The Drug Master File (DMF) system in Japan serves as a critical regulatory mechanism enabling pharmaceutical manufacturers, both domestic and foreign, to confidentially register the quality and manufacturing data of drug substances, intermediates, and related materials with Japan’s review authority. Managed by the Pharmaceuticals and Medical Devices Agency (PMDA), this system is designed to facilitate the approval of pharmaceutical products by allowing finished drug manufacturers to reference the DMF during the drug approval process. This article provides a comprehensive overview of the DMF system, its scope, procedures, requirements, and implications for international stakeholders.
Purpose and Overview of the DMF System
The Japanese DMF system is primarily intended to protect the proprietary information of manufacturers while allowing regulatory authorities to verify the quality and consistency of components used in finished pharmaceutical products. By submitting an DMF, drug component manufacturers can ensure that their confidential manufacturing and quality control information remains protected, even as it is used during drug product evaluation.
DMF registration is voluntary, yet it is often essential for manufacturers whose materials are used in multiple pharmaceutical products. Registered information typically includes manufacturing methods, specifications, test procedures, and stability data.
Eligibility and Registration Requirements
Foreign manufacturers are also required to appoint an in-country caretaker—a person or entity residing in Japan—to handle administrative matters and correspondence and act as a liaison with the PMDA. Importantly, all documents submitted must be in Japanese, necessitating close coordination with the in-country caretaker.
The DMF system covers a broad range of substances and materials used in pharmaceuticals. These include:
- Drug substances, intermediates, and materials for pharmaceutical products, especially those with special dosage forms. However, substances used in over-the-counter (OTC) drugs—except those with new active ingredients—are typically excluded.
- New excipients and novel pre-mix excipients that differ from existing formulations.
- Containers and packaging materials, particularly those used in drug delivery or storage.
DMF Application and Submission Process
Application Format and Documentation
The DMF application must be submitted using designated forms outlined in Japan’s pharmaceutical regulations, accompanied by:
- Two copies of the registration form (original and duplicate).
- A Flexible Disk (FD) or CD-R containing the application data.
- Supporting documentation including specifications, test methods, stability data, and manufacturing process descriptions.
Notably, the application form must be physically signed by the representative of the foreign manufacturer. The in-country caretaker may not sign or seal the form on behalf of the foreign applicant.
Content of DMF Registration
DMF registration includes the following key items:
- Drug substance name and site of manufacture.
- Manufacturing method and controls.
- Specifications and test methods.
- Stability data, storage conditions, and shelf life.
- Safety data, particularly for new excipients.
- License or accreditation details.
- Information about the in-country caretaker.
The DMF essentially forms a subset of the documentation required for drug product approval and is subject to review during that process.
Confidentiality and Public Disclosure
Upon registration, a Master File Certificate is issued to the applicant. This certificate contains no confidential information. However, the PMDA publishes non-confidential details on its website, including the DMF number, registration date, registrant name and address, and a general description of the registered item.
Applicants for drug product approval who intend to reference a DMF must also include certain publicly available DMF details in their applications, along with a copy of the DMF certificate and an agreement with the DMF holder.
Updates and Changes to the DMF
Changes to registered items are categorized as either major changes, requiring an application for amendment, or minor changes, which can be notified post hoc. Minor changes must be reported within 30 days of implementation, and the DMF holder must provide documentation demonstrating adequate validation and control.
Examples of minor changes include modifications that do not impact product quality, efficacy, or safety. Major changes – such as alterations in manufacturing methods that affect product characteristics – require prior approval and submission of updated documentation.
Before making any change, the DMF holder must notify any affected drug product manufacturers. If the change significantly impacts a product’s characteristics, a new DMF registration may be required rather than a simple amendment.
Special Procedures for DMF Consultations
The PMDA offers simple consultations for DMF-related matters. These sessions allow applicants to confirm whether a proposed change qualifies as a minor update, requires a partial change approval, or mandates a new DMF registration. Consultations are classified based on the product type – new drug or generic drug.
DMF holders are advised to seek guidance in complex cases, particularly those involving safety concerns or potential changes in drug substance properties.
Responsibilities of the In-Country Caretaker
Given the requirement that all documentation be in Japanese and the PMDA’s communication protocol, the in-country caretaker plays a pivotal role in the DMF process. This representative:
- Acts as the primary contact for PMDA inquiries.
- Manages the submission of applications and notifications.
- Coordinates with the foreign manufacturer to ensure data integrity and regulatory compliance.
Changes to the in-country caretaker must be submitted as a minor change notification.
Transferring DMF Ownership
The transfer of an DMF to a third party must follow formal procedures, including:
- Submission of a contract between the transferor and transferee.
- Confirmation that no manufacturing site or process changes have occurred.
- Reissuance of relevant documentation under the new owner’s name.
Implications for Drug Approval Applications
If a pharmaceutical product references an DMF, the drug approval application must:
- Indicate the DMF registration number and issue date.
- Specify the version of the registered data being quoted.
- Include a copy of the DMF certificate and relevant contractual documentation.
In cases where the DMF registration is still in progress, the drug application may proceed with a provisional notation. However, the approval process will only commence once the DMF number is issued and updated in the application.
During the product approval review, the PMDA may contact the DMF holder (via the in-country caretaker for foreign applicants) for additional information. If any updates to the DMF are required, they must be submitted before the product can be approved.
Conclusion
Japan’s DMF system offers a robust framework for protecting proprietary manufacturing information while ensuring the quality and safety of pharmaceutical products. It enables both domestic and international manufacturers to contribute to the Japanese drug market while maintaining confidentiality and regulatory compliance.
Foreign manufacturers seeking to enter the Japanese pharmaceutical market must carefully navigate the DMF system, ensuring they meet all procedural, linguistic, and regulatory requirements. The role of the in-country caretaker is particularly critical in bridging regulatory and communication gaps.
Ultimately, the DMF system reinforces Japan’s commitment to transparency, safety, and efficacy in pharmaceutical regulation, while recognizing the global nature of modern drug manufacturing.
Written by: Ames Gross – President and Founder, Pacific Bridge Medical (PBM)
Mr. Gross founded PBM in 1988 and has helped hundreds of medical companies with regulatory and business development issues in Asia. He is recognized nationally and internationally as a leader in the Asian medical markets. Mr. Gross has a BA degree, Phi Beta Kappa, from the University of Pennsylvania and an MBA from Columbia University.