Drug Master Files Guidance for Industry

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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., 4 th 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Draft — Not for Implementation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
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Drug Master Files	1
Guidance for Industry1
2
3
4
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	5
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	6
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	7
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	8
for this guidance as listed on the title page.	9
10
11
12
13
I. 	INTRODUCTION	14
15
This guidance provides FDA’s current thinking on drug master files (DMFs), which are	16
submissions to FDA that may be used to provide confidential, detailed information about	17
facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of	18
human drug products. DMFs can contain other types of information as well (e.g., toxicology	19
information, shared system REMS (risk evaluation and mitigation strategy)).	20
21
DMF holders can authorize one or more applicants or sponsors to incorporate by reference	22
information contained in the DMF without having to disclose that information to the applicants	23
or sponsors. DMFs are submitted solely at the discretion of their holders and are not required by	24
statute or regulation. They are not typically submitted for nonproprietary materials. Ordinarily,	25
FDA neither independently reviews nor approves DMF submissions. Instead, FDA customarily	26
reviews the technical contents of DMFs only in connection with the review of applications that	27
reference them.2	
28
29
DMFs can be used to support (but are not substitutes for) applications reviewed by FDA. This	30
guidance focuses on the following submissions to the Center for Drug Evaluation and Research	31
(CDER) and the Center for Biologics Evaluation and Research (CBER):	32
33
• 	DMFs under 21 CFR 314.420 that are used to support new drug applications (NDAs),	34
abbreviated new drug applications (ANDAs), and investigational new drug applications	35
(INDs) under the Federal Food, Drug, and Cosmetic Act (FD&C Act).	36
37
• 	DMFs and other master files under 21 CFR 601.51(a) that are used to support biologics	38
license applications (BLAs) under the Public Health Service Act (PHS Act).	39
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.

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40
Additionally, information contained in DMFs can generally be referenced in premarket	41
submissions for devices (e.g., premarket approvals) and animal drugs (e.g., new animal drug	42
applications). Although the focus of this guidance is on the submissions to CDER and CBER	43
described above, in general, FDA believes the contents of this guidance will assist other master	44
file holders in providing complete and up-to-date master files to FDA.	45
46
This guidance provides information about preparing and submitting DMFs. It describes DMF	47
types, the information needed in DMF submissions, and FDA’s DMF review processes. For	48
additional information, see FDA’s DMF web pages.3	
49
50
This guidance revises the guidance for industry Drug Master Files: Guidelines that published in	51
September 1989. Most of the information contained in the 1989 guidance has been retained here,	52
with significant reorganization.	53
54
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	55
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	56
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	57
the word should in Agency guidances means that something is suggested or recommended, but	58
not required.	59
60
61
II. 	TYPES OF DMFS	62
63
Four types of DMFs are covered by § 314.20, as illustrated in the table below.	64
65
Types of DMFs	66
DMF
Type* Subject of Information Provided in the DMF
Type II** Drug substance, drug substance intermediate, and materials used in their
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
* Type I DMFs were discontinued in 2000 but the numbering of the other DMF types has not changed. FDA’s	67 approach to the terminology for types of master files used for products subject to approval under the PHS Act has	68 generally tracked its approach to the types of DMFs (e.g., Type II, Type III) used for products regulated under the	69 FD&C Act.	70 ** Although FDA’s approach to the use of master files in BLAs under the PHS Act largely parallels its approach to	71 the use of DMFs in applications under the FD&C Act, there is a significant difference: a BLA holder is generally	72 expected to have knowledge of and control over the manufacturing process for the biological product for which it	73 has a license. For biological products in BLAs under the PHS Act, FDA has, as a scientific matter, generally not	74
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.

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permitted applicants to incorporate information about drug substance, drug substance intermediate, or drug product	75 by reference to a master file; rather, FDA generally expects such information to be submitted directly to the BLA.	76
77
78
III. 	DMF SUBMISSIONS	79
80
This section describes the format and delivery of DMF submissions, outlines the content of	81
original and subsequent DMF submissions, offers submission recommendations specific to the	82
four types of DMFs, and ends with some broader recommendations for DMF holders to consider	83
when submitting DMFs.	84
85
A. 	Format and Delivery	86
87
DMF submissions are subject to the electronic submission requirements as set forth in guidance	88
implementing section 745A of the FD&C Act, including the guidance for industry Providing	89
Regulatory Submissions in Electronic Format—Certain Human Pharmaceutical Product	90
Applications and Related Submissions Using the eCTD Specifications (Rev. 6) (Providing	91
Regulatory Submissions guidance).4 The Drug Master Files guidance is not issued under section	92
745A of the FD&C Act and does not establish legally enforceable responsibilities. To the extent	93
it discusses binding requirements for DMFs, such requirements have been promulgated in	94
previously issued guidance under section 745A and FDA regulations.	95
96
Unless otherwise stipulated in the Providing Regulatory Submissions guidance or successor	97
guidance under section 745A, DMF submissions must have a DMF number, must be submitted	98
in the electronic format specified in such guidance, and, if 10 gigabytes or smaller, must be	99
submitted through the Electronic Submissions Gateway (ESG).5 Submissions over 10 gigabytes	100
can be submitted through ESG or they can be submitted on physical media (e.g., CD-ROM)	101
accompanied by a cover letter as described below and with prepaid delivery charges.6 The	102
standard electronic format for DMFs is electronic common technical document (eCTD) format.7	
103
104
For proper routing of DMFs, it is important to choose the appropriate center—CDER or	105
CBER—from the menu of choices when submitting through ESG. DMF holders who wish to	106
submit information that may be reviewed in multiple centers should consult the respective	107
centers. See the CDER and CBER DMF web pages for contact information.8	
108
4 Revision 7 of Providing Regulatory Submissions is available as a draft guidance. When final, this guidance will
represent the FDA’s 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 FDA’s 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.

