances nominated for the 503B bulks list with 
202  sufficient supporting information for evaluation.  FDA is considering a number of factors in 
203  prioritizing the order in which it reviews these nominated bulk drug substances, including but not 
204  limited to the following:    
205   
206    Safety concerns about use of the bulk drug substance in compounding  
207   
208    Whether the bulk drug substance was nominated by multiple parties or identified as 
209  necessary by medical professional organizations  
210   
 
subject to the conditions in section 503B(a)(2) 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 503B(a)(2), and need 
not appear on the 503B 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 503B(a)(3), which applies to ingredients other than 
bulk drug substances used in compounded drugs.  
12 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/human-drug-compounding/information-outsourcing-facilities#subscribe.   
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
211    The efficiency with which the evaluation can be completed, based on ease of acquiring 
212  the necessary information to conduct the review, available resources, and other logistical 
213  issues 
214   
215  FDA may also group some nominated drug substances to facilitate efficient review and 
216  discussion.  These include drug substances that raise similar issues (e.g., vitamins or botanicals) 
217  or that are nominated for the treatment of the same condition (e.g., warts).    
218   
219  FDA intends to publish a notice in the Federal Register that describes its proposed position on 
220  each substance it has evaluated along with the rationale for that proposal, for public comment.  
221  We note that there is no requirement in section 503B to consult the Pharmacy Compounding  
222  Advisory Committee (PCAC) before developing a 503B bulks list, as is required by section 
223  503A(c)(1) for the 503A bulks list.  However, after considering public comment on the 
224  nominated substances, FDA will determine whether PCAC input on any of the substances would 
225  be helpful to the Agency in making its determination, and if so, it will seek PCAC input.  Once 
226  FDA makes a determination, it will publish in the Federal Register a list identifying the bulk 
227  drug substances for which it has determined there is a clinical need and FDAs rationale in 
228  making that determination.  FDA will also publish in the Federal Register a list of those 
229  substances it considered but found that there is no clinical need to use in compounding and 
230  FDAs rationale in making this determination.   
231   
232  Once FDA publishes a 503B bulks list in the Federal Register that reflects its determination 
233  regarding particular bulk drug substances, drug products compounded with substances on the 
234  503B bulks list will be eligible for the 503B exemptions, provided the drug products are 
235  compounded in compliance with the other conditions of section 503B.13 Once FDA has 
236  published in the Federal Register its decision not to place a particular substance on the 503B 
237  bulks list, the substance is no longer within the scope of the policy described in this guidance.     
238   
239  FDA intends to evaluate the substances nominated for the 503B list on a rolling basis.  FDA will 
240  begin by publishing a Federal Register notice identifying a group of substances (e.g., 10 
241  substances) that it has considered and whether it proposes the substances for inclusion on the list.   
242  Under section 503B, an outsourcing facility may only compound using bulk drug substances that 
243  are on FDAs 503B bulks list or that are used to compound drugs that appear on the shortage list 
244  in effect under section 506E of the FD&C Act at the time of compounding, distribution, and 
245  dispensing. To avoid unnecessary disruption to patient treatment while FDA considers the 
246  substances that were nominated with sufficient support to permit FDA to evaluate them, FDA is 
247  issuing this guidance stating that at this time it does not intend to take action against an 
248  outsourcing facility for failing to compound in accordance with section 503B(a)(2) if certain 
249  conditions are met.  Those conditions include that the nomination for the relevant bulk drug 
250  substance appears on Category 1 on FDAs website. As described below, FDA does not intend to 
251  categorize bulk drug substances as described in section II.B.2 on or after the date this guidance is 
252  finalized.    
253   
 
