202102 FDA行业指南：根据GDUFA的II类原料药DMF完整性评估

1、202102 FDA行业指南：根据GDUFA的II类原料药DMF完整性评估202102 FDA行业指南：根据GDUFA的II类原料药DMF完整性评估Completeness Assessments for Type II API DMFs Under GDUFAGuidance for Industry根据GDUFA的II类原料药DMF完整性评估行业指南Additional copies are available from:Office of Communications, Division of Drug InformationCenter for Drug Evaluation and

2、ResearchFood and Drug Administration10001 New Hampshire Ave. , Hillandale Bldg., 4th FloorSilver Spring, MD 209930002Phone: 8555433784 or 3017963400; Fax: 3014316353Email: druginfo/doc/2197b2a9336c1eb91b375dca.html/doc/2197b2a9336c1eb91b375dca.html/Drugs

3、/GuidanceComplianceRegulatoryInformation/Guidances/default.htmorOffice of Communication, Outreach and DevelopmentCenter for Biologics Evaluation and ResearchFood and Drug Administration10903 New Hampshire Ave., Bldg. 71, Room 3128Silver Spring, MD 209930002Phone: 8008354709 or 2404028010Email: ocodh

4、ttp://doc/2197b2a9336c1eb91b375dca.html/doc/2197b2a9336c1eb91b375dca.html/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation an

5、d Research (CDER)Center for Biologics Evaluation and Research (CBER)February 2021Pharmaceutical Quality/CMC/Generics TABLE OF CONTENTS目录I. INTRODUCTION概述II. BACKGROUND背景III. COMPLETENESS ASSESSMENT完整性评估A. Information Confirmed During the Completeness Assessment 完整性评估期间所确认的信息B. Check of Completeness

6、Assessment Elements完整性评估检查要点IV. COMPLETENESS ASSESSMENT OUTCOMES完整性评估结果V. API INFORMATION INCLUDED IN A GENERIC DRUG SUBMISSION 仿制药申报中的原料药信息VI. SUMMARY总结DEFINITIONS定义APPENDIX 1附录1Completeness Assessments for Type II API DMFs UnderGDUFA Guidance for Industry1根据GDUFA的II类原料药DMF完整性评估行业指南This guidance re

7、presents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. T

8、o discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.I. INTRODUCTION概述This guidance is intended for holders of Type II active pharmaceutical ingredient (API) drug master files (DMFs) that are or will be referenced in an abbreviated new d

9、rug application (ANDA), an amendment to an ANDA, a prior approval supplement (PAS) to an ANDA, or an amendment to a PAS (generic drug submissions). The guidance explains that, as of October 1, 2021, under the Generic Drug User Fee Amendments of 2021, commonly referred to as GDUFA2: 2本指南意在指导已经或将要被简略新

10、药申报（ANDA）、ANDA增补、ANDA 预批准增补（PAS）或对PAS（仿制药申报）所引用的II类活性物质（API）药物主文件（DMF）持有人。指南解释了按照2021年10月1日起实施的仿制药收费法案，通常称为GDUFA：z DMF holders are required to pay a DMF fee when first authorizing the reference of their DMF in a generic application33z DMF持有人需要为仿制药申报对其DMF的首次授权引用支持DMF费用z Type II API DMFs must undergo

11、an FDA completeness assessment (CA)z II类原料药DMF必须接受FDA完整性评估（CA）The guidance makes recommendations about the information that should be included in the DMF to facilitate a GDUFA CA. The guidance does not apply to Type II APIDMFs used to support new drug applications (NDAs), biologics license applicati

12、ons (BLAs)4,4 other submissions that are not generic drug submissions, or any other types of DMFs5.5指南给出了应包括在DMF里以便进行GDUFA完整性评估的内容。指南并不适用于支持新药申报（NDA）、生物制品许可申报（BLA）和其它非仿制药申报的II类原料药DMF，以及其它类型的DMF。In general, FDAs guidance documents do not establish legally enforceable responsibilities. Instead, guidan

13、ces describe the Agencys current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.一般来说，FDA的指南文件并不会建立法律强制责

14、任。指南只是描述药监机构当前对一个问题的想法，除了对法规或法律要求的引用外，应仅被看作是建议。单词SHOULD在官方指南中表示建议或推荐，并不是强制。II. BACKGROUND背景Under GDUFA, beginning October 1, 2021, the holder of a Type II API DMF must pay a onetime DMF fee when the DMF is first referenced in a generic drug submission submitted to FDA on the basis of a letter of aut