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109
CDER’s DMF web page links to templates for certain submissions (e.g., cover letters, annual	110
reports) that recommend elements that DMF holders can include in these submissions.9 This	111
guidance refers to these templates where applicable rather than listing each element that FDA	112
recommends be included in a particular submission.	113
114
B. 	Original Submissions	115
116
Before submitting an original DMF in eCTD format, DMF holders must obtain a pre-assigned	117
number.10 For CDER submissions, see Requesting a Pre-Assigned Application Number at	118
https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/requesting-pre-	119
assigned-application-number. For CBER submissions, send requests for application numbers via	120
secure email to cberrims@fda.hhs.gov and include the sponsor/applicant name and address, point	121
of contact name and number, product name, and anticipated submission date.	122
123
Original submissions should contain a cover letter and complete administrative and technical	124
information in the appropriate eCTD modules. Although some eCTD module section headings	125
refer to change and sponsor/applicant, they are applicable to original and subsequent	126
submissions to DMFs.	127
128
This section reviews the eCTD modules and module sections that are relevant for original	129
submissions. For a complete list of eCTD section headings, see FDA’s Comprehensive Table of	130
Contents Headings and Hierarchy, which can be found in the eCTD Submission Standards on	131
FDA’s eCTD website (https://www.fda.gov/ectd). For additional formatting recommendations,	132
see the following:	133
134
• 	Providing Regulatory Submissions guidance.	135
136
• 	International Council for Harmonisation (ICH) guidance for industry M4 Organization	137
of the Common Technical Document for the Registration of Pharmaceuticals for Human	138
Use.	139
140
• 	ICH guidance for industry M4Q: The CTD—Quality.	141
142
• 	Draft guidance for industry Submitting Marketing Applications According to the ICH-	143
CTD Format—General Considerations.11	
144
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 FDA’s current thinking on this topic.

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1. 	Module 1	147
148
a. 	Cover letter (eCTD section 1.2)	149
150
FDA recommends using the cover letter template for original submissions on CDER’s DMF web	151
page at https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs.12 As	152
laid out in this template, the cover letter should specify the submission type (e.g., original, agent	153
appointment). A table of submission types is available on CDER’s DMF web page. The cover	154
letter should also include a statement of commitment signed by the DMF holder stating that the	155
DMF is current and that the holder will comply with the statements made in the DMF.	156
(Alternatively, the statement of commitment can be a separate document included in eCTD	157
section 1.2.) See the template for additional information to include.	158
159
b. 	Administrative information (eCTD section 1.3)	160
161
The administrative information section should include information about the DMF holder, the	162
agent (if applicable), the manufacturer, and debarment certification (for more information about	163
debarment certification, see section III.B.1.b.iv in this guidance).	164
165
i. 	DMF holder	166
167
DMF holders should provide their name and address. Only one company should be listed as the	168
DMF holder. Joint submissions are not accepted.	169
170
ii. 	Contact/Agent	171
172
DMF holders should provide the name, telephone and fax numbers, email address, and specific	173
responsibilities of the contact person and the responsible official (if different from the contact	174
person).	175
176
To facilitate communication, FDA strongly encourages foreign DMF holders to appoint an agent,	177
preferably in the United States, who is familiar with FDA regulations, guidances, and	178
procedures. However, DMF holders, not their agents, are responsible for the contents of their	179
DMFs (e.g., all aspects of the chemistry, manufacturing, and controls (CMC) information).	180
Agents can submit to the DMF on behalf of DMF holders. They can sign DMF submissions as	181
well, with the following exceptions:	182
183
• 	Agent appointment letters.	184
• 	Statements of commitment.	185
• 	Name changes.	186
• 	Holder transfers.	187
• 	New holder acceptance letters.	188
• 	DMF closure requests.	189
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.

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190
An agent for DMF purposes is not the same as an agent for the purposes of the Drug Listing and	191
Registration System (DRLS). DMF holders should not include the name of the agent for	192
registration purposes in the DMF unless the same person or company is the agent for both the	193
DMF and DRLS.	194
195
DMF holders can have different agents for different DMFs.	196
197
DMF holders should submit agent appointment letters in their original submissions or in	198
administrative amendments. The letter should be on the DMF holder’s letterhead and should	199
contain the agent’s name, address, contact person’s name (if different from the agent’s name),	200
telephone and fax numbers, and email address, among other information. FDA recommends	201
using the agent appointment letter template on CDER’s DMF web page at	202
https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs.	203
204
iii. 	Manufacturer	205
206
DMF holders should provide the manufacturer’s name, site address, and contact person’s name,	207
telephone and fax numbers, and email address.	208
209
iv. 	Debarment certification	210
211
DMF holders are included in the category of “Persons whose services were used in any capacity	212
in connection with the application” required under section 306(k)(1) of the FD&C Act. DMF	213
holders can submit their own debarment certifications in eCTD section 1.3.3.	214
215
For more information on debarment certifications, see draft guidance for industry Submitting	216
Debarment Certification Statements.13	
217
218
c. 	References (eCTD section 1.4)	219
220
i. 	Letter of authorization	221
222
FDA will not review a DMF until the DMF holder submits a letter of authorization (LOA) to the	223
DMF regarding a specific application or other DMF (§ 314.420(d)). LOAs can be submitted as	224
part of the original submission or in a subsequent submission. The LOA permits FDA to review	225
the DMF and permits the authorized party (i.e., the company or individual who submits an	226
application or another DMF) to incorporate information into an application or another DMF by	227
reference (eCTD section 1.4.1). An LOA should still be submitted even if the authorized party	228
and the DMF holder are the same company.	229
230
The DMF holder should send a copy of the LOA to the authorized party. The authorized party	231
must include a copy of the LOA in its application (§ 314.50(a)(1)) or DMF (eCTD section 1.4.2).	232
An LOA does not give an authorized party permission to view or access a DMF.	233
13 When final, this guidance will represent FDA’s current thinking on this topic.