13 See section 503B(a)(11) of the FD&C Act.  
 
7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
254  C.  Categorization Under FDAs Interim Policy 
255   
256  Section 503B of the FD&C Act directs FDA to establish a list of bulk drug substances for which 
257  there is a clinical need.14  Stakeholders advised FDA that some of the compounded drug products 
258  which patients may have received before enactment of the Drug Quality and Security Act 
259  (DQSA) in 2013 were important for patient care.  Stakeholders further advised FDA that some of 
260  the compounded drug products containing nominated bulk drug substances were important for 
261  office stock or for office use by hospitals, clinics, or health care practitioners to administer 
262  to patients who present with an immediate need for a compounded drug product.15  In 2016, 
263  FDA issued a guidance setting forth its interim policy on compounding using bulk drug 
264  substances by outsourcing facilities.  The guidance explained that the purpose of the interim 
265  policy was to avoid unnecessary disruption to patient treatment while the Agency considers the 
266  bulk drug substances that were nominated with sufficient support to permit FDA to evaluate 
267  them.16  As described in the guidance, FDA categorized bulk drug substances that had been 
268  nominated by a certain date and explained an interim policy under which the Agency did not 
269  intend to take action against an outsourcing facility for compounding drug products using those 
270  bulk drug substances if certain conditions were met.  However, stakeholders advised FDA that, 
271  less than three years after DQSA was enacted, certain compounded drug products containing 
272  bulk drug substances that had not yet been nominated were important for patient care.  
273  Accordingly, in 2017, FDA published a guidance revision (the guidance for industry Interim 
274  Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, 
275  Drug, and Cosmetic Act (January 2017) (2017 503B Interim Policy Guidance)) to provide for 
276  ongoing categorization of bulk drug substances newly nominated to the October 2015 docket.  
277   
278  As discussed further below, since FDA developed the 2017 503B Interim Policy Guidance, 
279  stakeholders have had substantial opportunity to nominate new bulk drug substances for 
280  categorization.  As reflected in the updated policy described in section III below, FDA has 
281  determined that ongoing categorization of newly nominated substances, as described in the 2017 
282  503B Interim Policy Guidance, no longer serves the interim policys stated objective of avoiding 
283  unnecessary disruption to patient treatment and does not otherwise benefit public health.  
284  Categorizing substances nominated on or after the date of finalization of this guidance would 
285  unnecessarily expose patients to the risks associated with drugs compounded from such bulk 
286  drug substances. 
287   
288  Drug products compounded from bulk drug substances nominated for inclusion on the 503B 
289  bulks list may present particular risks when FDA has not yet completed the process to conclude 
 
14 See section 503B(a)(2)(A)(i) of the FD&C Act. 
 
15 In contrast to compounders operating under section 503A, outsourcing facilities can distribute compounded drug 
products to healthcare practitioners or healthcare facilities without first receiving a prescription for an identified 
individual patient.  Compare sections 503B(d)(4)(C) and section 503A(a) of the FD&C Act; see also the guidance 
for industry Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act (December 
2016). 
16 See the guidance for industry Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B 
of the Federal Food, Drug, and Cosmetic Act (June 2016) at 7, available at 
https://www.regulations.gov/docket/FDA-2015-D-3539/document.  
 
