Notifying FDA of a Discontinuance or 
Interruption in Manufacturing of 
Finished Products or Active 
Pharmaceutical Ingredients Under 
Section 506C of the FD&C 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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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 60 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Drug Shortage Staff, 240-402-
7770, or (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-
402-8010.  
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
February 2024 
Procedural 
Revision 1 
43146039dft.docx 
2/5/2024   
Notifying FDA of a Discontinuance or 
Interruption in Manufacturing of 
Finished Products or Active 
Pharmaceutical Ingredients Under 
Section 506C of the FD&C 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 
 
and/or 
 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
February 2024 
Procedural 
Revision 1 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  NOTIFYING FDA OF A PERMANENT DISCONTINUANCE OR AN 
INTERRUPTION IN MANUFACTURING .................................................................. 3 
A.  Who Must Notify FDA and What Products are Subject to the Notification Requirements ... 4 
B.  When To Notify FDA ..................................................................................................................... 6 
C.  What Information To Include in Notifications About Discontinuances or Interruptions in 
Manufacturing of Covered Finished Products ............................................................................ 8 
D.  What Information to Include in Notifications About Discontinuances or Interruptions in 
Manufacturing of API ................................................................................................................. 11 
E.  How To Notify FDA ..................................................................................................................... 12 
F.  Failure To Notify FDA ................................................................................................................. 12 
IV.  HOW FDA COMMUNICATES INFORMATION ABOUT DRUGS AND 
BIOLOGICAL PRODUCTS IN SHORTAGE ............................................................ 13 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Notifying FDA of a Discontinuance or Interruption in  
2  Manufacturing of Finished Products or Active Pharmaceutical 
3  Ingredients Under Section 506C of the FD&C Act 
4  Guidance for Industry1 
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 
16   
17  FDA is issuing this guidance to assist applicants and manufacturers in providing FDA timely, 
18  informative notifications about changes in the production of certain finished drugs and biological 
19  products2 as well as certain active pharmaceutical ingredients (API)3 that may, in turn, help the 
20  Agency in its efforts to prevent and mitigate shortages.  
21   
22  The guidance discusses the notification requirements under section 506C of the Federal Food, 
23  Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 356c) and FDAs regulations. Generally, 
24  section 506C of the FD&C Act requires applicants and manufacturers of certain finished drugs 
25  and biological products to notify FDA of (1) a permanent discontinuance in the manufacture of 
26  such products, (2) an interruption in the manufacture of such products that is likely to lead to a 
27  meaningful disruption in supply of those products in the United States, (3) a permanent 
28  discontinuance in the manufacture of API for such products, or (4) an interruption in the 
29  manufacture of API for such products that is likely to lead to a meaningful disruption in the 
30  supply of the API for those products. This guidance recommends that applicants and 
 
1 This guidance has been prepared by the Drug Shortage Staff and the Office of Regulatory Policy in the Center for 
Drug Evaluation and Research (CDER), in conjunction with the Office of Compliance and Biologics Quality in the 
Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration. You may submit 
comments on this guidance at any time. Submit comments to Docket No. FDA-2020-D-1057 (available at 
https://www.regulations.gov/docket?D=FDA-2020-D-1057). See the instructions in that docket for submitting 
comments on this Level 2 guidance. 
 
2 For purposes of this guidance, a finished drug or biological product refers to a specific strength, dosage form, and 
route of administration of a drug or biological product. See 80 FR 38915 at 38919 and 38928; see also section 
506C(h)(1) of the FD&C Act (defining drug for purposes of section 506C). 
 
3 For purposes of this guidance, active pharmaceutical ingredient means any substance that is intended for 
incorporation into a finished drug product and is intended to furnish pharmacological activity or other direct effect in 
the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the 
body. Active pharmaceutical ingredient does not include intermediates used in the synthesis of the substance (see 21 
CFR 207.1). 
1  Contains Nonbinding Recommendations 
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31  manufacturers provide additional details and follow additional procedures to ensure FDA has the 
32  specific information it needs to help prevent or mitigate shortages. In addition, the guidance 
33  explains how FDA communicates information about products in shortage to the public.  
34   
35  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
36  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
37  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
38  the word should in Agency guidances means that something is suggested or recommended, but 
39  not required. 
40   
41  II.  BACKGROUND 
42   
43  Title X of the Food and Drug Administration Safety and Innovation Act (FDASIA), enacted on 
44  July 9, 2012,4 and section 3112 of the Coronavirus Aid, Relief, and Economic Security Act 
45  (CARES Act), enacted on March 27, 2020,5 amended the FD&C Act to help the Agency address 
46  the problem of drug shortages in the United States, including by adding requirements related to 
47  notifying FDA about finished product and API manufacturing discontinuances and interruptions. 
48  While some supply disruptions and product shortages cannot be predicted or prevented, early 
49  communication and detailed notifications from manufacturers to the Agency play a significant 
50  role in decreasing the incidence, impact, and duration of supply disruptions and product 
51  shortages. Timely notifications that include specific information about the situation allow the 
52  Agency to evaluate the situation and determine an appropriate course of action.6 When FDA 
53  does not receive timely, informative notifications, the Agencys ability to respond appropriately 
54  is limited. 
55   
56  Please note that notifications regarding discontinuances or potential manufacturing issues that 
57  are sent to FDA to meet other reporting requirements, for example, under section 506I of the 
58  FD&C Act (reports of marketing status) or 21 CFR 314.81(b)(1) (field alert reports), are not a 
59  substitute for the notifications required under section 506C of the FD&C Act. It is important that 
60  notifications pursuant to section 506C contain detailed information and be submitted to the 
61  appropriate staff in the Center for Drug Evaluation and Research (CDER) and the Center for 
62  Biologics Evaluation and Research (CBER) (as described in section III.E) to enable timely 
63  review and action by the Agency. 
64   
 