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234
Note:	235
236
• 	An LOA should not be used to authorize an agent or representative to act on behalf of a	237
company.	238
239
• 	An LOA should not be used to authorize DMF holder employees to submit information to	240
the DMF.	241
242
• 	An LOA can be submitted by an agent but ultimately the DMF holder is responsible for	243
the LOA.	244
245
• 	An LOA should not have multiple authorized parties; DMF holders should submit a	246
separate LOA for each party.	247
248
• 	If the DMF holder changes its name, the DMF holder should submit a new LOA using	249
the “Replace” function in the electronic submission.	250
251
• 	If an authorized party changes its name, the DMF holder should submit a new LOA using	252
the “Replace” function in the electronic submission.	253
254
• 	An LOA does not need to include the name of the individual employed by the authorized	255
party (i.e., a contact person). The name of the applicant is sufficient.	256
257
• 	An LOA should distinguish between those facilities that will be used for purposes of the	258
authorization versus other facilities that are part of the DMF but are not applicable to the	259
authorization. Unless this specification is present in the LOA, FDA will assume that all	260
facilities listed in a DMF apply to the referencing application.	261
262
FDA recommends using the LOA template on CDER’s DMF web page at	263
https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs. As laid out	264
in this template, the LOA should include, among other information, a statement of commitment	265
signed by the DMF holder stating that the DMF is current and that the holder will comply with	266
the statements made in the DMF. (Alternatively, the statement of commitment can be included in	267
eCTD section 1.2 and referenced in the LOA.)	268
269
ii. 	List of authorized persons to incorporate by reference	270
271
In eCTD section 1.4.3, DMFs must list each party currently authorized to incorporate by	272
reference any information in the DMF (§ 314.420(d)). The list should only contain authorized	273
parties for which LOAs have been submitted and should be updated whenever a new LOA is	274
submitted or an authorized party is withdrawn. The list should contain the following information	275
for each authorized party:	276
277
• 	Name of the authorized party.	278
279

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• 	Date of the LOA.	280
281
• 	Specific products, items, or processes referenced by the LOA, including submission	282
dates, eCTD section numbers, and page numbers.	283
284
• 	Application number referencing the DMF (optional).	285
286
To withdraw authorization, DMF holders should submit a “Withdrawal of Authorization” letter	287
to the DMF and notify the authorized party. The withdrawal letter should replace the LOA in	288
eCTD section 1.4.1. FDA recommends using the withdrawal of authorization template on	289
CDER’s DMF web page at https://www.fda.gov/drugs/forms-submission-requirements/drug-	290
master-files-dmfs.	291
292
d. 	Application status (eCTD section 1.5)	293
294
DMF holders can use eCTD section 1.5.5 to close a DMF. See section VI for information about	295
DMF closures.	296
297
e. 	Meetings (eCTD section 1.6)	298
299
Holders of Type II active pharmaceutical ingredient (API)14 DMFs referenced in ANDAs can	300
request teleconferences in response to first-cycle DMF deficiency letters.15	
301
302
f. 	Information amendment: Information not covered under modules 2	303
through 5 (eCTD section 1.11)	304
305
In general, changes reported in eCTD section 1.11 should only include a summary of changes to	306
modules 2 through 5 or changes that do not fit in modules 2 through 5. Documents included in	307
eCTD section 1.11 should contain references and links to any sections in modules 2 through 5	308
that are changed. For example, a change in the drug substance specification should be mentioned	309
in eCTD section 1.11 but should also be changed in sections 2.3.S.4.1 and 3.2.S.4.1.	310
311
g. 	Other correspondence (eCTD section 1.12)	312
313
Because DMFs are neither approved nor disapproved, an environmental assessment should not	314
be submitted in a DMF (eCTD section 1.12.14).16 However, DMF holders should include in their	315
DMFs a commitment to operate their facilities in compliance with applicable environmental	316
laws.	317
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).

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h. 	Labeling (eCTD section 1.14)	319
320
For DMFs related to drug substances, drug substance intermediates, drug products covered by	321
Type II DMFs, and excipients covered by Type IV DMFs, DMF holders should provide a copy	322
of the shipping label in the Labeling section.	323
324
i. 	Risk evaluation and mitigation strategy (eCTD section 1.16)	325
326
In the REMS section, DMF holders should provide REMS-related documents, if applicable.17	
327
328
2. 	Module 2	329
330
Module 2 summarizes the appropriate module 3 sections (and 4 and 5, if applicable).	331
332
3. 	Module 3	333
334
See section III.D in this guidance for information to include in this module, organized by DMF	335
type.	336
337
4. 	Module 4	338
339
This module is not necessary for DMFs unless nonclinical evaluations are included in the DMF.	340
The following information is appropriate to submit in module 4:	341
342
• 	Nonclinical evaluations to support the safety of:	343
344
o 	An excipient whose CMC information is provided in module 3 in a Type IV	345
DMF; or	346
347
o 	An impurity whose CMC information is provided in module 3 in a Type II DMF.	348
349
• 	Nonclinical evaluations in a Type V DMF.	350
351
5. 	Module 5	352
353
Module 5 should be submitted for clinical information only, such as in a Type V DMF.	354
355
C. 	Subsequent Submissions	356
357
Amendments and additions or deletions of information in the DMF, including LOAs, must be	358
submitted to the DMF (§ 314.420(c)). These subsequent submissions should contain a cover	359
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 FDA’s current thinking on this topic.

