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201006 FDA行业指南 可在年报中报告的CMC已批准生产变更草案（中英文）2013-01-22 16:04:09| 分类： FDA|字号 订阅
Guidance for Industry
行业指南
CMC Postapproval Manufacturing Changes Reportable in Annual Reports
可在年报中报告的CMC已批准生产变更
DRAFT GUIDANCE
指南草案
This guidance document is being distributed for comment purposes
only.本指南文件仅供征求意见。
Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.Submit comments to the Division of Dockets Management(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm.1061, Rockville, MD 20852.All comments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)Jon E.Clark at 301-796-2400.关于本草案的问题请联系CDER Jon E.Clark at 301-796-2400
U.S.Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research(CDER)
June 2010
CMC
Guidance for Industry
行业指南
CMC Postapproval Manufacturing Changes Reportable in Annual Reports
可在年报中报告的CMC已批准生产变更 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 20993-0002 Phone: 301-796-3400;Fax: 301-847-8714
druginfo@fda.hhs.gov
www.daodoc.complianceRegulatoryInformation/Guidan
ces/default.htm
U.S.Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research(CDER)
June 2010
TABLE OF CONTENTS I.INTRODUCTION.介绍............................................................................................................1 II.BACKGROUND.背景..............................................................................................................1 III.DISCUSSION..讨论..................................................................................................................2 IV.CONTENTS OF ANNUAL REPORT NOTIFICATION.年报通知的内容.........................4 APPENDIX A: CMC POSTAPROVAL MANUFACTURING CHANGES REPORTABLE IN ANNUAL REPORTS......................................................附件A：可在年报中报告的CMC已批准生产变更
Guidance for Industry[1] 行业指南
CMC Postapproval Manufacturing Changes Reportable in Annual Reports
可在年报中报告的CMC已批准生产变更
This draft guidance, when finalized, will represent the Food and Drug Administration’s(FDA’s)current thinking on this topic.It does not create or confer any rights for or on any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 discu 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 recommendations to holders of new drug applications(NDAs)and abbreviated new drug applications(ANDAs)regarding the types of changes that may be reported in annual reports.Specifically, the guidance describes chemistry, manufacturing, and controls(CMC)postapproval manufacturing changes that we have determined will likely present minimal potential to have adverse effects on product quality and, therefore, may be reported by applicants in an annual report.[2][3] 本指南给NDA和ANDA持有人提供建议，说明哪些变更可以在年报中进行报告。指南专门针对的是化学、生产和控制（CMC）批准后生产变更，哪些可能对产品质量产生潜在不良影响很小，因此可以在年度报告中进行报告。
Appendix A lists the CMC postapproval manufacturing changes previously submitted under manufacturing supplements that we have determined to be generally of low risk to product quality(product identity, strength, quality, purity, and potency as they relate to the safety or effectivene of the product).附件A列出了CMC已批准生产变更，我们认为一般来说对产品质量（与产品安全性或有效性相关的属性，如产品鉴别、剂量、质量、纯度和效价）影响较低，但之前要求在生产增补中提交的变更。
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, unle 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，包括本文件，并未设立法律强制责任。它只是描述了当局目前对某一主题的想法，如果未引用特定的法律法规要求的话，应仅作为推荐。“应当should”一词在指南中表示建议或推荐的做法，并非强制。
II.BACKGROUND 背景
An applicant must notify FDA of a change to an approved application in accordance with all statutory and regulatory requirements—including section 506A of the Federal Food, Drug, and Cosmetic Act(21 U.S.C.356a)(the Act), which was added by section 116 of the Food and Drug Modernization Act,[4] and 21 CFR 314.70.Section 506A of the Act provides requirements for making and reporting manufacturing changes to an approved application and for distributing a drug product made with such changes.Under 21 CFR 314.70, all postapproval CMC changes beyond the established variations in an approved NDA and ANDA are categorized into one of three reporting categories: major, moderate, or minor.对于已根据相关的法规要求—包括联邦食品药品和化妆品法案（21 U.S.C.356a）第506A条（该条款经由食品和药品现代化法案和21CFR第314.70条增加）获得批准的申请，申请人必须将相关变更通知FDA。法案的第506A条说明了对已批准的申请生产变更报告要求，和对药品的销售变更报告要求。根据21CFR314.70，所有超出已批准的NDA和ANDA中已有变更范围的预批准CMC变更均属于三个报告类别之一：重大、中等、轻微。
