China excipient – Accestra Consulting https://www.accestra.com Your long term strategic partner for regulatory compliance. Sat, 26 Jun 2021 04:13:17 +0000 en-US hourly 1 https://wordpress.org/?v=6.5.5 https://www.accestra.com/wp-content/uploads/2019/03/cropped-accestra2-32x32.png China excipient – Accestra Consulting https://www.accestra.com 32 32 China Drug Master File (DMF) Regulations & Standards https://www.accestra.com/china-drug-master-file-dmf-regulations-standards/ Sat, 26 Jun 2021 04:05:59 +0000 https://www.accestra.com/?p=4081

China Drug Master File (DMF) for APIs, packaging Materials, and pharmaceutical excipients are regulated by China NMPA formerly CFDA. The related DMF regulations and standards clarify the drug master file structure, process, requirements, timelines, and costings in the regulations listed below.

Contact Accestra Consulting Group for English translations or questions on China’s Drug Master File (DMF) requirements.

General Laws

Drug Administration Law (2019 No. 31)

The regulatory basis for the development, manufacture, business operation, practical use, supervision, and administration of drug products, substances, excipients, and packaging materials.

Provisions for Drug Registration (2020 No. 27)

The regulatory basis for DMF approval pathways in Section 3 of Chapter 3.

DMF Standards

Announcement for Adjusting Evaluation and approval for APIs, Excipients and Packaging Materials (2017 No. 146)

Basic requirements for the binding review and approval of a drug and its related APIs, excipients, and packaging materials.

Announcement on Issues Concerning the Further Improvement of Drug-related Associated Review & Approval and Supervision (2019 No. 56)

Detailed requirements for DMF filing, incl. scope of DMF, dossier requirements, filing process and timeline under the framework of binding review and approval.

Provisions for Administration of Drug-related Associated Review & Approval for APIs, Excipients and Packaging Materials (2020 Draft for Comments)

Comprehensive administrative practices of DMF filing, incl. API independent review & approval, DMF holder responsibilities & obligations, changes to approved DMFs, and product supervision by the authorities.

Learn more about the China DMF filing approval process
]]> China Drug Master File (DMF) VS US DMF https://www.accestra.com/china-dmf-vs-us-dmf/ Wed, 17 Jul 2019 14:37:38 +0000 http://www.accestra.com/?p=2532
China has implemented a separate filing and review regime with drug products since December 2017.
 
This was announced in the publication “Announcement on adjusting the review and approval system of drug substance, pharmaceutical excipients and pharmaceutical packaging materials (No. 146, 2017)” by CFDA (the new rule was published as Announcement No. 56, 2019).
 
The regime covers:
  • APIs,
  • Excipients,
  • Packaging materials.
The new filing system is referred to as the China Drug Master File (DMF) system.
While the current management system is more like the US DMF, there is still some significant differences between the two.

1- The scope

The FDA Drug Master File (DMF) is a voluntary submission of information to the FDA.
 
It is 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 mandatory that manufacturers submit information to the FDA in a DMF.
 
But in China, the filing work is more forceful.
 
All the APIs (except the API of innovative drug), excipients (except the exemption list), and packaging materials need to be registered to CDE.
 
They will then be published on the CDE 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 separate 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. Generally, though, the CMC information of used excipients listed on the USP-NF will not be reviewed by FDA.
 
In China, the same filing rule applies to excipients as API and Packaging Material.
 
There is only one exemption list given of items that can waive the filing work to China NMPA:
  • The names of some flavors,
  • essences,
  • pigments,
  • certain inorganic salts,
  • pH regulators,
  • and benzene-free ink for printing.

2- Types of DMF

US FDA

  • Type 1 Manufacturing site, facilities, operating procedures, and personnel (no longer applicable.
  • Type 2 Drub Substance, Drug Substance Intermediate, and Material used in their preparation, or Drug Product.
  • Typ 3 Packaging Material.
  • Typ 4 Excipient, Colorant, Flavor, Essence, or Material Used in their Preparation.
  • Typ 5 FDA Accepted Reference Information.

