英文译稿《化学原料药、药用辅料及药包材与药品制剂关联审评审批管理规定（征求意见稿）》

1、Annex 1Provisions for Bundling Review and Approval ofChemical Drug Substances, Pharmaceutical Excipients, Pharmaceutical Packaging Materials and Drug Product (Draft for Comments)Chapter I General ProvisionsArticle 1 (Basis & Purpose) In order to improve the quality and efficiency of drug registratio

2、n and ensure the safety, effectiveness and quality controllability of drugs, the Provisions have been formulated in accordance with the “Drug Administration Law of The Peoples Republic of China” and the “Drug Registration Regulation”. Article 2 (General Requirements) The chemical drug substance (DS)

3、, pharmaceutical excipients, packaging materials and containers in direct contact with drugs (hereinafter referred to as the pharmaceutical packaging materials) shall meet the pharmaceutical use requirements, and their quality, safety and functions shall meet the needs of drug product (DP).Article 3

4、 (Bundling Review and Approval System) The National Medical Products Administration (hereinafter referred to as NMPA) shall review and approve DP with the chemical drug substances, and review the bundling pharmaceutical excipients and pharmaceutical packaging materials together.The standalone review

5、 and approval can be applied for the chemical drug substance used for imitating the marketed drugs in China (hereinafter referred to as “generic chemical DS”).Article 4 (Registry of DS, Pharmaceutical Excipients and Pharmaceutical Packaging Materials) The chemical DS, excipients and pharmaceutical p

6、ackaging materials shall be managed through registry. In principle, the registrant of DS, pharmaceutical excipients and pharmaceutical packaging materials shall be the manufacturer of DS, pharmaceutical excipients and pharmaceutical packaging materials, and the overseas companies of DS, pharmaceutic

7、al excipients and pharmaceutical packaging materials shall designate an enterprise legal person within China to complete the relevant registry. The relevant product information shall be registered on the registry platform of chemical drug substances, excipients, packaging materials and containers in

8、 direct contact with drugs (the registry platform), and the registry dossiers shall be submitted. All foreign language dossiers shall be provided with Chinese translations as required.Article 5 (Disclosure of Bundling Review Result) The Center for Drug Evaluation of NMPA (hereinafter referred to as

9、CDE) shall establish a registry platform and set up an information disclosure column to disclose basic information such as registry number of DS, pharmaceutical excipients and pharmaceutical packaging materials, product name, enterprise name, and the route of administration, etc. to the public for s

10、election by relevant applicants or holders.The CDE shall update the identifier of registry status on the registry platform, provided that the bundling or standalone review and approval of the chemical DS or the bundling review of pharmaceutical excipients and the pharmaceutical packaging material su

11、cceed.Article 6 (Management Principle of Registry Number) The same registry number shall be followed in case where the same products of DS, pharmaceutical excipients and pharmaceutical packaging materials are produced by the same enterprise with the same manufacturing process and quality standard at

12、 the same manufacturing site.The same type of DS produced by different principles of manufacturing processes (such as fermentation, synthesis, semi-synthesis, etc.) can be registered under different registry numbers, and the same type of DS produced by the same principle of manufacturing process sha

13、ll be registered by selecting the optimal process.Chapter II Responsibilities and ObligationsArticle 7 (Responsibilities of Marketing Authorization Holder MAH) MAH shall bear the main responsibility for the quality of DP and establish a quality management system with the DP as the core and the DS, p

14、harmaceutical excipients and pharmaceutical packaging materials as the basis. The MAH shall select the appropriate DS, pharmaceutical excipients and pharmaceutical packaging materials pursuant to the quality requirements of DP, submit the Authorization Letter for Use (see Annex 1-1) associated with

15、the registered DS, pharmaceutical excipients and pharmaceutical packaging materials when proposing a registration application, and be responsible for the quality of the selected DS, pharmaceutical excipients and pharmaceutical packaging materials. The quality of the used DS, pharmaceutical excipient

16、s and pharmaceutical packaging materials shall be traceable, with definite source, batch, production, quality control and changes.Article 8 (Responsibilities of Registrant of DS, Pharmaceutical Excipients and Pharmaceutical Packaging Materials) The registrant of DS, pharmaceutical excipients and pha

17、rmaceutical packaging materials shall be responsible for the maintenance of registry information on the registry platform, and be held accountable for the authenticity and integrity of the registry information.The overseas companies of DS, pharmaceutical excipients and pharmaceutical packaging mater

18、ials and the designated enterprise legal person within China shall share the responsibilities of authenticity and integrity of the registry information.Article 9 (Responsibilities of Manufacturer of Drug Substance, Pharmaceutical Excipients and Pharmaceutical Packaging Materials) The manufacturer of

19、 DS, pharmaceutical excipients and pharmaceutical packaging materials shall establish a supply chain management and quality assurance system of the DS, pharmaceutical excipients and pharmaceutical packaging materials, continuously and stably supply products meeting the quality requirements of DP acc

20、ording to the agreement, provide necessary information for MAH to evaluate and control the quality risks of DP introduced by DS, pharmaceutical excipients and pharmaceutical packaging materials, and accept enterprise audits conducted by MAH and supervision and inspection by regulatory authorities at

21、 all levels. The manufacturer of DS, pharmaceutical excipients and pharmaceutical packaging materials shall be responsible for the quality of their products and ensure that quality, safety and functionality of DS, pharmaceutical excipients and pharmaceutical packaging materials meet the needs of DP.

