A2: The background information provided is insufficient to give an accurate answer to this question. To determine whether an API with an intermediate manufactured at two different sites can be registered under one DMF, more specific information is needed. We suggest contacting the Accestra team for a detailed discussion.

A3: According to the “Chinese Provisions of Drug Registration” and the “Announcement on further improving the associated review and approval with drug product and its related supervision matters” (Decree No. 56, 2019) published by NMPA, DMF filing for packaging materials is usually only required for primary packaging materials. However, for finished drugs that require additional functional secondary packaging materials (such as high barrier property outer bags), or for drugs that are sterilized after being packed with both primary and secondary packaging materials, the primary and secondary packaging materials should be considered as a packaging system, and the materials of the secondary packaging materials should also be provided.

A4: After successfully passing the technical review and final approval process, NMPA will issue a digital “Notice of Approval” to the API product applicant. Along with this notice, other relevant documents such as the approved specification, label, and manufacturing process information, which have been verified by NMPA, will also be attached.

A5: As per the regulation of Decree No. 56 (2019), products sharing the same production process, materials, and function may be registered under a single DMF. Therefore, if your products vary only in their shape or size design for different pharmaceutical customers, but have the same material, production process, and intended use, they can be registered as a single DMF. Similarly, if it is a packaging system, all the detailed materials of each packaging component can be included in a single DMF. However, if the materials of different product types differ, they should be registered in separate DMFs. For instance, bromobutyl rubber stopper and chlorobutyl rubber stopper should be registered as two DMFs.

Your product may have many different type numbers, which could make it complicated to determine the required DMF numbers. To assess your specific needs, we recommend contacting the Accestra team to evaluate how many DMF numbers are necessary for your product.

A6: DMF registration usually will not directly trigger on-site inspections for overseas produced AEPs.

According to “Regulations on the Administration of overseas Inspection of drugs and medical devices（No.101,2018）”, Article 8 : NMPA shall determine inspection tasks through risk assessment and random inspection according to the proposals of relevant departments for products to be inspected and its research and production sites. When necessary, it may carry out extended inspection on production sites, suppliers or other contract agencies of APIs, Excipients and packaging materials (AEPs).

Therefore, on-site inspection for AEP DMF is not mandatary, it’s risk assessment or for-cause based when NMPA inspect finished drugs.

DMF registration for overseas-produced AEPs usually does not directly trigger on-site inspections. But after the binding review with the drug product, an extended on-site inspection on AEP products may be triggered based on the risk level of the drug product.

According to the “Regulations on the Administration of Overseas Inspection of Drugs and Medical Devices” (No.101, 2018), NMPA determines inspection tasks for products and their research and production sites through risk assessment and random inspection based on proposals from relevant departments. If necessary, it may carry out extended inspections on production sites, suppliers, or other contract suppliers of APIs, excipients, and packaging materials (AEPs). Therefore, on-site inspection for AEP DMFs is not mandatory for all applications; instead, it is based on risk assessment or for-cause inspection when NMPA inspects finished drugs.

A7: According to the regulations of AEP associated review (draft for public comments) released in 2020, for excipients that have been used in food and drugs for a long time and whose safety has been recognized (such as non-high-risk excipients included in USP, EP, JP, BP & ChP) with usage, dosage, and function within the scope of routine use, data requirements can be simplified. The applicant can decide whether to apply for DMF for this product.

In this case, the finished drug applicants can include excipient information in the application materials for the drugs, and CDE may require supplementary technical data during the technical evaluation as necessary.

CDE will publish and update a list of such products. In case of any uncertainty, we suggest the applicant provide the product name to the Accestra team to confirm its eligibility.

A8: Renewal is not required for a packaging material DMF, and there is also no approval notice issued for packaging materials. Once approved, the status of the DMF number in the CDE platform will change from “I” (inactive) to “A” (active).

A9: NMPA has applied and launched the pre-accession program at PIC/S since September 2021, and currently NMPA is still actively promoting the work.

A10: The current China DMF policy applies only to chemical APIs, meaning that DMF registration is not typically applicable to APIs for biological products. However, for certain products, the classification may differ in China compared to other countries. Therefore, it is strongly recommended that applicants provide specific product information to the Accestra team for confirmation. For instance, heparin derived products are classified as chemical APIs in China, while they may be classified as biological APIs in other countries.

For biological product origin excipients, they can be registered in a DMF according to Decree No. 56 (2019).

A11: Yes, for different DMFs, you can have more than 1 local agent.

A12: In China, stability data is usually required for packaging materials made of polymers such as plastics and rubber products. The stability study should include accelerated stability data and long-term stability data for at least one batch of representative samples. If you need more information on how to design the stability study for packaging materials, please contact the Accestra team for assistance.

A13: In general, products are required to comply with the standards set by the Chinese Pharmacopoeia (ChP). Therefore, when an applicant sets the product specification, they should also consider ChP and conduct a thorough comparison study with the European Pharmacopoeia (EP), United States Pharmacopeia (USP), or Japanese Pharmacopoeia (JP). However, in some cases, meeting both EP/USP and ChP simultaneously can be difficult, particularly for certain test items or special requirements from drug manufacturers. In such situations, it is essential to provide detailed information for further evaluation.

A14: The Chinese DMF annual report is similar to that of the US, and a CMC update is not required. Currently, the NMPA has only issued a general requirement for the AEP annual report in 2019, with few details provided. For example, the annual report should include a summary of product changes in the last year, as well as information on drug companies authorized to refer to the DMF. Accestra team can provide a template and prepare the annual report for applicants.