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letter18 and updated administrative and technical information, as needed. DMF holder name	360
changes and acceptance notifications should also include the statement of commitment as	361
described in section III.B.1.a.	362
363
If information in a subsection (e.g., 3.2.S.2.3) of a DMF changes, DMF holders should replace	364
documents in that subsection. For more information, see the eCTD Technical Conformance	365
Guide at https://www.fda.gov/media/93818/download.	366
367
All amendments and LOAs should reference the updated DMF. A cumulative change history	368
should be submitted with each subsequent submission.	369
370
DMF holders must notify affected authorized parties of any DMF changes, additions, or	371
deletions (§ 314.420(c)) and should provide sufficient information to enable authorized parties to	372
determine the appropriate reporting procedure for their applications (see §§ 314.60, 314.70,	373
314.96, and 314.97). This notification should occur well before making any changes to permit	374
authorized parties to report application changes within an appropriate time frame.	375
376
1. 	Cover Letter	377
378
FDA recommends using the cover letter template for subsequent submissions on CDER’s DMF	379
web page at https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs.	380
Among other information as laid out in this template, the cover letter should specify the change	381
and reference the date and eCTD section or page number of any previous submission affected by	382
the change.	383
384
In addition, the cover letter should specify the submission type: for example, changes in	385
administrative information (e.g., change in agent) should be reported as an administrative	386
amendment, changes in technical information (e.g., change in a test procedure) should be	387
reported as a quality amendment (also referred to as a technical amendment), and changes in	388
REMS information (e.g., major REMS modification) should be reported as a REMS—Risk	389
Evaluation and Mitigation Strategy.	390
391
Multiple submission types (e.g., LOAs, administrative and quality amendments) can be	392
submitted together with a single cover letter and sequence number. In these cases, the DMF	393
holder should list each submission type in the cover letter. The DMF holder can also further	394
delineate the submission type by amendment type (e.g., change of holder). A table of submission	395
and amendment types is available on CDER’s DMF web page at	396
https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs.	397
398
2. 	Administrative Amendments	399
400
These types of amendments include, but are not limited to, the following changes.	401
402
18 See footnote 12.

Contains Nonbinding Recommendations
Draft — Not for Implementation
11
a. 	Name changes, acquisitions, or transfers of ownership	403
404
DMF holders must notify FDA of any name changes (§ 314.420(c)); such changes should be	405
submitted in an administrative amendment to each DMF they own. Name changes can occur	406
through a change in name only or because the DMF holder is acquired by or transfers ownership	407
to another company. If an agent had been appointed by the previous DMF holder and that agent	408
is being retained by the new DMF holder or if a new agent is being retained, the current DMF	409
holder should submit an agent appointment letter on the DMF holder’s letterhead (eCTD section	410
1.3.1.2).	411
412
If transfer of ownership is involved, the original DMF holder should submit a transfer	413
notification to the DMF and the new DMF holder should submit an acceptance notification. A	414
statement of commitment signed by the new DMF holder should be included in name change and	415
acceptance notifications stating that the DMF is current and that the holder will comply with the	416
statements made in the DMF. (Alternatively, the statement of commitment can be included in	417
eCTD section 1.2 and referenced in these notifications.)	418
419
Templates for name changes, transfer notifications, and acceptance notifications are on CDER’s	420
DMF web page at https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-	421
dmfs.	422
423
b. 	Changes to the DMF subject	424
425
Changes to the DMF’s subject (title) should be submitted in an administrative amendment. If a	426
title change is necessary because of a change in technical information (e.g., change in the grade	427
of a drug substance that is the subject of the DMF), a quality amendment should also be	428
submitted.	429
430
c. 	Changes to the DMF type	431
432
Changes to DMF type should be submitted in an administrative amendment. If the change in type	433
necessitates changes in the DMF’s technical information, the DMF holder should submit those	434
changes in a quality amendment.	435
436
3. 	Quality Amendments	437
438
Any changes to technical information should be submitted in a quality amendment.	439
440
4. 	Conversion of Existing DMFs To Comply With eCTD Format	441
442
Although there is no requirement to resubmit existing DMF submissions in eCTD format, DMF	443
holders wishing to do so should include a list of content changes occurring as a result of the	444
conversion in an attachment to the cover letter.19 It is not necessary to request a new DMF	445
19 See the eCTD Technical Conformance Guide for more information on resubmission of non-eCTD documents.

