2013.8 FDA指南：ANDA：原料药和制剂稳定性试验问答(中英文)

.201308 FDA指南：ANDA：原料药和制剂稳定性试验问答（中英文）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and ProductsQuestions and AnswersANDA：原料药和制剂稳定性试验问答DRAFT GUIDANCE指南草案This guidance document is being distributed for comment purposes only.本指南文件发布仅供讨论。Comments and suggestions regarding this draft document should be submitted within 60 days of publication in theFederal Registerof the notice announcing the availability of the draft guidance. Submit electronic comments to. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in theFederal Register.For questions regarding this draft document contact (CDER) Radhika Rajagopalan 240-276-8546.U.S.Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)August 2013GenericsGuidance 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: 301-847-8714/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmU.S.Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)August 2013GenericsContains Nonbinding RecommendationsDraft Not for ImplementationTABLE OF CONTENTSI. INTRODUCTION介绍II. QUESTIONS AND ANSWERS问与答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for Industry1ANDAs: Stability Testing of Drug Substances and ProductsQuestions and AnswersANDA：原料药和制剂稳定性试验问答This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current thinking on this topic.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.本指南草案，如果最终定稿，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 draft guidance provides answers to questions from the public comments we received on the draft guidance for industry onANDAs: 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. 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.本指南草案是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。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 wordshouldin 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 finalguidance availability will be announced in the Federal Register. 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。最终指南将在联邦注册上公布。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 onFixed Dose Combinations, Co-Packaged Drug Products, and Single-Entity Versions of Previously Approved Antiretrovirals for the Treatment of HIV1.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 onFDA 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。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 change2or 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变化或任何属性失败，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): In the event accelerated data show significant change or failure of any attribute in one or more batches, intermediate data is recommended for all three batches.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，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 proposed expiry period of two times the available long-term data at the time of approval (up to 24 months) following the ICH Q1E Evaluation of Stability Data (ICH Q1E) guidance, provided the submitted data are satisfactory, and data evaluation is 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.FDA会给出一个有效期，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: No. You should follow the recommendations in the stability guidance where three pilot scale batches or two pilot scale batches and one small scale batch are recommended. This applies to all dosage forms.不可以。应该满足稳定性指南的要示，即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。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 expiration dating. 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. Stability data from three ANDA submission batches at 12 months long-term are recommended for 24-month extrapolation.ICH Q1E原则可以帮助计算有效期。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。三批ANDA申报批次12个月长期稳定性数据可以外推为24个月有效期。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: For 6 months accelerated data, will 24 weeks be the timeframe required because 12 weeks is accepted as equivalent to 3 months?对于6个月加速数据，是否会因为12周可以接受等同于3个月，所以需要24周的时间框架？A8: No. The ICH stability guidances have indicated time recommendation only in terms of months.不需要。ICH稳定性指南已经指出时间推荐仅用月计。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 regardless of patent status; 6 months of accelerated data are recommended at the time of filing the ANDA.不可以。不论专利状态如何，必须遵守ICH稳定性指南。递交ANDA时，必须要有6个月加速稳定性数据。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 addition, the guidance for industry onHandling and Retention of BA and BE Testing Samplesmay be helpful. 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 should be stored following requirements listed in the CFR citations and recommendations in the guidance listed above.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。另外，行业指南“BA和BE试验样品的处理和保留”也会有帮助。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CFR中列出的要求以及上述指南中的推荐。