China's drug review & approval system has undergone substantial reforms since it joined the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) in 2017. One of the reforms is changing of the review & approval system for active pharmaceutical ingredients (APIs), pharmaceutical excipients and packaging materials (the three materials for making finished drugs will be referred to as AEPs in the following text).
The article's content:
Chronology of China's AEP Review & Approval System
Obligations of Pharma Companies
DMF Filing for AEPs: Regulatory Requirements
General Procedures for DMF Filing, Review and Approval of AEPs in China
Impacts of the New Associated Review & Approval System
Comparison of AEP Management Systems in China, the US, and EU
1. Chronology of China's AEP Review & Approval System
Before Aug. 10, 2016, AEPs are managed under the Separate Review & Approval System in China. Companies need to apply for AEP product registration first and can only produce or import them after receiving the license for production or importation.
On Aug 10, 2016, the former China Food and Drug Administration (CFDA) released the Associated Review & Approval of Pharmaceutical Excipients, Packaging Materials and Finished Drug Products (No. 134 Announcement in 2016) 1. Since then, manufacturers of pharmaceutical excipients and packaging materials are required to submit DMFs (Drug Master Files) to the regulator for format reviews. Upon submission of the drug registration application, excipients and packaging materials will undergo technical reviews along with the associated finished drug products. The API registration system remained unchanged.
On Nov. 30, 2017, CFDA published the Announcement on Adjusting the Review & Approval System for APIs, Pharmaceutical Excipients and Packaging Materials（No. 146 Announcement in 2017)2. APIs got included into the associated review & approval system. In addition, an online DMF filing system for AEPs was launched by the Center for Drug Evaluations (CDE).
In July 2019, China National Medical Products Administration (NMPA), founded based on CFDA, issued the Announcement on Improving the Associated Review & Approval and Supervision of Drugs (No. 56 Announcement in 2019)3. The announcement currently functions as effective regulations on AEPs.
In Apr. 2020, NMPA released the consultation draft of Administrative Provisions for Associated Review & Approval of Chemical APIs, Pharmaceutical Excipients and Packaging Materials.4 The draft, though not effective yet, specified more details for AEP management in the future.
2. Competent Authorities
National Medical Products Administration (NMPA)
(1) Making regulations on the review, approval and supervision of AEPs;
(2) Organizing on-site inspections of AEP manufacturing site and testing of products as required.
Center for Drug Evaluation (CDE)
(1) Establishing the DMF filing platform and database for AEPs;
(2) DMF acceptance, DMF format review, DMF number release, technical reviews for associated AEPs and finished drug products.
Provincial Drug Regulatory Departments
(1) Affiliated to NMPA;
(2) Responsible for routine supervision and management of AEP manufacturers in local administrative regions.
3. Obligations of Pharma Companies
(1) Marketing authorization holders (MAHs) of finished drug products shall bear the main responsibility for drug quality. They shall select AEPs according to the drug's quality requirements, and audit the AEP manufacturers' quality management system to ensure that the AEPs comply with the requirements for medical use.
(2) AEP manufacturers are obliged to file DMFs of their products on CDE's platform and update the filed information. Overseas AEP manufacturers can submit the files through a Chinese third party agent or its resident representative office in China. All documents must be in Chinese. Both the overseas AEP applicant and their agents shall assume the responsibility for the information's authenticity and completeness.
4. DMF Filing for AEPs: Regulatory Requirements
4.1. DMF Filing Scope
DMF filing requirements apply to AEPs which are developed, produced, imported or used in China.
On April 30, 2020, CDE issued the consultation draft of Administrative Provisions for Associated Review & Approval of APIs, Pharmaceutical Excipients and Packaging Materials. The provisions stated new requirements (not implemented yet) for DMF filing:
DMF Filling Requirements
APIs under the drug registration Class 1 and Class 2.1 in the stage of clinical trial application
Filing not required
APIs marketed in China
APIs in associated application with drug products
Generic APIs applying for separate review and approval
On-file excipients that apply to be used as APIs
Re-filing as APIs
APIs that are used in overseas-produced drug products not being sold in China
Allowed to submit its technical files with the registration application of associated drugs
Pharmaceutical excipients and packaging materials
Excipients and packaging materials (including packaging systems and functional components without direct contact with liquid medicine) used in any drug products that apply for marketing approval
Filing DMFs separately or submitting technical files together with the registration application of associated drugs
The current excipients and packaging materials that are used in marketed drug products after change. The MAH shall first submit supplemental applications for changing the product's excipients and packaging materials.
Inner packaging materials for APIs
Filing DMFs separately or submitting technical files together with the API's registration application
4.2. What Information Should a DMF Include
Container closure system
Safety and compatibility studies
4.3. DMF Filing Instructions
(1) AEP manufacturers or their agents shall submit DMFs on CDE's online filing platform, and then provide DMF numbers and authorization letters to the MAHs (also the drug registration applicants). An MAH shall submit the finished drug product’s registration application with the DMF numbers of AEPs.
(2) For AEPs whose DMFs cannot be filed due to special reasons, MAHs can incorporate the AEP research information into the drug registration application and submit them together.
(3) After DMF filing, generic APIs can apply for separate review & approval without being associated to finished drugs.
