More Foreign Drug Companies Registering Drug Master Files (DMFs) in China

This article was originally published on FDLI.


China’s drug market has exploded over the last few years, and future growth is estimated at 6-7% over the next five years. Valued at about $140 billion, it is now the second-largest drug market in the world. With such growth, there have also been positive regulatory reforms. Since China joined the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in June 2017, key regulatory reforms include: 1) reduction of the Investigational New Drug (IND) clinical trial approval timelines from one to two years to sixty days; 2) creation of conditional approval for drugs that fulfill unmet needs; and 3) increased acceptance of foreign clinical data, among others. Opportunities for foreign drug and biotech firms in China have never been greater. In addition, Active Pharmaceutical Ingredient (API), excipient, and drug packaging manufacturers can also export their products and benefit from China’s strong drug market growth by filing Drug Master Files (DMFs) in China.

Regulatory Background of DMFs in China

 The National Medical Products Administration (NMPA) was founded on the basis of the former China Food and Drug Administration (CFDA). In August 2016, to simplify the drug review procedure, the CFDA announced that the review and approval of APIs, excipients, and pharmaceutical packaging materials would be reviewed individually and would be approved with a registration license for pre-market approval. This expensive and time-consuming registration process was separate from drug approval. In November 2017, the CFDA changed their position and announced that the review and approval of APIs, excipients, and packaging materials would no longer be reviewed individually and approved with a separate registration license. CFDA published this change in the “Announcement on Adjusting the Review and Approval of a Drug Substance, Pharmaceutical Excipient, and Pharmaceutical Packaging Materials” on November 23, 2017.

On January 1, 2018, the NMPA announced that DMFs are required for the importation of APIs, excipients, and packaging materials. In July 2019, the NMPA announced that if the manufacturer cannot file a DMF for certain reasons, the technical dossiers must be submitted by the final drug manufacturer. A DMF is considered “inactive” after a DMF number is issued. A DMF is considered “active” only after an Administrative Review. Only an activated DMF can be imported for marketing purposes into China. A product with an inactive DMF can only be imported for research and development purposes.

Overseas API, excipient, or packaging material manufacturers must then authorize their domestic subsidiary or a China agent to file the DMF. Both the manufacturer and China agent are responsible for the authenticity and integrity of the filed DMF dossiers. The DMF holder will then authorize the final drug applicant to use their DMF for the drug registration. The drug applicant, or the market authorization holder, bears the major responsibility for the quality of the drug.

 Steps of the DMF Filing Procedure

 The first step is to appoint a local China agent or utilize the manufacturer’s subsidiary in China as the local agent. Because of the language differences and the ever-changing regulations in China, a reliable local agent is critical for an overseas manufacturer to deal with the complex regulatory issues in China. Clear correspondence is critical to the overall process and will help expedite the process.

The second step is putting together the required dossier. The local agent will provide a critical checklist to guide the collection of technical dossiers. The local agent or consultant from China will also prove appropriate templates and interpretations.

Third, the local agent will put together the registration dossiers. It may take three months for the compilation of the registration dossier and its translation from English to Chinese to be completed. Generally, the DMF number for excipient or packaging materials is released in about one to two weeks upon receipt by China’s Center for Drug Evaluation (CDE); for an API, it may take about two to four weeks. Of course, this could go longer if the registration dossier is not complete and the CDE requires more information.

Finally, the details of the DMF file are not reviewed closely until the file goes through Administrative Review. An annual report on the API, excipient, or packaging material must be submitted by the local China agent in the first quarter every year; otherwise, the DMF will be canceled.

Chinese DMF Versus U.S. DMF

In general, the Chinese DMF is similar to the U.S. DMF, but there are some notable differences. A few of these are outlined below.

First, the U.S. DMF is submitted in English, whereas the Chinese DMF is submitted in Chinese.

As of March 2020, there is a new fee for DMFs for APIs in China (discussed later), but there are no government fees when submitting a DMF for excipients or packaging materials. Most DMFs submitted to the U.S. Food and Drug Administration (FDA) require a fee.

In the U.S., the DMF system is voluntary, and the U.S. FDA offers guidance in fulfilling regulatory requirements. Confidential information about the manufacturing plant; the processes for manufacturing, storage, and packaging; and other restricted details are normally included in a U.S. DMF. China, on the other hand, has obligatory system, and the requirements are more stringent when submitted to CDE. Only designated or self-use products can be submitted without a DMF.

The review of the DMF is also different. Chinese DMFs must be complete with both technical and administrative documentation. If the CDE claims that the dossier is not complete, additional information will be requested before a DMF number is issued. On the other hand, FDA will issue a letter acknowledging receipt of the DMF, focusing more on administrative issues than technical issues.

How Many DMFs are Required per Product?

Generally, only one DMF is required for each API, excipient, or drug packaging material. An API that has for the same route of administration as a drug, has similar processing, and has differences only in quality control on the crystalline form and particle size could be filed in the same DMF. An excipient that has differences in quality control on density, crystalline form, particle size, viscosity, etc., or is a premix coating material for solid oral preparation could be filed in the same DMF.

However, an API that is manufactured in different manufacturing sites must be filed in different DMFs. Excipient and packaging materials that are manufactured in different manufacturing sites or have different models or types also need to be filed in different DMFs. An API, excipient, or packaging material that will be supplied for different routes of administration of a drug and has differences in quality must be filed in different DMFs.