1This guidance has been prepared by the Office of Generic Drugs, Office of Pharmaceutical Science in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.2We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.我们会周期更新指南。为保证你所获得的是最新版本，请核对FDA官网。3See the International Conference on Harmonisation (ICH) guidance to industry onQ1A(R2) Stability Testingof New Drug Substances and Products, section .参见ICH行业指南Q1A(R2)新原料药和制剂稳定性试验指南，第部分。4Defined in ICH Q1A(R2) Glossary.5Ibid.6For nasal aerosols (meter-dose inhalers) and nasal sprays (meter-dose spray pumps), you should submit three different lots of drug substance.7See the guidance for industry onResidual Drug in Transdermal and Related Drug Delivery Systems.8See the CDER Data Standards Manual,/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/DataStandardsManualmonographs/default.htm.9This recommendation also applies to nasal spray, inhalation solution, suspension, aerosols, and liposomal drug products.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): Are stability data from three current good manufacturing practice (CGMP) batches required to be filed in the DMF to support the API retest date?为了支持原料药的复验期，包括在DMF里的三批稳定性数据是否需要在GMP状态下生产？A1(i): ICH Q1A(R2) recommends three primary batches1(at least of the pilot scale2size) for the drug substance filed in the DMF. These batches should be made under Current Good Manufacturing Practices (CGMP). The stability guidance recommends a minimum of 6 months of accelerated and 6 months of long-term data for the pilot scale batches to be submitted initially. Additional long-term data for all three batches, as the data becomes available through the proposed retest period, should be submitted as an amendment. ICH Q1A (R2)建议三个基本批次（至少为中试批量）用于原料药DMF申报。这些批次应在CGMP的条件下生产。稳定性试验指南推荐在初始申报中包括中试批至少6个月加速试验和6个月长期稳定性试验数据。除了3批长期稳定性数据外，由于在提出的复试期内，能获得更多数据，这些后续数据应在增补中提交。Q1(ii): 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 the same?在对DMF进行“完整性评估”时，需要多少个月的长期和加速稳定性试验数据？DMF稳定性部分应包括哪些内容？A1(ii): To pass the Completeness Assessment (see the draft guidance for industry onInitial Completeness Assessments for Type II API DMFs under GDUFA), DMFs should have 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. The DMF holder should amend the DMF with updated stability data to prepare for the full scientific review, if the DMF does not meet the recommendations under A1(i) above at the time of the Completeness Assessment.要通过完整性评估（见行业指南草案：对二类原料药DMF根据GDUFA法案进行的初始完整性评估），DMF应包括稳定性试验方案、承诺、数据证明稳定性研究已开始。初始检验数据和一个时间点的加速和长期稳定性研究应足够了。如果DMF在完整性评估时不符合A1(i)中的要求，DMF持有人应提交更新的稳定性数据作为补充，为全面的科学性审阅作好准备。Q2: Will submissions to DMFs be accepted based on stability data from production scale batches?基于生产批量的批次的稳定性数据的DMF申报能被接受吗？A2:Yes. Per ICH Q1A(R2), section II, A, 8, Stability Commitment (2.1.8), the submission is appropriate if satisfactory stability data from three production batches made under CGMP are filed in the DMF with 6 months of accelerated data and long-term data covering the proposed retest period.是的。根据ICH Q1A(R2)，第II部分，A，8，稳定性承诺（2.1.8），申报文件中如果是在GMP条件下三个大生产批次，具有6个月加速和长期稳定性试验数据，覆盖建议的复验期，是可以接受的。1Defined in ICH Q1A(R2) Glossary.2Ibid.C. Drug Product Manufacturing and Packaging药品生产和包装Q1: Can the split bulk solution filled into different fill volumes be considered different batches?将散装溶液装入不同分装体积应作为不同批号吗？A1: No. Split filling one batch of bulk solution into different fill volume sizes does not constitute discrete batches.不。分装一个批号散装溶液至不同分装体积不构成分批。Q2: Can you clarify the packaging recommendations for the submission batches for blow-fill-seal containers?可否说明一下对吹瓶/灌装/封口的包装形式申报批有什么包装方面的建议？A2: Blow-fill-seal containers are not an exception from regular packaging and are usually packaged inside a secondary container or a carton. The secondary packaging should be included in all three batches. ICH Q1A(R2) addresses secondary packagingusefulness(see section II, B, 4, Drug Product Container Closure System (2.2.4).吹瓶/灌装/封口的包装形式仍是常规包装的一种，通常还会有外包装或纸箱包装。三个批次均应进行外包装。ICH Q1A(R2)里说明了外包装是有用的。（参见第II部分，B，4，药品包装（2.2.4）Q3: Should all three batches be stored in final proposed packaging?所有三个批次均应以完整的包装形式存贮吗？A3: Yes. You should package all three batches in the container closure system proposed for marketing. Q1A(R2) addresses this question (see section II, B, 4, Drug Product Container Closure System (2.2.4).是的。需要将三批产品以上市申请的包装形式进行包装。Q1A(R2)中说明了该问题（参见第II部分，B，4，药品包装（2.2.4）。Q4: What is the Agencys position on using different lots of APIs and/or packaging materials? How many API lots should be used in the manufacture of finished product lots used to support the ANDA?法规当局对于采用不同批次原料药和/或包装材料是什么态度？在药品生产中可以使用多少批次原料药来支持ANDA？A4: A minimum of two lots of the drug substance1should be used to prepare the three primary batches of drug product. It is not necessary to use different lots of packaging material, except in cases where the packaging material could affect drug product performance and/or delivery.应至少使用2个批次的原料用于制备3个批次基本批的药品生产。不需要采用不同批次的包装材料，除非包装材料可能会对药品的性能和/或运输产生影响。Q5: Should the small scale batches be packa