What is a Drug Master File (DMF)?

In the pharmaceutical industry, a vast amount of confidential information is handled throughout the process from product development to regulatory approval and manufacturing. Among these, a document system called the “Drug Master File (DMF)” plays a crucial role in ensuring the quality, safety, and efficacy of pharmaceutical products.

A DMF is a documentation system for submitting confidential information about pharmaceuticals, their raw materials, and manufacturing processes to regulatory authorities. The DMF provides a mechanism that allows pharmaceutical manufacturers and raw material suppliers to directly provide information to regulatory authorities without disclosing confidential information to their customers (pharmaceutical applicants).

This arrangement enables raw material suppliers to protect confidential information such as their manufacturing know-how, while customers can smoothly proceed with approval applications for pharmaceuticals using those raw materials.

Types of DMFs

DMFs are classified differently depending on the country or region, but the U.S. FDA classification is often referenced internationally. The main types are as follows:

U.S. FDA DMF Classification:

• Type I: Information on manufacturing site, facilities, operating procedures, and personnel (no longer accepted for new submissions since 1989)
• Type II: Information on drug substances, intermediates, materials, and raw materials, including manufacturing methods and quality control (most common type)
• Type III: Information on packaging materials
• Type IV: Information on excipients, colorants, flavors, essences, or materials used in their preparation
• Type V: Information accepted by FDA for reference or any other information that does not fit into Types I through IV

In Japan, the system was introduced in 2005 as the “Master File (MF) System for Drug Substances, etc.” (原薬等登録原簿制度) and is managed by the Pharmaceuticals and Medical Devices Agency (PMDA). The Japanese MF system covers drug substances, excipients, and other raw materials.

In Europe, it is known as the “Active Substance Master File (ASMF)” or “European Drug Master File (EDMF)” and is operated based on guidelines from the European Medicines Agency (EMA). The ASMF is specific to drug substances and is characterized by a two-part structure consisting of the “Open Part,” which is disclosed to the applicant, and the “Closed Part,” which contains confidential information.

Roles and Importance of DMFs

1. Protection of Intellectual Property

One of the most important roles of a DMF is to protect the intellectual property of raw material manufacturers. For example, a drug substance manufacturer can include proprietary synthesis methods and manufacturing techniques in the DMF and disclose them to regulatory authorities while maintaining confidentiality from pharmaceutical manufacturers (customers). This is managed as the “Closed Part” (in Europe) or confidential section (in the U.S.), protecting critical manufacturing information from competitors.

2. Streamlining of Approval Applications

Pharmaceutical manufacturers can reference a DMF, eliminating the need to include all detailed information about raw materials in their own approval applications. This streamlines the preparation of application materials and shortens the time from application to approval. Particularly when the same drug substance or excipient is used in multiple pharmaceuticals, referencing the DMF in each application avoids duplicative documentation efforts.

3. Consistency of Quality Assurance

A DMF contains detailed information including manufacturing methods, specifications, test methods, stability data, and impurity profiles of raw materials. This enables regulatory authorities to evaluate whether the quality of raw materials is consistently maintained. Furthermore, through the Change Control System, reporting to regulatory authorities is mandatory when changes are made to manufacturing methods, test methods, or specifications, ensuring a mechanism for quality consistency.

4. Rationalization of Regulatory Compliance

Since a single DMF can be referenced by multiple customers, raw material manufacturers do not need to repeatedly provide the same information for each customer’s application. This rationalizes regulatory compliance operations for both raw material manufacturers and pharmaceutical manufacturers.

DMF Application and Review Process

The application and review of a DMF generally proceed through the following process:

Application Process:

1. DMF Registration: The raw material manufacturer prepares a DMF and submits it to the regulatory authority (U.S. FDA, Japan PMDA, European EMA, etc.) to obtain a registration number. In the U.S., submissions are made electronically through the eDMF system.
2. Issuance of Letter of Authorization (LOA): The DMF holder issues an LOA (authorization letter, consent letter) to customers (pharmaceutical applicants) who are permitted to reference their DMF. The LOA includes the DMF registration number, the scope of reference permitted, and the validity period.
3. Reference by Applicant: The pharmaceutical manufacturer references the DMF registration number and LOA in pharmaceutical approval application materials (NDA, ANDA, MAA, etc.) and utilizes it as information regarding raw materials.
4. Review by Regulatory Authority: The regulatory authority reviews the contents of the DMF as part of the pharmaceutical application. The DMF is not reviewed independently but is always evaluated in connection with a pharmaceutical application.