If a change is considered to be major, an applicant must submit and receive FDA approval of a supplement before the product made with the manufacturing change is distributed.If a change is considered to be moderate, an applicant must submit a supplement at least 30 days before the product is distributed or, in some cases, submit a supplement at the time of distribution.If a change is considered to be minor, an applicant may proceed with the change, but must notify FDA of the change in an annual report.For any change, applicants must ae the effects of the change as they relate to product safety and efficacy and demonstrate those effects through appropriate studies to determine whether it would be more appropriate to submit a supplement.For additional background information regarding the reporting categories for NDAs and ANDAs, see FDA’s guidance for industry on Changes to an Approved NDA or ANDA(April 2004).[5] 如果变更被作为是重大变更，则申请人必须提交变更至FDA，并在收到FDA批准后才能将变更后工艺生产的产品用于销售。如果变更被作为是中等，申请人必须在产品销售前30天提交变更申请，或在某些情况下，在销售同时提交变更申请。如果变更被作为是轻微的，则申请人可以直接进行变更，但必须在变更当年的年报中通知FDA。对于任何变更，申请人均必须评价变更对产品安全性和有效性的影响，通过适当的研究证明该变更是否需要提交变更申请。更多与NDA和ANDA报告分类相关的背景资料，请参见FDA指南“已批准的NDA和ANDA的变更”（2004年4月）（注释5）。
In our September 2004 final report, Pharmaceutical Current Good Manufacturing Practices(CGMPs)for the 21st Century – A Risk-Based Approach(Pharmaceutical Product Quality Initiative), FDA stated that to keep pace with the many advances in quality management practices in manufacturing and to enable the Agency to more effectively allocate our limited regulatory resources, we would implement a cooperative, risk-based approach for regulating pharmaceutical manufacturing.As part of this approach, FDA determined that to provide the most effective public health protection, our CMC regulatory review should be based on an understanding of product risk and how best to manage this risk.在我们2004年9月最终报告“21世纪药品CGMP—基于风险的方法”（药品质量创新）中，FDA申明继续进行质量管理规范倡议，促进当局更有效利用我们有限的法规资源。我们将建立一个合作的，基于风险的方法对药品生产进行管理。作为该方法的一部分，FDA决定提供更有效的公共安全保护，我们的CMC法规审核将基于对产品风险的理解，以及如何更好地管理这种风险。
In addition to the requirements in section 506A of the Act and 21 CFR 314.70, applicants are required to comply with other applicable laws and regulations, including the CGMP for Finished Pharmaceutical regulations in 21 CFR Parts 210 and 211.除了法案第506A部分和21CFR 314.70之外，申请人还需要符合其它与申报相关的法律法规，包括在21CFR（美国联邦法规）第210和211中关于制剂CGMP的法规。
III.DISCUSSION 讨论
The number of CMC manufacturing supplements for NDAs and ANDAs has continued to increase over the last several years.In connection with FDA’s Pharmaceutical Product Quality Initiative and our risk-based approach to CMC review, we have evaluated the types of changes that have been submitted in CMC postapproval manufacturing supplements and determined that many of the changes being reported present very low risk to the quality of the product and do not need to be submitted in supplements.在过去几年中，对NDA和ANDA的CMC生产变更申请数目持续增长。与FDA的“药品质量倡议”和我们对CMC基于风险的审核方法相关连，我们对已提交的CMC批准后生产变更进行了评价，并认为其中许多变更对产品质量的风险极小，不需要提交变更批准。
Based on this recent evaluation, we developed a list(see Appendix A)to provide current recommendations to companies regarding which postapproval manufacturing changes for NDAs and ANDAs may be considered to have a minimal potential for an adverse effect on the identity, strength, quality, purity, or potency of the drug product and, therefore, may be claified as a change reportable in an annual report(e.g., notification of a change after implementation)rather than in a supplement.The changes are categorized according to types of manufacturing changes and are either additions or revisions to the claification of changes listed in the guidance, Changes to an Approved NDA or ANDA.基于最近的评价，我们列出了一个清单（见附件A），向公司建议，对于一些可以认为对药品的鉴别、剂量、质量、纯度或效价只有非常小的潜在负面影响的已批准的NDA和ANDA生产变更，可以归类为年报变更（例如实施后通知类型），而不需要提交增补。根据生产变更的类型分类的变更，以及对变更分类的增加和修订已在指南“已批准NDA或ANDA”中列出。
