Drug Master File (DMF): FDA Guidelines

A Drug master file is a submission form, that is required to submit to the Food and Drug Administration (FDA). A US DMF (Drug Master File) is a document that is submitted to regulatory agencies to provide confidential, detailed information about a drug API, drug product, or excipient. It is used to support the approval of a drug product or a new drug application (NDA). DMFs are typically used when the information about a drug substance or product is proprietary and the company does not want to disclose the information in a public forum, such as in an application for drug approval. Drug Master Files are provided as per 21 CFR 314.420.

DMF required for: DMF is mainly used to support an investigational new drug application (NDA). The DMF file is only reviewed in connection with these files (IND, NDA, and ANDA)

DMF is not required by: Any Law and by the US FDA

Types and content of the DMFs or FDA Master file:

There are five types of Drug Master Files, and they include:

Type I: Manufacturing Site, Facilities, Operating Procedures, And Personnel: 

A type-I DMF is suggested for a person outside the US to assist the FDA in conducting on-site inspections of their manufacturing facilities. The DMF should describe the manufacturing site, equipment capabilities, and operation layout. The description of the site includes areas, the actual site address, and a map showing its location for the nearest city. An aerial photograph and a diagram of the site may be included.

A diagram of major production and processing areas helps understand operational Layout. Major equipment should be described in terms of capabilities, application, and location. Make and model would not normally be needed unless the equipment is new or unique.

A diagram of major corporate organizational elements, with key manufacturing, quality control, and quality assurance positions highlighted at both the manufacturing site and corporate headquarters, is additionally helpful.

Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product:

A Type-II DMF should, in general, be limited to a single drug intermediate, drug substance, drug product, or type of material used in their Preparation. For drug intermediate, drug substance summaries all significant steps in the manufacturing and controls of the drug intermediate or substance.

For drug product manufacturing procedures and controls for finished dosage forms should ordinarily be submitted in an IND, NDA, ANDA, or Exports Application. If all this information cannot be submitted in an IND, NDA, ANDA, or Export Application, It should be submitted in a DMF. When Type-II DMF is submitted for a drug product, an intermediate product special guide should be followed.

Type-III: Packing material:

Each packaging material should be identified by the intended use, Components, compositions, and controls for its release. The names of the Suppliers or fabricators of the Components used in the Preparation of packaging material and acceptance specifications should be given. Data supporting the acceptability of the packaging material for its intended use should even be submitted as outlined within the guideline.

For submission requirements related to Type III DMFs, see guidance for industry Providing Regulatory Submissions in Electronic Format—Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (Rev.6).  Revision 7

Type IV: Excipient, Colourant, Flavour, essence, or Material used in their Preparation:

Each additive should be identified and characterized by its manufacturer method, release specifications, and testing methods. Toxicological data on these materials would be included under this sort of DMF, if not, otherwise available by cross-reference to another document.

Usually, the official compendia and FDA regulations for Colour additives (21 CFR Parts 70 through 82), Direct food additives (21 CFR parts 170 through 173), indirect food additives (21 CFR parts 174 through 178), and Food substances (21 CFR Park I S I through 186) may be used as a source for release, tests, specifications, and safety.

Type V: FDA Accepted Reference Information :

FDA discourages the utilization of type-V DMFs for miscellaneous information, duplicate information, or information that ought to be included in one among the opposite sorts of DMFs.

If any holder wishes to submit the information supporting data in DMF that is not covered by Type-I through type-IV, a holder must first submit a letter of intent to the DMF Staff. FDA will then contact the holder to debate the proposed submission.

Type 1 Type II and Sort IV DMFs should contain a commitment by the firm that its facilities be operated in compliance with applicable environmental laws.

Document Format Required for US DMFs:

• Drug master file holders and their agents/representatives should retain an entire reference copy that’s similar to and maintained within the same chronological order as their submissions to the FDA.
• The original and duplicate copies must be collated, fully assembled, and individually jacketed. Each volume of a DMF should, generally, be no over 2 inches thick. For multi-volume submissions, number each volume. For example, for a 3 volume submission, the volumes would be numbered one of three, two of three, and three of three.
• US standard paper size (8-1/2 by 11 inches) is preferred. Paper length shouldn’t be less than 10 inches or over 12 inches. However, it should occasionally be necessary to use individual pages larger than the standard paper size to present a plan.
• Synthesis diagram, batch formula, or manufacturing instructions. Those pages should be folded and mounted to permit the page to be opened for review without disassembling the jacket and refolded without damage when the quantity is shelved.
• The agency’s system for filing DMFs provides for assembly on the left side of the page. The left margin should be at least three-fourths of an inch to ensure that text is not obscured in the fastened area. The right margin should be a minimum of one-half an inch. The submitter should punch holes 8 1/2 inches apart on each page.