22、 The manufacturing process of the chemical DS shall conform to the requirements of the Good Manufacturing Practice. Article 10 (Changes in Source of Drug substance, Pharmaceutical Excipients and Pharmaceutical Packaging Materials) Where the sources of the DS, pharmaceutical excipients and pharmaceut

23、ical packaging materials are subject to changes for a marketed drug product, MAH shall conduct studies in accordance with relevant guidelines and other requirements, and submit the application pursuant to relevant registration regulations. Where the bundling review and approval has not been obtained

24、 regarding the DS, pharmaceutical excipients and pharmaceutical packaging materials to be used for DP, the relevant application shall be submitted to the NMPA and the identifier of the DS, pharmaceutical excipients and pharmaceutical packaging materials shall be updated according to evaluation resul

25、ts after the bundling review with DP.Article 11 (Changes in Drug Substance, Pharmaceutical Excipients and Pharmaceutical Packaging Materials after Drug Product Entering the Market) Any changes in the chemical DS shall be implemented in accordance with the current registration regulations and MAH of

26、the bundling DP shall be informed thereof in a timely manner. MAH shall fully evaluate the impact on the quality of DP and submit an application for registration as per relevant provisions.In case of minor change, moderate change or major change in the marketed drug product caused by changes in phar

27、maceutical excipients and pharmaceutical packaging materials, MAH shall conduct an self-assessment and submit an application in accordance with the requirements of the current regulations.Article 12 (Requirements for Annual Report) The manufacturer of DS, pharmaceutical excipients and pharmaceutical

28、 packaging materials shall submit an annual report to the CDE within three months upon the completion of each full year after DS, pharmaceutical excipients and pharmaceutical packaging materials passing technical review. The annual report shall include product changes and relevant study data, and th

29、e relevant statement shall be provided if there is no change. With respect to the DS, it is necessary to state whether the application for change has been submitted and the relevant information after such a change. The relevant study data shall be provided in relation to the changes in pharmaceutica

30、l excipients and pharmaceutical packaging materials, and the authorized use to MAH during the year newly occurring shall be stated (see Annex 1-2 for details of requirements). If the manufacturer of DS, pharmaceutical excipients and pharmaceutical packaging materials fails to submit the annual repor

31、t on time, the registry platform will not publicize this registry number anymore.Chapter III Registry, Review and Approval of Chemical Drug Substance Article 13 (Basic Requirements) For the chemical DS that needs to be registered in compliance with the Provisions and applies for bundling review and

32、approval, the DS registry shall be completed in accordance with the Provisions before the submission of DP marketing authorization application or a DP supplement involving changes of DS. For generic chemical DS, a standalone review and approval could be applied at the time of registry.Article 14 (Sc

33、ope of Registry) All the chemical DS sold and used within China shall be registered. Where the registered pharmaceutical excipients are used as the chemical DS, the re-registry shall be made in accordance with relevant requirements of the chemical DS.The chemical DS used in the overseas production o

34、f DP do not have to do registry if the chemical DS is not sold in China, and the submission dossiers of the chemical DS that conform to requirements shall be submitted together with the application of DP.The registry is not required for chemical DS used in the clinical stage of new drug application

35、(the registration of chemical drugs classified as Class 1 and Class 2.1) and submission dossiers that meet requirements shall be submitted together with the application of DP.Article 15 (Submission and Acceptance of Dossiers) The chemical DS registrant shall log in the registry platform of CDE, fill

36、 in and submit the Chemical Drug Substance Registry Form (see Annex 1-3) which shall be mailed together with the electronic version (CD) of the registry information to the CDE. The CDE shall conduct the formal examination for the registry information within 5 working days after the receipt of such i

37、nformation. Where the information is incomplete, the required supplementary information shall be informed at one time; if the information conforms to the requirements, it shall be accepted and publicized in the information disclosure platform of DS, pharmaceutical excipients and pharmaceutical packa

38、ging materials. The registrant can print the relevant documents for acceptance on the registry platform.Article 16 (Payment Made by Registrant) Where the DS is accepted through formal examination, the acceptance department of CDE shall issue a payment notice to the DS registrant in accordance with r

39、elevant requirements, except small and micro enterprises as the registrant conforming to the regulations of the State Council.Article 17 (Bundling Review and Timeline) The timeline for review and approval of the chemical DS shall be consistent with that for the review of DP bundled. For the suppleme

