Regulatory Requirements for Drug Master File (DMF) Submission in the United States

The filing of a Drug Master File (DMF) in the United States plays a crucial role in ensuring the quality, safety, efficacy, purity, and potency of medicinal products. DMFs are prepared by manufacturers of drug products or excipients and submitted to the regulatory authority in the targeted market, specifically the Food and Drug Administration (FDA) in the United States. While DMF submission is not compulsory, it serves as a valuable tool to support various regulatory applications, including Investigational New Drug Applications (INDs), New Drug Applications (NDAs), and Abbreviated New Drug Applications (ANDAs). This article explores the essential aspects of DMF filing in the U.S. regulatory landscape.

Types of DMF Submission

In the United States, DMFs are categorized based on the type of application they support. The primary submission types include:

1. New Drug Application (NDA) for new drugs.
2. Abbreviated New Drug Application (ANDA) for generic drugs.
3. Biologics License Application (BLA) for biologics.

DMF Filing in the USA (US-DMF)

DMF filing in the United States, often referred to as US-DMF, serves the purpose of meeting regulatory requirements and demonstrating the quality, safety, efficacy, purity, and potency of medicinal products. It is important to note that a DMF is neither approved nor disapproved; instead, it complements INDs, NDAs, ANDAs, or export applications. The regulatory framework governing DMFs in the United States is outlined in 21 CFR 314.420, which provides detailed guidance on DMF preparation and submission.

ALSO READ: Drug Approval Process in Canada

Types of DMFs

In the United States, there are five main types of DMFs:

1. TYPE 1: This type contains information about manufacturing sites, facilities, operating procedures, and personnel. It is particularly recommended for entities outside of the United States seeking FDA assistance in conducting site inspections of their manufacturing facilities.
2. TYPE 2: TYPE 2 DMFs provide comprehensive information about drug substances, drug products, their intermediates, and materials used in their preparation. This includes manufacturing processes, quality control, validation, stability data, impurities, and more. Any information not submitted in INDs, ANDAs, or NDAs should be included in a TYPE 2 DMF.
3. TYPE 3: This category pertains to packaging materials, requiring detailed information about their use, composition, and controls, as well as the name of the manufacturer and acceptance criteria.
4. TYPE 4: TYPE 4 DMFs encompass excipients, colorants, flavors, or materials used in their preparations. It includes information on manufacturing methods and toxicological data.
5. TYPE 5: TYPE 5 DMFs pertain to reference information used for sterile manufacturing plants and contract facilities for biotech products, as accepted by the FDA.

DMF Submission Process

The submission of each DMF should include a transmittal letter and administrative information about the submission. Some key points to consider include:

• Transmittal Letters: These letters specify the type of DMF, identification of the application it supports, the name and address of sponsors, applicants, or holders, the signature of the holder, and the typewritten name and title of the signer.
• Administrative Information: This section should include details such as the DMF holder's information, DMF number, corporate headquarters, manufacturing facility, agents involved, and a statement of commitment.

Formatting Requirements should be filed in electronic format

Information in the Common Technical Document (CTD) format should be transparent for ease of review.

• Text and tables should use appropriate margins for printing on A4 sheets.
• Times New Roman, 12-point font is recommended for narrative text.
• Standard US paper size (8.5 by 11 inches) should be used.
• Page length should fall between 10 and 12 inches.

ALSO READ: Drug Approval Process in the USA

Address for Submission

All DMF submissions and correspondence should be addressed to: 

Drug Master File Staff,

Food and Drug Administration,

5901-B Ammendale Road Beltsville, 

MD 20705-1266

Letter of Authorization

A DMF holder must submit a letter of authorization to the FDA, permitting the agency to reference the DMF. This letter should include the 

• Date, 
• DMF holder's name, 
• DMF number, 
• Authorized person's name, 
• The specific product covered by the DMF, 
• Section, 
• Page numbers for reference, 
• A commitment statement, and 
• The signature of an authorizing official.

Filing, Assessing, and Review of DMFT 

The DMF holder should send two copies to the FDA.

• Upon entry into the FDA's database system, an acknowledgment letter is issued.
• DMFs are reviewed only when referenced in an application, requiring the submission of a letter of authorization with the application.
• Reviewers may issue deficiency letters to the holder without specifying the nature of the deficiencies.

Holder Obligations

• Any changes or additions to the DMF or authorizations related to specific customers should be submitted in duplicate copies with references to previous submissions.
• The DMF should maintain a list of authorized persons for incorporation of information.
• The list should be updated annually with the holder's name, DMF number, and update date.
• Withdrawal of authorization should be documented appropriately.

Transfer of Ownership

If a DMF holder intends to transfer ownership, written notification should be provided to the FDA and the authorized person. The letter should include details such as the 

• The transferee's name, 
• Address, 
• Responsible official's name, 
• The effective date of transfer, 
• Signatures of transferring and accepting officials. 

The new holder should submit a letter of acceptance and update all DMF information related to the new ownership.

Closure of a DMF

A DMF holder seeking closure should submit a request to the DMF staff, stating the reason for closure and confirming fulfillment of all obligations. The FDA may initiate closure if the holder consistently fails to update references and the list of changes in annual reports.

Reactivating a Closed DMF

To reactivate a closed DMF, the holder must submit a reactivation request along with a complete copy of the DMF, including any revisions made since the last submission. Once the reactivation request enters the Document Archiving Reporting and Regulatory Tracking System (DARRTS), the DMF status changes to "ACTIVE."

Fees

Certainly, for the most up-to-date information regarding fees related to DMF submission in the United States, it is recommended to visit the official website of the Food and Drug Administration (FDA) or consult relevant regulatory authorities. Fee structures may change over time, and it is essential to rely on the latest guidance and fee schedules provided by the regulatory agency to ensure accurate and current information.

Conclusion

Understanding the regulatory requirements for DMF submission in the United States is vital for manufacturers and holders of drug products and excipients. Proper DMF preparation and compliance with FDA guidelines are essential to support various regulatory applications and maintain transparency throughout the drug development process. Additionally, adherence to submission and administrative standards ensures efficient communication with regulatory authorities and facilitates the review process.

ALSO READ: What is an Investigational New Drug Application?