Review of Drug Master 
Files in Advance of 
Certain ANDA 
Submissions Under 
GDUFA  
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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 90 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Ziyang Su 240-402-6004.  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
October 2022 
Pharmaceutical Quality / CMC 
   
Review of Drug Master 
Files in Advance of 
Certain ANDA 
Submissions Under 
GDUFA  
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) 
 
October 2022 
Pharmaceutical Quality / CMC 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  CONDITIONS FOR REQUESTING ASSESSMENT OF DMF PRIOR TO AN 
ANDA SUBMISSION ................................................................................................................... 2 
A.  Request for assessment of a DMF 6 months prior to submission of an ANDA or its 
amendments ............................................................................................................................................ 3 
B.  Request for assessment of a DMF 6 months prior to submission of a PAS to add a new API 
source ....................................................................................................................................................... 4 
IV.  ADDITIONAL INFORMATION .................................................................................... 5 
APPENDIX: RECOMMENDED CONTENT FOR A PRIOR ASSESSMENT REQUEST . 6 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Review of Drug Master Files in Advance of Certain ANDA 
2  Submissions Under GDUFA  
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  This guidance is intended for holders of Type II active pharmaceutical ingredient (API) drug 
17  master files (DMFs) that will be referenced in an abbreviated new drug application (ANDA), or a 
18  prior approval supplement (PAS) to an ANDA. This guidance explains how FDA incorporates a 
19  program enhancement agreed upon by the Agency and industry as part of the negotiations 
20  relating to reauthorization of the Generic Drug User Fee Amendments (GDUFA), as described in 
21  GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-
22  2027 (GDUFA III commitment letter).2 Specifically, this guidance describes instances when an 
23  early assessment,3 or DMF prior assessment, could be requested by a DMF holder and the 
24  circumstances under which FDA would commence an early assessment4 of Type II API DMFs 6 
25  months prior to an ANDA or PAS submission referencing the DMF. It also provides 
26  recommendations for such DMF holders when making a request.  
27   
28  The guidance does not apply to Type II API DMFs used to support new drug applications 
29  (NDAs), submissions related to ANDAs that are not described above, or any other types of 
30  DMFs.5   
31   
32  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
33  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
34  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
 
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and 
Research at the Food and Drug Administration.  
2 The GDUFA III commitment letter is available at https://www.fda.gov/media/153631/download. 
3 In this guidance, the terms assessment and review are used interchangeably.  
4 For the purposes of this guidance, DMF assessment consists of evaluation of all chemistry-related quality 
information for the API, including all related consults. It does not include assessment of sterility assurance 
information for a sterile API, which should be reviewed concurrently with an application submission. 
5 For additional information on the types of DMFs, see FDA draft guidance for industry Drug Master Files (October 
2019). When final, the Drug Master Files guidance will represent the FDAs current thinking on the topic. For the 
most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents. 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
35  the word should in Agency guidances means that something is suggested or recommended, but 
36  not required.  
37   
38  II.  BACKGROUND 
39   
40  The Generic Drug User Fee Amendments of 2012 (GDUFA I)6 amended the Federal Food, 
41  Drug, and Cosmetic Act (FD&C Act) to authorize FDA to assess and collect user fees to provide 
42  FDA with resources7 to help ensure patients have access to quality, affordable, safe, and 
43  effective generic drugs. GDUFA fee resources bring greater predictability and timeliness to the 
44  review of generic drug applications. GDUFA must be reauthorized every 5 years to continue 
45  FDAs ability to assess and collect GDUFA fees, and this user fee program has been 
46  reauthorized two times since GDUFA I, most recently in the Generic Drug User Fee 
47  Amendments of 2022.8 As described in the GDUFA III commitment letter applicable to this 
48  latest reauthorization,9 FDA has agreed to performance goals and program enhancements 
49  regarding aspects of the generic drug assessment program that build on previous authorizations 
50  of GDUFA. New enhancements to the program are designed to maximize the efficiency and 
51  utility of each assessment cycle, with the intent of reducing the number of assessment cycles for 
52  ANDAs and facilitating timely access to generic medicines for American patients.  
53   
54  One of the enhancements included in the GDUFA III commitment letter is a mechanism to 
55  enable assessment of DMFs in advance of certain ANDA and PAS submissions. This early 
56  assessment of DMFs is understood by FDA to, in general, address Type II API DMFs and, 
57  accordingly, subsequent references to DMFs in this guidance are references to Type II API 
58  DMFs.  
59   
60  The purpose of this guidance is to provide information and recommendations on the early 
61  assessment of certain Type II DMFs 6 months prior to the submission of certain ANDAs or 
62  PASs. It describes the process outlined in the GDUFA III commitment letter in greater detail and 
63  provides recommendations on how to provide the relevant information to FDA. 
64   
65  III.  CONDITIONS FOR REQUESTING ASSESSMENT OF DMF PRIOR TO AN 
66  ANDA SUBMISSION 
67   
68  This section describes in detail the conditions set forth in the GDUFA III Commitment Letter 
69  applicable to a DMF, and the planned ANDAs or PASs that reference it, in order for the DMF 
70  holder to request an assessment of the DMF 6 months prior to the planned submission of certain 
71  ANDAs or PASs under the GDUFA III agreement.  
72   
73  Though the DMF holder should submit the DMF prior assessment request, close communication 
74  and coordination with the ANDA applicant is strongly encouraged to maximize the chance of a 
75  successful request by ensuring that all appropriate materials are provided with the request. For 
 