Reasons a Chinese DMF Could be Questioned or Rejected by the NMPA

  1. Common clerical mistakes, including inconsistent expressions of the product name, addresses on your licenses, or abbreviations that differ;
  2. The validity of licenses, especially if the licenses have already expired or are close to expiring. For example, such licenses may include the certificate of incorporation, the manufacturer’s facility production permit, International Organization for Standardization, Good Manufacturing Practices, etc.; or
  3. Confidential information. Oftentimes API, excipient, and packaging material companies are not willing to provide full technical information, including critical processing parameters, technical data, processing flow, etc. If the manufacturer does not provide all this information, the DMF filing may be rejected, and supplementary data will be requested. If the CDE does not think they have all the correct information (especially for APIs), they may request a site visit to inspect the manufacturing process. Thus, it is critical that the dossier information is consistent with the actual manufacturing process. In addition, the NMPA specialists will request supplementary data when they review the final drug application if they do not feel comfortable with the DMF (e.g., they do not think the processing flow can support the drug).

New DMF Fees and Requirements for APIs

While there had not historically been any government fees for DMFs for APIs, excipients, and packaging materials, this changed in March 2020. In March, the NMPA announced they were now charging API manufacturers an activation fee (including the administrative evaluation and review process) of about $50,000 to process a DMF and get an approval for an API. In short, the position of APIs in China will now be the same as a drug; only APIs will be issued with a license while excipients and packaging materials will not. The evaluation and review will still be done by the CDE, and the China National Institutes for Food and Drug Control (NIFDC) will serve to verify the product quality as per the specifications and the analytical procedures. For now, there are still no fees on DMFs for excipients or packaging materials.

In addition, for API DMFs, the NMPA is now requiring more paperwork and samples to be tested in China. The testing of samples is not applied to all APIs. It depends on the evaluation by the CDE and on the risk of each API product. Generally, high-risk products include injections, inhalation products, infusion products, stimulant-containing drugs, hormone drugs, some biological products, narcotic and psychotropic substances that can make people addicted, etc. The risk profile may result from the product itself or from the history of the manufacturer (e.g., a failed GMP inspection recently or a problem in random sampling testing in the past).

The following documents and samples must be provided to the NIFDC for drug registration inspections. While some of this information may have been provided for the DMF number (inactive status), it may not be enough now for API DMF approval.

  • The Chinese and English quality specifications, analytical procedures, and relevant production process document for the product (one hard copy and one electronic copy);
  • Three batches of samples that have been marketed abroad or domestically and certificates of batch release; the quantity of each batch is triple the amount for all full tests; and
  • Standard substances (reference substances) and their clinical outcome assessments (COAs).

In other words, after submitting the initial required dossier to get the API DMF number in China, you will still get a DMF number. However, this DMF is classified as inactive until the fees, documents, and samples are tested in China and the information goes through an administrative review to be approved and listed as active. The API manufacturer can choose to have its DMF be evaluated by itself without the finished drug after getting the DMF number and approval or choose to have its DMF evaluated together with the drug product when the drug application is sent in. Having the DMF evaluated and approved earlier on its own should enable the manufacturer to get more Chinese customers sooner.

With regards to the sample amount, the lab requires that the samples and references be sufficient to conduct the full tests three times for all parameters. If any in-house analytical procedures are adopted, it is good practice to provide extra amounts of samples for the NIFDC as it may need to try different methods. Some manufacturers have provided samples up to ten times for all parameters. The purpose of the sample testing is to inspect and review the product quality and verify the feasibility and scientific nature of the analytical procedures. Moreover, the analysis could be biased depending on the operations of the lab. Therefore, the lab will repeatedly conduct the analysis to ensure the reproducibility of the analytical procedures. That is why three times the amount for full tests are required in the notice. The first is for testing, the second is for double-checking, and the third is for reserve. If the review process does not go smoothly, the Chinese lab will request that the manufacturer deliver further samples and reference substances. To avoid the repeated shipments of samples from the overseas API manufacturers to China, manufacturers should consider sending extra samples in the first delivery.

Final Thoughts  

If the API, excipient, or packaging materials comply with the United States Pharmacopeia, European Pharmacopoeia, and/or Japanese Pharmacopoeia, then it is not mandatory that they comply with the Chinese Pharmacopoeia (ChP) Regardless, manufacturers may want to optionally comply with the ChP if they would like to sell their product in China. For example, a U.S. company has a drug registered in the United States, which must be compliant with the USP. If the U.S. company wants to register this product in China, then China will generally approve it, and there is no regulatory risk. However, Chinese companies may prefer to purchase APIs or excipients that are compliant with the ChP because these Chinese companies, as drug manufacturers, will ultimately be responsible for the quality of the drugs in China.

General Requirements for APIs

  1. Manufacturer
  2. General information of drug substances
  3. Manufacturing information
  4. Special nature evaluation
  5. Quality control
  6. Control substance
  7. Packaging materials and containers
  8. Stability data
  9. Packaging specification
  10. Patent situation
  11. Contact information
  12. Information on any third-party lab
  13. Commitment letter
  14. Other supportive information

General Requirements for Excipients and Packaging Materials

  1. Manufacturer
  2. General information of excipient
  3. Manufacturing information
  4. Special nature evaluation
  5. Quality control
  6. COAs
  7. Stability data
  8. Safety and compatibility study
  9. Route of administration
  10. Strength/weight/size
  11. Packaging materials
  12. Packaging size
  13. Patent status
  14. Contact information
  15. Commitment letter
  16. Other supportive information