Thus, if you are submitting supplemental applications that are based on the recommendations for CMC changes provided in Changes to an Approved NDA or ANDA, you also should refer to the list of risk-based recommendations that are provided in Appendix A of this guidance to determine if a particular change may now be reported in an annual report.[6] In addition, the recommendations in this guidance should help clarify when to submit a supplement and when a change may be reported in an annual report.因此，如果你正准备根据“已批准NDA或ANDA”中CMC变更建议提交增补申请，你需要同时参考基于风险的建议清单，该清单是本指南附件A，以决定某个具体的变更现在是否可以在年报中报告。另外，本指南中的建议可以帮助澄清什么时候需要提交一个增补，什么时候变更可以包括在年报中。
We expect NDA and ANDA holders to evaluate the specific change that they are planning to make in the context of their particular circumstances to determine whether the proposed change would present a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product.Based on such an analysis, an NDA or ANDA holder may decide that a change described in Appendix A would more appropriately be submitted as a supplement rather than in an annual report.We, therefore, consider this guidance to provide recommendations for changes that may be appropriately submitted in an annual report rather than to provide a mandatory requirement for reporting these changes in annual reports pursuant to 21 CFR 314.70(a)(3).[7] 我们希望NDA和ANDA持有人对具体的计划中的变更进行评价，根据其具体的环境来决定提议的变更是否对药品的鉴别、剂量、质量、纯度或效价只有非常小的潜在负面影响。基于该分析，NDA或ANDA持有人可以决定在附件A中所述的变更是否更适合提交一个增补，而不是在年报中报告。在此，我们认为本指南仅是提供一些建议，说明一些变更可能可以在年报中报告，而不是根据21CFR 314.70(a)(3)强制要求这些变更必须在年报中报告。
Applicants should remember that regardle of the reporting category for the postapproval manufacturing change, they are required to comply with the CGMP for Finished Pharmaceuticals regulations at 21 CFR Parts 210 and 211.Also, applicants should note FDA’s recommendations for active pharmaceutical ingredient manufacturing that are provided in the guidance for industry, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients.CGMP regulations for finished pharmaceuticals contain specific requirements relevant to the types of changes addreed in this guidance, and compliance with the CGMP regulations is required regardle of how the change is reported to the Agency.CGMP requirements include the need to qualify equipment as suitable for its intended use, the need to aure validated test methods and ongoing state of control of manufacturing procees, and the requirement to maintain appropriate written procedures that the quality unit has reviewed and approved.[8] 申请人应记住，不管已批准的生产变更如何分类，这些变更都需要符合21CFR 210和211中CGMP对制剂法规的要求。同时，申请人还要注意FDA对活性原料药生产的建议已包括在行业指南“Q7A 原料药GMP”中。CGMP对制剂的法规包括对本指南中所述的变更类型的特定要求，不管变更类型如何，所有变更均需要符合CGMP法规要求。CGMP要求包括了需要确认设备是否符合其用途，需要使用验证过的检验方法，生产工艺应处于受控状态，需要维护适当、经过质量部分审核和批准的书面程序。
If you have specific questions aociated with whether or not the change may be claified as requiring a supplement or is reportable in an annual report, we recommend that you contact the appropriate CDER review division in the Office of New Drug Quality Aement(ONDQA), Office of Generic Drugs(OGD), or New Drug Microbiology Staff(OPS-NDMS).如有关于某个变更是否需要提交增补还是可以在年报中报告的问题，建议联系我们ONDQA的CDER审核部门、OGD或OPS-NDMS.IV.CONTENTS OF ANNUAL REPORT NOTIFICATION 年度通知的内容 To submit a notification of change in an annual report in accordance with 21 CFR 314.81(b)(2)(iv)(b)and 314.70(d)(3), the applicant must include a full description of the CMC changes that were made that the applicant believes did not require a supplemental application under sections 314.70(b)and(c).This description should include a(1)list of each change by the date the change was made;(2)relevant summary of data from studies and tests performed to evaluate the effects of the change, including cro references to validation protocols and standard operating procedures and policies;and(3)list of all drug products involved.The applicant should describe each change in an annual report in enough detail to allow us to quickly determine whether the appropriate reporting category has been used.In addition, the applicant should include the list of changes in the summary section of the annual report.