2013.8 FDA指南：ANDA：原料药和制剂稳定性试验问答（中英文）

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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 Products

Questions and Answers

ANDA：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DRAFT GUIDANCE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This guidance document is being distributed for comment purposes only.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be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. 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 the Federal Register.

For questions regarding this draft document contact (CDER) Radhika Rajagopalan 240-276-8546.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

August 2013

Generics

Guidance for Industry

ANDAs: Stability Testing of Drug Substances and Products

Questions and Answers

ANDA：原料药和制剂稳定性试验问答

Additional copies are available from:

Office of Communications

Division of Drug Information, WO51, Room 2201

Center for Drug Evaluation and Research

Food and Drug Administration

10903 New Hampshire Ave., Silver Spring, MD 20993

Phone: 301-796-3400; Fax: 301-847-8714

druginfo@fda.hhs.gov

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

August 2013

Generics Contains Nonbinding Recommendations Draft — Not for Implementation

TABLE OF CONTENTS

I. 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 Industry[1]

ANDAs: Stability Testing of Drug Substances and Products

Questions and Answers

ANDA：原料药和制剂稳定性试验问答

This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic.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 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. 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。

FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the wordshould 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 final guidance availability will be announced in the Federal Register. The implementation date is June 20, 2014.
. V4 ?; ^; ?$ C% S- k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 President’s 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[1].
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。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?
: G( v* c. E! J4 R. W9 nANDA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 change[2] or failure of any attribute, 6 months of intermediate data are also recommended at the time of submission.
5 s/ w$ G' Z! t. n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.
: e% Q7 u4 ]$ {7 k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?
& f( p! }& s; D% O4 d0 c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.
7 ?7 T+ }, B, l2 I& N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?
* b8 H( H2 o- o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.
9 O! W$ r# _% R5 i' u5 t: QFDA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?
) s1 [4 U8 E: Y! R+ g! ~' a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.
- L% V5 S! ~. ?% t1 i2 k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?
2 V. h3 o+ z( Y+ v4 R$ P& O0 ]/ E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?
/ }( `- b; k- N7 u/ p! z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 on Handling and Retention of BA and BE Testing Samples may 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.
+ q+ L* W* Z; {! \; [, X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。

[1] This 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.

[2] We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page athttp://www.fda.gov/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。

[3] See the International Conference on Harmonisation (ICH) guidance to industry on Q1A(R2) Stability Testing of New Drug Substances and Products, section 2.2.7.1.

参见ICH行业指南Q1A(R2)新原料药和制剂稳定性试验指南，第2.2.7.1部分。

[4] Defined in ICH Q1A(R2) Glossary.

[5] Ibid.

[6] For nasal aerosols (meter-dose inhalers) and nasal sprays (meter-dose spray pumps), you should submit three different lots of drug substance.

[7] See the guidance for industry on Residual Drug in Transdermal and Related Drug Delivery Systems.

[8] See the CDER Data Standards Manual,http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/DataStandardsManualmonographs/default.htm.

[9] This 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 batches[1] (at least of the pilot scale[2] size) 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 on Initial 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。

[1] Defined in ICH Q1A(R2) Glossary.

[2] Ibid.

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 packaging usefulness (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 Agency’s 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 substance[1] should 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 packaged with commercial equipment, or is it acceptable to package using research equipment or by hand?

小批量的产品是否必须采用商业化设备进行包装，还是可以采用研发设备或手工包装？

A5: Small scale batches should be packaged with commercial equipment. Packaging systems used should be the same as or similar to packaging proposed for storage and market distribution. Please refer to ICH Q1A(R2) section II, B, 3, Selection of Batches (2.2.3) and the glossary definition for primary batches.

小批量应采用商业化设备进行包装。所采用的包装系统应与目标存贮和市售包装相同或相似。请参见ICH Q1A(R2)第II部分，B，3 批次的选择（2.2.3）和内包装的术语定义。

Q6: What will the recommendation for secondary packaging be?

对外包装有什么建议？

A6: We recommend following ICH Q1A(R2) section II, B, 4, Drug Product Container Closure System (2.2.4).

我们建议遵守ICH Q1A(R2)第II部分，B，4 药品包装密封系统（2.2.4）的要求。

Q7: What are the recommendations for stability testing of modified release products?

对于缓释产品的稳定性试验有什么建议？

A7: FDA recommends following the guidance for data on three batches per ICH Q1A(R2). ICH stability guidances do not distinguish among different dosage forms.