8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
290  whether they will be placed on the 503B bulks list.  Pursuant to the clinical need standard in 
291  section 503B(a)(2)(A) of the FD&C Act, FDA places a bulk drug substance on the 503B bulks 
292  list if the Agency concludes that there is a clinical need for an outsourcing facility to compound a 
293  drug product, and the drug product must be compounded using the bulk drug substance.17 Under 
294  this standard, FDA proposes adding a bulk drug substance to the 503B bulks list only after 
295  Agency medical and scientific experts have, among other things, evaluated the physical and 
296  chemical characterization of the substance; any safety issues raised by the use of the substance in 
297  compounded drug products; current and historical use of the substance in compounded drug 
298  products; and available evidence of effectiveness or lack of effectiveness of a drug product 
299  compounded with the substance, if any such evidence exists, and preliminarily concluded that 
300  these factors weigh in favor of inclusion of the bulk drug substance on the list.  FDA must 
301  consider public comment regarding a proposal before making its final determination.18  Although 
302  FDAs evaluation of a substance for the 503B bulks list is, necessarily, far less rigorous and less 
303  comprehensive than the Agency's review of drugs as part of the new drug approval process, this 
304  evaluation process for clinical need is important to help limit patient exposure to compounded 
305  drug products, which have not been demonstrated to be safe and effective, to those situations in 
306  which the compounded drug product is necessary for patient treatment, and serves an important 
307  role in preserving the integrity of the drug approval process.19   
308   
309  In the early days of DQSA implementation, FDA recognized that patients may have a medical 
310  need for treatment with certain drugs that they may have received prior to enactment of the 
311  DQSA, but that were compounded from bulk drug substances that the Agency had not yet 
312  evaluated for inclusion on the 503B bulks list.  In developing the 2017 503B Interim Policy 
313  Guidance, FDA weighed these public health interests and concluded that, at that early stage of 
314  section 503B implementation, the potential patient benefits of such a policy outweighed the 
315  risks.  Importantly, FDA characterized the guidance as an interim policy because the Agency 
316  intended for it to be temporary.  For the reasons that follow, FDA is ending categorization of 
317  newly nominated substances because the Agency believes such a policy no longer serves the 
318  guidances stated objective of preventing unnecessary disruption to patient treatment and, 
319  therefore, the balance of public health interests supporting the policy has changed.   
320   
321  In the approximately 6 years since FDA issued the 2017 503B Interim Policy Guidance, 
322  providing for ongoing categorization of bulk drug substances newly nominated to the October 
323  2015 docket, nominators have had substantial opportunity to nominate bulk drug substances with 
324  sufficient supporting information for placement in Category 1.  A substance that has not been 
325  used to compound drug products during that period cannot reasonably be considered necessary to 
326  avoid disruption to patient treatment.  Nor do we expect the policy in section III.B to adversely 
 
17 In addition, with respect to a bulk drug substance that is a component of an FDA-approved drug, FDA considers 
whether there is an attribute of the FDA-approved drug that makes it medically unsuitable for the proposed 
condition and the compounded drug is intended to address that attribute, and whether the drug must be compounded 
from a bulk drug substance.  See the 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) (503B Evaluation 
Guidance) at 9. 
 
18 Sections 503B(a)(2)(A)(i)(II) and (III) of the FD&C Act. 
 
19 503B Evaluation Guidance at 9. 
9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
327  affect market stability because, among other reasons, FDA intends to retain the policy, described 
328  in section III.A of this guidance, for bulk drug substances already placed in existing Category 1.  
329  In addition, FDA intends to continue to receive and evaluate new nominations for inclusion on 
330  the 503B bulks list consistent with the process and clinical need standard established in the 
331  FD&C Act. 
332   
333  Accordingly, the balance of public health interests relating to categorization of newly nominated 
334  bulk drug substances has changed.  As discussed above, FDAs process for evaluating and 
335  proposing inclusion of bulk drug substances on the 503B bulks list ensures that FDA and the 
336  public can carefully consider a bulk drug substance nominated for the 503B bulks list before 
337  outsourcing facilities can use it in compounding under section 503B.  During this process, FDA 
338  may, for example, uncover safety risks or effectiveness concerns, or concerns about the physical 
339  and chemical characterization of the substance, that could place patients at risk.  These concerns 
340  may not be apparent until FDA and other experts conduct an in-depth review of the substance for 
341  consideration for the 503B bulks list.20  FDA also believes that the public health is best served by 
342  FDA leveraging its limited resources to develop the 503B bulks list rather than to categorize 
343  newly nominated substances. 
344   
345  FDA does, however, recognize that certain substances that currently appear in Category 1 may 
346  be important for patient care and that the Agency has not yet made a final determination as to 
347  whether these substances will appear on the 503B bulks list. Thus, at this time, FDA is retaining 
348  the policy outlined in section III.A of this guidance until the Agency publishes a notice in the 
349  Federal Register making a final listing determination, or unless the Agency removes the 
350  substances from Category 1 based on, for example, information about safety risks.   
351   
352   
353  III.  POLICY 
354   
355  As discussed below, FDA does not intend to categorize bulk drug substances that the public 
356  nominates for inclusion on the 503B bulks list on or after the date this guidance is finalized.19  
357  Although the Agency intends to continue to receive and evaluate new nominations of bulk drug 
358  substances for possible inclusion on the 503B bulks list, FDA does not intend to place such bulk 
359  drug substances in categories published on FDAs website prior to evaluating them in 
360  accordance with section 503B(a)(2).  FDA is evaluating bulk drug substances nominated for the 
361  503B bulks list on a rolling basis. 
362   
 
