INSIGHTS FROM THE BDO LIFE SCIENCES PRACTICE

A GUIDE
TO DRUG
MASTER
FILES
2  INSIGHTS FROM THE BDO LIFE SCIENCES PRACTICE

Introduction
A master file is a confidential document that covers detailed information about
facilities, processes and articles used in the manufacturing, processing, packaging, and storing
of biologic, drug, and device products. Master files may also cover other types of information
including toxicology and shared system Risk Evaluation and Mitigation Strategies (REMS).

Master files are submitted directly to the Food and Drug and There are four types of master files:
Administration (FDA) by a manufacturer and can subsequently
be referenced in applicant or sponsor applications to the X Type II: Drug substance, drug substance intermediates, and
FDA. This allows the manufacturer to protect its intellectual material used in their preparation, or drug product
information from disclosure to an applicant or sponsor X Type III: Packaging material
while allowing the applicant or sponsor to comply with the
regulatory requirements to provide the information as part X Type IV: Excipients, colorant, flavor, essence, or material
of an application to the FDA. A Drug Master File (DMF) is not used in their preparation
reviewed by the Agency until it is referenced in an applicant or
sponsor submission. X Type V: FDA-accepted reference information

Master files may be referenced in applications submitted for In 2000, the Type I master file was discontinued but the
both drugs, biologics, and medical devices. numbering of the other types of master files remain same.
 INSIGHTS FROM THE BDO LIFE SCIENCES PRACTICE   3

It is noteworthy that for Biologics License Applications This article is written to support and guide manufacturers that
(BLAs), the FDA has not generally accepted the inclusion are interested in preparing and submitting DMFs to the FDA.
of information about a drug substance, drug substance
intermediate, or drug product by reference to a Type II DMF.
DMF FORMAT AND DELIVERY
The Agency expects such information to be submitted
directly to the BLA 1,2. However, an investigational new drug The DMF submission must have a DMF number which is
(IND) application for a biological product may incorporate requested via the CDER NextGen Portal 5. The DMF should
by reference any information, including drug substance, typically be submitted in the standard electronic Common
drug substance intermediate, and drug product information, Technical Document (eCTD) format 6,7,8 through the FDA
contained in a master file 3. Electronic Submissions Gateway (ESG) 9. The ESG allows the
secure submission of regulatory information for review and
The terminology used for master file depends on the division is the FDA chosen method of transmission. At the time of
of the FDA which will use the master file during a review of an submission through the ESG, the DMF holder should select the
application. Master file (MF) (21 CFR 601.51(a)) are reviewed proper center at the FDA. The DMF might be submitted to the
by the Center for Biologics Evaluation and Research (CBER), CDER, the CBER or multiple centers at the FDA.
DMFs (21 CFR 314.420) are reviewed by the Center for Drug
Evaluation and Research (CDER), and Device Master Files For submission larger than 10 GB and for MF and MAF
(MAFs) (21CFR 814.20(c)) are reviewed by the Center for submissions, an electronic copy (e.g., on a compact disc or
Devices and Radiological Health (CDRH). Throughout this flash drive) or a paper copy may be mailed directly to the
document, the term DMF will be used to refer to master files, selected Agency center rather than submitting through
unless otherwise noted. the ESG.

CDER maintains a database containing a publicly available

list of DMFs filed with CDER 4. The list contains information
about the DMF number, activity status (active or inactive),
type, holder name and subject (title). The list is updated on a
quarterly basis.
4  INSIGHTS FROM THE BDO LIFE SCIENCES PRACTICE

DMF SUBMISSION CONTENT

DMF submissions must include the FDA form 3938 1, a cover letter and administrative and technical information. Multiple templates
are available on the FDA website to assist in the preparation of the administrative information contained in a DMF submission 10.
The original submission should contain complete administrative and technical information whereas subsequent submission should
contain information pertaining to changes and updates. The relevant eCTD modules for a DMF submission are discussed below 2.

Module 1: X Other correspondence: An environmental assessment

X Cover letter: this letter contains the submission type and should not be submitted because the DMF is neither
the DMF holder’s statement of commitment specifying that approved nor disapproved by the FDA 12. Nevertheless,
the DMF is current and the holder will fulfill statements DMF holders should include a commitment to operate their
made in DMF. facilities in agreement with applicable environmental laws.