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12
number. If the existing number is four digits (e.g., 1234), the DMF holder will need to add two	446
zeros to the front of the number to convert it to the eCTD six-digit format (e.g., 001234).	447
448
D. 	Submission Recommendations, by DMF Type	449
450
The information recommended below is not intended to be all-inclusive. Please refer to	451
supplemental guidances related to information to be included in DMFs as well as the DMF	452
website.20	
453
454
1. 	Type II: Drug Substance, Drug Substance Intermediate, and Materials Used in	455
Their Preparation, or Drug Product	456
457
Each Type II DMF should be limited to a single drug substance, drug substance intermediate,	458
type of material used in their preparation, or drug product.21 Drug product intermediates are also	459
included in the category of Type II DMF. Separate DMFs should be submitted for drug	460
substances manufactured using different processes.	461
462
DMFs for drug substances, drug substance intermediates, drug products, and drug product	463
intermediates should state that the material covered by the DMF is manufactured under current	464
good manufacturing practices (eCTD sections 3.2.S.2 or 3.2.P.3).	465
466
Type II DMFs for APIs submitted in support of ANDAs should follow the recommendations in	467
guidances for industry such as Completeness Assessments for Type II API DMFs Under GDUFA.	468
Such recommendations do not apply to Type II DMFs for APIs that are only used to support	469
INDs or NDAs.	470
471
a. 	Drug substance or drug substance intermediate	472
473
The definition and criteria for designating starting materials and intermediates are discussed in	474
ICH guidances for industry Q7 Good Manufacturing Practice Guidance for Active	475
Pharmaceutical Ingredients (Rev. 1) and Q11 Development and Manufacture of Drug	476
Substances and ICH Q7 and Q11’s corresponding Questions and Answers guidances.	477
478
Drug substance manufacturers should collect stability data according to their stability protocol	479
and should continue to submit data from ongoing studies in a quality/stability amendment.22	
480
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 FDA’s current thinking on this topic.
21 Although FDA’s 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.

Contains Nonbinding Recommendations
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13
481
For sterilization of drug substances to be used in sterile products, the same sterility assurance	482
information should be submitted as for sterile drug products, as outlined in the guidance for	483
industry Submission Documentation for Sterilization Process Validation in Applications for	484
Human and Veterinary Drug Products (Submission Documentation guidance) and other	485
supporting documents included on CDER’s DMF web page.23 Building and facility information,	486
including floor plans, can be submitted in the Type II DMF if a Type V DMF is not cross-	487
referenced for this information.	488
489
b. 	Material used in the preparation of a drug substance or drug substance	490
intermediate	491
492
If material used in the preparation of a drug substance or drug substance intermediate requires	493
FDA review of CMC information (e.g., defined artificial cell growth media), this information	494
should be submitted in a Type II DMF.	495
496
c. 	Drug product or drug product intermediate	497
498
21 CFR 314.420 permits DMF submissions for drug products.	499
500
2. 	Type III: Packaging Material	501
502
Packaging materials should be identified by type (e.g., bottle) and material of construction	503
(MOC) (e.g., high-density polyethylene). Packaging materials can be combined to prepare a	504
container-closure system (e.g., a syringe barrel and a plunger).	505
506
Information, including safety information, about the components of an MOC can be provided	507
directly to the authorized party without filing a DMF.	508
509
For most MOCs (e.g., plastics and glass) and the packaging materials made from them, safety	510
and quality information can be provided by referring to appropriate sections of the Code of	511
Federal Regulations. Additional quality information can be provided by referring to appropriate	512
sections of the United States Pharmacopeia–National Formulary (USP–NF). MOCs should be	513
identified by their names as listed in the appropriate regulations, where applicable.	514
515
Data supporting the protection, compatibility, and performance of a packaging material or	516
container-closure system for its intended use should be submitted in the application for the drug	517
product that uses the packaging material.	518
519
Type III DMFs can include information about the packaging materials or container-closure	520
system’s components, MOCs, controls for release, and intended use. The names of the suppliers	521
or fabricators of the MOCs or components and the specifications for their acceptance can also be	522
provided.	523
23 See footnote 3; see also FDA’s MAPP 5040.1 Product Quality Microbiology Information in the Common
Technical Document—Quality (CTD-Q).

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14
524
Information regarding mixtures of color additives and plastics (often called masterbatches) for	525
use in manufacturing plastic packaging components (e.g., to make a bottle blue) is appropriately	526
filed as a Type III DMF.	527
528
For sterilization and depyrogenation of packaging materials to be used in sterile products, the	529
same sterility assurance information should be submitted as for sterile drug products, as outlined	530
in the Submission Documentation guidance and other supporting documents included on	531
CDER’s DMF web page.24 Building and facility information, including floor plans, is	532
appropriately filed in the Type III DMF if a Type V DMF is not cross-referenced for this	533
information.	534
535
The different eCTD sections within 3.2.S or 3.2.P should be populated as appropriate. For multi-	536
item DMFs, each item (e.g., different MOCs) would have a different name (e.g., 3.2.S.[MOC 1],	537
3.2.S.[MOC 2]). It is appropriate for DMF holders to point to information that is common to	538
different products (e.g., analytical procedures) by reference (or via links in the case of an	539
electronic DMF) to the relevant section for that product (e.g., 3.2.P.4.2 [MOC 1]).	540
541
3. 	Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their	542
Preparation	543
544
Information for most excipients (e.g., lactose or microcrystalline cellulose) should be submitted	545
in eCTD section 3.2.S. Information for excipients that are mixtures of multiple compounds (e.g.,	546
flavor mixtures) should be submitted in eCTD section 3.2.P.	547
548
DMFs should be submitted only for excipients for which CMC and safety information is not	549
available through reference to appropriate regulations or quality information through the USP-	550
NF. These include new excipients and colorants, flavors, essences, and material used in their	551
preparation.	552
553
a. 	New excipients	554
555
As defined in guidance for industry Nonclinical Studies for the Safety Evaluation of	556
Pharmaceutical Excipients, new excipients are inactive ingredients that are not fully qualified by	557
existing safety data with respect to the currently proposed level of exposure, duration of	558
exposure, or route of administration.25 Nonclinical evaluations to support the safety of an	559
excipient whose CMC information is provided in module 3 of a Type IV DMF can be provided	560
in module 4 of the same DMF. Alternatively, this information can be provided in module 4 of a	561
separate Type V DMF.	562
563
Excipients listed in the current USP–NF (i.e., compendial excipients) are usually considered to	564
be qualified when administered under conditions that would not be considered new, as defined	565
24 See footnote 3.
25 To search for inactive ingredients, consult FDA’s web page Inactive Ingredient Search for Approved Drug
Products at https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.

