Drug Master Files 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Rick Ensor 240-402-2733, 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) 
 
October 2019 
Pharmaceutical Quality/CMC 
 
Revision 1
 
   
Drug Master Files 
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) 
  
October 2019 
Pharmaceutical Quality/CMC 
 
Revision 1
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  TYPES OF DMFS ............................................................................................................. 2 
III.  DMF SUBMISSIONS ....................................................................................................... 3 
A.  Format and Delivery ...................................................................................................................... 3 
B.  Original Submissions ..................................................................................................................... 4 
1. Module 1 .......................................................................................................................................... 5 
2. Module 2 .......................................................................................................................................... 9 
3. Module 3 .......................................................................................................................................... 9 
4. Module 4 .......................................................................................................................................... 9 
5. Module 5 .......................................................................................................................................... 9 
C.  Subsequent Submissions ................................................................................................................ 9 
1. Cover Letter ................................................................................................................................... 10 
2. Administrative Amendments ........................................................................................................... 10 
3. Quality Amendments ...................................................................................................................... 11 
4. Conversion of Existing DMFs To Comply With eCTD Format ..................................................... 11 
D.  Submission Recommendations, by DMF Type .......................................................................... 12 
1. Type II: Drug Substance, Drug Substance Intermediate, and Materials Used in Their 
Preparation, or Drug Product ............................................................................................................ 12 
2. Type III: Packaging Material ........................................................................................................ 13 
3. Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation .............. 14 
4. Type V: FDA-Accepted Reference Information ............................................................................. 16 
E.  Other Recommendations ............................................................................................................. 16 
1. English Translations ...................................................................................................................... 16 
2. Public Availability of Information in a DMF ................................................................................. 16 
3. Holder Not the Manufacturer ........................................................................................................ 16 
4. Primary and Secondary DMFs ...................................................................................................... 17 
5. Referencing Own Application Material ......................................................................................... 17 
6. Retention of Reference Copy by the Holder ................................................................................... 17 
IV.  ANNUAL REPORTS...................................................................................................... 17 
V.  FDA PROCESSING AND REVIEWING POLICIES ................................................ 18 
A.  Administrative Review ................................................................................................................ 18 
B.  Technical Review ......................................................................................................................... 18 
VI.  DMF CLOSURE ............................................................................................................. 19 
VII.  GLOSSARY..................................................................................................................... 19 
VIII.  REFERENCES ................................................................................................................ 20 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Drug Master Files 
2  Guidance for Industry1 
3   
4   
5  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
6  Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 
7  binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 
8  applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 
9  for this guidance as listed on the title page.  
10   
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  This guidance provides FDAs current thinking on drug master files (DMFs), which are 
17  submissions to FDA that may be used to provide confidential, detailed information about 
18  facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of 
19  human drug products. DMFs can contain other types of information as well (e.g., toxicology 
20  information, shared system REMS (risk evaluation and mitigation strategy)).  
21   
22  DMF holders can authorize one or more applicants or sponsors to incorporate by reference 
23  information contained in the DMF without having to disclose that information to the applicants 
24  or sponsors. DMFs are submitted solely at the discretion of their holders and are not required by 
25  statute or regulation. They are not typically submitted for nonproprietary materials. Ordinarily, 
26  FDA neither independently reviews nor approves DMF submissions. Instead, FDA customarily 
27  reviews the technical contents of DMFs only in connection with the review of applications that 
28  reference them.2 
29   
30  DMFs can be used to support (but are not substitutes for) applications reviewed by FDA. This 
31  guidance focuses on the following submissions to the Center for Drug Evaluation and Research 
32  (CDER) and the Center for Biologics Evaluation and Research (CBER): 
33   
34    DMFs under 21 CFR 314.420 that are used to support new drug applications (NDAs), 
35  abbreviated new drug applications (ANDAs), and investigational new drug applications 
36  (INDs) under the Federal Food, Drug, and Cosmetic Act (FD&C Act). 
37   
38    DMFs and other master files under 21 CFR 601.51(a) that are used to support biologics 
39  license applications (BLAs) under the Public Health Service Act (PHS Act). 
                                                 
1 This guidance has been prepared by the Center for Drug Evaluation and Research in cooperation with the Center 
for Biologics Evaluation and Research and in consultation with the Center for Veterinary Medicine at the Food and 
Drug Administration. 
2 In this guidance, the term review also means assessment. Both terms refer to the process of evaluating and 
analyzing submitted data and information to determine whether the application meets the requirements for approval 
and documenting that determination. 
     1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
40   
41  Additionally, information contained in DMFs can generally be referenced in premarket 
42  submissions for devices (e.g., premarket approvals) and animal drugs (e.g., new animal drug 
43  applications). Although the focus of this guidance is on the submissions to CDER and CBER 
44  described above, in general, FDA believes the contents of this guidance will assist other master 
45  file holders in providing complete and up-to-date master files to FDA. 
46   
47  This guidance provides information about preparing and submitting DMFs. It describes DMF 
48  types, the information needed in DMF submissions, and FDAs DMF review processes. For 
49  additional information, see FDAs DMF web pages.3  
50   
51  This guidance revises the guidance for industry Drug Master Files: Guidelines that published in 
52  September 1989. Most of the information contained in the 1989 guidance has been retained here, 
53  with significant reorganization. 
54   
55  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
56  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
57  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
58  the word should in Agency guidances means that something is suggested or recommended, but 
59  not required.  
60   
61   
62  II.  TYPES OF DMFS  
63   
64  Four types of DMFs are covered by  314.20, as illustrated in the table below. 
65   
66  Types of DMFs 
DMF 
Subject of Information Provided in the DMF 
Type* 
Drug substance, drug substance intermediate, and materials used in their 
Type II** 
preparation, or drug product  
Type III  Packaging material 
Type IV  Excipient, colorant, flavor, essence, or material used in their preparation 
Type V  FDA-accepted reference information 
67  * Type I DMFs were discontinued in 2000 but the numbering of the other DMF types has not changed. FDAs 
68  approach to the terminology for types of master files used for products subject to approval under the PHS Act has 
69  generally tracked its approach to the types of DMFs (e.g., Type II, Type III) used for products regulated under the 
70  FD&C Act. 
71  ** Although FDAs approach to the use of master files in BLAs under the PHS Act largely parallels its approach to 
72  the use of DMFs in applications under the FD&C Act, there is a significant difference: a BLA holder is generally 
73  expected to have knowledge of and control over the manufacturing process for the biological product for which it 
74  has a license. For biological products in BLAs under the PHS Act, FDA has, as a scientific matter, generally not 
                                                 