4 Public Law 112-144. The FDASIA amendments to section 506C of the FD&C Act took effect on July 9, 2012. 
 
5 Public Law 116-136. The CARES Act amendments to section 506C of the FD&C Act took effect on September 
23, 2020. 
 
6 See CDERs Manual of Policies and Procedures (MAPP) 4190.1 Drug Shortage Management for information 
about CDERs policies and procedures for evaluating and managing drug shortage situations. CDER MAPPs can be 
found on the Manual of Policies and Procedures web page at https://www.fda.gov/about-fda/center-drug-evaluation-
and-research/cder-manual-policies-procedures-mapp. See CBERs Standard Operating Procedures and Policies 
(SOPPS) 8506 Management of Shortages of CBER-Regulated Products for information about CBERs policies and 
procedures for evaluating and managing shortage situations. CBER SOPPs can be found on the Biologics 
Procedures web page at https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-
information-biologics/biologics-procedures-sopps.   
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
65   
66  III.  NOTIFYING FDA OF A PERMANENT DISCONTINUANCE OR AN 
67  INTERRUPTION IN MANUFACTURING 
68   
69  Under section 506C of the FD&C Act and FDAs regulations,7,8 certain persons must notify 
70  FDA of (1) a permanent discontinuance in the manufacture of certain finished drug and 
71  biological products, (2) an interruption in the manufacture of certain finished drug and biological 
72  products that is likely to lead to a meaningful disruption9 (or, in the case of blood or blood 
73  components intended for transfusion, a significant disruption10) in supply of those products in the 
74  United States, (3) a permanent discontinuance in the manufacture of API for certain finished 
75  drugs and biological products, or (4) an interruption in the manufacture of API for certain 
76  finished drugs and biological products that is likely to lead to a meaningful disruption11 in the 
 
7 Section 506C(i) of the FD&C Act (as amended by FDASIA) required FDA to issue regulations implementing 
section 506C of the FD&C Act. On July 8, 2015, FDA issued the final rule, Permanent Discontinuance or 
Interruption in Manufacturing of Certain Drug or Biological Products (80 FR 38915) to implement section 506C 
and other drug shortage provisions of the FD&C Act, as amended by FDASIA (see 21 CFR 310.306, 
314.81(b)(3)(iii), and 21 CFR 600.82). Section 506C(i)(3) of the FD&C Act permitted FDA to apply the section, by 
regulation, to biological products (as defined in section 351 of the Public Health Service Act), including plasma 
products derived from human plasma protein and their recombinant analogs, if FDA determined that including these 
products would benefit the public health. FDAs 2015 final rule extended drug shortage notification requirements to 
applicants of certain biological products, including recombinant therapeutic proteins, monoclonal antibody products, 
vaccines, allergenic products, plasma derived products and their recombinant analogs, blood or blood components 
for transfusion, and cellular and gene therapy products (see  600.82 and 80 FR 38915 at 38918). 
 
8 As noted above, the CARES Act amended section 506C of the FD&C Act by, among other things, adding 
requirements related to notifying FDA about discontinuances and interruptions in manufacturing of certain 
APIs. Prior to the CARES Act, section 506C contained notification requirements applicable to covered finished 
products (as described below in section III.A) only. As such, the regulations implementing section 506C, which 
FDA promulgated in 2015 (80 FR 38915), contain notification requirements applicable to covered finished products 
only. These regulations do not contain the notification requirements described in this guidance that are applicable to 
API for covered finished products; rather, such API notification requirements arise directly under section 506C, as 
amended by the CARES Act.  
 