Contains Nonbinding Recommendations
Draft — Not for Implementation
15
above. However, use of such excipients in a drug product that leads to increased exposure may	566
require additional safety information, either in a DMF or in the drug product application.	567
Additionally, it is important to note that the inclusion of an excipient in a USP-NF monograph or	568
other non-FDA document is not an indication that FDA reviewed the substance or determined it	569
to be safe for use.	570
571
Manufacturers of excipients derived from animal sources (e.g., gelatin) should provide	572
information regarding safety of the material from contamination by infectious agents. This	573
information can be provided directly to the authorized party.	574
575
b. 	Colorant, flavor, essence, or material used in their preparation	576
577
Colorants are used to impart color to a drug product and are composed of one or more color	578
additives and other ingredients.	579
580
Flavor or essence is an excipient that is added to a drug product whose significant function is to	581
impart flavor and not to produce pharmacological activity.	582
583
DMFs for mixtures of materials used to prepare a flavor (e.g., artificial strawberry flavor) should	584
include information about the components and composition of mixtures. For example, for flavors	585
containing multiple components, a quantitative breakdown of the components in the mixture	586
should be provided.	587
588
Refer to USP-NF for quality information. Data to support the safety of colorant and flavor	589
mixtures can be provided by referring to FDA regulations, including:	590
591
• 	Color additives (21 CFR parts 70 through 82).	592
• 	Direct food additives (21 CFR parts 170 through 173).	593
• 	Indirect food additives (21 CFR parts 174 through 178).	594
• 	Food substances (21 CFR parts 181 through 186).	595
596
Components should be identified by their names as cited in FDA regulations, where applicable.	597
598
Information about the components and compositions, as well as safety information, can be	599
provided directly to the authorized party without filing a DMF.	600
601
If provided in a DMF, information about excipients that are mixtures of multiple compounds	602
(e.g., flavor mixtures) should be submitted in eCTD section 3.2.P. The different sections within	603
3.2.S or 3.2.P should be populated as appropriate. For multi-item DMFs, each product (e.g.,	604
different flavors) would have a different name (e.g., 3.2.P.[Flavor 1], 3.2.P.[Flavor 2]). In this	605
case, the components and composition would be described in 3.2.P.1 [Flavor 1], 3.2.P.1 [Flavor	606
2]. DMF holders can access information that is common to different products (e.g., analytical	607
procedures) by reference (or via links in the case of an electronic DMF) to the relevant eCTD	608
section for that product (e.g., 3.2.P.5.2 [Flavor 1]).	609
610

Contains Nonbinding Recommendations
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16
4. 	Type V: FDA-Accepted Reference Information	611
612
If a DMF holder wishes to submit information that is not covered by Types II through IV, the	613
DMF holder can submit a Type V DMF (e.g., shared system REMS, sterile processing facility,	614
toxicology studies for compound X) but must first email a letter of intent to the DMF staff at	615
dmfquestion@fda.hhs.gov.26 FDA will then contact the DMF holder to discuss the proposed	616
submission.	617
618
The emailed letter of intent should include:	619
620
• 	The specific information to be included in the DMF.	621
622
• 	The proposed subject (title) of the DMF.	623
624
• 	A clear statement regarding why this information could not be submitted in an	625
application (i.e., why the information is considered to be confidential).	626
627
• 	The clinical division(s) that should review the information, if applicable.	628
629
Information regarding the manufacturing site, facilities, operating procedures, and personnel for	630
sterile manufacturing plants can be filed as a Type V DMF without first submitting a letter of	631
intent. The subject field should specify what the DMF covers (e.g., sterile processing facility).	632
633
E. 	Other Recommendations	634
635
1. 	English Translations	636
637
Applicants must submit an accurate and complete English translation of each part of the NDA or	638
ANDA that is not in English (§§ 314.50(g)(2), 314.94(a)(11)). The same is true for DMFs. A	639
certified translation is not required.	640
641
2. 	Public Availability of Information in a DMF	642
643
Public availability of the information in a DMF is determined under 21 CFR part 20 and other	644
applicable FDA disclosure regulations, including §§ 314.420(e), 314.430, and 601.51. DMF	645
holders and authorized parties are free to share any information with each other.	646
647
3. 	Holder Not the Manufacturer	648
649
In general, FDA expects the DMF holder to be the manufacturer of the material covered by the	650
DMF. If the DMF holder is not the manufacturer, the DMF should include a statement that the	651
DMF holder assumes full responsibility for the manufacturing of the material covered by the	652
DMF.	653
654
26 See § 314.420(a)(5).