3 For CDER, see https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs; for CBER, see 
https://www.fda.gov/vaccines-blood-biologics/new-drug-application-nda-process-cber/drug-master-files-cber-
regulated-products. 
     2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
75  permitted applicants to incorporate information about drug substance, drug substance intermediate, or drug product 
76  by reference to a master file; rather, FDA generally expects such information to be submitted directly to the BLA. 
77   
78   
79  III.  DMF SUBMISSIONS  
80   
81  This section describes the format and delivery of DMF submissions, outlines the content of 
82  original and subsequent DMF submissions, offers submission recommendations specific to the 
83  four types of DMFs, and ends with some broader recommendations for DMF holders to consider 
84  when submitting DMFs.  
85   
86  A.  Format and Delivery 
87   
88  DMF submissions are subject to the electronic submission requirements as set forth in guidance 
89  implementing section 745A of the FD&C Act, including the guidance for industry Providing 
90  Regulatory Submissions in Electronic FormatCertain Human Pharmaceutical Product 
91  Applications and Related Submissions Using the eCTD Specifications (Rev. 6) (Providing 
92  Regulatory Submissions guidance).4 The Drug Master Files guidance is not issued under section 
93  745A of the FD&C Act and does not establish legally enforceable responsibilities. To the extent 
94  it discusses binding requirements for DMFs, such requirements have been promulgated in 
95  previously issued guidance under section 745A and FDA regulations.  
96   
97  Unless otherwise stipulated in the Providing Regulatory Submissions guidance or successor 
98  guidance under section 745A, DMF submissions must have a DMF number, must be submitted 
99  in the electronic format specified in such guidance, and, if 10 gigabytes or smaller, must be 
100  submitted through the Electronic Submissions Gateway (ESG).5 Submissions over 10 gigabytes 
101  can be submitted through ESG or they can be submitted on physical media (e.g., CD-ROM) 
102  accompanied by a cover letter as described below and with prepaid delivery charges.6 The 
103  standard electronic format for DMFs is electronic common technical document (eCTD) format.7  
104   
105  For proper routing of DMFs, it is important to choose the appropriate centerCDER or 
106  CBERfrom the menu of choices when submitting through ESG. DMF holders who wish to 
107  submit information that may be reviewed in multiple centers should consult the respective 
108  centers. See the CDER and CBER DMF web pages for contact information.8 
                                                 
4 Revision 7 of Providing Regulatory Submissions is available as a draft guidance. When final, this guidance will 
represent the FDAs current thinking on this 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. 
5 See the Providing Regulatory Submissions guidance. 
6 Ibid. 
7 For more information on electronic submissions, see FDAs Electronic Regulatory Submissions and Review web 
page at https://www.fda.gov/drugs/forms-submission-requirements/electronic-regulatory-submission-and-review, 
eCTD web page at https://www.fda.gov/ectd, ESG web page at https://www.fda.gov/industry/electronic-
submissions-gateway, and Transmitting Electronic Submissions Using eCTD Specifications at 
https://www.fda.gov/media/76812/download. 
8 See footnote 3. 
 
     3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
109   
110  CDERs DMF web page links to templates for certain submissions (e.g., cover letters, annual 
111  reports) that recommend elements that DMF holders can include in these submissions.9 This 
112  guidance refers to these templates where applicable rather than listing each element that FDA 
113  recommends be included in a particular submission. 
114   
115  B.  Original Submissions  
116   
117  Before submitting an original DMF in eCTD format, DMF holders must obtain a pre-assigned 
118  number.10 For CDER submissions, see Requesting a Pre-Assigned Application Number at 
119  https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/requesting-pre-
120  assigned-application-number. For CBER submissions, send requests for application numbers via 
121  secure email to cberrims@fda.hhs.gov and include the sponsor/applicant name and address, point 
122  of contact name and number, product name, and anticipated submission date. 
123   
124  Original submissions should contain a cover letter and complete administrative and technical 
125  information in the appropriate eCTD modules. Although some eCTD module section headings 
126  refer to change and sponsor/applicant, they are applicable to original and subsequent 
127  submissions to DMFs.  
128   
129  This section reviews the eCTD modules and module sections that are relevant for original 
130  submissions. For a complete list of eCTD section headings, see FDAs Comprehensive Table of 
131  Contents Headings and Hierarchy, which can be found in the eCTD Submission Standards on 
132  FDAs eCTD website (https://www.fda.gov/ectd). For additional formatting recommendations, 
133  see the following: 
134   
135    Providing Regulatory Submissions guidance.  
136   
137    International Council for Harmonisation (ICH) guidance for industry M4 Organization 
138  of the Common Technical Document for the Registration of Pharmaceuticals for Human 
139  Use.  
140   
141    ICH guidance for industry M4Q: The CTDQuality. 
142   
143    Draft guidance for industry Submitting Marketing Applications According to the ICH-
144  CTD FormatGeneral Considerations.11 
145   
146     
                                                 
9 Holders submitting DMFs that contain information that is intended for use by applications for biological products 
may also use these templates. 
10 See the Providing Regulatory Submissions guidance. 
11 When final, this guidance will represent FDAs current thinking on this topic. 
     4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
147  1.  Module 1 
148   
149  a.  Cover letter (eCTD section 1.2)  
150   
151  FDA recommends using the cover letter template for original submissions on CDERs DMF web 
152  page at https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs.12 As 
153  laid out in this template, the cover letter should specify the submission type (e.g., original, agent 
154  appointment). A table of submission types is available on CDERs DMF web page. The cover 
155  letter should also include a statement of commitment signed by the DMF holder stating that the 
156  DMF is current and that the holder will comply with the statements made in the DMF. 
157  (Alternatively, the statement of commitment can be a separate document included in eCTD 
158  section 1.2.) See the template for additional information to include. 
159   
160  b.  Administrative information (eCTD section 1.3) 
161   
162  The administrative information section should include information about the DMF holder, the 
163  agent (if applicable), the manufacturer, and debarment certification (for more information about 
164  debarment certification, see section III.B.1.b.iv in this guidance).  
165   
166  i.  DMF holder 
167   
168  DMF holders should provide their name and address. Only one company should be listed as the 
169  DMF holder. Joint submissions are not accepted. 
170   
171  ii.  Contact/Agent 
172   
173  DMF holders should provide the name, telephone and fax numbers, email address, and specific 
174  responsibilities of the contact person and the responsible official (if different from the contact 
175  person).  
176   
177  To facilitate communication, FDA strongly encourages foreign DMF holders to appoint an agent, 
178  preferably in the United States, who is familiar with FDA regulations, guidances, and 
179  procedures. However, DMF holders, not their agents, are responsible for the contents of their 
180  DMFs (e.g., all aspects of the chemistry, manufacturing, and controls (CMC) information). 
181  Agents can submit to the DMF on behalf of DMF holders. They can sign DMF submissions as 
182  well, with the following exceptions:  
183   
184    Agent appointment letters.  
185    Statements of commitment. 
186    Name changes. 
187    Holder transfers. 
188    New holder acceptance letters. 
189    DMF closure requests. 
                                                 