20 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 under the statutory clinical 
need standard and obtains public comment. 
 
10  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
363  A.  Compounding From Bulk Drug Substances Nominated for the 503B Bulks 
364  List 
365   
366  Under section 503B of the FD&C Act, a bulk drug substance cannot be used in compounding 
367  unless it is used to compound a drug that appears on the FDA drug shortage list at the time of 
368  compounding, distribution, and dispensing, or it appears on the 503B bulks list.    
369   
370  FDA does not intend to take action against an outsourcing facility for compounding a drug 
371  product using a bulk drug substance that is not on the 503B bulks list if the drug compounded 
372  from the bulk drug substance: (i) appeared on FDAs drug shortage list within 60 days of 
373  distribution and dispensing, and (ii) was to fill an order that the outsourcing facility received for 
374  the drug while it was on FDAs drug shortage list.21      
375   
376  In addition, at this time FDA does not intend to take action against an outsourcing facility for 
377  compounding a drug using a bulk drug substance that does not appear on the 503B bulks list and 
378  that is not used to compound a drug that appears on the FDA drug shortage list at the time of 
379  compounding, distribution, and dispensing, provided that the following conditions are met:   
380   
381  (1) The bulk drug substance appears on 503B Category 1 on FDAs website at 
382  http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Phar
383  mac yCompounding/UCM467374.pdf.  A Category 1 substance may be eligible for 
384  inclusion on the 503B bulks list, was nominated for inclusion on the 503B bulks list with 
385  adequate supporting information for FDA to evaluate it, and has not been identified by 
386  FDA as a substance that appears to present a significant safety risk in compounding 
387  before a determination as to whether to place it on the 503B bulks list has been made; 
388   
389  (2) The original manufacturer and all subsequent manufacturers of the bulk drug substance 
390  are establishments that are registered under section 510 (including foreign establishments 
391  that are registered under section 510(i)) of the FD&C Act;   
392   
393  (3) The bulk drug substance is accompanied by a valid COA;  
394   
395  (4) If the bulk drug substance is the subject of an applicable USP or NF monograph, the bulk 
396  drug substance complies with the monograph; and  
397   
398  (5) The drug product compounded using the bulk drug substance is compounded in 
399  compliance with all other provisions of section 503B of the FD&C Act.    
400   
 