FDA对稳定性试验数据的推荐是依据ICH Q1A(R2)三批的要求。ICH稳定性指南并未对不同剂型进行区分。

Q8: What are the recommendations for the submission of oral solutions, ophthalmic solutions, oral and ophthalmic suspensions, transdermal patches, ointments, creams, granules for reconstitution, and parenterals?

对于口服溶液、眼药水、口服和眼用悬混剂、透皮贴剂、软膏剂、擦剂、重塑颗粒剂和注射剂申报有什么建议？

A8: Our recommendations follow ICH Q1A(R2), and we recommend three discrete batches and 6 months of accelerated and long-term data at the time of submission for all dosage forms. Also, refer to other questions and corresponding answers that specifically discuss other dosage forms included in this document.

我们的建议是遵守ICH Q1A(R2)要求，我们建议针对任何剂型均提交三个非连续批次，6个月加速和长期稳定性数据。同时，请参见本文件中针对其它剂型的其它问题和相关回答。

Q9: Are 6 months of stability data required on all three batches, or would one batch at 6 months and two lots at 3 months be acceptable?

是否申报中的三个批次均需要提交6个月稳定性试验数据，还是只要一批有6个月，其它2批可以只有3个月数据呢？

A9: Following ICH stability guidances, 6 months (accelerated) stability is recommended on all three submission batches.

根据ICH稳定性试验指南，建议所有申报批次均提交6个月（加速）稳定性试验数据。

Q10: Should the executed batch records for the three batches be included in the ANDA submission?

三批生产填写的批记录是否需要包括在ANDA申报中？

A10: Yes.

是的

Q11: Does all relevant CMC batch information for the three stability batches need to be included in the application (i.e., excipient Certificate of Analysis (COA))?

是否所有与三个稳定性试验批次的相关CMC批次信息都需要包括在申报资料中（即辅料检验报告）？

A11: Yes. When more than one lot of API or excipients is used, the corresponding section in Module 3 should contain that information.

是的。如果使用了不止一个批号的原料药或辅料，则在模块3中，应包括所有的信息。

Q12: If you are an applicant submitting an ANDA with two API sources, are you required to perform stability on three batches of drug product for each API source?

如果我要提交的ANDA有两个原料药来源，是否需要对每个原料药来源制成的药品各取3批进行稳定性试验呢？

A12: If you propose to add a second or more than two sources of API for the same drug substance, we recommend you provide the following CMC information:

如果你需要增加一个或更多的原料药来生产同一种药品，我们建议你提供以下CMC信息

               

Comparison and justification of comparability (by the firm) of the physico-chemical properties and impurities of the drug substance from each source.

所有不同来源原料药的理化特性和杂质比较和判定

Appropriate stability data on three batches of drug product qualifying the first API source used in the bioequivalence (BE) studies as recommended by the stability guidance.

在稳定性试验指南中，建议用于生物等效性（BE）研究的第一个原料药所生产的3批药品应有适当的稳定性数据。

A single pilot scale batch of the drug product bio-strength(s) manufactured using the second or each of the other proposed API source(s) used to support the ANDA application, along with comparative dissolution data.

第二个及其它来源的原料药生产一个中试批次药品的数据，用以支持ANDA申报，以及比较性溶出度数据。

Appropriate stability data (accelerated and long-term for 6 months at the time of filing) on the strength(s) manufactured for each API source. Appropriate stability data may in some cases include intermediate condition stability data.

每个原料药来源生产的不同剂量下适当的稳定性数据（申报时有长期和加速6个月数据）。有些情况下，适当的稳定性数据需要包括中间条件稳定性数据。

Q13: What is meant by “small” scale? “Small” is not a defined word in ICH guidance. What are the packaging expectations from the small batch, as well as from the two pilot scale batches? Traditionally, ANDAs are submitted with 100,000 units for solid oral dosage forms. Is this still applicable?

“小”批量是什么意思？在ICH指南中“小”是没有定义的。小批量的包装期望是怎么样的，是要求与两个中试批准相同吗？传统意义上，ANDA固体口服制剂申报批要求是100，000个最小单位包装，现在还适用吗？

A13: The interpretation of what constitutes a small scale batch for the purpose of filing ANDAs is further elaborated below for various dosage forms and their packaging recommendations. Unless specifically noted below, one primary batch should be fully packaged.