12 FDA is developing a form to replace the cover letter used for original and subsequent submissions. The form 
should be available by the time this guidance is finalized. 
     5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
190   
191  An agent for DMF purposes is not the same as an agent for the purposes of the Drug Listing and 
192  Registration System (DRLS). DMF holders should not include the name of the agent for 
193  registration purposes in the DMF unless the same person or company is the agent for both the 
194  DMF and DRLS. 
195   
196  DMF holders can have different agents for different DMFs. 
197   
198  DMF holders should submit agent appointment letters in their original submissions or in 
199  administrative amendments. The letter should be on the DMF holders letterhead and should 
200  contain the agents name, address, contact persons name (if different from the agents name), 
201  telephone and fax numbers, and email address, among other information. FDA recommends 
202  using the agent appointment letter template on CDERs DMF web page at 
203  https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs.  
204   
205  iii.  Manufacturer 
206   
207  DMF holders should provide the manufacturers name, site address, and contact persons name, 
208  telephone and fax numbers, and email address.  
209   
210  iv.  Debarment certification 
211   
212  DMF holders are included in the category of Persons whose services were used in any capacity 
213  in connection with the application required under section 306(k)(1) of the FD&C Act. DMF 
214  holders can submit their own debarment certifications in eCTD section 1.3.3. 
215   
216  For more information on debarment certifications, see draft guidance for industry Submitting 
217  Debarment Certification Statements.13 
218   
219  c.  References (eCTD section 1.4) 
220   
221  i.  Letter of authorization 
222   
223  FDA will not review a DMF until the DMF holder submits a letter of authorization (LOA) to the 
224  DMF regarding a specific application or other DMF ( 314.420(d)). LOAs can be submitted as 
225  part of the original submission or in a subsequent submission. The LOA permits FDA to review 
226  the DMF and permits the authorized party (i.e., the company or individual who submits an 
227  application or another DMF) to incorporate information into an application or another DMF by 
228  reference (eCTD section 1.4.1). An LOA should still be submitted even if the authorized party 
229  and the DMF holder are the same company. 
230   
231  The DMF holder should send a copy of the LOA to the authorized party. The authorized party 
232  must include a copy of the LOA in its application ( 314.50(a)(1)) or DMF (eCTD section 1.4.2). 
233  An LOA does not give an authorized party permission to view or access a DMF. 
                                                 
13 When final, this guidance will represent FDAs current thinking on this topic. 
     6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
234   
235  Note: 
236   
237    An LOA should not be used to authorize an agent or representative to act on behalf of a 
238  company. 
239   
240    An LOA should not be used to authorize DMF holder employees to submit information to 
241  the DMF. 
242   
243    An LOA can be submitted by an agent but ultimately the DMF holder is responsible for 
244  the LOA. 
245   
246    An LOA should not have multiple authorized parties; DMF holders should submit a 
247  separate LOA for each party. 
248   
249    If the DMF holder changes its name, the DMF holder should submit a new LOA using 
250  the Replace function in the electronic submission. 
251   
252    If an authorized party changes its name, the DMF holder should submit a new LOA using 
253  the Replace function in the electronic submission. 
254   
255    An LOA does not need to include the name of the individual employed by the authorized 
256  party (i.e., a contact person). The name of the applicant is sufficient. 
257   
258    An LOA should distinguish between those facilities that will be used for purposes of the 
259  authorization versus other facilities that are part of the DMF but are not applicable to the 
260  authorization. Unless this specification is present in the LOA, FDA will assume that all 
261  facilities listed in a DMF apply to the referencing application. 
262   
263  FDA recommends using the LOA template on CDERs DMF web page at 
264  https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs. As laid out 
265  in this template, the LOA should include, among other information, a statement of commitment 
266  signed by the DMF holder stating that the DMF is current and that the holder will comply with 
267  the statements made in the DMF. (Alternatively, the statement of commitment can be included in 
268  eCTD section 1.2 and referenced in the LOA.) 
269   
270  ii.  List of authorized persons to incorporate by reference 
271   
272  In eCTD section 1.4.3, DMFs must list each party currently authorized to incorporate by 
273  reference any information in the DMF ( 314.420(d)). The list should only contain authorized 
274  parties for which LOAs have been submitted and should be updated whenever a new LOA is 
275  submitted or an authorized party is withdrawn. The list should contain the following information 
276  for each authorized party: 
277   
278    Name of the authorized party. 
279   
     7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
280    Date of the LOA. 
281   
282    Specific products, items, or processes referenced by the LOA, including submission 
283  dates, eCTD section numbers, and page numbers. 
284   
285    Application number referencing the DMF (optional). 
286   
287  To withdraw authorization, DMF holders should submit a Withdrawal of Authorization letter 
288  to the DMF and notify the authorized party. The withdrawal letter should replace the LOA in 
289  eCTD section 1.4.1. FDA recommends using the withdrawal of authorization template on 
290  CDERs DMF web page at https://www.fda.gov/drugs/forms-submission-requirements/drug-
291  master-files-dmfs. 
292   
293  d.  Application status (eCTD section 1.5) 
294   
295  DMF holders can use eCTD section 1.5.5 to close a DMF. See section VI for information about 
296  DMF closures. 
297   
298  e.  Meetings (eCTD section 1.6) 
299   
300  Holders of Type II active pharmaceutical ingredient (API)14 DMFs referenced in ANDAs can 
301  request teleconferences in response to first-cycle DMF deficiency letters.15 
302   
303  f.  Information amendment: Information not covered under modules 2 
304  through 5 (eCTD section 1.11) 
305   
306  In general, changes reported in eCTD section 1.11 should only include a summary of changes to 
307  modules 2 through 5 or changes that do not fit in modules 2 through 5. Documents included in 
308  eCTD section 1.11 should contain references and links to any sections in modules 2 through 5 
309  that are changed. For example, a change in the drug substance specification should be mentioned 
310  in eCTD section 1.11 but should also be changed in sections 2.3.S.4.1 and 3.2.S.4.1. 
311   
312  g.  Other correspondence (eCTD section 1.12) 
313   
314  Because DMFs are neither approved nor disapproved, an environmental assessment should not 
315  be submitted in a DMF (eCTD section 1.12.14).16 However, DMF holders should include in their 
316  DMFs a commitment to operate their facilities in compliance with applicable environmental 
317  laws. 
318   
                                                 