21 An outsourcing facility may not be able to predict when a drug shortage will be resolved, and the facility may 
have orders for a compounded drug in-house that were in progress when the drug was removed from FDAs drug 
shortage list (e.g., the outsourcing facility may have compounded a drug while it was in shortage, but the shortage 
ended while the outsourcing facility awaits the results of sterility testing before release).  This policy provides some 
regulatory flexibility where an outsourcing facility fills orders that it received while a drug was in shortage.  
However, this policy does not pertain to an outsourcing facility continuing to fill orders received after the shortage 
ends, or if the outsourcing facility continues to fill orders more than 60 days after the drug was removed from FDAs 
drug shortage list. 
11  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
401  Original manufacturer means the entity that originally produced the bulk drug substance and not 
402  a subsequent packer, repacker, labeler, or distributor.   
403   
404  Drug products compounded using a bulk drug substance that does not meet each of the above 
405  conditions are not within the scope of the policy described in this guidance.  For example, drug 
406  products compounded from the following bulk drug substances are not within the scope of this 
407  policy: (1) substances not nominated for the 503B bulks list or that were nominated on or after 
408  [Insert date of final guidance]; (2) substances that are the subject of a final determination as to 
409  whether they will be included, or not included, on the 503B bulks list; (3) substances that are 
410  used to compound a drug product on FDAs drug shortage list at the time of compounding, 
411  distribution, and dispensing;22 and (4) substances that are used to compound a drug that appeared 
412  on the FDA drug shortage list within 60 days of distribution and dispensing.  
413   
414  B.  Substances Not Nominated, Nominated Without Adequate Support, or 
415  Nominated On or After the Date This Guidance Is Finalized 
416   
417  As stated above, one of the categories of bulk drug substances FDA has identified on its website 
418  contains nominated substances that may be eligible for inclusion on the 503B bulks list, but that 
419  FDA is unable to evaluate for inclusion on the list at this time because the substances were 
420  nominated with insufficient supporting evidence for FDA to evaluate them (503B Category 3).  
421  New nominations for these substances with sufficient supporting information or nominations for 
422  substances that were not previously nominated can be submitted to the October 2015 docket.      
423   
424  After a substance is nominated to the October 2015 docket,23 FDA will determine whether the 
425  nomination is supported with sufficient information to allow FDA to evaluate it.   
426   
427  Previously, after FDA made that determination, the nominated substance was placed in one of 
428  the three categories described in section II.B.2 above, and the categorization was published on 
429  the FDA website.  Section III.A of this guidance sets forth a policy that addresses substances 
430  once they have been categorized.  This guidance retains the policy described in section III.A with 
431  respect to substances that appear in the categories described in section II.B.2. 
432   
433  However, with respect to substances nominated on or after the date this guidance is finalized, 
434  including new nominations of substances that appear in Category 3,24 FDA no longer intends to 
435  place such substances into the categories described in section II.B.2. Accordingly, substances 
436  nominated on or after the date this guidance is finalized are not within the scope of the policy 
437  described in section III. A of this guidance. FDA intends to continue to evaluate such substances, 
438  provided they are nominated with sufficient supporting information to permit an evaluation, for 
439  inclusion on the 503B bulks list pursuant to section 503B(a)(2) of the FD&C Act.25 
 
22 See section 503B(a)(2)(A)(ii) of the FD&C Act. 
23 This includes new nominations of substances submitted with sufficient supporting information.   
 
24 This includes new nominations of substances in Category 3 that include sufficient supporting information to 
permit FDA evaluation for the 503B bulks list. 
 
25 See also the 503B Evaluation Guidance. 
12  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
440   
441  C.  Comments About Nominated Bulk Drug Substances  
442   
443  If you feel that a substance that you nominated prior to finalization of this guidance does not 
444  appear on the appropriate category as described in this guidance you can submit your comment 
445  to docket number FDA-2015-N-3469.  If you have additional information on a previously 
446  nominated substance that was placed in Category 3, you can submit a new nomination for the 
447  substance that includes the additional information. Consistent with the policy described in 
448  section III.B of this guidance, FDA does not intend to categorize the substance if the new 
449  nomination is submitted on or after the date this guidance is finalized.  However, if the new 
450  nomination includes sufficient supporting information to permit an evaluation, FDA expects to 
451  consider the substance for inclusion on the 503B bulks list. 
452   
453  A nominator may also submit a comment to the docket requesting withdrawal of any of its 
454  nominations.  If the substance that is the subject of such nomination appears in one of the 
455  categories, and the party nominating the substance was the sole nominator, FDA will update the 
456  categories described in this guidance to reflect the withdrawn nomination.26  FDA intends to 
457  provide notice to the public before removing any nominated substances from Category 1 or 
458  Category 2.  
459   
460  Withdrawal of a nomination upon the nominators request, and, if applicable, a resulting update 
461  to the categories described in this guidance, do not reflect a determination by FDA regarding the 
462  validity of the nomination or of any reasons given by the nominator for requesting withdrawal.  
463  In addition, FDA may continue to evaluate a substance at its discretion even if the nominator 
464  submits a comment requesting withdrawal of the nomination.    
 
26 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.  
13