15、horization (LOA) from the DMF holder6. 6 Also under GDUFA, holders of Type II API DMFs that were evaluated before October 1, 2021, must pay a one-time fee for the DMF when their DMF is first referenced in a new ANDA, an ANDA or PAS amendment, or an ANDA PAS on or after October 1, 20217. 7 Only Type

16、II API DMFs for use in generic drug submissions incur this one-time fee.根据2021年10月1日开始实施的GDUFA，当DMF首次被提交给FDA的仿制药申报根据DMF持有人出具的授权信（LOA）所引用时，II类原料药DMF持有人必须支持一次性DMF费用。还有，根据GDUFA，如果II类原料药DMF在2021年10月1日之前已被评审过了，在2021年10月1日之后，其首次被简略新药申报（ANDA）、ANDA增补、ANDA预批准增补（PAS）或对PAS（仿制药申报）所引用时，必须支付一次性DMF费用。只有在仿制药申报中使用的I

17、I类原料药DMF才需要缴纳此一性费用。Under GDUFA, Type II API DMFs intended for reference in a generic drug submission for which the fee is paid will undergo a CA. Section 744B(a)(2)(D)(iii) of the FD&C Act requires FDA to make publicly available on its Web site a list of DMF numbers that correspond to DMFs that, hav

18、ing successfully undergone a CA in accordance with criteria to be published by FDA, are available for reference.根据GDUFA，需要被仿制药申报所引用的II类原料药DMF在付费后，需要经过CA。FD&C法案的744B(a)(2)(D)(iii)部分要求FDA在其网站上公开一份DMF 编号清单，这些DMF已成功通过根据FDA公布的标准所进行的CA，可以被引用。Although the requirement for a CA for Type II API DMFs is new, F

19、DA has previously evaluated DMFs in accordance with the criteria set out in the GDUFA Completeness Assessment Checklist for Type II API DMFs (CA Checklist), attached to this guidance as Appendix 1. In order to ensure adequate time for the CA, FDA strongly encourages the DMF holder to submit a comple

20、te DMF and pay the DMF fee at least 6 months prior to the submission of an ANDA or PAS that will rely on the DMF. When submitting a DMF, the DMF holder should also submit Form FDA 3794, the Generic Drug User Fee Cover Sheet, which includes the minimum information necessary for FDA to determine wheth

21、er a DMF holder has satisfied all relevant user fee obligations8.8尽管II类原料药DMF的CA要求是新的，但FDA之前已根据II类原料药DMF 的GDUFA完整性评估清单（CA Checklist）中设定的标准对DMF进行了评估，该清单附在本指南中作为附录1.为了确保有足够的时间进行CA，FDA强烈建议DMF持有人提交完整的DMF，并在引用该DMF的ANDA或PAS提交之前6个月内支持DMF费用，DMF持有人还并提交FDA3794表格，仿制药用户费用封面表，其中含有FDA决定DMF持有人是否满足所有相关用户费用义务所必须的基本信

22、息。DMF holders are encouraged to submit their DMFs using the Electronic Common Technical Document (eCTD) format9.9 More information is available on the eCTD format on FDAs Web site10.10FDA鼓励DMF持有人采用电子通用技术文档（eCTD）格式提交DMF文件。更多信息可以在FDA官网上找到。III. COMPLETENESS ASSESSMENT 完整性评估FDA will perform a CA once a

23、DMF holder files a Type II API DMF11with the Form FDA 3794 and there is an initial verification of the fee payment. The CA does not replace the full scientific review, which determines whether the information contained in the DMF is adequate to support an ANDA regulatory action.收到II类原料药DMF及FDA3794表后

24、，FDA会进行CA，首先会确认费用支持情况。CA并不取代全面科学评审，科学评审将决定DMF里所包含的信息是否足以支持ANDA的法规行动。In brief, FDA will undertake a CA to determine the following:简要言之，FDA将进行CA以确定：?Is the DMF active?该DMF是否激活？?Has the fee been paid?是否付费？?Has the DMF been previously reviewed?该DMF是否之前被审核过？?Does the DMF pertain to a single API?该DMF是否只含有