40、nt for change in the source of the DS of DP, if the chemical DS is approved, the review timeline shall be 60 working days; if it has not been approved, the review timeline shall be 200 working days.Article 18 (Timeline for Standalone Review of Chemical Drug Substance) The review timeline of the chem

41、ical DS applying for standalone review and approval shall be 200 working days. The review timeline of the re-registration and supplement of the DS shall refer to similar application items for registration of drug product.Article 19 (Inspection and Testing of Chemical Drug Substance) The inspection a

42、nd testing procedures for the chemical DS subject to bundling review and approval shall be implemented in accordance with the “Drug Registration Regulation” and relevant regulations. The inspection and testing procedures for generic chemical DS subject to standalone review and approval shall be impl

43、emented in accordance with those for the similar drug product.Article 20 (Supplementary Information during Review of Chemical Drug Substance) In the event that the supplementary information is required during the process of review for the chemical DS, DP applicant or the chemical DS registrant shall

44、 provide such supplementary information based on the requirements of the procedure for supplementary information. The time consumed for supplement submission shall not be included in the review timeline. The CDE shall start the review after the receipt of all the supplement submission from the appli

45、cant, and the review timeline shall be extended by one third. The relevant provisions on the management of supplement submission for the chemical DS subject to the bundling review and approval are consistent with those for bundled DP.Article 21 (Explanation of Review for Chemical Drug Substance) The

46、 CDE shall notify DP applicant or the chemical DS registrant to submit relevant explanation as required within five days, provided that it is unnecessary for DP applicant or the chemical DS registrant to supplement new technical dossier, but to make explanations on the registry information.Article 2

47、2 (Approval and Result of Chemical Drug Substance) The “Notice of Approval for Chemical Drug Substance” with the registry number stated therein as well as the verified manufacturing process, specification and label shall be issued, provided that the bundling review and approval for the chemical DS a

48、nd DP have been passed, or the standalone review and approval for generic chemical DS has been passed. The relevant identifier on the registry platform shall be updated, and the “Notice of Disapproval for Chemical Drug Substance” shall be issued in cased of failure in the review and approval. The re

49、gistrant can print the relevant documents on the registry platform by itself.The DS can be approved for marketing separately, in the event that the conclusion made about the review of the DP marketing authorization application shows approval of clinical trials and the bundling DS conforms to require

50、ments for standalone review and approval.Article 23 (Changes in Chemical Drug Substance) In case of any changes in the DS during clinical trials, the clinical trial sponsor shall conduct studies as required and submit an application under the application for DP bundled according to relevant regulato

51、ry requirements for registration.In case of any change in approved chemical DS, the supplement, filing or report shall be submitted in accordance with the relevant provisions of the current drug registration regulation. The supplement subject to review and approval by NMPA shall be submitted on the

52、registry platform; filling and reporting changes that are managed by provincial drug regulatory departments shall be submitted to the drug regulatory departments of the provinces, autonomous regions and municipalities directly under the Central Government where they are located. The changes shall be

53、 updated on the registry platform within 5 days after the completion of filing or reporting.Article 24 (Main Responsibilities Related to Changes in Chemical Drug Substance) When the changes in chemical DS occur, its manufacturer shall take the initiative to conduct studies, submit an application as

54、required, state relevant information in the annual report and send a notice to the related MAH without delay. Upon the receipt of such notice, the MAH shall promptly evaluate or study the impact of corresponding changes on the quality of DP and submit an application as required.Article 25 (Change of

55、 Registry Agency) The overseas company for the chemical DS shall change its designated enterprise legal person for registry in China after submitting relevant documents and materials. Such documents and materials include: Power of Attorney from the overseas company for chemical DS, Notarization Docu

56、ment with Chinese version, photocopies of Business License from newly designated enterprise legal person within China, Document and Notarization Document (with Chinese version) of the overseas company for chemical DS that rescinds the commission relationship with originally designated enterprise leg

57、al person in China. The registry dossiers shall be submitted by the newly designated enterprise legal person in China.Article 26 (Re-registration of Chemical Drug Substance) The registrant shall apply for re-registration 6 months before the expiration of the “Notice of Approval for Chemical Drug Sub

58、stance”. The re-registration of the chemical DS manufactured within China shall be proposed by the registrant to the provincial drug regulatory department, while the re-registration of the chemical DS manufactured overseas shall be proposed by the registrant to CDE. After the approval of re-registra

59、tion of the chemical DS, the information shall be updated on the registry platform within 5 days.Article 27 (Termination of Registry of Chemical Drug Substance) If the chemical DS enterprise fails to re-register or its re-registration has not been approved, the registry of the chemical DS shall be terminated and the chemical DS shall not be used in marketed drug products; if the chemical DS is no longer manufactured, the manufacturer shall inform the relevant MAH in advance and apply for terminati