X Administrative information: this section should include X Labeling: A copy of the shipping label should be provided
information regarding the DMF holder’s name and address, for Type II DMFs (drug substance, drug substance
the contact/agent (if applicable), the manufacturer (name, intermediates, and drug products) and excipients covered
site address, contact’s name, telephone/fax number and by Type IV DMFs.
email address) and debarment certification 11. X REMS: The REMS documents should be provided, if
X References: The DMF holder should submit a Letter of applicable 13, 14.
Authorization (LOA) to the DMF to allow an applicant or
sponsor (the “authorized party”) to refer to the DMF as part Module 2:
of an application to the FDA. It should be noted that the Module 2 recaps the applicable module 3 sections (and
FDA will not review a DMF unless the applicant or sponsor Modules 4 and 5, if applicable)
provides the copy of the LOA with their application. To
withdraw an authorization, a letter of “Withdrawal of Module 3:
Authorization” should be submitted to the DMF and a
copy should be sent to the authorized party. The FDA and See “Module 3 Content Recommended based on DMF Type” in
the authorized party should be notified of any changes/ this article for information to include in this module.
additions/deletions to a DMF.
Module 4:
X Application status: See section “DMF Closure” for
This module is not required for DMF submission unless non-
procedures for DMF closures.
clinical evaluations are conducted in support of the safety
X Meetings: A teleconference can be requested only by evaluation of an excipient (Type III DMF) or an impurity (Type
holders of Type II drug substance DMFs referenced in an II DMF) described in module 3. Additionally, any non-clinical
ANDA in response to first cycle DMF deficiency letters. evaluation submitted in support of a Type V DMF should be
X Information amendments: This section includes the included in module 4.
information summary of changes to modules 2 through
5 or information that is not covered under modules 2 Module 5:
through 5. This module should be submitted for any clinical information
supporting a Type V DMF.
 INSIGHTS FROM THE BDO LIFE SCIENCES PRACTICE   5

MODULE 3 CONTENT RECOMMENDED BASED ON DMF TYPE

Type II: Drug Substance, Drug Substance Intermediate, and Type IV: Excipients, Colorant, Flavor, Essence, or material
materials used in their preparation, or Drug product used in their preparation
There should be only a single drug substance, drug substance Submission of a DMF is required for new excipients (including
intermediate, type of material used in their preparation, drug colorants, flavors, essences, and material used in their
product or drug product intermediate in each Type II DMF. preparation) for which CMC and safety information is not
For drug substances manufactured using different processes, accessible in appropriate regulations or in the USP-NF.
separate DMFs should be submitted. The manufacturers of Non-clinical safety evaluations 18 of a new excipient can be
drug substance should collect stability data based on the submitted in module 4 of the Type IV DMF or module 4 of
stability protocol and continue to submit data from ongoing a separate Type V DMF. For animal-derived excipients, the
studies in a quality/stability amendment 15. If a drug substance safety information with respect to contamination by infectious
is sterilized in order to be used in sterile products, the same agents should be presented and can be reported directly to the
sterility assurance data should be submitted as for sterile authorized parties.
products 16 . If a Type V DMF is not cross referenced for the
facility and building information including floor plans, it can be Type V: FDA-Accepted reference Information
submitted in the Type II DMF. If the Chemistry, Manufacturing
and Control (CMC) information for material used in the The information that is not covered by Type II through Type
preparation of a drug substance/drug substance intermediate IV, can be submitted by Type V DMF (e.g., non-clinical/clinical
(e.g., cell culture media) is required by the FDA, a Type II DMF study data, shared system REMS, contract manufacturing
may be submitted. facilities, sterilization processes and medical devices). Device
master files may contain detailed information regarding
specific manufacturing facilities, processes, methodologies, or
Type III: Packaging Material components used in the manufacture, processing, or packaging
The type (e.g., bottle) and Material of Construction of a medical device. They may also provide information
(MOC) (e.g., high-density polyethylene) of packaging regarding finished medical devices.
material(s) should be identified. The authorized party can
be informed about the components of an MOC, including Specifically for shared system REMS, sterile processing
safety information, without filing a DMF. Safety and quality facilities and toxicology studies, the DMF holder should first
information for packaging material can be provided by referral email a letter of intent to the FDA regarding a Type V DMF.
to the appropriate Code of Federal Regulations and the After receiving the email, the FDA will contact the DMF holder
United States Pharmacopeia-National Formulary (USP-NF). to discuss the proposed DMF submission.
Type III DMFs can contain data regarding packaging material Additional recommendations regarding sharing, incorporating
or container-closure system’s components (e.g., a syringe and referencing information in a DMF is provided in the FDA
barrel and a plunger), MOC, controls for release, intended guidance document Drug Master Files 2. The DMF holder can
use and the mixture of color additives and plastics used contact the FDA for all DMF-related submission questions at
in manufacturing of plastic packaging components. If the dmfquestion@fda.hhs.gov.
packaging materials are sterilized and depyrogenated in order
to be used in a sterile product, the same sterility assurance
data should be submitted as for sterile products 17. If a Type
V DMF is not cross referenced for the facility and building
information including floor plans, it can be submitted in the
Type III DMF.
6  INSIGHTS FROM THE BDO LIFE SCIENCES PRACTICE