14 This guidance uses the terms API and drug substance interchangeably. 
15 See page 19 of GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2018-
2022 at https://www.fda.gov/media/101052/download.  
16 See 21 CFR part 25 and the guidance for industry Environmental Assessment of Human Drug and Biologics 
Applications (Rev. 1). 
     8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
319  h.  Labeling (eCTD section 1.14) 
320   
321  For DMFs related to drug substances, drug substance intermediates, drug products covered by 
322  Type II DMFs, and excipients covered by Type IV DMFs, DMF holders should provide a copy 
323  of the shipping label in the Labeling section. 
324   
325  i.  Risk evaluation and mitigation strategy (eCTD section 1.16) 
326   
327  In the REMS section, DMF holders should provide REMS-related documents, if applicable.17 
328   
329  2.  Module 2 
330   
331  Module 2 summarizes the appropriate module 3 sections (and 4 and 5, if applicable). 
332   
333  3.  Module 3 
334   
335  See section III.D in this guidance for information to include in this module, organized by DMF 
336  type. 
337   
338  4.  Module 4  
339   
340  This module is not necessary for DMFs unless nonclinical evaluations are included in the DMF. 
341  The following information is appropriate to submit in module 4: 
342   
343    Nonclinical evaluations to support the safety of: 
344   
345    An excipient whose CMC information is provided in module 3 in a Type IV 
o
346  DMF; or 
347   
348    An impurity whose CMC information is provided in module 3 in a Type II DMF. 
o
349   
350    Nonclinical evaluations in a Type V DMF. 
351   
352  5.  Module 5 
353   
354  Module 5 should be submitted for clinical information only, such as in a Type V DMF. 
355   
356  C.  Subsequent Submissions 
357   
358  Amendments and additions or deletions of information in the DMF, including LOAs, must be 
359  submitted to the DMF ( 314.420(c)). These subsequent submissions should contain a cover 
                                                 
17 For information on REMS submissions, see draft guidance for industry Use of a Drug Master File for Shared 
System REMS Submissions and the Technical Conformance Guide for Shared System REMS Drug Master File 
Submissions. When final, the guidance will represent FDAs current thinking on this topic. 
 
     9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
360  letter18 and updated administrative and technical information, as needed. DMF holder name 
361  changes and acceptance notifications should also include the statement of commitment as 
362  described in section III.B.1.a.  
363   
364  If information in a subsection (e.g., 3.2.S.2.3) of a DMF changes, DMF holders should replace 
365  documents in that subsection. For more information, see the eCTD Technical Conformance 
366  Guide at https://www.fda.gov/media/93818/download. 
367   
368  All amendments and LOAs should reference the updated DMF. A cumulative change history 
369  should be submitted with each subsequent submission. 
370   
371  DMF holders must notify affected authorized parties of any DMF changes, additions, or 
372  deletions ( 314.420(c)) and should provide sufficient information to enable authorized parties to 
373  determine the appropriate reporting procedure for their applications (see  314.60, 314.70, 
374  314.96, and 314.97). This notification should occur well before making any changes to permit 
375  authorized parties to report application changes within an appropriate time frame. 
376   
377  1.  Cover Letter 
378   
379  FDA recommends using the cover letter template for subsequent submissions on CDERs DMF 
380  web page at https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs. 
381  Among other information as laid out in this template, the cover letter should specify the change 
382  and reference the date and eCTD section or page number of any previous submission affected by 
383  the change.  
384   
385  In addition, the cover letter should specify the submission type: for example, changes in 
386  administrative information (e.g., change in agent) should be reported as an administrative 
387  amendment, changes in technical information (e.g., change in a test procedure) should be 
388  reported as a quality amendment (also referred to as a technical amendment), and changes in 
389  REMS information (e.g., major REMS modification) should be reported as a REMS Risk 

390  Evaluation and Mitigation Strategy.  
391   
392  Multiple submission types (e.g., LOAs, administrative and quality amendments) can be 
393  submitted together with a single cover letter and sequence number. In these cases, the DMF 
394  holder should list each submission type in the cover letter. The DMF holder can also further 
395  delineate the submission type by amendment type (e.g., change of holder). A table of submission 
396  and amendment types is available on CDERs DMF web page at 
397  https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs. 
398   
399  2.  Administrative Amendments 
400   
401  These types of amendments include, but are not limited to, the following changes. 
402   
                                                 
18 See footnote 12. 
     10  Contains Nonbinding Recommendations 
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403  a.  Name changes, acquisitions, or transfers of ownership 
404   
405  DMF holders must notify FDA of any name changes ( 314.420(c)); such changes should be 
406  submitted in an administrative amendment to each DMF they own. Name changes can occur 
407  through a change in name only or because the DMF holder is acquired by or transfers ownership 
408  to another company. If an agent had been appointed by the previous DMF holder and that agent 
409  is being retained by the new DMF holder or if a new agent is being retained, the current DMF 
410  holder should submit an agent appointment letter on the DMF holders letterhead (eCTD section 
411  1.3.1.2). 
412   
413  If transfer of ownership is involved, the original DMF holder should submit a transfer 
414  notification to the DMF and the new DMF holder should submit an acceptance notification. A 
415  statement of commitment signed by the new DMF holder should be included in name change and 
416  acceptance notifications stating that the DMF is current and that the holder will comply with the 
417  statements made in the DMF. (Alternatively, the statement of commitment can be included in 
418  eCTD section 1.2 and referenced in these notifications.) 
419   
420  Templates for name changes, transfer notifications, and acceptance notifications are on CDERs 
421  DMF web page at https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-
422  dmfs. 
423   
424  b.  Changes to the DMF subject  
425   
426  Changes to the DMFs subject (title) should be submitted in an administrative amendment. If a 
427  title change is necessary because of a change in technical information (e.g., change in the grade 
428  of a drug substance that is the subject of the DMF), a quality amendment should also be 
429  submitted. 
430   
431  c.  Changes to the DMF type 
432   
433  Changes to DMF type should be submitted in an administrative amendment. If the change in type 
434  necessitates changes in the DMFs technical information, the DMF holder should submit those 
435  changes in a quality amendment. 
436   
437  3.  Quality Amendments 
438   
439  Any changes to technical information should be submitted in a quality amendment. 
440   
441  4.  Conversion of Existing DMFs To Comply With eCTD Format  
442   
443  Although there is no requirement to resubmit existing DMF submissions in eCTD format, DMF 
444  holders wishing to do so should include a list of content changes occurring as a result of the 
445  conversion in an attachment to the cover letter.19 It is not necessary to request a new DMF 
                                                 