25、一个API？?Does the DMF contain certain administrative information?该DMF是否含有特定的行政信息？?Does the DMF contain all the information necessary to enable a scientific review12?该DMF是否含有所有进行科学审评所必须的资料？?Is the DMF written in English13?该DMF是否以英文写就？FDA will conduct the CA by determining the answers to a series of que

26、stions listed in the CA Checklist, which is included in Appendix 1. DMFs for which the fee has been paid and which have been found complete in accordance with the criteria for a CA set out in the CA Checklist will be identified on FDAs public Web site as available for reference in support of a gener

27、ic drug submission.FDA会实施CA，确定CA检查清单中所列的一系列问题的答案。检查清单见附录1。已支付费用，且根据CA检查清单设定的CA标准经检查认为完整的DMF 就会被列在FDA官网上，可以支持仿制药申报。For complex APIs, in addition to the recommendations in the CA Checklist, DMF holders should ensure the DMF provides the data necessary for the Agency to review the DMF with respect to a

28、ctive ingredient sameness. Information on active ingredient sameness is discussed in the products specific bioequivalence (BE) guidance when it becomes available on FDAs Web site14.对于复杂的原料药，除了CA检查清单中的建议外，DMF持有人应确保DMF提供了药监机构审核DMF所必须的数据。活性成分的信息在FDA官网上能找到的药品特定生物等效性（BE）指南中有讨论。A. Information Confirmed Du

29、ring the Completeness Assessment完整性检查中所确认的信息FDA will use the CA Checklist to perform the CA. At the top of the cover page of the CA Checklist, FDA will fill in basic information about the DMF, including its name, number, receipt date, and whether the DMF was submitted in electronic or paper format.F

30、DA将利用CA检查清单进行CA。在CA检查清单封面页最上端，FDA将填写关于DMF的基本信息，包括其名称、编号、收到日期，以及DMF是采用电子提交还是纸质提交。The FDA will also note whether the primary DMF the ANDA references refers to any other DMFs (subject DMFs). A primary DMF can reference subject DMFs, which provide additional information needed to completely describe the

31、 manufacture of an API15.15 Before submitting its DMF, the primary DMF holder should check with theholders of any referenced subject DMFs to make sure the subject DMFs are filed with FDA and FDA still considers them active.FDA还会注意ANDA引用的基本DMF是否有引用另一个DMF（主题DMF）。基本DMF可以引用主题DMF，其中有提供描述一个完整的原料药生产的额外信息。在

32、提交其DMF之前，基本DMF持有人应与需要引用的所有主题DMF持有人核对，确保主题DMF被提交给FDA，并且FDA仍认为其是激活状态。1. Is the DMF Active? DMF是否在激活状态？Before assigning a DMF to a reviewer for a CA, FDA will confirm that the DMF is active16. 16 If the primary DMF or any referenced subject DMFs on file at FDA are inactive, FDA will consider the primar

33、y DMF incomplete and send a letter notifying the DMF holder.在给一份DMF指定审核员进行CA之前，FDA会确认DMF是否在激状态。如果基本DMF或任何所引用的主题DMF为非激活状态，则FDA会认为基本DMF 不完整，并发送一封通知函告知DMF持有人。2. Has the DMF fee been paid? 是否已支付DMF费用？Before assigning a DMF to a reviewer for a CA, FDA will confirm that the DMF fee has been paid. If it ha

34、s not, FDA will not assign the DMF for CA. ANDA applicants that reference a DMF for which a fee is due will be notified that the DMF holder has not paid the fee. If the DMF fee is not paid within 20 days after notification, FDA will refuse to receive the ANDA referencing the DMF.在给一份DMF指定CA审核员之前，FDA

35、会确认DMF费用是否已缴付。如果没有，则FDA不会给该DMF指定CA审核员。FDA会通知要引用该DMF的ANDA申报人，告知说DMF持有人尚未付费。如果DMF费用在发出通知后20天内仍未支付，则FDA会拒绝接收引用该DMF的ANDA。3. Has the DMF been previously reviewed for chemistry, manufacturing, and controls (CMC) by FDA in the context of a review of a prior application? 在之前的申报审核中，DMF之前是否在FDA已经被合成、生产和控制（CMC

36、）审核过？If FDA has reviewed the DMF for CMC after November 30, 2021, the DMF will be considered to have passed the CA without further analysis. If the DMF was reviewedfor CMC prior to November 30, 2021, a CA assessment will need to be performed. For all DMFs that have not previously received a full CMC

