Navigating China’s Drug Master File (DMF) System

ivd market

China’s pharmaceutical market, the second largest in the world, continues to attract international manufacturers of active pharmaceutical ingredients (APIs), excipients, and packaging materials. While the opportunities are vast, accessing this market requires a thorough understanding of China’s Drug Master File (DMF) registration process. This process, managed by the National Medical Products Administration (NMPA), involves stringent regulatory requirements aimed at ensuring product safety and efficacy. This article explores the DMF system in China, discussing its regulatory evolution, procedural requirements, and the steps needed for successful compliance.

A Changing Regulatory Landscape

China’s DMF system has undergone significant changes over the years, reflecting the country’s efforts to align with international pharmaceutical standards. The NMPA, previously known as the China Food and Drug Administration (CFDA), introduced these reforms to streamline drug approvals and enhance transparency.

In 2016, the CFDA issued Announcement No. 134, simplifying drug review procedures. According to this announcement, excipients and packaging materials were no longer reviewed individually but as part of a joint review with corresponding drug applications. This was followed by Announcement No. 146 in 2017, which extended the same approach to APIs.

Subsequent regulations, such as Announcement No. 8 in 2018, clarified the requirements for DMFs. This announcement distinguished between inactive DMFs, which could only be used for research and development, and active DMFs, which were required for marketing purposes. By 2019, Announcement No. 56 added further clarity, emphasizing the importance of annual reporting and outlining the shared responsibilities between drug applicants and DMF holders for maintaining product quality.

Steps for DMF Registration

Successfully navigating the DMF registration process requires careful planning and adherence to specific guidelines. The process involves several key steps:

Pre-Submission Preparation

Before initiating the DMF registration, manufacturers must ensure that all necessary documentation is complete. This involves translating and compiling the registration dossiers, a task that can take up to three months. For foreign companies, appointing a local agent for your DMF in China is essential. These agents not only handle regulatory filings but also maintain communication with the NMPA, bridging potential language and procedural gaps.

Dossier Submission

The DMF dossier must include detailed technical information demonstrating the quality, safety, and efficacy of the API, excipient, or packaging material. For APIs, the dossier must address manufacturing processes, quality control measures, and specifications. For excipients and packaging materials, information such as material composition and performance characteristics is critical.

Once submitted, the NMPA typically reviews DMFs to ensure the correct documents have been submitted for excipients and packaging materials within 1–2 weeks, while reviews for APIs may take 2–4 weeks. The timeline depends on the completeness and accuracy of the submitted documents. Once the DMF number is issued, the DMF is considered inactive.

Post-Approval Obligations

After the DMF number is released, if the drug substance is used in a final drug product, and this drug product undergoes product registration in China, the DMF holder needs to issue a letter of authorization (LoA) to the final drug product applicant. This LoA allows the drug application to reference the DMF of the drug substance and enables the reviewer to review the technical information contained in the DMF. Once the final drug product is registered in China, the status of the DMF becomes active.

After obtaining approval, DMF holders must submit annual reports during the first quarter of each calendar year. These reports should detail any changes in manufacturing, quality control, or other critical aspects of the product. Failing to meet this requirement may result in the DMF being deactivated, jeopardizing the product’s marketability.

Detailed Dossier Requirements

The NMPA’s requirements for DMF dossiers vary depending on the product category. For APIs, each manufacturing site must have a separate DMF, and variations in product quality or intended use require additional filings. However, minor differences, such as particle size or crystalline form, can be consolidated under a single DMF if the manufacturing processes are similar.

For excipients and packaging materials, unique models or significant quality variations must be filed separately. Manufacturers should provide comprehensive details on aspects like viscosity, density, and other material properties. Using standardized templates and checklists can help streamline the preparation process and reduce the risk of errors.

Some excipients are eligible for a simplified dossier submission instead of a traditional DMF submission. These excipients still need to provide some general information, including at least the general information of the manufacturer, general information of the excipient, manufacturing process, specification, COAs, and the history of uses in drug products. According to a notice issued by the Center of Drug Evaluation (CDE) in 2019, excipients that are qualified for this type of dossier are mostly simple chemicals with low risks such as pigments/colorants, pH regulators, inorganic salts, etc.