Contains Nonbinding Recommendations
Draft — Not for Implementation
17
4. 	Primary and Secondary DMFs	655
656
A primary DMF can incorporate information in a secondary DMF by reference. The secondary	657
DMF holder can submit an LOA authorizing either the primary DMF holder or the drug product	658
applicant to reference the secondary DMF. Where possible, consistent with confidentiality	659
agreements, secondary DMF holders are encouraged to submit LOAs authorizing drug product	660
applicants to reference the secondary DMF directly.	661
662
5. 	Referencing Own Application Material	663
664
An applicant need not create a new DMF when referencing its own material but can include the	665
information directly in its own application.	666
667
6. 	Retention of Reference Copy by the Holder	668
669
DMF holders and their agents should retain a complete reference copy that is identical to, and	670
maintained in the same chronological order as, their submissions to FDA.	671
672
When a DMF is transferred from one DMF holder to another, all documents associated with the	673
DMF should be transferred to the new DMF holder.	674
675
676
IV. 	ANNUAL REPORTS	677
678
Annual reports should not be used to report changes in the DMF. If it is necessary to submit an	679
amendment and an annual report, they must be submitted under separate eCTD sequence	680
numbers.27	
681
682
DMF holders should submit a cover letter28 when submitting their annual report. The annual	683
report should include a statement of commitment signed by the DMF holder stating that the	684
DMF is current and that the holder will comply with the statements made in the DMF.	685
(Alternatively, the statement of commitment can be included in eCTD section 1.2 and referenced	686
in the annual report. However, agents submitting annual reports on behalf of DMF holders	687
should not refer to eCTD section 1.2 for the statement of commitment; rather they should include	688
a statement of commitment signed by the DMF holder with the annual report.) The annual report	689
should also include the appropriate administrative information, dates of any amendments	690
reporting changes since the last annual report (or original filing date), a list of authorized parties,	691
and a list of parties whose authorization has been withdrawn and the dates of withdrawal. See the	692
annual report template and subsequent submissions cover letter template on CDER’s DMF web	693
page at https://www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs.	694
695
Annual reports help assure FDA that the statement of commitment is current. Failure to submit	696
this report annually may result in the termination of a DMF (see section VI, DMF Closure).	697
27 See the Providing Regulatory Submissions guidance.
28 See footnote 12.

Contains Nonbinding Recommendations
Draft — Not for Implementation
18
698
699
V. 	FDA PROCESSING AND REVIEWING POLICIES	700
701
A. 	Administrative Review	702
703
If the administrative information in an original DMF is found acceptable, FDA sends an	704
acknowledgment letter to the DMF holder (and agent, if applicable) listing the DMF number,	705
subject (title), type, and holder’s name as specified in the cover letter. For submissions with	706
incomplete administrative information, FDA contacts the DMF holder (and the agent, if	707
applicable) to request the missing information. The DMF will not be available for technical	708
review until all administrative filing issues have been adequately addressed and the DMF is	709
referenced in an application or another DMF (see section V.B).	710
711
FDA examines subsequent submissions (e.g., amendments, LOAs) to ensure that the subject,	712
holder name, and type match the information for that DMF number on file at FDA. FDA also	713
checks these submissions for other administrative information, such as the holder’s address,	714
agent’s address (if applicable), and appropriate submission type and, if applicable, amendment	715
type (e.g., change of holder, change of DMF subject). If administrative issues are noted, FDA	716
contacts the DMF holder (and agent, if applicable) to request that the information be corrected or	717
the discrepancies be resolved.	718
719
FDA does not send acknowledgment letters for subsequent submissions. If this practice changes,	720
FDA intends to update the DMF web pages to describe which types of documents will be	721
acknowledged.	722
723
B. 	Technical Review	724
725
FDA performs a complete review of the referenced technical information in a DMF when an	726
authorized party submits a copy of the DMF holder’s LOA in its application or in another	727
DMF.29 The review is performed to support a particular use (e.g., a drug substance used to	728
manufacture a solid oral dosage form). Whether a DMF is acceptable depends on the specific use	729
described in an application or in another DMF referencing the DMF.	730
731
Reviewers may find that additional information is needed to continue a review or that the DMF	732
cannot be used to support approval of an ANDA, NDA, or BLA or, in the case of an IND, allow	733
clinical trials to proceed. In these cases, FDA will contact the DMF holder and the agent, if	734
applicable, regarding its concerns.	735
736
Certain Type II DMFs for APIs that require a user fee under the Generic Drug User Fee	737
Amendments of 2017 (GDUFA II) will receive a completeness assessment.30	
738
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 FDA’s current thinking on this topic.
30 See the guidance for industry Completeness Assessments for Type II API DMFs Under GDUFA.

Contains Nonbinding Recommendations
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19
740
VI. 	DMF CLOSURE	741
742
DMFs may be closed either because the DMF holder requests closure or because FDA cannot be	743
assured that the DMF is current. In the latter case, FDA will notify the holder or agent, as	744
applicable, that the DMF needs to be updated. If the DMF holder or agent, as applicable, does	745
not respond by submitting an annual report in a timely manner, FDA could close the DMF and	746
would notify the holder or agent, as applicable, of this action.	747
748
To close a DMF, DMF holders should submit an administrative amendment requesting closure.	749
The request should include a statement that all authorized parties have been notified of the	750
closure (eCTD section 1.5.5). FDA recommends using the template for requesting closure on	751
CDER’s DMF web page at https://www.fda.gov/drugs/forms-submission-requirements/drug-	752
master-files-dmfs.	753
754
A closed DMF cannot be reviewed in support of a new or amended application or another DMF,	755
a new or amended supplement to an approved application, a new IND, or an amendment to an	756
existing IND. Thus, an applicant can no longer incorporate the information from a closed DMF	757
in support of its application and will need to submit an amendment or supplement to FDA to	758
replace the information contained in the closed DMF.	759
760
If a DMF has been closed, the holder can submit a new DMF to FDA to replace the closed DMF.	761
The new DMF should reference the closed DMF number.	762
763
764
VII. 	GLOSSARY	765
766
Active pharmaceutical ingredient (API): Any substance intended for incorporation into	767
a finished drug product and intended to furnish pharmacological activity or other direct	768
effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect	769
the structure or any function of the body; does not include intermediates used in the	770
synthesis of the substance (21 CFR 207.1).	771
772
Agent: A legal entity, whether a company or an individual, that is not employed but is appointed	773
to act on behalf of a DMF holder.	774
775
Authorized party: Any person who is authorized to reference a DMF.	776
777
Contact person: An employee of the DMF holder or agent to whom communication from FDA	778
should be sent. The contact person may or may not be the same individual as the responsible	779
official.	780
781
DMF holder: A person who owns a DMF.	782
783