9 With respect to finished product notifications under section 506C of the FD&C Act, meaningful disruption means 
a change in production that is reasonably likely to lead to a reduction in the supply of a drug by a manufacturer that 
is more than negligible and affects the ability of the manufacturer to fill orders or meet expected demand for its 
product, and does not include interruptions in manufacturing due to matters such as routine maintenance or 
insignificant changes in manufacturing so long as the manufacturer expects to resume operations in a short period of 
time (see section 506C(h)(3) of the FD&C Act and  314.81(b)(3)(iii)(f) and 600.82(f)). 
 
10 Significant disruption means a change in production that is reasonably likely to lead to a reduction in the supply of 
blood or blood components by a manufacturer that substantially affects the ability of the manufacturer to fill orders 
or meet expected demand for its product, and does not include interruptions in manufacturing due to matters such as 
routine maintenance or insignificant changes in manufacturing so long as the manufacturer expects to resume 
operations in a short period of time (see  600.82(f)). FDA intends to consider an interruption in manufacturing that 
leads to a reduction of 20 percent or more of an applicants own supply of blood or blood components over a 1-
month period to substantially affect the ability of the applicant to fill orders or meet expected demand; 
accordingly, such an interruption would be considered a significant disruption in supply (see 80 FR 38915 at 
38920-21).  
 
11 For purposes of this guidance, and with respect to API notifications under section 506C of the FD&C Act, 
meaningful disruption means a change in production that is reasonably likely to lead to a reduction in supply of an 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
77  supply of the API for those products. Notifications under section 506C must include disclosure 
78  of reasons for the discontinuation or interruption.12  The sections below describe the notification 
79  requirements under section 506C in greater detail and provide recommendations about the 
80  notifications, including the timing and contents. 
81   
82  A.  Who Must Notify FDA and What Products are Subject to the Notification 
83  Requirements  
84   
85  The persons who must submit notifications under section 506C (collectively referred to in this 
86  guidance as manufacturers) are as follows:  
87   
88    Applicants with approved new drug applications (NDAs) or approved abbreviated new 
89  drug applications (ANDAs) for certain finished drug products13  
90   
91    Applicants with approved biologics license applications (BLAs) for certain finished 
92  biological products other than blood or blood components14  
93   
94    Applicants with approved BLAs for blood or blood components for transfusion that 
95  manufacture a significant percentage of the U.S. blood supply15,16 
96   
97    Manufacturers of certain finished drug products marketed without approved NDAs or 
98  ANDAs17    
99   
100  The notification requirement regarding discontinuances and interruptions in manufacturing of 
101  API under section 506C of the FD&C Act applies only to the manufacturers that are listed 
102  above; other entities in the supply chain for a drug, including third-party API manufacturers and 
103  suppliers, are not required to submit such notifications.  
104   
 
API by its manufacturer that is more than negligible and affects the ability of the API manufacturer to fill orders or 
meet expected demand for the API, and does not include interruptions in manufacturing due to matters such as 
routine maintenance or insignificant changes in manufacturing so long as the API manufacturer expects to resume 
operations in a short period of time. 
 
12 See section 506C(a) of the FD&C Act. 
 
13 See  314.81(b)(3)(iii). 
 
14 See  600.82(a)(1). 
 
15 See  600.82(a)(2). 
 
16 FDA intends to consider an applicant that holds a BLA for blood or blood components to be a manufacturer of a 
significant percentage of the U.S. blood supply if the applicant manufactures 10 percent or more of the U.S. blood 
supply (see 80 FR 38915 at 38917). 
 
17 See  310.306, which applies  314.81(b)(3)(iii) in its entirety to covered drug products marketed without an 
approved NDA or ANDA. 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
105  The finished products for which notifications must be submitted under section 506C of the 
106  FD&C Act (referred to in the guidance as covered finished products) are prescription drugs and 
107  biological products18 (including blood or blood components for transfusion) that are (1) life 
108  supporting, life sustaining,19 or intended for use in the prevention or treatment of a debilitating 
109  disease or condition,20 including any such product used in emergency medical care or during 
110  surgery or any such drug that is critical to the public health during a public health emergency 
111  declared by the Secretary under section 319 of the Public Health Service Act; and (2) not 
112  radiopharmaceutical drug products or any other products designated by FDA.21,22 In addition, the 
113  manufacturers listed above must submit notifications under section 506C of the FD&C Act for 
114  API of covered finished products.23 
115   
116  In general, the notification requirements for covered finished products apply to each individual 
117  manufacturer regardless of market share, number of other manufacturers marketing products that 
118  are therapeutically equivalent, or the amount of product that may be in distribution.24 Similarly, 
119  with respect to notifications for an API of a covered finished product, FDA recommends that a 
120  manufacturer consider its current API manufacturers supply of the API, regardless of the API 
121  manufacturers market share, the number of other API manufacturers marketing the same or 
122  similar APIs, or the amount of the API that may be in distribution. If a manufacturer is not 
123  certain whether the notification requirements under section 506C of the FD&C Act apply to the 
124  products it manufactures or the API(s) for the products it manufactures, we recommend that the 
125  manufacturer contact the Agency as described in section III.E below.  
126   
127  In the case of a covered finished product that is marketed under an approved application and API 
128  for such a product, the applicant is solely responsible for submitting notifications to FDA under 
129  section 506C of the FD&C Act concerning the covered finished product or API for the covered 
130  finished product, regardless of whether the product or API is manufactured by the applicant itself 
 
18 See footnote 2. 
 
19 Life supporting or life sustaining means a product that is essential to or that yields information that is essential to, 
the restoration or continuation of a bodily function important to the continuation of human life (see  
314.81(b)(3)(iii)(f) and 600.82(f)). 
 