China NMPA

  • Drug Substance.
  • Excipient, Colorant, Flavor, Essence, or Material used in their preparation.
  • Packaging material.

*There is no number given to each DMF category.

3- Submission pathway

In the United States 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 came into effect on May 5, 2020.
 
In China, the eCTD is not enforced yet so the whole dossier must be submitted in CD form and paper formats still.
 

4- Fees

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.
 
In China it’s 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.
 
But, unlike US, the fee will still be changed if API DMFs are used to support NDAs in China.
 

5- Review of DMFs

In the US, after receipt, the original DMF undergoes an administrative review to determine whether it is has been sufficiently completed.
 
Elements checked during the process are administration-related, including:
  • The information of holder,
  • Manufacturing facility,
  • Contact,
  • Agent,
  • 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.
 
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 is placed in the queue for a “Completeness Assessment”.
 
In China, the review of all DMFs begins with the “Completeness Assessment”, which means the DMF number will only be issued after CDE makes sure the holder submitted all required information (both administrative and technical).
 
The linked technical review procedure after the application of the finished drug is generally the same in China and US.
 
Although, China CDE seems to have much stricter standards in the technical review process, especially:
  • Impurity research,
  • Quality control of starting materials,
  • The package material information of the APIs.
The close cooperation and timely communication between DMF holders and drug product manufacturers are important to pass the technical review in China.
 

6- The different meaning of the status mark

In the 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.
 
In China, all the DMF published with a DMF number indicates the Completeness Assessment is done, and the status shows the technical review progress.

US FDA

  • A:  Active. This means that the DMF was found acceptable for filing, administratively, and has not been closed.
  • I:  Inactive. This means a DMF that has been closed either by the holder or by the FDA.

CHINA NMPA

  • A: Active. This means that the APIs, excipients or packaging materials are approved to be used in finished drugs.
  • I: Inactive. This means the MDF was found acceptable for filing after complete assessment, but the technical linked review with finished drugs is not completed yet.
  • A#: Active. This means that the APIs, excipients or packaging materials were approved to be used in finished drugs, but there are technical amendments that may significantly affect the quality, and the amendments are not reviewed yet.
  • A*: Active. This means that the APIs, excipients or packaging materials are registered and reviewed solely, but the technical linked review with finished drugs is not completed yet.

7- Confidentiality

In the US, there is a DMF list covering all DMF information and an Available for Reference List containing Type II DMFs that 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 the China CDE website platform:
  • DMF filing number,
  • APIs/Excipients/Packaging Material name,
  • Company name,
  • Company address,
  • Packing specification,
  • Announcement date and approval status.
Like the US, there are no “open” or “closed” parts of DMFs filed in China as well.
 
If the APIs/Excipients/Packaging Material hasn’t been filed to CDE already, the DMF holder only needs to send the LoA to drug product manufacturers and the linked review can begin.
 

8- Annual report

In China, there is also an annual report obligation according to the No. 146 “Announcement” but no template so far.
 
It’s 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.
]]> Is China DMF really a “DMF”? https://www.accestra.com/is-china-dmf-really-a-dmf/ Tue, 09 Jul 2019 08:50:16 +0000 http://www.accestra.com/?p=2467
China has implemented a separate filing and review regime with drug products since December 2017.
 
This was announced in the publication “Announcement on adjusting the review and approval system of drug substance, pharmaceutical excipients and pharmaceutical packaging materials (No. 146, 2017)” by CFDA (the new rule was published as Announcement No. 56, 2019).
 
The regime covers:
  • APIs,
  • Excipients,
  • Packaging materials.
The new filing system is referred to as the China Drug Master File (DMF) system.
While the current management system is more like the US DMF, there is still some significant differences between the two.
 

1- The scope

The FDA Drug Master File (DMF) is a voluntary submission of information to the FDA.
 
It is 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 mandatory that manufacturers submit information to the FDA in a DMF.
 
But in China, the filing work is more forceful.
 
All the APIs (except the API of innovative drug), excipients (except the exemption list), and packaging materials need to be registered to CDE.
 