19 See the eCTD Technical Conformance Guide for more information on resubmission of non-eCTD documents. 
     11  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
446  number. If the existing number is four digits (e.g., 1234), the DMF holder will need to add two 
447  zeros to the front of the number to convert it to the eCTD six-digit format (e.g., 001234). 
448   
449  D.  Submission Recommendations, by DMF Type 
450   
451  The information recommended below is not intended to be all-inclusive. Please refer to 
452  supplemental guidances related to information to be included in DMFs as well as the DMF 
453  website.20 
454   
455  1.  Type II: Drug Substance, Drug Substance Intermediate, and Materials Used in 
456  Their Preparation, or Drug Product 
457   
458  Each Type II DMF should be limited to a single drug substance, drug substance intermediate, 
459  type of material used in their preparation, or drug product.21 Drug product intermediates are also 
460  included in the category of Type II DMF. Separate DMFs should be submitted for drug 
461  substances manufactured using different processes.  
462   
463  DMFs for drug substances, drug substance intermediates, drug products, and drug product 
464  intermediates should state that the material covered by the DMF is manufactured under current 
465  good manufacturing practices (eCTD sections 3.2.S.2 or 3.2.P.3). 
466   
467  Type II DMFs for APIs submitted in support of ANDAs should follow the recommendations in 
468  guidances for industry such as Completeness Assessments for Type II API DMFs Under GDUFA. 
469  Such recommendations do not apply to Type II DMFs for APIs that are only used to support 
470  INDs or NDAs. 
471   
472  a.  Drug substance or drug substance intermediate
 
473   
474  The definition and criteria for designating starting materials and intermediates are discussed in 
475  ICH guidances for industry Q7 Good Manufacturing Practice Guidance for Active 
476  Pharmaceutical Ingredients (Rev. 1) and Q11 Development and Manufacture of Drug 
477  Substances and ICH Q7 and Q11s corresponding Questions and Answers guidances.  
478   
479  Drug substance manufacturers should collect stability data according to their stability protocol 
480  and should continue to submit data from ongoing studies in a quality/stability amendment.22 
                                                 
20 See, e.g., guidances for industry Completeness Assessments for Type II API DMFs Under GDUFA and Drug 
Master Files for Bulk Antibiotic Drug Substances. See also draft guidance for industry Postapproval Changes to 
Drug Substances, which, when final, will represent FDAs current thinking on this topic. 
21 Although FDAs approach to the use of master files in BLAs under the PHS Act largely parallels its approach to 
the use of DMFs in applications under the FD&C Act, there is a significant difference. A BLA holder is generally 
expected to have knowledge of and control over the manufacturing process for the biological product for which it 
has a license. For biological products in BLAs under the PHS Act, FDA has, as a scientific matter, generally not 
permitted applicants to incorporate information about drug substance, drug substance intermediate, or drug product 
by reference to a master file; rather, FDA generally expects such information to be submitted directly to the BLA.
 
22 See ICH guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products. 
 
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481   
482  For sterilization of drug substances to be used in sterile products, the same sterility assurance 
483  information should be submitted as for sterile drug products, as outlined in the guidance for 
484  industry Submission Documentation for Sterilization Process Validation in Applications for 
485  Human and Veterinary Drug Products (Submission Documentation guidance) and other 
486  supporting documents included on CDERs DMF web page.23 Building and facility information, 
487  including floor plans, can be submitted in the Type II DMF if a Type V DMF is not cross-
488  referenced for this information. 
489   
490  b.  Material used in the preparation of a drug substance or drug substance 
491  intermediate 
492   
493  If material used in the preparation of a drug substance or drug substance intermediate requires 
494  FDA review of CMC information (e.g., defined artificial cell growth media), this information 
495  should be submitted in a Type II DMF. 
496   
497  c.  Drug product or drug product intermediate 
498   
499  21 CFR 314.420 permits DMF submissions for drug products.  
500   
501  2.   Type III: Packaging Material 
502   
503  Packaging materials should be identified by type (e.g., bottle) and material of construction 
504  (MOC) (e.g., high-density polyethylene). Packaging materials can be combined to prepare a 
505  container-closure system (e.g., a syringe barrel and a plunger). 
506   
507  Information, including safety information, about the components of an MOC can be provided 
508  directly to the authorized party without filing a DMF. 
509   
510  For most MOCs (e.g., plastics and glass) and the packaging materials made from them, safety 
511  and quality information can be provided by referring to appropriate sections of the Code of 
512  Federal Regulations. Additional quality information can be provided by referring to appropriate 
513  sections of the United States PharmacopeiaNational Formulary (USPNF). MOCs should be 
514  identified by their names as listed in the appropriate regulations, where applicable. 
515   
516  Data supporting the protection, compatibility, and performance of a packaging material or 
517  container-closure system for its intended use should be submitted in the application for the drug 
518  product that uses the packaging material. 
519   
520  Type III DMFs can include information about the packaging materials or container-closure 
521  systems components, MOCs, controls for release, and intended use. The names of the suppliers 
522  or fabricators of the MOCs or components and the specifications for their acceptance can also be 
523  provided.  
                                                 