20 Intended for use in the prevention or treatment of a debilitating disease or condition means a product intended for 
use in the prevention or treatment of a disease or condition associated with mortality or morbidity that has a 
substantial impact on day-to-day functioning (see  314.81(b)(3)(iii)(f) and 600.82(f)). 
 
21 See section 506C(a) of the FD&C Act;  310.306, 314.81(b)(3)(iii)(a), and 600.82(a). 
 
22 The notification requirement applies regardless of any determination with respect to whether the product is 
medically necessary (see generally CDERs MAPP 4190.1 Rev. 3).   
 
23 See section 506C(a) of the FD&C Act. 
 
24 As explained in the preamble to the final rule (80 FR at 38920), ...[T]he rule requires an applicant to report an 
interruption in manufacturing likely to lead to a meaningful disruption in its own supply of a covered drug or 
biological product...Consistent with the statute, the rule does not require an applicant to predict the market-wide 
impact of an interruption in its own manufacturing... But see above regarding the requirement for blood or blood 
components intended for transfusion which only applies to applicants that manufacture a significant percentage of 
the U.S. blood supply.  
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
131  or for the applicant under contract with one or more different entities.25 Accordingly, the 
132  applicant should establish a process with any third-party API suppliers, any relevant contract 
133  manufacturers, and other relevant entities to ensure that the applicant can provide a complete and 
134  accurate notification to FDA within the required time frame. Likewise, for a covered finished 
135  drug product marketed without an approved NDA or ANDA, the manufacturer should establish a 
136  process with any third-party API suppliers, any relevant contract manufacturers, and other 
137  relevant entities to ensure the manufacturer can provide complete and accurate notification to 
138  FDA within the required time frame. 
139   
140  B.  When To Notify FDA 
141   
142  In general, manufacturers of covered finished products must submit a notification to FDA at least 
143  6 months in advance of (1) a permanent discontinuance in manufacturing of a covered finished 
144  product, (2) an interruption in manufacturing of a covered finished product that is likely to lead 
145  to a meaningful disruption in supply of the product in the United States, (3) a permanent 
146  discontinuance in manufacturing of API for a covered finished product, or (4) an interruption in 
147  manufacturing of API for a covered finished product that is likely to lead to a meaningful 
148  disruption in supply of the API for the product.26 However, if 6 months advance notice is not 
149  possible, the notification must be submitted as soon as practicable thereafter27; furthermore, a 
150  notification concerning a permanent discontinuance or interruption in manufacturing of a 
151  covered finished product must be submitted no later than 5 business days after the 
152  discontinuance or interruption in manufacturing occurs.28    
153   
154  For covered finished products and API, FDA interprets a permanent discontinuance to be a 
155  decision by its manufacturer to cease manufacturing and distributing its product indefinitely for 
156  business or other reasons. Notification must be provided within the time frame described 
157  above.29 Upon receiving such notifications, FDA assesses the potential public health impact of 
158  the reported discontinuance and, if appropriate, may request further discussion with the reporting 
159  manufacturer. With respect to covered finished products in particular, to the extent possible, 
160  manufacturers should not delay notifying FDA of a permanent discontinuance until after 
161  production has ceased; FDA should be notified well before any decline in supply occurs.  
162   
163  In the case of interruptions in manufacturing of a covered finished product, when assessing 
164  whether a meaningful disruption in supply is likely to occur, the relevant analysis is whether a 
165  change in production is likely to lead to a reduction in the supply of a product by the 
166  manufacturer that is more than negligible and would affect the manufacturers ability to fill 
 