The Role of Local Agents

Navigating China’s regulatory landscape can be challenging, especially for foreign manufacturers unfamiliar with local laws and practices. Appointing a reliable China local agent is critical for ensuring a smooth registration process. These agents handle the submission of dossiers, maintain communication with the NMPA, and manage post-approval reporting. They are also instrumental in addressing queries and ensuring compliance with evolving regulations.

Beyond managing the technical aspects of the registration process, local agents play a vital role in bridging cultural and linguistic differences. Their expertise can help foreign companies avoid common pitfalls, such as incomplete documentation or missed deadlines.

Market Trends and Opportunities

China’s growing pharmaceutical market has prompted an increasing number of foreign companies to register their DMFs. According to recent reports, the number of DMFs filed by international manufacturers has surged in recent years, reflecting the market’s attractiveness. This trend is driven by several factors, including the Chinese government’s focus on fostering innovation and the rising demand for high-quality APIs, excipients, and packaging materials.

For foreign companies, registering a DMF in China not only provides access to a vast market and security for their manufacturing intellectual property but also enhances their global reputation. By meeting China’s stringent regulatory requirements, manufacturers demonstrate their commitment to quality and compliance, which can strengthen their competitive position internationally.

Challenges and Strategies for Success

While China’s DMF registration system offers significant opportunities, it also presents notable challenges that manufacturers must address to achieve success. These challenges include the complexity of the regulatory framework, the technical demands of dossier preparation, and the ongoing requirements for post-market compliance.

One of the primary challenges is the frequent updates to regulations. The regulatory environment in China is dynamic, with policies being revised or introduced regularly. Manufacturers need to stay informed about these changes to ensure their compliance efforts remain up-to-date. Failing to adapt to new requirements could lead to delays or even rejection of DMF applications.

Another major challenge lies in the preparation of comprehensive technical dossiers. The NMPA requires detailed and accurate documentation that meets strict quality standards. This process can be time-consuming and resource-intensive, especially for foreign manufacturers unfamiliar with the specific demands of the Chinese regulatory system. Even minor errors in the dossier can lead to significant delays in the review process.

To overcome these challenges, manufacturers should adopt several key strategies for success.

  1. Stay informed about regulatory changes: It is essential for manufacturers to monitor updates to Chinese pharmaceutical regulations continuously. Engaging with local experts, consultants, or industry groups can help companies stay abreast of policy changes and their implications.
  2. Invest in high-quality documentation: Preparing accurate and complete dossiers is critical to the success of any DMF application. Manufacturers should allocate sufficient resources to ensure that their documentation meets NMPA standards. Using standardized templates and checklists can streamline this process and minimize the risk of errors.
  3. Leverage local expertise: Collaborating with reliable local agents or consultants can help bridge the gap between foreign manufacturers and the Chinese regulatory system. Local agents can manage the filing process, communicate with the NMPA, and provide valuable insights into best practices for compliance.
  4. Proactively manage post-market obligations: Maintaining compliance after DMF approval is just as important as the initial registration. Manufacturers should establish internal systems to track reporting deadlines, monitor changes in product or manufacturing conditions, and ensure that all required updates are submitted to the NMPA promptly.

By addressing these challenges with a proactive and informed approach, manufacturers can navigate the complexities of China’s DMF system effectively.

Conclusion

China’s DMF registration system offers a clear pathway for international pharmaceutical companies to enter the country’s dynamic market. However, the process requires careful planning, meticulous documentation, and a deep understanding of local regulations. By appointing reliable local agents, staying informed about regulatory changes, and adopting best practices for dossier preparation, manufacturers can navigate the complexities of the DMF system with confidence.

The growing interest in DMF registrations among foreign companies underscores the market’s potential and the importance of compliance. For manufacturers willing to invest the necessary time and resources, China offers unparalleled opportunities for growth and innovation. As the regulatory landscape continues to evolve, staying agile and informed will be key to long-term success in this competitive market.


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.