在提交ANDA时所要求的小批量是什么，在下面对不同剂型及其包装情况进行了说明。如果以下未另加说明，则一个基本批的数据应全部进行包装。

Oral dosage forms 口服制剂

(a) Tablets/Capsules (e.g., immediate release, extended release, chewable, orally disintegrating and delayed release tablets or capsules): 片剂、胶囊（例如中间释放、缓释、咀嚼、口腔崩解、延时释放片剂或胶囊）

Two of the three batches should be of at least 10 percent of the proposed production batch or 100,000 finished dosage units, whichever is greater (i.e., pilot scale batches). The third batch can be smaller than the 10 percent of the proposed production batch, but not less than 25 percent of the pilot scale batch. We recommend stability data be generated for the three ANDA submission batches in the proposed marketing container. A minimum of 100,000 units in all proposed presentations is recommended. Representative samples from all three batches must be packaged in a sufficient number of proposed marketing presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b).

三批中的两批应达到目标批量的至少10%，或至少100,000最小制剂单位，取其中较大者（即中试批次）。第三批可以比目标批量的10%小，但不能低于中试批量的25%。我们建议稳定性数据由目标市售包装三批ANDA申报批产生。建议所有包装形式至少包括100,000个最小制剂单位。三批申报批中具有代表性的样品应有足够数量进行市售包装，满足21CFR211.166(a)（1-5）和211.166（b）的要求。

(b) Powders/Solutions/Suspensions: 粉剂/溶液/混悬剂

Two of the three batches should be at least 10 percent of the proposed maximum size commercial batch. The third batch can be smaller than 10 percent of the proposed commercial batch, but not less than 25 percent of the pilot scale batch. To capture variability introduced by packaging, the product from all the batches should be used in the packaging process. We recommend packaging representative samples from all three batches of a sufficient number of proposed marketing presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b) .

3批中的2批要求是商业最小批量10%的批量。第3批可以小于提出的商业批量的10%，但不小于中试批准的25%批量。为了发现包装引起的差异，所有批次产品均应采用申报的包装工艺进行包装。 我们建议根据21 CFR 211.166(a)(1-5) 和 211.166(b)中的要求，对所有3批中均按申请的上市包装对足够数据样品进行包装获得代表性样品。

Parenterals Solutions/Powders for Solutions (lyophilized cakes)/Suspensions/Sterile Topicals (Ophthalmic and Otic drug products):

注射液/溶液用粉剂（冻干粉）/混悬剂/无菌局部（眼用和耳用剂）

Two of the three batches should be at least 10 percent of the proposed maximum size commercial batch (i.e., pilot scale size) or 50 L (per batch), whichever is larger. The third batch can be smaller than 10 percent of the proposed commercial batch, but not less than 25 percent of the pilot scale batch. To capture variability introduced by packaging, the product from all the batches should be used in the packaging process. Representative samples from all the three batches should be packaged in a sufficient number of proposed marketing presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b). We recommend manufacturing all the batches to meet sterility requirements.

3批中的2批应是申报的商业批量至少10%批量（即中试批量）或50L（每批），取大者。第3批可以小于申请的商业批次的10%，但不小于中试批量的25%。应根据21 CFR 211.166(a)(1-5) 和211.166(b)中的要求，对所有3批中均按申请的上市包装对足够数据样品进行包装获得代表性样品。我们建议所有批准生产均满足无菌要求。

Transdermal Patches 经皮给药贴剂

Two of the three batch sizes for each strength should be at least 10 percent of the proposed commercial production batch or 25,000 units (for each strength), whichever is greater. The third batch can be smaller than 10 percent of the proposed commercial batch, but not less than 60 percent of the pilot scale batch. For transdermal matrix products, where different strengths are identified by the transdermal patch size (surface area), to comply with the three batch size recommendation, we recommend providing data on patches manufactured using three distinct matrix laminates at the time of submission. (Each laminate can be cut to support multiple strengths in the application, where applicable.) We recommend you contact the appropriate review division if you are manufacturing transdermal patches using other technologies (e.g., reservoir).[2]

各不同剂量的3批中的2批批量应至少为申报商业批量的10%，或23000个最小单位（每个剂量），取其大者。第3批可以小于申报的商业批量的10%，但不能小于中试批量的60%。对于经皮给药支架产品，如果剂量差异与贴剂尺寸（表面积）差异相同，符合3个批量的推荐，我们建议在申报时提供采用3个明显区别的支架压板（适用时，每个压板可以剪切以支持申报中的不同剂量）。如果你采用了其它技术（例如膏药）来生产经皮给药贴剂，我们推荐你联系适当的审核部门，

You should include a representative sample from all three batches using different components of backing, adhesives, release liner, and other critical excipients used in packaging a sufficient number of proposed marketing presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b).