DMFs Review:

A DMF (Drug Master File) review is the process by a regulatory like FDA and EMA. These regulatory bodies evaluate the information contained in a DMF to determine if a drug substance, drug product, or excipient meets the required standards for safety and efficacy. The regulatory bodies will review the DMFs to ensure that the information provided is complete, accurate, and up-to-date.

During the DMF review process, the regulatory agency may request additional information or clarification (if required) from the company that submitted the DMF. The agency may also conduct its own inspections or audits to verify whether the information contained in the DMF is accurate or not. If the DMF is found to be complete and accurate, the regulatory agency may accept the DMF and allow the drug substance or product to be used in the manufacture of a drug product.

Companies need to ensure that the information contained in a DMF is accurate and complete, as the DMF review process is likely to be 60 days after file submission. If a DMF is found to be incomplete or inaccurate, the regulatory agency may reject the DMF, which could delay or prevent the approval of a drug product.

TGA DMF Submission

TGA is required to submit the file in electronic Common Technical Document (eCTD) or Non eCTD electronic Submission (NeeS) format. Find the TGA submission form here.

Advantages:

There are several advantages to using a DMF (Drug Master File), Some of the benefits of using a DMF include:

• Confidentiality: DMFs are considered confidential documents, it is not made public. This can be important for companies that want to protect proprietary information about their products.
• Efficiency: DMFs allow pharmaceuticals to submit all information in a single file, which can be more efficient if provided the information is in multiple documents.
• Simplicity: DMFs provide a standardized format for companies to follow when submitting information about their products to regulatory agencies. This can simplify the process of providing information to the agencies.
• Reduced Time: Using a DMF can speed up the process of getting product approval. because it contains all information about a drug product the agency can review it more quickly and make a decision on whether to approve the product.

You may like to Read: Factory Acceptance Test (FAT)

DMF Submission and Amendment Types

Submission Type	Amendment Type
Original (New)
Administrative Amendment	Change of Agent/Address/Contact Person
	Change of Holder/Address/Contact Person
	Change of DMF Subject (Title)
	Change of DMF Type
	Agent Appointment
	Annual Report
Letter of Authorization
Withdrawal of Letter of Authorization
Meeting	Meeting Package
	Meeting Request
Quality Amendment	Controls Information
	Facility Information
	Formulation Information
	Manufacturer Information
	Microbiology Information
	New Item*
	Packaging Information
	Stability Information
	Response to Administrative Filing Issue
Response to Deficiency, Complete Response, Information Request, or Additional Comments Letter
REMS—Risk Evaluation and Mitigation Strategy	REMS Final
	REMS Assessment
	REM Assessment Methodology
	REMS Revision
	REMS Modification—Due to Safety Labeling Changes
	REMS Modification—Major
	REMS Modification—Minor
	REMS Proposal—Standard
	REMS Correspondence
Other	Other

* For Type III and Type IV DMFs, a new item represents a new item in the DMF, such as a rubber stopper, cap, and so forth.

Drug Master File Submission Resource:

Topic	Description
Draft Guidance for Industry Drug Master Files	Describes how to prepare and submit DMFs.
Pre-Assigned Application Number	To be included in DMF submissions to CDER. For CBER submissions, send a secure email to [email protected] with sponsor/applicant name and address, point of contact details, product name, and anticipated submission date.
Electronic Common Technical Document (eCTD) Website	CDER’s standard format for electronic regulatory submissions, including DMFs.
Electronic Submissions Gateway	Central transmission point for sending information electronically to the FDA.
Providing Regulatory Submissions in Electronic Format—Certain Human Pharmaceutical Product Applications and Related Submissions Using eCTD Specifications (Rev. 6)	Guidance for the industry on organizing electronic submissions. Revision 7 was issued as a draft for public comment. Represents FDA’s current thinking on the topic when final.
Comprehensive Table of Contents Headings and Hierarchy	Complete list of CTD section headings.
FDA IND, NDA, ANDA, or Drug Master File Binders	Information about binders for certain submissions.
FDA Form 3938	A standardized fillable electronic form for DMF submissions.
Instructions for filling out FDA Form 3938	Guidelines for completing FDA Form 3938.
Quick Guide to Creating a Structure-Data File (SD File) for DMF Submissions	Guidance on creating an SD File for DMF Submissions.

Address for submitting 21 CFR 314.420 Drug Master Files:

Drug Master File Staff
Food and Drug Administration
5901-B Ammendale Rd.
Beltsville, MD 20705-1266

Reference:

• Food and Drug Administration guidelines
• DMF by TGA