Contains Nonbinding Recommendations
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20
Drug product: A finished dosage form (e.g., tablet, capsule, solution) that contains a drug	784
substance, generally, but not necessarily, in association with one or more other ingredients	785
(§ 314.3(b)).	786
787
Drug product intermediate: A defined mixture of one or more drug substances with one or	788
more inactive ingredients that is not a finished dosage form. This is to be distinguished from a	789
mixture when the drug substance is unstable or cannot be transported on its own.	790
791
Drug substance: An active ingredient that is intended to furnish pharmacological activity or	792
another direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to	793
affect the structure or any function of the human body but does not include intermediates used in	794
the synthesis of such an ingredient (§ 314.3(b)).	795
796
Drug substance intermediate: A material produced during steps of the processing of an API	797
that undergoes further molecular change or purification before it becomes an API. Drug	798
substance intermediates may or may not be isolated. See ICH Q7.	799
800
Letter of authorization (LOA): A letter from a DMF holder that authorizes an applicant or	801
another DMF holder to incorporate by reference all or part of the DMF’s contents to support an	802
application, supplement, or another DMF or an amendment to any of these documents. The LOA	803
also authorizes FDA to review applicable portions of the DMF.	804
805
Person: An individual, partnership, corporation, or association (section 201(e) of the FD&C	806
Act).	807
808
Primary DMF: A DMF that references another DMF and itself may be referenced by an	809
application.	810
811
Responsible official: The employee of the DMF holder or agent who is responsible for	812
submitting information to the DMF.	813
814
Risk evaluation and mitigation strategy (REMS): A required risk management strategy that	815
employs tools beyond prescribing information to ensure that the benefits of a drug outweigh its	816
risks. For more information, see section 505-1 of the FD&C Act.	817
818
Secondary DMF: A DMF that is incorporated by reference into a primary DMF.	819
820
Subject: Title of the DMF.	821
822
823
VIII. 	REFERENCES	824
825
FDA, 2018, Comprehensive Table of Contents Headings and Hierarchy.	826
827
FDA, 2018, eCTD Technical Conformance Guide.	828
829

Contains Nonbinding Recommendations
Draft — Not for Implementation
21
FDA, 2017, MAPP 5040.1 Product Quality Microbiology Information in the Common Technical	830
Document—Quality (CTD-Q).	831
832
FDA, 2017, Technical Conformance Guide for Shared System REMS Drug Master File	833
Submissions.	834
835
FDA, 2017, Transmitting Electronic Submissions Using eCTD Specifications.	836
837
Guidances for Industry	838
839
Guidance for industry Completeness Assessments for Type II API DMFs Under GDUFA,	840
October 2017	841
842
Guidance for industry Drug Master Files for Bulk Antibiotic Drug Substances, November 1999	843
844
Guidance for industry Environmental Assessment of Human Drug and Biologics Applications	845
(Rev. 1), July 1998	846
847
Guidance for industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical	848
Excipients, May 2005	849
850
Guidance for industry Providing Regulatory Submissions in Electronic Format—Certain Human	851
Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications	852
(Rev. 6), January 2019 (see Rev. 7 in “Draft Guidances for Industry” below)	853
854
Guidance for industry Quality Considerations in Demonstrating Biosimilarity of a Therapeutic	855
Protein Product to a Reference Product, April 2015	856
857
Guidance for industry Submission Documentation for Sterilization Process Validation in	858
Applications for Human and Veterinary Drug Products, November 1994	859
860
ICH guidance for industry M4 Organization of the Common Technical Document for the	861
Registration of Pharmaceuticals for Human Use, October 2017	862
863
ICH guidance for industry M4Q: The CTD—Quality, August 2001	864
865
ICH guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products,	866
November 2003	867
868
ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active	869
Pharmaceutical Ingredients (Rev. 1), September 2016	870
871
ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active	872
Pharmaceutical Ingredients: Question and Answers, April 2018	873
874

Contains Nonbinding Recommendations
Draft — Not for Implementation
22
ICH guidance for industry Q11 Development and Manufacture of Drug Substances, November	875
2012	876
877
ICH guidance for industry Q11 Development and Manufacture of Drug Substances: Questions	878
and Answers, February 2018	879
880
Draft Guidances for Industry31	881
882
Draft guidance for industry Assessing User Fees Under the Generic Drug User Fee Amendments	883
of 2017, October 2017	884
885
Draft guidance for industry Postapproval Changes to Drug Substances, September 2018	886
887
Draft guidance for industry Providing Regulatory Submissions in Electronic Format—Certain	888
Human Pharmaceutical Product Applications and Related Submissions Using the eCTD	889
Specifications (Rev. 7), July 2019 (see Rev. 6 in “Guidances for Industry” above)	890
891
Draft guidance for industry Submitting Debarment Certification Statements, September 1998	892
893
Draft guidance for industry Submitting Marketing Applications According to the ICH-CTD	894
Format—General Considerations, August 2001	895
896
Draft guidance for industry Use of a Drug Master File for Shared System REMS Submissions,	897
November 2017	898
31 When final, these guidances will represent FDA’s current thinking on these topics.