你应该包括所有3个批号采用不同基底成份、粘性材料、防粘衬里和其它用于包装的关键辅料的代表性样品，采用上市包装获得足够数量的样品，以满足21 CFR 211.166(a)(1-5) 和 211.166(b)的要求。

Topicals 局部用药

(a) Creams/Lotions/Gels: 膏剂/洗液/胶

For nonsterile semi-solid dosage forms[3], the two pilot scale batches should be at least 100 Kg or 10 percent of the production batch, whichever is larger. The third batch can be smaller than 10 percent of the proposed commercial batch, but not less than 40 percent of the pilot scale batch. We recommend packaging representative samples from all the three batches in a sufficient number of proposed marketing presentations to comply with 21 CFR 211.166(a)(1-5) and 211.166(b) .

对于非无菌半固体剂型，应有2批中试批次，批量至少100kg或商业批量的10%，取其大者。第3批可以小于商业批量的10%，但不得小于中试批量的40%。我们推荐所有3个批次均有足够数据上市包装的代表性样品，以符合21 CFR 211.166(a)(1-5) 和 211.166(b)的要求。

(b) Inhalation Solutions/Nasal Sprays (nasal nonmetered dose atomizer): 吸入溶液/鼻腔喷剂（鼻腔非定量喷雾器）

Please refer to the following guidances for industry for information: Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products – Chemistry, Manufacturing, and Controls Documentation, and Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action.

请参见以下行业指南：鼻腔喷雾剂和吸入溶液，混悬液，和喷雾药品------化学，生产，和控制文件，和鼻腔气雾剂和鼻腔喷剂的生物有效性和生物等效性研究

Please contact OGD to discuss other dosage forms and/or routes of administration not covered in this document.

如需讨论其它剂量形式和/或在本文件中未涵盖的给药方法，请联系OGD。

Q14: Is it acceptable to use a technical grade of the drug substance for the small scale batches or one of the two pilot scale batches of finished product?

是否可以采用技术级的原料药用于小批量或两个中试批中的一批的药品生产？

A14: No. CGMP requirements for ANDA submission are expected for the drug substance and drug product. Because the drug substance quality can affect the drug product stability, the drug substance used for the ANDA batches (supporting the application) should be of the same quality intended for the market product. We would consider data from the use of a different grade drug substance for a product as supporting data. This does not satisfy the submission batch recommendations.

不可以。ANDA申报要求原料药和制剂均在CGMP状态下生产。由于原料药质量可能会影响药品稳定性，用于ANDA批次的原料药（支持申报）应具有上市药品相同的品质。我们会考虑采用不同级别原料药生产所得的数据作为支持性数据，但这并不符合申报批次的要求。

[1] For nasal aerosols (meter-dose inhalers) and nasal sprays (meter-dose spray pumps), you should submit three different lots of drug substance.

[2] See the guidance for industry on Residual Drug in Transdermal and Related Drug Delivery Systems.

[3] See the CDER Data Standards Manual,http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/DataStandardsManualmonographs/default.htm.

15: Do the small scale batches need to be manufactured in accordance with all CGMP regulations, or is it acceptable to manufacture the small scale batches in a research setting?

小批是否需要根据所有CGMP法规要求进行生产，还是可以在小规模的研发设施中进行？

A15: All ANDA submission batches should be made under CGMP.

所有ANDA申报批应在CGMP条件下生产。

Q16: Do the small scale batches need to meet the same finished product specification as the pilot scale batches?

小批是否需要符合中试批次的药品质量标准？

A16: Yes. The specification should be the same for all three ANDA submission batches.

是的。质量标准应与所有三批ANDA申报批次相同。

Q17: For sterile products, is it acceptable to manufacture the small scale batches in a nonsterile facility and allow variance from sterility and particulate criteria?

对于无菌产品，是否可以在非无菌设施中生产小批量，允许无菌质量与特定的标准有一些差异？

A17: No. Batches should not be manufactured in a nonsterile facility. Sterility is a critical quality attribute (CQA) for sterile products.