6 Title III of the Food and Drug Administration Safety and Innovation Act, Public Law 112-144. 
7 User fees are available for obligation in accordance with appropriations Acts. 
8 Enacted as Title III of Division F (the FDA User Fee Reauthorization Act of 2022) of the Continuing 
Appropriations and Ukraine Supplemental Appropriations Act, 2023. 
9 See footnote 2. 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
76  example, the DMF holder is encouraged to obtain sufficient information from the ANDA 
77  applicant so the DMF holder can provide the information detailed under the conditions listed in 
78  sections A and B below.  
79   
80  As described in section VI.E.3 of the GDUFA III Commitment Letter, to be eligible for this 
81  assessment, a DMF holder would submit with its request the following:  
82   
83  a.  At least one Letter of Authorization (LOA) with one pre-assigned ANDA number;  
84   
85  b.  A reference to the corresponding reference listed drug (RLD)10 listed in in FDAs 
86  Approved Drug Products With Therapeutic Equivalence Evaluations (the Orange Book);11 
87  and  
88   
89  c.  Documentation that the DMF holder has paid a GDUFA DMF fee as described in section 
90  744B(a)(2)(A) of the FD&C Act (21 U.S.C. 379j-41(a)(2)(A)).  
91   
92  Regarding condition a, if the LOA was previously submitted to the DMF, it does not need to be 
93  re-submitted with the request. Regarding condition b, a reference to the RLD listed in the Orange 
94  Book is only needed when the request is to support an original ANDA. A reference is not needed 
95  when the request is to support an ANDA amendment or supplement.  
96   
97  A.  Request for assessment of a DMF 6 months prior to submission of an ANDA 
98  or its amendments 
99   
100  Under the terms of the GDUFA III commitment letter, a holder of a DMF may submit a request 
101  for assessment of the DMF 6 months prior to the planned submission date for: 1) an original 
102  ANDA, 2) an ANDA amendment containing a response to a Complete Response Letter (CRL), 
103  or 3) an amendment seeking approval of an ANDA that previously received a tentative approval. 
104  In each case, as described in section VI.E.1 of the GDUFA III Commitment Letter, the 
105  submission would include reference to a DMF for which FDA has not conducted a substantive 
106  assessment, and one of the following conditions should be met:  
107   
108  1.  All patents and exclusivities will expire within 12 months of the planned submission 
109  date; 
110   
111  2.  The submission is for a drug product for which there are not more than three approved 
112  drug products listed in the Orange Book, for which there are no blocking patents or 
113  unexpired exclusivities listed for the RLD, and the ANDA applicant is not seeking 
114  approval for less than all of the conditions of use on the RLD labeling, i.e., a carve-out. 
115  In other words, there are fewer than four approved therapeutically equivalent drug 
116  products, including the RLD, listed in the Orange Book, no blocking patents or unexpired 
117  exclusivities for the RLD in the Orange Book, and the applicant is not seeking to carve 
118  out any conditions of use; 
 