25 See  314.81(b)(3)(iii)(a) and 600.82(a)(1). 
 
26 See section 506C(b) of the FD&C Act;  310.306(b), 314.81(b)(3)(iii)(b)(1), and 600.82(b)(1). 
 
27 See section 506C(b) of the FD&C Act. 
 
28 See section 506C(b) of the FD&C Act;  310.306(b), 314.81(b)(3)(iii)(b)(2), and 600.82(b)(2). 
 
29 See section 506C(a) of the FD&C Act;  310.306(b), 314.81(b)(3)(iii)(a), and 600.82(a). 
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
167  orders or meet expected demand for its product.30 In other words, the assessment is to be based 
168  solely on the reporting manufacturers capacity and supply. The manufacturer should not 
169  consider other manufacturers or competitors capacities or assumed capacities, or what it 
170  understands about market demand for the product.31 To the extent it is possible to do so, 
171  manufacturers must notify FDA of an interruption in manufacturing that is likely to lead to a 
172  meaningful disruption in their own supply of the covered finished product in the United States 
173  prior to the interruptions occurrence.32 In all cases, manufacturers should notify the Agency 
174  before a meaningful disruption in their own supply of a covered finished product occurs. For 
175  example, FDA should not first learn of a meaningful supply disruption resulting from an 
176  interruption in manufacturing when a manufacturer is unable to fill an order. Note that after 
177  providing the initial notification of an interruption in manufacturing of a covered finished 
178  product under section 506C of the FD&C Act, FDA recommends that manufacturers provide 
179  updates approximately every 2 weeks on the situation, including the expected timeline for 
180  resuming normal operations, even if the status remains unchanged. These updates are important 
181  to ensure that FDA remains informed and can act on the most current information. We 
182  recommend that such updates be submitted until the situation has been resolved. 
183   
184  If a manufacturer is unsure of whether to notify FDA of an interruption in manufacturing 
185  because the firm does not know whether it is likely to lead to a meaningful disruption in its 
186  supply,33 FDA urges the manufacturer to submit a notification anyway. This would allow FDA 
187  to monitor the overall market and take timely steps, as necessary, to help prevent or mitigate any 
188  resulting shortage. In addition, if a manufacturer is considering taking an action that may lead to 
189  a meaningful disruption in the supply of a product (e.g., holding production to investigate a 
190  quality issue or transfer of ownership), FDA requests that the manufacturer notify FDA 
191  immediately through the process explained below in section III.E. 
192   
 
30 See 80 FR 38915 at 38920.  Manufacturers are not required to report interruptions in manufacturing due to matters 
such as routine maintenance or insignificant changes in manufacturing, so long as the manufacturer expects to 
resume operations in a short period of time (see section 506C(h)(3)(B) of the FD&C Act). 
 
31 See 80 FR 38915 at 38920 (explaining that manufacturers are not required or expected to predict the market-wide 
impact of an interruption in their own manufacturing).  But see section III.A (explaining that the regulatory 
requirement for blood or blood components intended for transfusion only applies to applicants that manufacture a 
significant percentage of the U.S. blood supply) (emphasis added).  
 
32 See section 506C(b) of the FD&C Act;  310.306(b), 314.81(b)(3)(iii)(b), and 600.82(b). 
 
33 See footnote 9. 
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193  In the case of interruptions in manufacturing of API, a covered finished product manufacturer is 
194  required to notify FDA of interruptions in the manufacture of the API of such products that are 
195  likely to lead to a meaningful disruption in the supply of API. When assessing whether a 
196  meaningful disruption is likely to occur in this context, the manufacturer should consider 
197  whether a change in production of the API is likely to lead to a reduction in the supply of API by 
198  the API supplier that is more than negligible and would affect the API suppliers ability to fill 
199  orders or meet expected demand for the API.34 As noted in section III.A, to ensure the 
200  manufacturer is able to satisfy the notification requirement with respect to API, manufacturers 
201  should establish a process to ensure they receive sufficient, timely information about changes in 
202  production of their suppliers API. 
203   
204  As described above, the notification requirements under the FD&C Act and FDAs regulations 
205  are triggered by a permanent discontinuance or an interruption in manufacturing that is likely to 
206  lead to a meaningful disruption in supply of certain finished drugs or biological products or API 
207  for those products. However, FDA requests that manufacturers also notify the Agency when they 
208  are unable to meet demand for covered finished products, even in the absence of an interruption 
209  in manufacturing, for example, when there is a sudden, unexpected spike in demand. Though 
210  manufacturers are not required to report this type of situation to FDA, reporting under these 
211  circumstances provides an important signal to the Agency about a potential shortage and allows 
212  FDA to take appropriate steps to address the potential shortage. 
213   
214  C.  What Information To Include in Notifications About Discontinuances or 
215  Interruptions in Manufacturing of Covered Finished Products 
216   
217  Under section 506C of the FD&C Act and FDAs regulations, notifications concerning a 
218  permanent discontinuance or interruption in the manufacture of a covered finished product that is 
219  likely to lead to a meaningful disruption in supply must include, at a minimum:35 
220   
221    Name of the product, including the National Drug Code (NDC) number, or, for biological 
222  products, an alternative standard for identification and labeling if one has been 
223  recognized as acceptable by the Center Director.36 
224   
225    Name of the applicant (for approved products) or manufacturer (for unapproved drugs).  
226   
227    Whether the notification relates to a permanent discontinuance of the product or an 
228  interruption in manufacturing of the product. 
229   
230    Description of the reason(s) for the discontinuation or interruption in manufacturing. 
231   
 
34 FDA recommends that a manufacturer consider its current API manufacturers supply of the API regardless of the 
API manufacturers market share, the number of other API manufacturers marketing the same or similar APIs 
(including, for approved products, the number of approved API sources the manufacturer may have), or the amount 
of the API that may be in distribution.  
 
