Drug Master File (DMF) Systems in Asia

Leave a comment

Introduction

Quality, safety, and efficacy are of the utmost importance for drug products. A vital part in achieving this is having a Drug Master File (DMF). A DMF is a confidential submission to a health authority to provide detailed information about the manufacturing, processing, packaging, and storing of the drug substance/drug product components.

The main purpose of a DMF is to protect manufacturers from disclosing proprietary information to final drug manufacturers, while giving the regulatory body sufficient information to assess the quality and compliance of pharmaceutical components. There are many advantages of having a DMF system. The DMF system provides all manufacturers with the same access to detailed information, facilitates the regulatory process with a comprehensive source of information, and helps to expedite approvals. DMF systems will also keep sensitive manufacturing information confidential, which promotes innovation and competition. With Asia becoming a major player in the drug manufacturing sector in the global pharmaceutical market, understanding the complexities of DMF systems in various countries is increasingly important.

DMF in China

Regulatory Evolution

China’s DMF system, overseen by the National Medical Products Administration (NMPA), has become more standardized to reflect current global expectations. Regulatory reforms of this system began with the release of CFDA Announcement No. 134 (2016) and No. 146 (2017) (initially only in 2016), in which the review of excipients, packaging materials, and active pharmaceutical ingredients (API) was incorporated into the evaluation of the drug product. Further amendments to the CFDA provided the criteria for the DMF, such as No. 8 (2018), No. 56 (2019), and No. 137 (2020). These amendments included clarifications such as the requirement for an annual report if any changes occurred, distinctions between inactive and active DMFs, etc.

Registration Process

Pre-submission: Foreign drug component manufacturers must designate a local agent to be responsible for communication with the NMPA. A China-based representative is necessary for foreign companies as they are in charge of completing dossier submissions, replying to NMPA questions, and ensuring overall compliance. Their local knowledge helps prevent delays that can arise from documentation and/or communication issues. It usually takes 3-4 months to prepare the application dossier, including translation of the dossier into Chinese.

Submission: the Chinese DMF must contain adequate technical documentation—manufacturing process, quality controls, specifications, etc. The NMPA usually reviews excipient and packaging DMFs in about 2 weeks, and API DMFs in about a month to make sure that all required documents have been submitted. A DMF is considered inactive until it is referenced in a drug product application.

Post-approval: If the API or excipient is used in a registered drug, the DMF holder must provide a Letter of Authorization (LoA) to the drug manufacturer, which enables the drug application to reference the DMF of the drug substance, allowing the reviewer to view the proprietary technical information in the DMF. Once the drug product is approved in China, the DMF is considered active. The DMF holder must provide an annual report of any changes. If the DMF holder fails to provide this report, the DMF is subject to deactivation.

Dossier Requirements

Dossier content depends on the type of product.

For APIs, each manufacturing site requires a separate DMF. If there are just minor differences (e.g., particle size), there can be a rationale to consolidate some aspects. The main elements of a DMF will be the manufacturing process, quality controls, specifications, and stability data.

Excipients should have a separate DMF for each different grade or function. The information needed includes the excipient’s composition, specifications (e.g. pH, viscosity), and the prior history of the excipient being employed in drug products. For low risk excipients, such as low-risk colorants or buffers, there may be a mechanism to provide a simplified submission for a new excipient.

DMFs for Packaging materials must include the quality specifications and supportive information on material properties and drug product compatibility. Different models or different materials require their own DMF.

It is best practice to use standardized templates and checklists to ensure the dossier is complete and compliant.

DMF in Japan

Eligibility and Registration Requirements

Japan’s DMF system is voluntary but typically very beneficial for manufacturers whose products are used in a variety of pharmaceutical products. Registered information would generally encompass manufacturing processes, specifications, test methods, and stability data.

Japanese DMF Application and Submission Process

Application Format and Documentation: The Japanese DMF application should be filed on the standardized forms according to Japan’s pharmaceutical law, including two copies of the registration form, a soft copy of the application data, and supporting material such as specifications, test methods, stability data, etc.

Content of MF Registration: The DMF registration includes the drug substance name, site of manufacture, manufacturing method and controls, specifications and test methods, stability data, storage conditions, shelf life, safety data for new excipients, license or accreditation details, and information about the in-country caretaker. The DMF serves as a subset of the documentation required for final drug product approval and is reviewed during that process.