37、 review, a CA assessment will need to be performed. If the DMF has not previously received this full review, it will be assigned to a reviewer for a CA.如果FDA已在2021年11月30日之后对DMF进行过审核，则DMF会被认为通过CA，无需进一步检查。如果DMF在2021年11月30日之前被审核过，则需要进行CA评估。所有之前没有接受过完整的CMC审核的DMF，均将进行CA审核。如果该DMF在之前没有进行过此全面审核，则会为其指定CA审核员进

38、行CA评估。B. Check of Completeness Assessment Elements完整性评估要素检查FDA will complete the administrative part of the CA Checklist (i.e., “General Information”) during the CA. If the DMF is incomplete, FDA will send the DMF holder a GDUFA DMF Incomplete Letter. With certain exceptions specified in this guidan

39、ce document, this letter will provide comments about each element that resulted in an incomplete designation for the CA.FDA会在CA过程中填写完成CA检查清单的行政部分（即一般信息）。如果DMF不完整，则FDA会给DMF持有人发送一封GDUFA DMF不完整通知函。在此指南文件中期望该信函会提供评估，说明导致CA不完整结论的所有要素。If an item is marked “n/a” and does not apply to the DMF, the element i

40、s treated the same as if it were marked “yes.”如果一个项目标记为“不适用”，不适用于该DMF，则该要素等同于标记为“是”。1. Is the subject of the DMF a single API produced by one manufacturing process? DMF是否应该是由一个生产工艺生产出的一个原料药？The subject of a DMF should be limited to one API and one manufacturing process. If a DMF includes information

41、 on more than one API or more than one manufacturing process for an API, the DMF will be deemed incomplete. If the DMF describes multiple APIs, the DMF holder should file separate DMFs for each API. Similarly, if there are multiple manufacturing processes for an API, the DMF holder should file separ

42、ate DMFs for each manufacturing process.DMF的标题应限于一个生产工艺的一个原料药。如果一份DMF含有多于1个原料药或一个原料药但多于1个生产工艺的资料，则DMF会被判定为不完整。如果DMF描述了多个原料药，DMF持有人应分别为每个原料药提交DMF。类似地，如果一个原料药有多个生产工艺，则DMF持有人应为每个生产工艺单独提交DMF。2. Does the DMF holder need to submit a complete update? DMF持有人需要提交一份完整更新吗？If the DMF is in paper format and it h

43、as been five years or more since the DMF received a complete update17,17 or if there have been more than five amendments to the DMF, the DMF holder should provide a complete and comprehensive update to it. If such a DMF has not received an update, FDA will consider the DMF incomplete. The DMF holder

44、 must submit a complete update for FDA to determine whether it passes the CA18.如果DMF是纸质格式，并且是在五年前或更早时经过全面更新，或者如果对该DMF已有多于五个增补，DMF持有人应提交一份完整的综合更新。如果未提交此DMF更新，则FDA会判定该DMF不完整。DMF持有人必须提交一份完整更新给FDA以决定其是否通过CA。FDA believes that the remainder of the CA Checklist is self-explanatory.FDA认为CA检查清单提醒就是自证。IV. COM

45、PLETENESS ASSESSMENT OUTCOMES完整性评估结果Following the CA, FDA will find the DMF either complete or incomplete.在CA后，FDA会决定DMF是完整的还是不完整的：z If the DMF is found complete, FDA will post the DMF number on a publicly available list on FDAs Web site to indicate the DMF is available for reference by generic drug

46、 submission applicants19.z如果DMF是完整的，FDA会将DMF编号公开在FDA网站上公开可查询，显示该DMF现在可以被仿制药申报人引用。z If the DMF is found incomplete, the CA findings and comments will be compiled in a GDUFA DMF Incomplete Letter to the DMF holder that explains why theDMF was deemed incomplete. Information about the CA status of a DMF

47、, other than the lack of a public listing on the FDAs Web site, will not be provided to anyone except the DMF holder and, as necessary, any generic drug submission applicant that the DMF holder has authorized to rely on the DMF.z如果DMF被认为是不完整的，则CA缺陷和建议会被汇集在GDUFA DMF不完整信函中给DMF持有人，解释为什么DMF被认为不完整。关于DMF的

