Chemical Compliance
Intelligence & Solutions
China Drug Master File (DMF) Filing for APIs, Excipients and Packaging Materials
May 16, 2022
Grace Wang
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CONTENTS

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:

  1. Chronology of China's AEP Review & Approval System

  2. Competent Authorities

  3. Obligations of Pharma Companies

  4. DMF Filing for AEPs: Regulatory Requirements

  5. General Procedures for DMF Filing, Review and Approval of AEPs in China

  6. Impacts of the New Associated Review & Approval System

  7. 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

Competent Authority

Main Responsibility

National Medical Products Administration (NMPA)

China 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)China 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 DepartmentsZhejiang Medical Products Administration

(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:

Category

DMF Filling Requirements

 

 

 

APIs

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

Filing required

APIs in associated application with drug products

Filing required

Generic APIs applying for separate review and approval

Filing required

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


DMF Information


API

Pharmaceutical Excipient

Packaging Material

Ÿ   Application form

Ÿ   Manufacturing process

Ÿ   Characterization

Ÿ   Quality control

Ÿ   Reference substance

Ÿ   Container closure system

Ÿ   Stability study

Ÿ  

Ÿ   Application form

Ÿ   Manufacturing process

Ÿ   Quality control

Ÿ   Testing report

Ÿ   Stability study

Ÿ   Toxicology study

Ÿ  

Ÿ   Application form

Ÿ   Manufacturing process

Ÿ   Testing report

Ÿ   Stability study

Ÿ   Safety and compatibility studies

Ÿ  

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

  • Product name

  • 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")

  • Package information;

  • Product specification;

  • DMF update time and other necessary information

*AEP Filing Status:

AEP Filing Status

Associated with Finished Drug Products

Passed the Technical Review

"A (Active)"

Yes

Yes

"I (Inactive)"

No

No

Yes

No

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

(1) Submitter:

  • 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

APIs

Domestic (Chinese)

Imported (International)

Generic APIs

183,600 yuan

367,600 yuan

Other APIs

216,000 yuan

296,950 yuan

5. General Procedure for DMF Filing, Review and Approval of AEPs in China

General Procedures for DMF Filing, Review and Approval of AEPs in ChinaGeneral Procedures for DMF Filing, Review and Approval of APIs, Pharmaceutical Excipients,and Packaging Materials 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


China

US

EU


Filing

DMF6

CEP (Certification of suitability to the monographs of the European Pharmacopoeia)7

ASMF (Active Substance Master File)

Scope

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

Review

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.

Separate review

Associated review with finished drugs

Filing manage-ment

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.

 

Result

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.

CEP certificate

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.

China DMF Filing Webinar

BaiPharm has held a webinar on DMF filing in China and the video recording is now on-demand. 

Contact BaiPharm

BaiPharm is powered by pharmaceutical professionals experienced in DMF filing. We can introduce you similar cases, help prepare the required documents, and guide you through the whole filing process. Welcome to contact us via contact@chemlinked.com.