23 See footnote 3; see also FDAs MAPP 5040.1 Product Quality Microbiology Information in the Common 
Technical DocumentQuality (CTD-Q). 
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524   
525  Information regarding mixtures of color additives and plastics (often called masterbatches) for 
526  use in manufacturing plastic packaging components (e.g., to make a bottle blue) is appropriately 
527  filed as a Type III DMF. 
528   
529  For sterilization and depyrogenation of packaging materials to be used in sterile products, the 
530  same sterility assurance information should be submitted as for sterile drug products, as outlined 
531  in the Submission Documentation guidance and other supporting documents included on 
532  CDERs DMF web page.24 Building and facility information, including floor plans, is 
533  appropriately filed in the Type III DMF if a Type V DMF is not cross-referenced for this 
534  information.  
535   
536  The different eCTD sections within 3.2.S or 3.2.P should be populated as appropriate. For multi-
537  item DMFs, each item (e.g., different MOCs) would have a different name (e.g., 3.2.S.[MOC 1], 
538  3.2.S.[MOC 2]). It is appropriate for DMF holders to point to information that is common to 
539  different products (e.g., analytical procedures) by reference (or via links in the case of an 
540  electronic DMF) to the relevant section for that product (e.g., 3.2.P.4.2 [MOC 1]).  
541   
542  3.  Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their 
543  Preparation 
544   
545  Information for most excipients (e.g., lactose or microcrystalline cellulose) should be submitted 
546  in eCTD section 3.2.S. Information for excipients that are mixtures of multiple compounds (e.g., 
547  flavor mixtures) should be submitted in eCTD section 3.2.P. 
548   
549  DMFs should be submitted only for excipients for which CMC and safety information is not 
550  available through reference to appropriate regulations or quality information through the USP-
551  NF. These include new excipients and colorants, flavors, essences, and material used in their 
552  preparation. 
553   
554  a.  New excipients 
555   
556  As defined in guidance for industry Nonclinical Studies for the Safety Evaluation of 
557  Pharmaceutical Excipients, new excipients are inactive ingredients that are not fully qualified by 
558  existing safety data with respect to the currently proposed level of exposure, duration of 
559  exposure, or route of administration.25 Nonclinical evaluations to support the safety of an 
560  excipient whose CMC information is provided in module 3 of a Type IV DMF can be provided 
561  in module 4 of the same DMF. Alternatively, this information can be provided in module 4 of a 
562  separate Type V DMF. 
563   
564  Excipients listed in the current USPNF (i.e., compendial excipients) are usually considered to 
565  be qualified when administered under conditions that would not be considered new, as defined 
                                                 
24 See footnote 3. 
25 To search for inactive ingredients, consult FDAs web page Inactive Ingredient Search for Approved Drug 
Products at https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm. 
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566  above. However, use of such excipients in a drug product that leads to increased exposure may 
567  require additional safety information, either in a DMF or in the drug product application. 
568  Additionally, it is important to note that the inclusion of an excipient in a USP-NF monograph or 
569  other non-FDA document is not an indication that FDA reviewed the substance or determined it 
570  to be safe for use. 
571   
572  Manufacturers of excipients derived from animal sources (e.g., gelatin) should provide 
573  information regarding safety of the material from contamination by infectious agents. This 
574  information can be provided directly to the authorized party. 
575   
576  b.  Colorant, flavor, essence, or material used in their preparation 
577   
578  Colorants are used to impart color to a drug product and are composed of one or more color 
579  additives and other ingredients. 
580   
581  Flavor or essence is an excipient that is added to a drug product whose significant function is to 
582  impart flavor and not to produce pharmacological activity. 
583   
584  DMFs for mixtures of materials used to prepare a flavor (e.g., artificial strawberry flavor) should 
585  include information about the components and composition of mixtures. For example, for flavors 
586  containing multiple components, a quantitative breakdown of the components in the mixture 
587  should be provided. 
588   
589  Refer to USP-NF for quality information. Data to support the safety of colorant and flavor 
590  mixtures can be provided by referring to FDA regulations, including: 
591   
592    Color additives (21 CFR parts 70 through 82). 
593    Direct food additives (21 CFR parts 170 through 173). 
594    Indirect food additives (21 CFR parts 174 through 178). 
595    Food substances (21 CFR parts 181 through 186). 
596    
597  Components should be identified by their names as cited in FDA regulations, where applicable. 
598   
599  Information about the components and compositions, as well as safety information, can be 
600  provided directly to the authorized party without filing a DMF. 
601   
602  If provided in a DMF, information about excipients that are mixtures of multiple compounds 
603  (e.g., flavor mixtures) should be submitted in eCTD section 3.2.P. The different sections within 
604  3.2.S or 3.2.P should be populated as appropriate. For multi-item DMFs, each product (e.g., 
605  different flavors) would have a different name (e.g., 3.2.P.[Flavor 1], 3.2.P.[Flavor 2]). In this 
606  case, the components and composition would be described in 3.2.P.1 [Flavor 1], 3.2.P.1 [Flavor 
607  2]. DMF holders can access information that is common to different products (e.g., analytical 
608  procedures) by reference (or via links in the case of an electronic DMF) to the relevant eCTD 
609  section for that product (e.g., 3.2.P.5.2 [Flavor 1]). 
610     
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611  4.  Type V: FDA-Accepted Reference Information 
612   
613  If a DMF holder wishes to submit information that is not covered by Types II through IV, the 
614  DMF holder can submit a Type V DMF (e.g., shared system REMS, sterile processing facility, 
615  toxicology studies for compound X) but must first email a letter of intent to the DMF staff at 
616  dmfquestion@fda.hhs.gov.26 FDA will then contact the DMF holder to discuss the proposed 
617  submission.  
618   
619  The emailed letter of intent should include: 
620   
621    The specific information to be included in the DMF. 
622   
623    The proposed subject (title) of the DMF. 
624   
625    A clear statement regarding why this information could not be submitted in an 
626  application (i.e., why the information is considered to be confidential). 
627   
628    The clinical division(s) that should review the information, if applicable. 
629   
630  Information regarding the manufacturing site, facilities, operating procedures, and personnel for 
631  sterile manufacturing plants can be filed as a Type V DMF without first submitting a letter of 
632  intent. The subject field should specify what the DMF covers (e.g., sterile processing facility). 
633   
634  E.  Other Recommendations  
635   
636  1.  English Translations 
637   
638  Applicants must submit an accurate and complete English translation of each part of the NDA or 
639  ANDA that is not in English ( 314.50(g)(2), 314.94(a)(11)). The same is true for DMFs. A 
640  certified translation is not required. 
641   
642  2.  Public Availability of Information in a DMF 
643   
644  Public availability of the information in a DMF is determined under 21 CFR part 20 and other 
645  applicable FDA disclosure regulations, including  314.420(e), 314.430, and 601.51. DMF 
646  holders and authorized parties are free to share any information with each other.
 