35 See section 506C(a) of the FD&C Act;  310.306(b), 314.81(b)(3)(iii)(c), and 600.82(c). 
 
36 See  600.82(c)(1). 
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Draft  Not for Implementation 
232    If an API is a reason for, or risk factor in, the discontinuation or interruption, the source 
233  of the API, and any alternative sources for the API known by the manufacturer. 
234   
235    Whether any associated device used for preparation or administration included in the 
236  covered finished product37 is a reason for, or risk factor in, the discontinuation or 
237  interruption in manufacturing of the covered finished product.  
238   
239    The estimated duration of an interruption in manufacturing of the covered finished 
240  product. 
241   
242  As noted above, this information is the minimum that manufacturers must provide. However, to 
243  ensure that FDA is better equipped to help prevent or mitigate a drug shortage, FDA 
244  recommends that manufacturers provide additional details about the situation and has included 
245  below a list of types of additional information for manufacturers to consider providing in their 
246  notifications to FDA. This list is not intended to be exhaustive; it provides information that FDA 
247  generally finds helpful in assessing the situation and determining appropriate steps to help 
248  prevent or mitigate a shortage. The more information manufacturers provide, the better FDA will 
249  be able to assist. 
250   
251  We recommend including the following additional information, as relevant to the situation, when 
252  notifying FDA of a permanent discontinuance or interruption in manufacturing concerning a 
253  covered finished product: 
254   
255    Whether the notification concerns an unavoidable supply disruption or a supply 
256  disruption that may be preventable. 
257   
258    The underlying reason or root cause leading to this notification. (A detailed and thorough 
259  explanation beyond manufacturing delay or a recitation of the broad categories of 
260  reasons listed below in section IV is especially important and allows FDA to identify and 
261  use the most appropriate and effective mitigation tools.) 
262   
 
37 For purposes of the notification requirement under section 506C of the FD&C Act, FDA considers the term any 
associated device used for preparation or administration included in the drug to be a device constituent part of a 
covered finished product that is a drug-led, drug-device or biologic-led, biologic-device combination product (i.e., a 
single entity, co-packaged, or cross-labeled combination product, as defined in 21 CFR 3.2(e)). Under section 506J 
of the FD&C Act, manufacturers of certain medical devices are required to notify the Agency of a permanent 
discontinuance in the manufacture of the device or interruption in manufacture of the device that is likely to lead to a 
meaningful disruption in the supply of the device in the United States. For more information about such device 
notifications, see section 506J of the FD&C Act. Regarding the shortage of a device, if you have questions about 
your notification, you can contact the Center for Devices and Radiological Health at 
CDRHManufacturerShortage@fda.hhs.gov and include Question in the subject line of the email.  
 
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263    The estimated date of onset of the interruption in manufacturing or supply disruption for 
264  this product.  If a supply disruption has already occurred, provide the estimated 
265  duration.38  
266   
267    The anticipated time frame for all existing product (on hand and in distribution channels) 
268  to be exhausted if the notification is for a permanent discontinuance. 
269   
270    The estimated market share for the product and whether the entire market share is 
271  affected by this issue.  
272   
273    The estimated volume of historic monthly sales, usage, or demand, as applicable, for this 
274  product. 
275   
276    Whether the product is manufactured on multiple lines or in multiple facilities. 
277   
278    Amount of current inventory of product at the manufacturing facility or warehouse. 
279   
280    If the notification is for an interruption in manufacturing, the date when the last 
281  remaining batch of finished product was or will be released into distribution and how 
282  long the supply is expected to last in the market without additional releases based on 
283  current demand. 
284   
285    Whether there is an emergency or reserve supply of this product and whether allocation39 
286  of supply on hand or reserve supply is an option. 
287   
288    Whether a redundancy risk management plan that identifies and evaluates risks to the 
289  supply of the drug is in place.40 
290   
291    Whether public information has been provided or will be provided for stakeholders and 
292  patients regarding this actual or potential shortage (e.g., Dear Healthcare Provider 
293  (DHCP) Letters, supply or shortage information posted on the manufacturers website). 
294   
295    Whether a proposal is available for FDA to review that may help to expedite availability 
296  of the product or suggestions for FDA actions that may help prevent or mitigate a supply 
297  disruption or shortage. 
298   
299  Manufacturers need not have all of these additional details available before submitting a 
300  notification; notifications can be updated at any time to include such additional information. 
 