A15: Yes, it is required.

A16: China pharmacopoeia is not aligned with EP. There are still many differences.

A17: CDE accepts the Chinese lab validation data. If the test method follows the requirements regarding the strains and source of strains set in Chinese Pharmacopoeia, this test method should be transferred to applicant’s lab for release test. However, if the Chinese lab proves the strains used in the Chinese pharmacopoeia method are equivalent to the trains used in the EP pharmacopoeia (ATCC method is equivalent to CMCC method for example), the EP method can still be used to routine testing.

The Center for Drug Evaluation (CDE) accepts Chinese laboratory validation data. If the test method follows the requirements regarding the strains and sources of strains set in the Chinese Pharmacopoeia, it should be transferred to the applicant’s laboratory for routine testing. However, if the Chinese laboratory proves that the strains used in the Chinese Pharmacopoeia method are equivalent to the strains used in the European Pharmacopoeia (for example, the ATCC method is equivalent to the CMCC method), the European Pharmacopoeia method can be used for routine testing.

This is a typical question for many imported APIs. The answer here is only for a reference and many details need to be considered. Please do not hesitate to contact us for a further discussion to make sure the work is comprehensive.

This is a common question for many imported APIs. The answer provided here is intended as a reference, but there are still many details that must be taken into consideration. We encourage you to contact us for further discussion to ensure that proposed work is comprehensive and meets your specific needs.

A18: An active or inactive API DMF can both be referenced for an associated drug product registration, as long as it is published on the CDE DMF platform.

A19: According to Decree No. 56 (2019), an annual report should be submitted for the AEP and drug product, regardless of whether any changes have occurred or not.

A20: In China, all API DMF data are considered confidential, and there is no concept of an open or closed part. For an IND application, a DMF can be directly registered with a Chinese local agent for the drug product to reference. Alternatively, the materials can be provided directly to the CDE through an appointed Chinese local agent without disclosing the information to the drug applicant, as DMF is not mandatory for API in the IND stage. Accestra team has extensive experience in dealing with this scenario.

A21: We will provide a general answer to the question of how to change the API supplier to China since the topic of this webinar is about China DMF.

To change the API supplier in China, a drug product applicant must refer to the “Technical Guidelines for Pharmaceutical Change Research of Marketed Chemical Drugs (Trial)”. The applicant should first evaluate the risk level of the change to identify if it is a major, moderate, or minor change. The applicant must conduct the necessary research and submit the change application dossier to CDE according to corresponding change application requirements. For more details, please contact Accestra team, and we will provide the necessary procedures and requirements.

A22: If an AEP product doesn’t have a DMF number in China, the dossier for the AEP can be submitted together with the drug product registration application. For AEP products, DMF is not mandatory.

A23: Yes, the information about the Chinese CRO should be included in the DMF. In the event of an on-site inspection, the Chinese CRO may be subject to inspection by CFDI, although an AEP DMF usually does not trigger an on-site inspection. For more information on on-site inspections, please refer to Q6 in this document.

A24:  Regulations and guidelines are published on various official websites such as NMPA, CDE, CMDE, CFDI, CDR, etc. Unfortunately, these regulations are not well-organized and may be updated from time to time. If you have any specific questions, please feel free to contact Accestra for assistance.

A25:  For an API DMF, it is necessary to provide specific numerical quantities of API per drum. Practically, a range is not acceptable, the solution is to submit many packaging sizes to cover different quantities.

A26: Different types of packaging materials may be used for different APIs or finished products, and the risk level varies depending on the administration route. Therefore, it is recommended to evaluate the test requirements on a case-by-case basis for your specific product. For instance, stability data is required for polymer materials such as plastic and rubber. For packaging materials for injectables, compatibility and biosafety studies are required. On the other hand, for oral drug use packaging materials that are considered low-risk, compatibility and biosafety studies are not mandatory.

A27. When filing DMF for APIs, there is no requirement to submit Deficiency Letters received from other regulatory agencies regarding the technical dossier. However, if Deficiency Letters were received from other regulatory agencies related to on-site inspections, they must be included in the DMF filing.

A28: When applying for a change to an API DMF, any modification that results in a change in specifications may trigger NIFDC sample testing. For more information on your specific situation, please contact the Accestra team.

A29: If you are applying for a drug clinical trial, it is recommended that you review the API dossier, if available, prior to submitting your application.

Regarding the DMF situation, if the API does not have a DMF number, it can be submitted along with the drug clinical trial application dossier. While an API DMF is not mandatory for a CTA application, the API dossier can also be submitted separately to the CDE by the API manufacturer or the appointed local agent, especially if there are confidentiality concerns. The Accestra team has extensive experience dealing with these application scenarios.

A30: China has developed its own local GxP systems, which referenced a lot of the GxP systems in other ICH countries. As a result, these systems are generally aligned with the GxP requirements in countries such as the USA, UK, EU, and Japan. Since there are still some differences in the details between these countries, it is strongly recommended that applicants research China’s local GxP systems and ensure compliance with them for imported products.

A31: When registering an AEP in China, it’s recommended that the product specification be compliant with ChP and national standards. This is a general requirement for CDE and NIFDC to evaluate the reasonability of the specification, especially for APIs. However, if it can be demonstrated that the product can meet the requirements of finished product manufacturers without including micro items in the specification, a risk assessment report can be submitted.

It’s important to keep in mind that the intended use of the AEP may differ for different drugs, and micro testing may be required for other drug manufacturers. As such, AEP manufacturers may want to consider establishing a general specification that meets the requirements of ChP, EP, USP, and other relevant standards.