不可以。所有批次不可以在非无菌设施中生产。无菌性无菌产品的关键质量属性。

Q18: Do small scale batches need to be produced at the proposed commercial site?

小批是否需要在申报的商业生产场所进行生产？

A18: Yes. The primary batch information submitted in the application is used to support the proposed commercial product manufacture. Product batches produced at a different site than the proposed commercial site would not be considered as primary batches.

是的。包括在申报中的基本批次信息是用于支持目标产品生产的。在不同于目标生产场所生产的产品批次将不会被作为基本批次。

Q19: In cases where an intermediate bulk material is identical between the various strengths (dose proportional blends, bulk solutions, etc.), is it sufficient to perform stability on one lot of each strength, when each strength is produced from a separate intermediate bulk?

如果中间体散装物料不同剂量（按剂量成比例混合、散装溶液等）中用量相同，每个剂量由一个独立的中间体散装批号生产得到，是否仅对每个剂量取一批进行稳定性试验就可以了？

A19: No. For ANDAs that contain multiple strengths (that are dose proportional), three separate intermediate bulk granulations (or blends) should be manufactured. One batch of bulk granulation (or blend) should be used to manufacture all the strengths proposed. The other two bulk granulations (or blends) can be used to manufacture only the lowest and the highest strengths, in addition to the strength used in BE studies. Stability testing should still use all three batches of drug product.

不可以。如果ANDA包括多剂量（按剂量成比例），应生产3个单独的中间体散装颗粒（或混合）批号。一批颗粒（或混合）应用于生产所有申报剂量的生产。其它2批颗粒（或混合）可用于生产最低和最高剂量，用于生物等效性研究的剂量除外。稳定性研究应使用所有3个制剂批号。

Q20: What are the exception criteria from meeting the minimum size for pilot scale recommendations for ANDA submission batches? What justification would be needed if we wanted to deviate from the guidance recommendations?

ANDA申报批次所规定的最小批量是否可以有例外？如果我们想采用的批量不符合指南推荐的批量，需要有哪些论述？

A20: The submission ANDA batches can have a smaller size than the established pilot scale, according to the ICH definition, when any one of the following circumstances prevails:

              根据ICH定义，在以下情况下，ANDA申报批次的批量可以小于中试批量。

The reference listed drug product has an orphan drug designation.

药品为相关清单所列的孤儿药

Use of a controlled drug substance is based on a Drug Enforcement Administration allocation.

对受控药品的使用受到药品实施管理要求的限制。

The test batch size is the same as the commercial batch size with the commitment that a prior approval supplement (PAS) will be provided when there is a scale-up.

测试批量与商业批量相同，同时提交“如果放大批量则会递交一个预批准补充申报（PAS）”的承诺。

Q21: Are scale-up and postapproval changes (SUPAC) level one and two variations and changes permitted among the three ANDA submission batches for components and composition?

3个ANDA申报批次中，是否允许对成分和组成进行批量放大和批准后变更（SUPAC）第1级和第2级变更？

A21: No. The three ANDA submission batches should maintain the chosen formula based on product development studies for components and composition.

不允许。3个ANDA申报批次中的成份和组成应保持研发时所选择的配方。

Q22: Can some specific examples of cases where statistical analysis is required and type of analysis needed be provided?

有些特殊例子时，是否需要进行统计分析，是否需要提供分析的类型？

A22: The stability guidance recommends analysis of data in accordance with ICH Q1E, Appendix A. The flowchart in that guidance provides clear situations where analysis is normally recommended or unnecessary. In addition, ICH Q1E B.7 figures provide example diagrams for assay and degradation products that illustrate how plots should be generated for the three batches using regression lines and upper and lower confidence limits.

稳定性指南推荐根据ICH Q1E附件A的要求进行数据分析。该指南中的流程图对不同情况作了明确说明是否需要进行统计分析。另外，ICH Q1E B.7图提供了含量和降解产物的样例，说明了如何从3批数据中产生线性回归和上下限置信区间限度的图表。

D. Amendments to Pending ANDA Application 未批准ANDA申请的增补

Q1: What are the recommendations for amendments and responses filed to pending ANDAs after issuance of the new guidance?

在新指南发布后，如何处理尚未批准的ANDA所需的增补和回复？

A1: All amendments submitted to pending ANDAs after the effective date of the final stability guidance will be held to the standards in place at the time of the original ANDA submission, unless there is a concern with the submitted stability data.