38 Notifications of interruptions in manufacturing must include the expected duration of the interruption in 
manufacturing. See section 506C(a) of the FD&C Act.  See also  310.306(b), 314.81(b)(3)(iii)(c)(5), and 
600.82(c)(5). 
 
39 Allocation generally refers to limiting the quantity distributed to customers to extend the life of the existing 
supply. 
 
40 See section 506C(j) of the FD&C Act. 
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301  Manufacturers must provide initial notification within the timeframe described in section 
302  506C(b) of the FD&C Act and applicable regulations (see section III.B for further discussion), 
303  and FDA recommends that manufacturers update their notifications with additional information 
304  as it becomes available. As described further in section IV below, information that is submitted 
305  to FDA will not be disclosed except in accordance with applicable disclosure law, which 
306  includes restrictions on the release of confidential commercial information and trade secrets.41 If 
307  FDA determines that a product is in shortage, the Agency intends to work with manufacturers to 
308  confirm the accuracy and appropriateness of information regarding the shortage before posting 
309  publicly on FDAs website. 
310   
311  D.  What Information to Include in Notifications About Discontinuances or 
312  Interruptions in Manufacturing of API 
313   
314  Under section 506C of the FD&C Act, notifications concerning API must include, at a 
315  minimum:42 
316   
317    Disclosure of reasons for the discontinuation or interruption in manufacturing of the API. 
318   
319    Source of the API and any alternative sources for the API known by the finished product 
320  manufacturer. 
321   
322    Expected duration of an interruption in manufacturing of the API. 
323   
324  To ensure these notifications provide information that is helpful to FDA in assessing the 
325  potential for a supply disruption or shortage, we recommend that manufacturers also include the 
326  additional information outlined below: 
327   
328    Name(s) of the finished product(s) for which the API is used, including the NDC 
329  number(s), or, for biological products, an alternative standard for identification and 
330  labeling if one has been recognized as acceptable by the Center Director.43 
331   
332    Name of the application holder (for approved products) or manufacturer (for unapproved 
333  drugs) of the covered finished product(s) for which the API is used. 
334   
335    Number of any drug master file associated with the API.44 
336   
337    Whether the notification relates to a permanent discontinuance of the API or an 
338  interruption in manufacturing of the API. 
339   
 
41 See section 506C(d) of the FD&C Act. 
 
42 See section 506C(a) of the FD&C Act. 
 
43 See  600.82(c)(1). 
 
44 See  314.420. 
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340    Estimated date of onset of the interruption in manufacturing or supply disruption for the 
341  API.  If a supply disruption has occurred, provide the estimated duration.45  
342   
343    Whether the discontinuance or interruption in manufacturing of the API has impacted or 
344  is expected to impact the supply of the covered finished product or ability to fill orders 
345  for the covered finished product. 
346   
347  E.  How To Notify FDA 
348   
349  Manufacturers of covered finished products regulated by CDER should submit initial 
350  notifications about such products46 and API for such products either via email to 
351  drugshortages@fda.hhs.gov or through the CDER Direct NextGen Portal at https://edm.fda.gov. 
352  Manufacturers of covered finished products regulated by CBER should submit initial 
353  notifications about such products47 and API for such products via email to 
354  cbershortage@fda.hhs.gov. All additional updates should be submitted by email to the applicable 
355  Center (CDER or CBER), not through the NextGen Portal.  
356   
357  Manufacturers should submit a separate notification for each permanent discontinuance or 
358  interruption in manufacturing. A single initial notification may include a list of all affected 
359  covered finished products48 or API. Manufacturers should not provide notification about a newly 
360  affected product (e.g., a new strength) in an update, even if the issue is related to a previously 
361  reported interruption in manufacturing. Rather, a separate initial notification should be submitted 
362  to ensure the newly affected product is tracked appropriately. In addition, as explained in section 
363  II, notifications submitted to FDA to satisfy other reporting requirements (e.g., under section 
364  506I of the FD&C Act) are not a substitute for the notifications required under section 506C. 
365   
366  F.  Failure To Notify FDA 
367   
368  If a manufacturer fails to provide notification with respect to covered finished products or API, 
369  as required by section 506C(a) of the FD&C Act and in accordance with the timelines set forth in 
370  section 506C(b) and the implementing regulations,49 FDA will issue a letter to that manufacturer 
371  stating that the applicable notification requirement was not met (a noncompliance letter).50 
372  Note that if FDA determines that an applicant experienced a reportable interruption in 
373  manufacturing that it could not reasonably anticipate 6 months in advance, but the applicant 
 
45 Notifications of interruptions in manufacturing must include the expected duration of the interruption in 
manufacturing. See section 506C(a) of the FD&C Act.   
 
46 Notifications for finished products under section 506C of the FD&C Act must be submitted to FDA electronically 
in a format that FDA can process, review, and archive. See  310.306(b), 314.81(b)(3)(iii)(b), and 600.82(b); see 
also 80 FR 38915 at 38922. 
 