Confidentiality and Public Disclosure

A DMF Certificate is sent to the applicant on registration, which excludes confidential data. Non-confidential data is published by the PMDA on its website, including the DMF number, registration date, registrant name and address, and a general outline of the item registered. Applicants for drug products who seek to refer to a DMF need to include publicly accessible DMF information as part of the application, with the submission of a copy of the DMF certificate and a consent statement from the DMF holder.

Updates to the DMF

There are two types of changes to the DMF – major changes, which need to be reported via an amendment application, and minor changes, which can be reported within 30 days after the changes occur. The DMF holder needs to submit documents that demonstrate sufficient validation and control.

Minor changes are those that do not affect the product’s effectiveness, quality, or safety. Major changes, such as changes in manufacturing processes that impact the product attributes, must be pre-approved. If the major change significantly changes the characteristics of the product, a new DMF registration, instead of an amendment submission, may be required.

DMF in Korea

In South Korea, the Ministry of Food and Drug Safety (MFDS) requires registration of all APIs utilized in medicinal products via a Korean DMF. The cover page of the application and Quality Overall Summary (Module 2) must be prepared in Korean, but supporting documents such as the Common Technical Document (CTD) or Good Manufacturing Practice (GMP) details may be prepared in English. The application dossier must be submitted by a Korean local agent, who also manages annual reporting, minor revisions, and issuing Letters of Authorization (LoAs). Typically, the Korean DMF application takes around 9 months, including dossier preparation and review by the health authority.

Required information for the Korean DMF includes:

  • Application form and checklist for submission data
  • Data on manufacturing and quality control facilities
  • Physical and chemical characteristics and stability data
  • Manufacturing processes, packaging, containers, and handling precautions
  • Batch analysis data, analytical procedures, and solvent information
  • Test samples for quality control
  • Registration details of foreign manufacturing sites
  • GMP evaluation reports

Local Korean agents play a crucial role in communicating with the MFDS, preparing and submitting necessary documents, answering inquiries from the MFDS, and assisting with on-site inspections, if needed. Usually, an on-site inspection is not required if it has been less than 3 years (for sterile substances) or 5 years (for non-sterile substances) from the last inspection to the day of the Korean DMF submission.

DMF in Singapore

Singapore’s DMF system under the Health Sciences Authority (HSA) consists of two parts: the open part (with access granted to the drug product applicant and the HSA) and the closed part (only available to the HSA).

Open Part (Applicant’s Part)

The open part contains general quality information required for drug product registration, such as:

  • Substance name, structure, and manufacturer details
  • Characterization and specifications
  • Reference standards, container closure system, and stability data

Closed Part (Confidential Part)

The closed part includes confidential manufacturing information not shared with the applicant, such as:

  • Manufacturing process and controls
  • Control of materials, validation data, and development rationale

Submission Process

The drug applicant submits the open part of the DMF and Letter of Authorization (LoA) issued by the DMF holder, while the DMF holder submits the full DMF electronically via the HSA’s online portal.

The HSA does not issue a public DMF number. Instead, its acknowledgment of receipt confirms the reference eligibility of the DMF. If there are any changes to the drug component, they must be reported by the DMF holder directly to the HSA.

DMF in Other Asian Countries

Taiwan

Taiwan’s DMF system under the Taiwan Food and Drug Administration (TFDA) was implemented to strengthen the management of API products. It requires the submission of two copies of electronic data in CTD format. The DMF is an overall database of information on the quality of an API product, and an abridged dossier or full dossier is acceptable. The TFDA has adopted the Pharmaceutical Inspection Co-operation Scheme (PIC/S) GMP Guide for API manufacturers.

India

Although the Central Drugs Standard Control Organization (CDSCO) does not require submission of a DMF for APIs, the practice is encouraged to promote regulatory transparency and safeguard proprietary information. Indian manufacturers usually adopt the U.S. DMF format and submit full details about the manufacturing process, quality control, and stability testing. Like the Taiwan FDA, the CDSCO has adopted the PIC/S Good Manufacturing Practice (GMP) guidelines, where API manufacturers need to adhere to high-quality standards.

ASEAN Countries

The Association of Southeast Asian Nations (ASEAN) has published the ASEAN Common Technical Dossier (ACTD) and ASEAN Common Technical Requirements (ACTR) in order to harmonize drug regulations among member countries. While DMF systems differ among ASEAN countries, the ACTD is considered a standardized framework for the submission of drug registration dossiers, including information on APIs.

Conclusion

The various DMF systems are instrumental in guaranteeing the quality, safety, and efficacy of pharmaceutical components in Asia. While the countries differ regarding the implementation and requirement of DMFs, the common objective remains the same: safeguarding confidential information and streamlining the regulatory review process.

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.