(4) DMF filing is NOT mandatory for pharmaceutical excipients used in food or drugs for a long time with recognized safety (an exemption list is provided by China NMPA in the No. 56 Announcement in 2019). The drug applicants shall list such excipients and their basic information in the registration application dossiers.
4.4. Only Part of DMF Information Will Be Made Public
All submitted technical data will remain confidential with the drug regulators. Only the following information will be made public on the filing platform:
DMF filing number
Manufacturer's name (and the agent's name if applicable)
Address of the manufacturing site
If it is a domestic product or imported product
DMF filing status ("A" or "I")
DMF update time and other necessary information
*AEP Filing Status:
AEP Filing Status
Associated with Finished Drug Products
Passed the Technical Review
For AEPs that meet any of the following conditions, CDE shall transfer the relevant information to the filing platform and give every of them a filing number with the filing status marked as "A":
(1) APIs whose licenses' expiration dates are no earlier than Nov. 27, 2017;
(2) APIs whose applications have been accepted, reviewed and approved (including the applications for the transfer of technology reviewed according to the No. 38 Announcement of the former CFDA);
(3) Pharmaceutical excipients and packaging materials whose applications have been accepted and reviewed;
(4) Pharmaceutical excipients which received licenses.
(5) Pharmaceutical packaging materials whose licenses' expiration dates are no earlier than Aug. 10, 2016.
Moreover, generic APIs can apply for separate review & approval after DMF filing. For APIs which have passed the review and got approval, the filing status mark will also be "A"; for those which haven't, the mark will be "I".
4.5. Annual Report After DMF Filing
domestic AEP manufacturers;
overseas AEP manufacturers and their agents.
(2) Submission time: One annual report should be submitted within every 12 months from the DMF filing completion date.
(3) Report content: An annual report shall list all the changes made to the product, summarize the main points of the changes and explain all the new authorization situations during the corresponding 12 months.
It is probable that CDE will no longer issue the DMF filing number for AEP manufacturers that fail to submit annual reports on time, according to the consultation draft of Administrative Provisions for Associated Review & Approval of Chemical APIs, Pharmaceutical Excipients and Packaging Materials.
4.6. Administrative Fees
The filing of pharmaceutical excipients and packaging materials is free of charge. The API filing fee standard is listed below.
API Filing Fee Standard5
5. General Procedure for DMF Filing, Review and Approval of AEPs in China
6. Impact of the New Associated Review & Approval System
1. The time to market for AEPs is much shorter. It used to take AEP manufacturers several years to get licenses. But now, they can usually complete DMF filing within 4 to 6 months. The on-file AEPs can be immediately provided to drug product companies for research & development so that the AEP manufacturers and drug applicants establish partnership in a faster pace. Moreover, time for reviewing & approving drug products is shorter now, so AEPs, part of drug products, can access the market more quickly than before.
2. Drug product manufacturers have a wider choice of AEPs as they no longer have to choose among the certified AEPs.
3. It is easier for drug product companies to contact appropriate AEP manufacturers and choose corresponding AEP products since CDE’s online platform presents the information of on-file AEPs.
7. Comparison of AEP Management Systems in China, the US, and EU
CEP (Certification of suitability to the monographs of the European Pharmacopoeia)7
ASMF (Active Substance Master File)
AEPs which are developed, produced, imported or used in China
1. Drug substance, drug substance intermediate, and materials used in the preparation of the above two or drug product; 2. Packaging material; 3. Excipient, colorant, flavor, essence, or material used in their preparation; 4. FDA-accepted reference information
Active substances included in the European Pharmacopoeia
Active substances except biological active substances
1. Associated review with finished drugs are applicable to all AEPs; 2. Generic APIs can apply for separate review & approval after DMF filing.
FDA customarily reviews the technical contents of DMFs only in connection with the review of applications that reference them.
Associated review with finished drugs
1. Single DMF filing number for each AEP product. Among the same type of products of different particle sizes or crystal shapes, only the one with the best production technology can get the DMF filing number. 2. Regulators treat mixed APIs as pharmaceutical intermediates and don't accept their DMF filing.
1. The same type of products of different particle sizes or crystal shapes can get different DMF filing numbers.
2. DMF filing for mixed APIs is accepted.
The same type of products of different particles sizes or crystal shapes can get different CEP certificates or ASMF numbers.
No certificate issued.
A: associated with drug product and has passed the technical review.
I: (1) not associated with drug product or (2) associated with drug product but hasn't passed the technical review
No certificate issued.
A: DMF is acceptable for filing administratively and not closed.
I: DMF has been closed either by the holder or by FDA.
No certificate issued, reference number only
8. Advice for Pharma Companies
(1) Drug applicants should foster deep partnership with AEP manufacturers to grasp the up-to-date changes of AEPs, timely evaluate the changes' influence on the drug product and reduce the risks caused by AEPs' quality problems.
After the drug gets marketing authorization, the applicant (MAH) should enhance the routine supervision and audit of the AEP manufacturers to ensure the drug's quality and production's stability and sustainability.
(2) It's better for pharmaceutical companies to establish a team to examine the AEP manufacturer's quality control system and the information of specific AEP products. The companies can also outsource this part of work to a professional third-party.
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