47 Ibid. 
 
48 See footnote 2. 
 
49 Section 506C(b) of the FD&C Act;  310.306(b), 314.81(b)(3)(iii)(b)(1) and (2), and 600.82(b)(1) and (2). 
 
50 See section 506C(f)(1) of the FD&C Act. 
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374  failed to notify FDA as soon as practicable, FDA will issue a noncompliance letter.51 The 
375  manufacturer must respond to FDAs letter not later than 30 calendar days after its issuance, 
376  providing the reason for noncompliance and the information on the discontinuance or 
377  interruption required under section 506C(a) of the FD&C Act.52 Not later than 45 calendar days 
378  after the issuance of the noncompliance letter to the manufacturer, FDA will post that letter and 
379  any response received on FDAs website,53 with appropriate redactions to protect trade secrets or 
380  confidential commercial information.54 However, FDA will not post the noncompliance letter 
381  and any response it receives if the Agency determines that the noncompliance letter was issued 
382  in error or, after review of the manufacturers response, that the manufacturer had a reasonable 
383  basis for not notifying FDA as required.55  
384   
385   
386  IV.  HOW FDA COMMUNICATES INFORMATION ABOUT DRUGS AND 
387  BIOLOGICAL PRODUCTS IN SHORTAGE  
388   
389  Consistent with section 506E of the FD&C Act (21 U.S.C. 356e) and FDAs regulations,56 FDA 
390  maintains public, up-to-date lists of finished drugs and biological products that FDA has 
391  determined to be in shortage in the United States.57 These lists include: 
392   
393    Established name of the product in shortage; brand name of the product in shortage, if 
394  applicable; the NDC number, presentation, strength(s), and package size, as available 
395   
396    Name of each application holder (for approved products) or manufacturer (for 
397  unapproved drugs)  
398   
399    Name of the distributor, if different from the application holder (for approved products) 
400  or manufacturer (for unapproved drugs) 
401   
402    Reason for the shortage from the following categories:58 
 
51 Ibid. 
 
52 See section 506C(f)(2) of the FD&C Act. 
 
53 Links to noncompliance letters can be found at 
http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm403902.htm.  
 
54 See section 506C(d), (f)(3) of the FD&C Act. 
 
55 See section 506C(f)(3) of the FD&C Act. 
 
56 See section 506E of the FD&C Act;  310.306(c), 314.81(b)(3)(iii)(d)(1), and 600.82(d)(1). 
 
57 See https://www.accessdata.fda.gov/scripts/drugshortages/default.cfm for shortages tracked by CDER; see 
https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/cber-regulated-products-current-
shortages for shortages tracked by CBER.  
 
58 The reason for the shortage identified is determined by FDA using the notification submitted and any 
supplementary information gathered, such as from manufacturing facility reviews conducted by FDA. 
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403   
404   Requirements related to complying with good manufacturing practices 
405   Regulatory delay 
406   Shortage of an active ingredient 
407   Shortage of an inactive ingredient component 
408   Discontinuation of the manufacture of the product 
409   Delay in shipping  
410   Demand increase 
411   Other reason 
412   
413    Estimated duration of the supply disruption or shortage, anticipated date of availability, 
414  and resolution dates (based on information provided by the manufacturer) 
415   
416    Any additional information related to the shortage that the manufacturer chooses to share 
417  (e.g., DHCP letters, informed consent forms, or patient letters)  
418   
419  FDA updates its lists regularly and strives to communicate in real-time so that patients and 
420  healthcare providers have the most current information on product shortages in the United States. 
421  A product is added to the CDER- or CBER-maintained list only after the Agency determines that 
422  it is in shortage; products are not added to the list(s) immediately upon receipt of a notification 
423  regarding a discontinuance or interruption in manufacturing. In cases where a shortage does not 
424  occur or is prevented through FDA or stakeholder intervention, the product will not be posted on 
425  the list. FDA generally considers a shortage to be resolved and removes the product from the 
426  current shortage section of the list based on an evaluation of the entire market, assessing 
427  whether all backorders have been filled and supply is meeting or exceeding demand. In making 
428  this evaluation, FDA may consider, among other factors, affected market share, ability of 
429  alternate manufacturers to cover the demand, and confirmed market stabilization. 
430   
431  The Agency does not include confidential commercial information or trade secrets in these 
432  lists.59 In general, FDA works with manufacturers to confirm the accuracy and appropriateness 
433  of information before posting publicly on its website(s). FDA will continue to post information 
434  on its website(s) consistent with section 506E of the FD&C Act and FDAs regulations, 
435  regardless of any additional information manufacturers provide to the Agency based on the 
436  recommendations in this guidance. 
 
59 See section 506E(c)(2) of the FD&C Act. 
14