FDA指南：ANDA原料药和制剂稳定性试验问答(201405).doc

201405 FDA指南：ANDA：原料药和制剂稳定性试验问答Guidance for Industry 行业指南ANDAs: Stability Testing of Drug Substances and ProductsQuestions and AnswersANDA：原料药和制剂稳定性试验问答Final GUIDANCE最终稿指南U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)May 2014GenericsGuidance for IndustryANDAs: Stability Testing of Drug Substances and ProductsQuestions and AnswersANDA：原料药和制剂稳定性试验问答Additional copies are available from:Office of CommunicationsDivision of Drug Information, WO51, Room 2201Center for Drug Evaluation and ResearchFood and Drug Administration10903 New Hampshire Ave., Silver Spring, MD 20993Phone: 301-796-3400; Fax: 301-847-8714druginfofda.hhs.govU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)May 2014Generics TABLE OF CONTENTS 目录I. INTRODUCTION介绍II. QUESTIONS AND ANSWERS提问和回答A. General一般问题B. Drug Master File药物主文件.C. Drug Product Manufacturing and Packaging药品生产和包装D. Amendments to Pending ANDA Application未批准ANDA申请的增补E. Stability Studies稳定性试验.Guidance for IndustryANDAs: Stability Testing of Drug Substances and ProductsQuestions and AnswersANDA：原料药和制剂稳定性试验问答This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.本指南代表的是FDA目前对这一专题的态度。它并未建立或赋予任何个人任何权利，并不与FDA或公众有任何绑定。你可以使用任何一种替代方法，只要所用的方法满足成文的法规要求。如果你想要讨论一个替代方法，请与FDA负责实施本指南的相关人员联系。如果你无法识别要联系的人，可以拨打本指南首页所列的相应的电话号。I. INTRODUCTION介绍This guidance provides answers to questions from the public comments we received on the draft guidance for industry on ANDAs: Stability Testing of Drug Substances and Products(stability guidance) that published on September 25, 2012. The final guidance for industry of the same title published on June 20, 2013.Comments received on the draft of this guidance published in the Federal Register of August 27, 2013 have also been incorporated. General issues; drug master files (DMFs); drug product manufacturing and packaging; and stability studies are discussed in this guidance and are intended to clarify the stability testing data recommendations for abbreviated new drug applications (ANDAs). In this document, the terms drug substance and active pharmaceutical ingredient (API) are used interchangeably.本指南是2012年9月25日公布的行业指南草案（ANDA：原料药和制剂稳定性试验（稳定性指南）起草中收到的公众问题的答复汇总。该指南终稿在2013年6月20日出版。本指南也吸收了2013年8月27日的草案意见。在本指南中，讨论了一般问题、DMF问题、药品生产和包装和稳定性研究，意在澄清对ANDA稳定性试验数据的一些意见。在本文件中，“药用物质”和“活性药用物质成份”交互使用。FDAs guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances 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.FDA的指南文件，包括本指南，并未建立法定的强制责任。指南中只是描述了官方对一个议题的当前的考虑，除非引用了特定的法规或法定要求，则应只当作建议看待。在官方指南中， “应该（should）”一词表示这是建议或推荐，而非必须。A. General一般Q1: What is the scope of and implementation date for the stability guidance?稳定性指南的范围和实施日期？A1: The stability guidance covers all new ANDAs under the Federal Food, Drug, and Cosmetic Act, section 505 (j), and DMFs (Type II for drug substances that support the ANDAs). It does not apply to postapproval changes.The implementation date is June 20, 2014.稳定性指南适用于所有联邦内食品、药品和化妆品法规第505（j）下提交的新ANDA申请，和DMF申请（支持ANDA的二类药用物质）。不适用于上市后变更。 实施日期2013年6月20日。-Q2: How will this guidance affect the Presidents Emergency Plan for AIDS Relief (PEPFAR)and positron emission tomography (PET) ANDAs?本指南对缓解艾滋病总统紧急法案（PEPFAR）和正电子成像术（PET）ANDA有何影响？A2: For chemistry, manufacturing, and controls (CMC) information, PEPFAR ANDAs should follow the guidance for industry on Fixed Dose Combinations, Co-Packaged Drug Products, and Single-Entity Versions of Previously Approved Antiretrovirals for the Treatment of HIV对于化学、生产和控制（CMC）信息，PEPFAR ANDA应遵守指南中对已批准的治疗艾滋病的抗逆转录病毒产品的固定剂量配方、组合包装药品、单化学体的规定。For PET ANDAs, the Agency recommends a minimum of three batches at or near the upper end of the proposed radio-concentration. If different synthesizers (methods of synthesis) are used, three batches from each method of synthesis at or near the upper end of the proposed radio-concentration are recommended. Batches do not have to be made in the same facility. For the additional manufacturing facilities, applicants should provide stability data on at least one batch from each facility, although bracketing approaches could be submitted for review. For additional information, the Agency has published a guidance for industry on FDA Oversight of PET Products, Questions and Answers.对于PET的ANDA，当局建议至少三个最高或接近最高辐射强度批次。