ANNUAL REPORTS
The annual report should be submitted on the anniversary date of the original DMF submission. The annual report should include
Form 3938, a cover letter, a statement of commitment signed by the DMF holder, the appropriate administrative information, a
tabulated summary of administrative and technical changes reported in amendments (including amendment number and date), a
list of authorized parties and a list of withdrawn parties with the dates of withdrawal 19. In the statement of commitment, it should
be mentioned that the DMF is recent, and the holder will fulfill the contents of the DMF. It is noteworthy to mention that the annual
report should not be used for any change of information. An amendment should be submitted to report changes.

FDA PROCESSING AND REVIEWING

Administrative Review Technical Review
Following the FDA's review and acceptance of the The FDA does not independently review or approve a DMF
administrative information, an acknowledgment letter will be and only reviews a DMF as part of an applicant or sponsor
sent to the DMF holder. This letter includes the DMF number, application. Hence, the technical information of a DMF is
subject (title), type and holder’s name. In the case of missing reviewed by the FDA once an authorized party submits a
information, the FDA will notify the DMF holder. The FDA will copy of the DMF holder’s LOA in its related application or in
not start the technical review until the administrative issues another DMF. The FDA will notify the DMF holder if additional
have been resolved and the DMF has been referenced in an information is required to support approval of an application.
applicant or sponsor application or another DMF. The FDA If the FDA has recommendations for additional information to
assesses subsequent submissions (e.g., amendment, LOA) to include in a DMF, an Advice/Information Request letter may
make sure that the administrative content matches that of the be sent to the DMF holder. Within the FDA, the center that
DMF on file at the FDA. No acknowledgment letter is sent to the DMF is allocated to is determined on a case-by-case basis,
the DMF holder for subsequent submissions. depending on the DMF topic and the jurisdiction of any of the
regulatory submissions authorized to reference the DMF when
receiving the original DMF 1.
 INSIGHTS FROM THE BDO LIFE SCIENCES PRACTICE   7

DMF CLOSURE Endnotes

The FDA can close a DMF if there is no assurance that the 1 https://fda.report/media/158382/SOPP-8301-Receipt-and-
DMF is current and if the DMF holder does not submit an Processing-of-Master-Files_V2.pdf
annual report in a timely manner. The FDA can also close a 2 https://www.fda.gov/media/131861/download
3 https://www.federalregister.gov/
DMF following a request for closure by the DMF holder. The documents/2019/06/28/2019-13753/biologics-license-applications-
DMF holder should submit an administrative amendment for and-master-files
the closure and inform all authorized parties. A new DMF can 4 https://www.fda.gov/drugs/drug-master-files-dmfs/list-drug-
master-files-dmfs
be submitted to the FDA to replace a closed one if the DMF
5 https://www.fda.gov/drugs/electronic-regulatory-submission-and-
holder wishes to re-establish the DMF. review/requesting-pre-assigned-application-number
6 https://www.fda.gov/media/135373/download
7 https://www.fda.gov/media/71551/download
8 https://www.fda.gov/media/71581/download
9 https://www.fda.gov/industry/electronic-submissions-gateway
Summary 10 https://www.fda.gov/drugs/drug-master-files-dmfs/drug-master-
file-dmf-templates
This article provides information pertaining 11 https://www.fda.gov/media/72557/download
12 https://www.fda.gov/media/70809/download
to the lifecycle management of DMFs which 13 https://www.fda.gov/media/109124/download
is relevant for manufacturers interested in 14 https://fda.report/media/108715/Technical-Conformance-Guide-for-
Shared-System-REMS-Drug-Master-File-Submissions.pdf
protecting confidential information while 15 https://www.fda.gov/media/71707/download
allowing applicants or sponsors to comply with 16 https://www.fda.gov/media/71442/download
17 https://www.fda.gov/media/71442/download
regulatory requirements for biologics, drugs 18 https://www.fda.gov/media/72260/download
and medical device applications. BDO has the 19 https://www.fda.gov/drugs/forms-submission-requirements/drug-
master-files-dmfs
technical and regulatory expertise to support
your company should questions arise or support
be needed during the DMF preparation, review
and submission process.
People who know Life Sciences, know BDO.
www.bdo.com/bptg

BDO wishes to acknowledge the authors:

Sanaz Momben Abolfath, Ph.D., Manager, BioProcess Technology Group
Lotte McNamara, Ph.D., Managing Director, BioProcess Technology Group

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