A separated filing and linked review regime with drug products for APIs, excipients and packaging materials has implemented in China since Dec, 2017, with the publication of the “Announcement on adjusting the review and approval system of drug substance, pharmaceutical excipients and pharmaceutical packaging materials (No. 146, 2017)” by CFDA (the new requirement was published as Announcement No. 56, 2019). Before that it’s a license approval system for API, excipients and packaging materials entering into Chinese market and this license system has lasted for more than ten years in China. Now the license system has switched to the new filing system, which is usually called the “China DMF” system. However, although comparing to the previous registration procedure, the current management way is more similar to US DMF, there are still some significant difference between these two systems.
1- The scope
Generally the FDA Drug Master File (DMF) is a voluntary submission of information to the FDA that may be used to provide confidential, detailed information about the facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drug products. It is not a mandatory requirement that those manufacturers should submit information to FDA in a DMF. But in China, the filing work is more forceful: generally all the APIs (except the API of innovative drug), excipients (except the exemption list) and packaging materials are required to be registered to CDE and will be published on the platform; only the APIs, excipients and packaging materials for self-use or designed for specific finished drug holders can submit the information together with the drug application dossier instead of the separated filing
( according to Announcement No. 146, 2017, in the follow-up Announcement No.56, 2019 the phrase “for special reason” is used to accept submission of APIs/excipients/packaging materials together with finished drugs ) .
In US, around 90% of the DMFs are API and Packaging Material DMF. Some non-pharmaceutical ingredients like excipients can also submit DMF, but generally the CMC information of commonly used excipients listed on the USP-NF will not reviewed by FDA.
And in China, the same filing requirement applies for excipients as API and Packaging Material. There is only one exemption list given the names of some flavors, essences, pigments, certain inorganic salts, pH regulators and benzene free ink for printing which can waive the filing work to China NMPA.
2- Types of DMF
3- Submission pathway
In US and China, the DMFs for drug substances should both be prepared in the format of CTD M4Q.
From May 5, 2018, new DMFs other than Type III DMFs, as well as all documents submitted to existing DMFs other than Type III DMFs, must be submitted using the Electronic Common Technical Document (eCTD) to FDA. For Type III DMFs, this eCTD requirement goes into effect on May 5, 2020.
However, in China the eCTD is not enforced yet so the whole dossier shall be submitted in CD form and paper formats still.
In US, under the Generic Drug User Fee Amendments of 2012, DMF holders of Type II API are required to pay a DMF fee when first authorizing the reference of their DMF in a generic application. And in China it’s the similar, the registration fee for API in the linked review process is retained while the filing of excipients and packaging materials is free of charge now. However, unlike US, the fee will still be changed if API DMFs are used to support NDAs in China.
5- Review of DMFs
In US, after receipt, the original DMF undergoes an administrative review to determine whether it is administratively complete. The elements to be checked in this period are mainly administration related, including the information of holder, manufacturing facility, contact, agent and Statement of Commitment. If the DMF is acceptable from an administrative point of view, an Acknowledgement Letter will be issued, notifying the holder of the DMF number. And only Type II DMFs to support ANDAs under GDUFA that have passed the Administrative review (have an active status) and have had the user fee paid are placed in the queue for a “Completeness Assessment”.
However, in China the review of all DMFs will start with the “Completeness Assessment”, which means the DMF number will only be issued after CDE make sure the holder submit all required information (both administrative and technical) at least in format.
The linked technical review procedure after the application of finished drug is generally the same in China and US. But it seems China CDE have much stricter standards in the technical review process, especially in terms of impurity research, quality control of starting materials and even the package material information of the APIs. The close cooperation and timely communication between DMF holders and drug product manufacturers are really important to successfully pass the technical review in China.
6- The different meaning of the status mark
In US the status of DMF conveys no information about whether it has been reviewed for technical content or whether it has undergone a Completeness Assessment. But in China, all the DMF published with a DMF number indicates the Completeness Assessment is done, and the status clearly shows the technical review progress.
In US, there is a “DMF list” covering all DMF information and an “Available for Reference List” containing Type II DMFs which have passed the Completeness Assessment and are available for reference by ANDAs under GDUFA.
In China, there is no such list but all the information will be available on China CDE website platform: http://www.cde.org.cn/yfb.do?method=main, including DMF filing number, APIs/Excipients/Packaging Material name, company name, company address, packing specification, announcement date and approval status.
Like US, there are no “open” or “closed” parts of DMFs filed in China as well. If the APIs/Excipients/Packaging Material haven been filed to CDE already, the DMF holder only need to send the LoA to drug product manufacturers and the linked review can be initiated.
8- Annual report
In China, there is also annual report obligation according to the No. 146 “Announcement” but no template is given so far. But it’s simply mentioned that DMF holders should submit the annual report including the amendment summary and also the authorized drug product/company information in Q1 of each year.