They will then be published on the CDE 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 separate 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 the US, around 90% of the DMFs are API and Packaging Material DMF. Some non-pharmaceutical ingredients, like excipients, can also submit DMF. Generally, though, the CMC information of used excipients listed on the USP-NF will not be reviewed by FDA.
 
In China, the same filing rule applies to excipients as API and Packaging Material.
 
There is only one exemption list given of items that can waive the filing work to China NMPA:
  • The names of some flavors,
  • essences,
  • pigments,
  • certain inorganic salts,
  • pH regulators,
  • and benzene-free ink for printing.

2- Types of DMF

The FDA Drug Master File (DMF) is a voluntary submission of information to the FDA.
 
It is 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 mandatory that manufacturers submit information to the FDA in a DMF.
 
But in China, the filing work is more forceful.
 
All the APIs (except the API of innovative drug), excipients (except the exemption list), and packaging materials need to be registered to CDE.
 
They will then be published on the CDE 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 separate 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. Generally, though, the CMC information of used excipients listed on the USP-NF will not be reviewed by FDA.
 
In China, the same filing rule applies to excipients as API and Packaging Material.
 
There is only one exemption list given of items that can waive the filing work to China NMPA:
  • The names of some flavors,
  • essences,
  • pigments,
  • certain inorganic salts,
  • pH regulators,
  • and benzene-free ink for printing.

 

 

3- Submission pathway

In the United States 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 came into effect on May 5, 2020.
 
In China, the eCTD is not enforced yet so the whole dossier must be submitted in CD form and paper formats still.
 

4- Fees

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.
 
In China it’s 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.
 
But, unlike US, the fee will still be changed if API DMFs are used to support NDAs in China.
 

5- Review of DMFs

In the US, after receipt, the original DMF undergoes an administrative review to determine whether it is has been sufficiently completed.
 
Elements checked during the process are administration-related, including:
  • The information of holder,
  • Manufacturing facility,
  • Contact,
  • Agent,
  • 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.
 
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 is placed in the queue for a “Completeness Assessment”.
 
In China, the review of all DMFs begins with the “Completeness Assessment”, which means the DMF number will only be issued after CDE makes sure the holder submitted all required information (both administrative and technical).
 
The linked technical review procedure after the application of the finished drug is generally the same in China and US.
 
Although, China CDE seems to have much stricter standards in the technical review process, especially:
  • Impurity research,
  • Quality control of starting materials,
  • The package material information of the APIs.
The close cooperation and timely communication between DMF holders and drug product manufacturers are important to pass the technical review in China.

6- The different meaning of the status mark

In the 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.
 
In China, all the DMF published with a DMF number indicates the Completeness Assessment is done, and the status shows the technical review progress.

US FDA

  • A:  Active. This means that the DMF was found acceptable for filing, administratively, and has not been closed.
  • I:  Inactive. This means a DMF that has been closed either by the holder or by the FDA.

CHINA NMPA

  • A: Active. This means that the APIs, excipients or packaging materials are approved to be used in finished drugs.
  • I: Inactive. This means the MDF was found acceptable for filing after complete assessment, but the technical linked review with finished drugs is not completed yet.
  • A#: Active. This means that the APIs, excipients or packaging materials were approved to be used in finished drugs, but there are technical amendments that may significantly affect the quality, and the amendments are not reviewed yet.
  • A*: Active. This means that the APIs, excipients or packaging materials are registered and reviewed solely, but the technical linked review with finished drugs is not completed yet.

 

 

7- Confidentiality

 

In the US, there is a DMF list covering all DMF information and an Available for Reference List containing Type II DMFs that 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 the China CDE website platform:
  • DMF filing number,
  • APIs/Excipients/Packaging Material name,
  • Company name,
  • Company address,
  • Packing specification,
  • Announcement date and approval status.
Like the US, there are no “open” or “closed” parts of DMFs filed in China as well.
 
If the APIs/Excipients/Packaging Material hasn’t been filed to CDE already, the DMF holder only needs to send the LoA to drug product manufacturers and the linked review can begin.
 

 

8- Annual report

 

In China, there is also an annual report obligation according to the No. 146 “Announcement” but no template so far.
 
It’s 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.
]]>