647 
 
648  3.  Holder Not the Manufacturer 
649   
650  In general, FDA expects the DMF holder to be the manufacturer of the material covered by the 
651  DMF. If the DMF holder is not the manufacturer, the DMF should include a statement that the 
652  DMF holder assumes full responsibility for the manufacturing of the material covered by the 
653  DMF.  
654   
                                                 
26 See  314.420(a)(5).  
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655  4.  Primary and Secondary DMFs 
656   
657  A primary DMF can incorporate information in a secondary DMF by reference. The secondary 
658  DMF holder can submit an LOA authorizing either the primary DMF holder or the drug product 
659  applicant to reference the secondary DMF. Where possible, consistent with confidentiality 
660  agreements, secondary DMF holders are encouraged to submit LOAs authorizing drug product 
661  applicants to reference the secondary DMF directly. 
662   
663  5.  Referencing Own Application Material 
664   
665  An applicant need not create a new DMF when referencing its own material but can include the 
666  information directly in its own application. 
667   
668  6.  Retention of Reference Copy by the Holder 
669   
670  DMF holders and their agents should retain a complete reference copy that is identical to, and 
671  maintained in the same chronological order as, their submissions to FDA.  
672   
673  When a DMF is transferred from one DMF holder to another, all documents associated with the 
674  DMF should be transferred to the new DMF holder. 
675   
676   
677  IV.  ANNUAL REPORTS  
678   
679  Annual reports should not be used to report changes in the DMF. If it is necessary to submit an 
680  amendment and an annual report, they must be submitted under separate eCTD sequence 
681  numbers.27 
682   
683  DMF holders should submit a cover letter28 when submitting their annual report. The annual 
684  report should include a statement of commitment signed by the DMF holder stating that the 
685  DMF is current and that the holder will comply with the statements made in the DMF. 
686  (Alternatively, the statement of commitment can be included in eCTD section 1.2 and referenced 
687  in the annual report. However, agents submitting annual reports on behalf of DMF holders 
688  should not refer to eCTD section 1.2 for the statement of commitment; rather they should include 
689  a statement of commitment signed by the DMF holder with the annual report.) The annual report 
690  should also include the appropriate administrative information, dates of any amendments 
691  reporting changes since the last annual report (or original filing date), a list of authorized parties, 
692  and a list of parties whose authorization has been withdrawn and the dates of withdrawal. See the 
693  annual report template and subsequent submissions cover letter template on CDERs DMF web 
694  page at https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs. 
695   
696  Annual reports help assure FDA that the statement of commitment is current. Failure to submit 
697  this report annually may result in the termination of a DMF (see section VI, DMF Closure). 
                                                 
27 See the Providing Regulatory Submissions guidance. 
28 See footnote 12. 
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698   
699   
700  V.  FDA PROCESSING AND REVIEWING POLICIES 
701   
702  A.  Administrative Review  
703   
704  If the administrative information in an original DMF is found acceptable, FDA sends an 
705  acknowledgment letter to the DMF holder (and agent, if applicable) listing the DMF number, 
706  subject (title), type, and holders name as specified in the cover letter. For submissions with 
707  incomplete administrative information, FDA contacts the DMF holder (and the agent, if 
708  applicable) to request the missing information. The DMF will not be available for technical 
709  review until all administrative filing issues have been adequately addressed and the DMF is 
710  referenced in an application or another DMF (see section V.B). 
711   
712  FDA examines subsequent submissions (e.g., amendments, LOAs) to ensure that the subject, 
713  holder name, and type match the information for that DMF number on file at FDA. FDA also 
714  checks these submissions for other administrative information, such as the holders address, 
715  agents address (if applicable), and appropriate submission type and, if applicable, amendment 
716  type (e.g., change of holder, change of DMF subject). If administrative issues are noted, FDA 
717  contacts the DMF holder (and agent, if applicable) to request that the information be corrected or 
718  the discrepancies be resolved.  
719   
720  FDA does not send acknowledgment letters for subsequent submissions. If this practice changes, 
721  FDA intends to update the DMF web pages to describe which types of documents will be 
722  acknowledged. 
723   
724  B.  Technical Review  
725   
726  FDA performs a complete review of the referenced technical information in a DMF when an 
727  authorized party submits a copy of the DMF holders LOA in its application or in another 
728  DMF.29 The review is performed to support a particular use (e.g., a drug substance used to 
729  manufacture a solid oral dosage form). Whether a DMF is acceptable depends on the specific use 
730  described in an application or in another DMF referencing the DMF. 
731   
732  Reviewers may find that additional information is needed to continue a review or that the DMF 
733  cannot be used to support approval of an ANDA, NDA, or BLA or, in the case of an IND, allow 
734  clinical trials to proceed. In these cases, FDA will contact the DMF holder and the agent, if 
735  applicable, regarding its concerns.  
736   
737  Certain Type II DMFs for APIs that require a user fee under the Generic Drug User Fee 
738  Amendments of 2017 (GDUFA II) will receive a completeness assessment.30  
739   
                                                 