在稳定性指南正式生效后，所有对未批准ANDA所提交的增补均按初始ANDA提交时的标准要求处理，除非其中涉及已提交的稳定性数据。

E. Stability Studies 稳定性研究

Q1: What will be the expected testing time points on accelerated conditions?

加速条件下试验时间点要求是怎样的？

A1: In general, we recommend four time points (i.e., 0 (initial release), 3 months, 6 months, and one additional time point) to the study design for all ANDAs[1].

一般来说，我们推荐对所有ANDA研究设计均使用4个时间点（即0点（初始检验放行）、3个月、6个月和1个附加时间点）。

Q2: Can the Agency clarify expectations for the storage positions for products placed into the stability program?

官方是否可以澄清一下对放入稳定性试验程序的产品的存贮位置有什么要求？

A2: For primary batches of liquids, solutions, semi-solids, and suspensions, the product should be placed into both inverted (or horizontal) position and upright (or vertical) position. For routine stability studies, the firm should pick the worst case orientation for the study.

对于液体、溶液、半固体和混悬剂的初始批次，产品应采用垂直和水平两种状态放置。对于常规稳定性研究，公司应选取最差情况进行研究。

Q3: When and how are reconstitution/dilution studies performed?

什么时间需要进行溶解/稀释研究？如何进行？

A3: Recommendations listed in Q1A(R2), section II, B, 7, Storage Conditions (2.2.7) should be followed for all three batches. These studies should be performed when the drug product is labeled for reconstitution or dilution.

在Q1A(R2)第II部分，B.7中，存贮条件（2.2.7）中给出了推荐意见，所有3批均应按该要求进行。如果产品标示需要溶解或稀释，则需要进行这些研究。

Q4: What type of containers are classified as semipermeable containers, and can the Agency clarify the stability expectations for the drug products in semipermeable containers?

什么类型的包装归类为半透包装，官方是否可以对半透包装的稳定性要求进行说明？

A4: Examples of semipermeable containers are provided in the Q1A(R2) glossary. The recommendations for stability expectations for semipermeable containers are detailed in ICH Q1A(R2) section II, B, 7, c. Drug products packaged in semipermeable containers (2.2.7.3).

在Q1A(R2)术语中已提供了半透包装的举例。对半透包装的稳定性要求在ICH Q1A(R2)第II部分，B.7.c.“半透包装药品”（2.2.7.3）中有详细说明。

Q5: Can the Agency clarify expectations around the number of batches to support tests such as preservative effectiveness and extractable leachable testing?

官方可否说明一下支持象具代表性有效性和溶出试验这样的支持性测试所需要的批次数是多少？

A5: One of the primary batches of the drug product should be tested for antimicrobial preservative effectiveness (in addition to preservative content) at the end of the proposed expiration dating period. The drug product specification should include a test for preservative content, and this attribute should be tested in all stability studies.

初始批次中的1批应进行在申报的有效期结束时测试抗微生物防腐效果（除防腐剂本身外）。药品质量标准应包括防腐成份检测，该属性应在包括在所有稳定性试验中。

Extraction/leachable studies are generally one time studies; however, if multiple types of containers/closures are employed for packaging, then additional studies could be recommended.

溶出物/浸出物研究一般是一次性研究，但是，如果采用了不同容器/密闭系统进行包装，则推荐进行更多研究。

Q6: When are in-use stability studies needed?

什么时候需要进行在用稳定性试验？

A6: Please refer to response A3 under section E Stability Studies.

请参见E稳定性研究部分对A3的答复。

Q7: Are there changes to postapproval protocols and commitments when ICH stability guidances are implemented because of scale or type of batches submitted?

在ICH稳定性指南实施后，会不会因为提交的批次批量或类型原因而需要对已批准稳定性方案和承诺进行变更？

A7: ICH Q1A(R2), section II, B, 8, Stability Commitment (2.2.8) addresses this question. Section 2.1.8 provides information regarding stability commitment for drug substances.

ICH Q1A(R2), 第II部分, B, 8, 稳定性试验承诺(2.2.8)对此问题进行了说明。在2.1.8部分说明了关于制剂产品稳定性承诺相关的信息。

[1] This recommendation also applies to nasal spray, inhalation solution, suspension, aerosols, and liposomal drug products.

感谢楼主分享，很棒的材料！