Key Points of Review:

Regulatory authorities primarily conduct reviews on the following points:

• Appropriateness and reproducibility of raw material manufacturing methods
• Validity and scientific basis of quality control tests
• Appropriateness of specifications (including consistency with pharmacopeial standards)
• Adequacy of stability data and validity of storage conditions
• Impurity profiles and their control methods (compliance with ICH Q3A/Q3B guidelines)
• GMP compliance of manufacturing facilities
• Appropriateness of change control systems
• Validity of risk assessments and control strategies

During the review process, regulatory authorities may issue requests for additional information or clarification (Deficiency Letters, questions, etc.), and DMF holders must respond appropriately and in a timely manner.

Important Considerations in DMF Management

1. Regular Updates and Change Control

A DMF is a “Living Document” and must be updated promptly when changes occur in manufacturing methods, test methods, facility updates, or specification revisions. In the U.S., submission of an Annual Report is recommended, and in Japan, notification is required when changes occur. It is important to appropriately classify Minor Changes and Major Changes and make reports in accordance with regulatory requirements.

2. Global Strategy and Harmonization

Since the requirements, formats, and review standards for DMF/MF/ASMF systems differ by country and region, it is important to understand the requirements of each country and develop an efficient application strategy when expanding business globally. In recent years, harmonization based on ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines (ICH Q7 GMP, ICH Q11 Drug Substance Development, etc.) has been progressing, although country-specific requirements still remain. Preparation in CTD (Common Technical Document) format is internationally recommended, and compliance with this format streamlines responses to multiple regions.

3. Communication and Transparency

Appropriate communication among the three parties—DMF holder, applicant (customer), and regulatory authority—is key to successful DMF management. In particular, prompt and appropriate responses to inquiries from regulatory authorities are required. Additionally, it is necessary to appropriately provide information to customers about DMF update status and change items to ensure that customers’ approval applications are not adversely affected.

4. Data Integrity and System Management

In recent years, regulatory authorities have strengthened requirements related to data integrity. Data recorded in DMFs must be reliable, traceable, and unaltered. Compliance with electronic records and electronic signatures (21 CFR Part 11, ER/ES guidelines, etc.), ensuring audit trails, and appropriate backup and archiving management are required.

5. Supply Chain Management

As raw material supply chains become increasingly complex, transparency and management of the entire supply chain—including the origin of raw materials (Starting Material), contract manufacturing sites, and impact assessments during changes—are being emphasized. In particular, the definition and management of starting materials for drug substances must be appropriately conducted in accordance with ICH Q11 guidelines.

Recent Regulatory Trends

Digitalization and eDMF

The U.S. FDA fully implemented the eDMF system in 2017 and abolished paper-based submissions. This has enabled all submissions, updates, and inquiry responses to be conducted electronically, resulting in faster processing and improved transparency. Digitalization is also advancing in Japan, requiring compliance with PMDA’s electronic application system.

Emphasis on Quality Risk Management

The concepts of ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) are now being applied to DMF management as well. In impact assessments of manufacturing changes and deviations, scientific judgments using risk-based approaches are required.

Sustainability and Environmental Considerations

In recent years, environmental considerations have been emphasized throughout the pharmaceutical industry, with solvent selection in manufacturing processes, waste management, and energy efficiency also becoming subjects of evaluation. Manufacturing methods based on green chemistry principles are increasingly being recommended.

Conclusion

The Drug Master File is an essential tool for achieving both intellectual property protection and quality assurance in the pharmaceutical supply chain. For raw material manufacturers, it serves as a means to protect technical know-how, while for pharmaceutical manufacturers, it leads to streamlined approval applications. For regulatory authorities, it provides a valuable source of information for evaluating pharmaceutical quality and safety.

Appropriate management of DMFs is indispensable for the global development and manufacturing of pharmaceuticals. The regulatory environment is constantly evolving, with advancing digitalization, emphasis on quality risk management, and strengthening of data integrity requirements, and it is necessary to monitor these trends and respond accordingly.

When all stakeholders understand the importance of DMFs, conduct appropriate management in compliance with the latest regulatory requirements, and collaborate closely, this leads to ensuring pharmaceutical quality and realizing the supply of safe pharmaceuticals to patients.