48、CA状态的信息，除了不会公布的FDA网站外，也不会被提供给DMF持有人以外的任何人，必要时，持有DMF持有人授权的仿制药申报人可以获得此信息。z To remedy a GDUFA DMF Incomplete Letter and pass the CA, the DMF holder should submit an amendment to its DMF to correct the deficiencies identified in the Incomplete Letter, or, if FDA has determined that the DMF should underg

49、o a complete update, the DMF holder should resubmit the DMF with that update.FDA will then assess the revised DMFs completeness. If there are nodeficiencies at this time, FDA will declare the DMF to be complete and to have passed the CA.z为了补救GDUFA的DMF不完整信函，通过CA，DMF持有人应提交一份增补，纠正不完整信函中指出的缺陷，或者如果FDA已决定

50、该DMF需要进行全面更新，则DMF持有人应重新提交更新后的DMF。FDA会再次评估修订后的DMF的完整性。如果此次审核没有缺陷，则FDA会宣布该DMF已完整，通过CA。z Although a DMF may be deemed incomplete upon its first CA, FDA will work with DMF holders to provide guidance on how to revise the DMF so it may be found complete after resubmission. Once the DMF passes the CA, FDA

51、 willmake the DMF number publicly available on its Web site20.z尽管一份DMF可能会在首次CA时不完整，但FDA会与DMF持有人一起努力，提供指导如何修订DMF，保证重新提交时是完整的。一旦DMF通过了CA，FDA就会将DMF编号公开在FDA网站上公开可查询。V. API INFORMATION INCLUDED IN A GENERIC DRUG SUBMISSION包括在仿制药申报中的原料药信息rely on information contained in a DMF, no CA will be performed. Ins

52、tead, this information will be evaluated during the ANDA filing review21.However, because GDUFA requires collection of a one-time fee for API information included in a generic drug submission (i.e., an (a)(3)(F) fee)22, the applicant submitting the generic drug submission containing the API informat

53、ion must pay this fee.如果一份仿制药申报中包括了所有必须的原料药信息，并不需要依赖于DMF中包含的信息，则需要进行CA。这时，在ANDA文件审评中将评估这些资料。但是，由于GDUFA要求针对仿制药申报中包含的原料药资料收取一次性费用（即（a）(3)费用），提交包括原料药资料的仿制药申报的申报人必须支付此费用。VI. SUMMARY总结Once the DMF fee is received, FDA will evaluate the DMF to make sure it meets the CA criteria.一旦收到DMF费用，FDA会评估DMF，以确定其是否符

54、合CA标准：z If the DMF passes the CA, it will be found complete and the DMF number will be made publicly available on FDAs Web site.z如果DMF通过CA，则被认为是完整的，DMF编号会出现在FDA官网的公众可查询清单上。z If the DMF fails the CA, FDA will send a GDUFA DMF Incomplete Letter describing to the DMF holder the missing elements in its

55、DMF.z如果DMF未通过CA，则FDA会发送一份GDUFA DMF不完整通知函，在其中向DMF持有人描述在其DMF中所缺失的要素。z If the DMF holder addresses all the deficiencies and amends the DMF or completely updates the DMF per the CA request, the FDA will complete its CA.If the DMF is then found complete, the DMF number will be made publiclyavailable on F

56、DAs Web site.z如果DMF持有人根据CA要求，回复了所有缺陷，修订了DMF或完整更新了DMF，FDA将完成其CA。经审核认为DMF完整的，则DMF编号会出现在FDA官网的公众可查询清单上。not reference a DMF, the generic drug submission applicant will be required to pay the (a)(3)(F) fee. No CA will be conducted.z如果有仿制药申报包括有所有必要原料药信息，并且不引用DMF，则仿制药申报人会被要求支付（a）(3)费用。不会进行CA检查。定义（略）CA检查表（略

57、）1 This guidance has been prepared by the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research at the Food and Drug Administration.2 Public Law 112144, Title III.3 For these purposes, such authorization is deemed to have occurred when the DMF “is referenced on

58、 or after October 1, 2021, in a generic drug submission by an initial letter of authorization,” Section 744B(a)(2)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 379j-42(a)(2)(A).4 Type II API, API intermediate, and drug product DMFs are not used to support BLAs submitted pursuant to sections 351(a) and 351(k) of the Public Health Service Act (42 U.S.C. 262).5 See section 744A(7) of the FD&C Act (21 U.S.C. 379j 41(7).6 Section 744B(a)(2) of the FD&C Act