10 An RLD is the listed drug identified by FDA as the drug product upon which an applicant relies in seeking 
approval of its ANDA. 21 CFR 314.3(b).  
11 The Orange Book is available at: https://www.accessdata.fda.gov/scripts/cder/ob/. 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
119   
120  3.  The submission is for a drug product that could help mitigate or resolve a drug shortage 
121  and prevent future shortages,12 including submissions related to products that are listed 
122  on FDAs Drug Shortage List13 at the time of the submission of the DMF assessment 
123  request; 
124   
125  4.  The submission is for a drug product that either could help address a public health 
126  emergency declared by the Secretary of the U.S. Department of Health and Human 
127  Services under section 319 of the Public Health Service Act (PHS Act),14 or anticipated 
128  under the same criteria as apply to such a declaration; or 
129   
130  5.  The submission is for a drug product for which (a) there is only one approved drug 
131  product listed in the Prescription Drug Product List (i.e., the Active Section) of the 
132  Orange Book and that product is approved under an ANDA (i.e., the RLD is in the 
133  Discontinued Section and there is not more than one ANDA in the Active Section); 
134  (b) the approved ANDA for the drug product listed in the Active Section was not 
135  approved pursuant to a suitability petition under section 505(j)(2)(C) of the FD&C Act; 
136  (c) there are no blocking patents or exclusivities for the RLD; and (d) the submission 
137  does not qualify for prioritization under any other factor listed in MAPP 5240.3: 
138  Prioritization of the Review of Original ANDAs, Amendments, and Supplements. 
139   
140  Regarding condition 1, this includes all of the patents listed in the Orange Book for the RLD 
141  identified as the basis of submission for the ANDA, and all exclusivities associated with the 
142  RLD. Regarding condition 2, for the purposes of the DMF prior assessment, a blocking patent is 
143  any unexpired patent for the RLD listed in the Orange Book.  
144   
145  B.  Request for assessment of a DMF 6 months prior to submission of a PAS to 
146  add a new API source 
147   
148  As also described in the GDUFA III Commitment Letter, a holder of a DMF may submit a 
149  request for assessment of the DMF 6 months prior to the planned submission date for a PAS that 
150  requests to add a new API source, provided that:  
151   
152  1.  The PAS is for a drug product that could help mitigate or resolve a drug shortage and 
153  prevent future shortages,15 including submissions related to products that are listed on 
154  FDAs Drug Shortage List16 at the time of the submission; or  
155   
156  2.  The PAS is for a drug product that either could help address a public health emergency 
157  declared by the Secretary of the U.S. Department of Health and Human Services under 
 
12 Additional information about drug shortages can be found at: https://www.fda.gov/drugs/drug-safety-and-
availability/drug-shortages.  
13 List of drug products currently in shortage and discontinuations reported to FDA are available at: 
https://www.accessdata.fda.gov/scripts/drugshortages/. 
14 See 42 U.S.C. 247d. 
15 See footnote 12. 
16 See footnote 13. 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
158  section 319 of the PHS Act, or anticipated under the same criteria as applies to such a 
159  declaration. 
160   
161  IV.  ADDITIONAL INFORMATION  
162   
163  Under the GDUFA III commitment letter, DMF prior assessment is only available for API 
164  information submitted in a DMF. DMF prior assessment is not available for the review of drug 
165  substance information in an ANDA. Prior assessment requests  should be limited to one DMF 
166  per API for each application because only one source per API is required for approval. Multiple 
167  prior assessment requests for a single API will not be accepted. However, if the drug product has 
168  multiple APIs, i.e., it is a fixed-combination product, one DMF prior assessment request can be 
169  submitted for each API. In addition, any secondary DMFs17 referenced by a primary DMF that is 
170  granted prior assessment will be assessed during the DMF prior assessment period. 
171   
172  To assist DMF holders in submitting these requests, a list of elements FDA recommends be 
173  included in the cover letter of the prior assessment request is provided in the appendix. The 
174  appendix checklist also recommends that the DMF holder state explicitly the basis on which the 
175  DMF holder believes their request qualifies for DMF prior assessment. For the sake of clarity 
176  and efficiency, DMF holders are encouraged to use the appendix as a checklist when submitting 
177  the request.  
178   
179  Once the prior assessment request is received by FDA, the DMF staff will evaluate the request 
180  and make a determination to grant or deny the request. If the determination is to grant the 
181  request, a grant letter will be sent to the DMF holder. The DMF staff will subsequently conduct 
182  the review to meet the date indicated in the grant letter. Any needed clarifications will be 
183  communicated via Information Request18 to the DMF holder. If the determination is to deny the 
184  request, a deny letter including the reason for the denial will be sent to the DMF holder.    
 