如果采用了不同的合成方式（合成方法），建议每个合成方式三个最高或接近最高辐射强度批次。每批不需要在同一个厂房合成。对于增加的生产场所，即使采用正交方法提交申报资料，申请人应提供每个场所至少一批供稳定性数据。对于增加的信息，当局已出版行业指南“FDA对PET产品的监管：问答”。-Q3(i): Can an ANDA be submitted with 6 months of accelerated stability and 6 months of long-term stability data?ANDA提交时可否只包括6个月的加速试验和6个月长期稳定性试验数据？A3(i): Yes. Stability data expectation at the time of ANDA submission is 6 months of accelerated and 6 months of long-term data. However, if 6 months accelerated data show significant change2 or failure of any attribute, 6 months of intermediate data are also recommended at the time of submission. 可以。要求提交的是6个月加速稳定试验和6个月长期稳定性试验数据。但如果6个月回事数据显示有显著的变化或任何失败的迹象，建议提交时同时包括6个月的中间条件数据。Q3(ii): When do intermediate stability studies need to be initiated in the event of failure at accelerated condition?如果加速条件失败，什么时候开始中间条件稳定性试验？A3(ii): We recommend starting intermediate stability, accelerated, and long-term studies at the same time so the data are available at the time of submission, if needed. 我们建议同时开展中间条件、加速和长期稳定性研究，这样在提交申报资料时就能获得所有需要的数据。Q3(iii): If one among the three batches in accelerated conditions show a significant change, what should be done?如果三批加速试验中有一批表现出显著性变更，应该怎么办？A3(iii): If accelerated data show a significant change or failure of any attribute in one or more batches, an applicant should submit intermediate data for all three batches. In addition, the submission should contain a failure analysis (i.e., discussion concerning the observed failure(s). 如果加速数据有一批或更多批次表现出显著性变更或任何一个属性失败，申请人应该提交每一批的中间条件数据。另外，还应提交失败的分析（比如讨论观察到的失败现象）则建议提交所有3批的中间条件的数据。-Q4: Can stability bracketing and/or matrixing be used to determine the configurations to be placed on stability for an original ANDA without prior approval from the Office of Generic Drugs (OGD)如果没有获得官方通用药（OGD）预批准，稳定性试验是否可以采用分类试验和/或正交试验来选择ANDA初始提交中的参数？A4: Yes. You should follow the International Conference on Harmonisation (ICH) guidance for industry on Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products and its example tables. 可以。你可以根据ICH行业指南Q1D“新原料药和新制剂稳定性试验分类和正交设计”及其样表的要求进行设计。-Q5(i): If an application that qualifies for the Generic Drug User Fee Act (GDUFA) 10-month review is filed with 6 months of accelerated and 6 months of long-term data, and there are no blocking patents or exclusivities, will 24 months of expiration dating be granted?如果申报符合仿制药付费法案（GDUFA）10个月审核要求，提交时包括了6个月的加速和长期稳定性试验数据，并且没有相关专利阻碍，也没有行政保护，那么会被批准24个月的有效期吗？Q5(ii): During the review cycle, will the application need to be updated with 12 months of long-term data?在审计过程中，是否需要提交12个月长期稳定性更新数据？A5(i,ii): FDA will grant a shelf life period of two times the available long-term data at the time of approval (up to 24 months) following the recommendation of the ICH Q1E Evaluation of Stability Data (ICH Q1E) guidance, provided the submitted data are satisfactory, and data evaluation and appropriate commitments are provided in accordance with ICH Q1E. Please refer to the decision tree (Appendix A) in ICH Q1E. The ANDA should be updated with 12 months of long-term data during the review cycle. FDA会给出一个保护期，根据ICH Q1E评价要求，如果提交的数据符合要求，对数据的评估符合ICH Q1E的要求，有效期长度为批准时长期稳定性试验数据的两倍时长（最长为24个月）。参见ICH Q1E中决策树（附件A）。ANDA应在更新12个月的长期稳定性试验数据。-Q6: Can only two lots of finished product at pilot scale batch size ever be sufficient to support the stability of an ANDA for simple dosage forms?如果仅有两批成品中试批量，是否足以支持ANDA单剂型稳定性试验要求？A6: According to the FDA stability guidance, the applicant should submit data from three pilot scale batches or should submit data from two pilot scale batches and one small scale batch. This applies to all dosage forms. If the size of the pilot scale batch does not follow ICH recommendations, the applicant should provide a justification. See also section C, question 20 for additional information regarding exceptions. 根据FDA稳定性指南，申请人应提交3批中试批量或2批中试批量加一批中试放大批量。该要求适用于所有剂型。如果批量大小不符合ICH，申请人应提交正当理由。见C部分，第20条问题了解更多关于免责声明。-Q7: How is the proposed expiration date supposed to be calculated? Will 6 months of accelerated data equal 24 months at long-term?应如何计算建议效期？6个月的加速数据等同于24个月的长期试验吗？