29 See the draft guidance for industry Assessing User Fees Under the Generic Drug User Fee Amendments of 2017. 
When final, this guidance will represent FDAs current thinking on this topic. 
30 See the guidance for industry Completeness Assessments for Type II API DMFs Under GDUFA. 
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740   
741  VI.  DMF CLOSURE 
742   
743  DMFs may be closed either because the DMF holder requests closure or because FDA cannot be 
744  assured that the DMF is current. In the latter case, FDA will notify the holder or agent, as 
745  applicable, that the DMF needs to be updated. If the DMF holder or agent, as applicable, does 
746  not respond by submitting an annual report in a timely manner, FDA could close the DMF and 
747  would notify the holder or agent, as applicable, of this action. 
748   
749  To close a DMF, DMF holders should submit an administrative amendment requesting closure. 
750  The request should include a statement that all authorized parties have been notified of the 
751  closure (eCTD section 1.5.5). FDA recommends using the template for requesting closure on 
752  CDERs DMF web page at https://www.fda.gov/drugs/forms-submission-requirements/drug-
753  master-files-dmfs. 
754   
755  A closed DMF cannot be reviewed in support of a new or amended application or another DMF, 
756  a new or amended supplement to an approved application, a new IND, or an amendment to an 
757  existing IND. Thus, an applicant can no longer incorporate the information from a closed DMF 
758  in support of its application and will need to submit an amendment or supplement to FDA to 
759  replace the information contained in the closed DMF. 
760   
761  If a DMF has been closed, the holder can submit a new DMF to FDA to replace the closed DMF. 
762  The new DMF should reference the closed DMF number. 
763   
764   
765  VII.  GLOSSARY 
766   
767  Active pharmaceutical ingredient (API): Any substance intended for incorporation into 
768  a finished drug product and intended to furnish pharmacological activity or other direct 
769  effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect 
770  the structure or any function of the body; does not include intermediates used in the 
771  synthesis of the substance (21 CFR 207.1). 
772   
773  Agent: A legal entity, whether a company or an individual, that is not employed but is appointed 
774  to act on behalf of a DMF holder. 
775   
776  Authorized party: Any person who is authorized to reference a DMF. 
777   
778  Contact person: An employee of the DMF holder or agent to whom communication from FDA 
779  should be sent. The contact person may or may not be the same individual as the responsible 
780  official. 
781   
782  DMF holder: A person who owns a DMF. 
783   
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784  Drug product: A finished dosage form (e.g., tablet, capsule, solution) that contains a drug 
785  substance, generally, but not necessarily, in association with one or more other ingredients 
786  ( 314.3(b)). 
787   
788  Drug product intermediate: A defined mixture of one or more drug substances with one or 
789  more inactive ingredients that is not a finished dosage form. This is to be distinguished from a 
790  mixture when the drug substance is unstable or cannot be transported on its own.  
791   
792  Drug substance: An active ingredient that is intended to furnish pharmacological activity or 
793  another direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to 
794  affect the structure or any function of the human body but does not include intermediates used in 
795  the synthesis of such an ingredient ( 314.3(b)).  
796   
797  Drug substance intermediate: A material produced during steps of the processing of an API 
798  that undergoes further molecular change or purification before it becomes an API. Drug 
799  substance intermediates may or may not be isolated. See ICH Q7. 
800   
801  Letter of authorization (LOA): A letter from a DMF holder that authorizes an applicant or 
802  another DMF holder to incorporate by reference all or part of the DMFs contents to support an 
803  application, supplement, or another DMF or an amendment to any of these documents. The LOA 
804  also authorizes FDA to review applicable portions of the DMF. 
805   
806  Person: An individual, partnership, corporation, or association (section 201(e) of the FD&C 
807  Act).  
808   
809  Primary DMF: A DMF that references another DMF and itself may be referenced by an 
810  application. 
811   
812  Responsible official: The employee of the DMF holder or agent who is responsible for 
813  submitting information to the DMF. 
814   
815  Risk evaluation and mitigation strategy (REMS): A required risk management strategy that 
816  employs tools beyond prescribing information to ensure that the benefits of a drug outweigh its 
817  risks. For more information, see section 505-1 of the FD&C Act. 
818   
819  Secondary DMF: A DMF that is incorporated by reference into a primary DMF. 
820   
821  Subject: Title of the DMF. 
822   
823   
824  VIII.  REFERENCES 
825   
826  FDA, 2018, Comprehensive Table of Contents Headings and Hierarchy. 
827   
828  FDA, 2018, eCTD Technical Conformance Guide. 
829   
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830  FDA, 2017, MAPP 5040.1 Product Quality Microbiology Information in the Common Technical 
831  DocumentQuality (CTD-Q). 
832   
833  FDA, 2017, Technical Conformance Guide for Shared System REMS Drug Master File 
834  Submissions. 
835   
836  FDA, 2017, Transmitting Electronic Submissions Using eCTD Specifications. 
837   
838  Guidances for Industry 
839   
840  Guidance for industry Completeness Assessments for Type II API DMFs Under GDUFA, 
841  October 2017 
842   
843  Guidance for industry Drug Master Files for Bulk Antibiotic Drug Substances, November 1999 
844   
845  Guidance for industry Environmental Assessment of Human Drug and Biologics Applications 
846  (Rev. 1), July 1998 
847   
848  Guidance for industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical 
849  Excipients, May 2005 
850   
851  Guidance for industry Providing Regulatory Submissions in Electronic FormatCertain Human 
852  Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications 
853  (Rev. 6), January 2019 (see Rev. 7 in Draft Guidances for Industry below) 
854   
855  Guidance for industry Quality Considerations in Demonstrating Biosimilarity of a Therapeutic 
856  Protein Product to a Reference Product, April 2015 
857   
858  Guidance for industry Submission Documentation for Sterilization Process Validation in 
859  Applications for Human and Veterinary Drug Products, November 1994 
860   
861  ICH guidance for industry M4 Organization of the Common Technical Document for the 
862  Registration of Pharmaceuticals for Human Use, October 2017 
863   
864  ICH guidance for industry M4Q: The CTDQuality, August 2001 
865   
866  ICH guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products, 
867  November 2003 
868   
869  ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active 
870  Pharmaceutical Ingredients (Rev. 1), September 2016 
871   
872  ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active 
873  Pharmaceutical Ingredients: Question and Answers, April 2018 
874   
     21  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
875  ICH guidance for industry Q11 Development and Manufacture of Drug Substances, November 
876  2012 
877   
878  ICH guidance for industry Q11 Development and Manufacture of Drug Substances: Questions 
879  and Answers, February 2018 
880   
881  Draft Guidances for Industry31 
882   
883  Draft guidance for industry Assessing User Fees Under the Generic Drug User Fee Amendments 
884  of 2017, October 2017 
885   
886  Draft guidance for industry Postapproval Changes to Drug Substances, September 2018 
887   
888  Draft guidance for industry Providing Regulatory Submissions in Electronic FormatCertain 
889  Human Pharmaceutical Product Applications and Related Submissions Using the eCTD 
890  Specifications (Rev. 7), July 2019 (see Rev. 6 in Guidances for Industry above) 
891   
892  Draft guidance for industry Submitting Debarment Certification Statements, September 1998 
893   
894  Draft guidance for industry Submitting Marketing Applications According to the ICH-CTD 
895  FormatGeneral Considerations, August 2001 
896   
897  Draft guidance for industry Use of a Drug Master File for Shared System REMS Submissions, 
898  November 2017 
                                                 
31 When final, these guidances will represent FDAs current thinking on these topics. 
     22