17 A secondary DMF is a DMF that is incorporated by reference into a primary DMF.  
18 As defined in the GDUFA III Commitment Letter, Information Request means a communication that is sent to an 
applicant during an assessment to request further information or clarification that is needed or would be helpful to 
allow completion of the discipline assessment (GDUFA III Commitment Letter Section XI.Q).  
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
185  APPENDIX: RECOMMENDED CONTENT FOR A PRIOR ASSESSMENT REQUEST 
186   
187  FDA recommends that the following elements be included in the cover letter of a prior 
188  assessment request submission to the DMF: 
189   
190  1.  Statement that the submission is a GDUFA DMF Prior Assessment Request.19 
191   
192  2.  A clear statement that the DMF holder is granting FDA permission to perform a 
193  substantive scientific review of the DMF.  
194   
195  3.  Statement indicating the type of ANDA submission that the DMF will support, for 
196  example, original ANDA, ANDA amendment, or a PAS.  
197   
198  4.  Statement certifying that the DMF is active and the GDUFA DMF user fee has been paid. 
199  DMF holders may submit a copy of Form FDA 3794 in the request submission to 
200  document payment of the GDUFA fee.  
201   
202  5.  Statement that there is at least one valid Letter of Authorization (LOA) in the DMF 
203  intended to support the planned application submission.20 
204   
205  6.  If the prior assessment request is to support an original ANDA submission, a citation to 
206  the Reference Listed Drug (i.e., the application number for the RLD), as provided in the 
207  Orange Book, and the drug product(s), including the strength(s), that will be included in 
208  the ANDA submission.  
209   
210  7.  The planned submission date of the ANDA, ANDA amendment, or PAS. This date 
211  should be at least 6 months from the date the request is submitted to the DMF.21 
212   
213  8.  (i). For an original ANDA, an ANDA amendment containing a response to a Complete 
214  Response Letter (CRL), or an amendment seeking approval of an ANDA that previously 
215  received a tentative approval, the applicable justification for the request from III.A items 
216  1-5 in this guidance22 should be clearly stated in the cover letter. 
217    
 
19 If DMF Form FDA 3938 is included with the submission, select other in field 7 and enter GDUFA DMF Prior 
Assessment Request. Also select Letter of Authorization (LOA) in field 7 if one or more LOAs are included with 
the submission.  
20 For a planned original ANDA submission, provide the pre-assigned ANDA number and the authorized party in 
the cover letter. For an ANDA amendment containing a response to a CRL which references a new original DMF, 
an amendment seeking approval of an ANDA that previously received a tentative approval that references a new 
original DMF, or a PAS to add a new API source, provide the ANDA number and the authorized party.  
21 For drug shortage or products that could help address a public health emergency, a request to waive this condition 
may be included in the cover letter when the DMF holder is unable to provide the request 6 months in advance. 
22 FDA strongly encourages DMF holders to communicate with their customers (applicants) regarding the proper 
justification for the prior assessment request. 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
218  (ii). For a PAS to add a new API source, the applicable justification for the request from 
219  III.B items 1-2 in this guidance23 should be clearly stated in the cover letter. 
220   
221  Note that the prior assessment request should be signed by the responsible official at the DMF 
222  holder company and not the DMF agent. In addition, upon the submission of a GDUFA DMF 
223  Prior Assessment Request, please send a notification email to DMFOGD@FDA.HHS.GOV to 
224  ensure timely processing. 
 
23 Ibid. 
  7