A7: ICH Q1E principles will help in the calculation of shield life. Data from the three ANDA submission batches (i.e., 6 months), accelerated data meeting all criteria (without significant change per ICH Q1A(R2), and 12 months long-term data without variability will not need statistical evaluation.and with appropriate post approval stability commitments, can be used to support extrapolation to a 24 months shelf life. ICH Q1E原则可以帮助计算保护期。三批ANDA申报批次（即6个月）稳定性数据，加速数据符合所有标准（根据ICH Q1A (R2)无显著变更），12个月长期稳定性数据无变化则不需要进行统计学评估。如果预申请包含合适的稳定性承诺，可以将保护期延长到24个月。If there is a significant change in the accelerated data, ICH Q1E, Appendix A, provides more detail regarding when intermediate condition stability data are recommended.如果加速数据有显著性变更，ICH Q1E 附件A，提供了建议什么时候采用中间条件数据的详细说明。-Q8: Will the recommendation for 6 months accelerated data be met by providing 24 weeks of data as 12 weeks is typically accepted as equivalent to 3 months?6个月加速数据与24个星期的数据可以对等吗？因为12个星期的数据与3个月的数据是已经对等了。A8：No. FDA, following the recommendations of ICH stability guidances refers to timeframes in terms of months and not weeks. 不可以，FDA根据ICH稳定性指南中的月时间为主，而不是星期。-Q9: When a patent is due to shortly expire and there are no approved ANDAs, can we file with 3 months stability data with a commitment to supply 6 months data when available?如果一个专利即将过效期，而并没有已批准的ANDA，我们可否提交3个月稳定性试验数据，并承诺在获得6个月数据时即进行补充？A9: No. ICH stability guidances should be followed irrespective of patent status; 不可以。不论专利状态如何，必须遵守ICH稳定性指南。-Q10: How long do the three pilot scale batches, submitted as a part of an ANDA, need to be stored before destruction?如果ANDA申报批次是三批中试放大批，是否需要存贮直至销毁？A10: Sample storage times are discussed in 21 CFR 320.38 and 21 CFR 320.63 for bioequivalence-study-samples when the pilot scale batch is used in the bioequivalence study or studies.In general, ANDA submission batch samples should be stored for 1 year after approval of the ANDA, and samples of the drug product used for bioequivalence studies must be stored following the requirements listed in 21 CFR 320.38 and 21 CFR 320.63. In addition, the guidance for industry on Handling and Retention of BA and BE Testing Samples may be helpful regarding the procedure for handling reserve samples from relevant bioavailability and bioequivalence studies. Additional information on sample quantities (for retention purposes) is discussed in 21 CFR 211.170 (a) and (b), Reserve Samples. 在21CFR 320.38和21CFR 320.63对于采用中试批准进行生物等效性研究的情况下，生物等效性研究样品的存贮时间进行了讨论。一般来说，ANDA申报批次样品存贮时间应至少在ANDA批准后1年，用于生物等效性研究的制剂样品应符合21 CFR 320.38 和21 CFR 320.63.另外，行业指南中关于处理和保留BA和BE测试样品的内容对处理BA和BE的保留样品有帮助。更多有关样品数量（供保存对照用）的讨论见21 CFR 211.170（a）和（b），保留样品。B. Drug Master File药物主文件Q1: Please clarify the effect of the stability guidance on Drug Master File (DMF) holders.请说明稳定性试验指南对DMF持有人的影响Q1(i): How many months of long-term and accelerated data are required when a “Completeness Assessment” is performed on the DMF? Also, what should the DMF stability section contain for a Completeness Assessment? 进行DMF完整性评估时，需要提供几个月的长期数据和加速数据？在DMF稳定性部分应为完整性评估提供什么？A1(i): To pass the Completeness Assessment, DMFs should include the stability protocol, commitments, and data demonstrating that stability studies have started. The initial and one additional time point for the accelerated studies and long-term studies are sufficient. If the DMF does not meet the recommendations under A1(ii) below at the time of the Completeness Assessment the DMF holder should amend the DMF with updated stability data to prepare for full scientific review. DMFs应包括稳定性实验方案、承诺和稳定性研究数据，才可以通过完整性评估。初始的数据和新增加的一个时间点的数据和长期研究数据已经足够。如果在提交完整性评估的时候DMF仍不符合下述A1（ii）的要求，DMF持有人应增补DMF最新的稳定性数据，准备接受全面的科学检查。Q1(ii): Are stability data from three current good manufacturing practice (CGMP) batches required to be filed in the DMF to support the API retest date? Also, how many months of long-term and accelerated data are required for pilot scale batches? 用于支持API再测试的稳定性数据是根据cGMP要求取的三批（填在DMF）吗？需要几个月的中试放大批的长期数据和加速数据？A1(ii): Yes. Per ICH Q1A(R2) data from formal stability studies should be provided on at least three primary batches and the batches should be manufactured to a minimum of pilot scale for the drug substance to be filed in the DMF. These batches should be made under CGMPs. The FDA stability guidance recommends 6 months of accelerated data and 6 months of long-term data for the pilot scale batches to be submitted for a full scientific review of the DMF. Additional long-term data for all thre