[9] If the submitted change is inappropriate for an annual report, the applicant will be notified of the correct category and additional information may be requested.为使用年报中通知的变更符合21CFR 314.81(b)(2)(iv)(b)和314.70(d)(3)的要求，申请人必须在年报中包括关于CMC变更的完整描述，说明申请人认为该变更不需要根据、314.70(b)和(c)部分提交增补。该描述应包括（1）变更清单（以实施日期为序）（2）用以评价变更影响的研究和检测数据总结，包括验证方案、标准操作程序和方针的交叉引用，（3）所有受影响产品的清单。申请人应在年报中对每个变更进行详细描述，使得审核人员可以快速决定该变更采用年报报告是否合适。另外，申请人应在年报的概述部分包括一个变更清单（注释9）。如果提交的变更不应该在年报中进行报告，申请人将被告知正确的分类是什么，并会被要求补充资料。
APPENDIX A: CMC POSTAPROVAL MANUFACTURING CHANGES REPORTABLE IN ANNUAL REPORTS
附件A：可在年报中报告的CMC生产类变更Components and Composition 组件和成份 1.1 Elimination or reduction of an overage from the drug product manufacturing batch formula that was previously used to compensate for manufacturing loes.Note that this does not apply to lo of potency during storage.去除或减少之前用于补偿生产损耗而比处方多出来的部分。注意本点不适用于在存贮过程中会损失的效价。
1.2 Change in qualitative and quantitative coating formulation for immediate-release solid dosage forms if the coating material and quantity have been approved in another product[10] and the change in the formulation does not alter release of the drug.立即放行固体制剂包衣配方及数量变更，而该变更后的包衣材料和数据已在另一产品中得到批准，且西方变更不会改变药品的放行。
1.3 New supplier of inactive ingredients that have a minimal effect on product performance in the drug product, providing that acceptance criteria remain unchanged.活性成分增加新供应商，该活性成分对制剂产品性能影响极小，且保持可接受标准不变。Manufacturing Sites 生产场所
2.1 Modification of an approved manufacturing facility that does not affect a product manufacturing area or sterility aurance and does not change product quality or specifications.对已批准的生产场所进行修改，不影响产品生产区域或无菌区域，不影响产品质量或标准。
2.2 Addition of barriers to prevent routine in-proce human intervention in a filling or compounding area that is qualified and validated by established procedures.增加隔断，以保护充填或合成区域不受常规人流干扰，并经过已有程序确认和验证
2.3 Manufacture of an additional drug product(including investigational or developmental products)in an approved multiple-product area that is producing another product(s)if: 在已批准的多功能区域生产另一种药品（包括临床或研发产品），如果满足以下条件 2.3.1 specific identity tests exist to differentiate between all products manufactured at the facility;and 有专属性鉴别试验可以区别在该场所生产的任何产品，且
2.3.2 a change-over procedure between manufacturing procees is established;and 建立了更换产品程序，且
2.3.3 the products do not represent an additional level of risk.Additional levels of risk might include, but are not limited to, the manufacture of highly toxic or potent products, highly immunogenic or allergenic products(e.g., penicillin), products that can accelerate degradation of another product(e.g., enzymes), products that represent a new or added risk for adventitious agents, or a product for adults added to a line manufacturing pediatric products.所有产品风险水平不会增加。风险水平增加可能包括，但不仅限于，高毒性或高效价产品，高免疫性或致敏性产品（例如，青霉素），会加快另一产品降解的产品（例如，酶），引入新的或外来风险的产品，或成人用药增加到幼儿用药生产线上。Manufacturing Proce 生产工艺
3.1 Proce changes including any of the following: 包括以下任一内容的工艺变更
3.1.1 Addition of a sieving step(s)for aggregate removal if it occurs under nonaseptic conditions.在非无菌条件下增加过筛步骤，以除去团料
3.1.2 Changes in mixing times for immediate-release solid oral dosage forms and for solution products.立即放行的固体口服制剂和液体产品混合时间变更
3.1.3 Changes in drying times for immediate-release solid oral dosage forms.立即放行的口服固体制剂干燥时间变更
3.2 A scale change of pooled or separated batches to perform the next step in the manufacturing proce if all batches meet the approved in-proce control limits and the critical operating parameters for the next step remain unaffected.在所有批准均符合已批准的过程控制限度，下一步关键操作参数均保持不受影响的前提下，对还需要进行下一步生产工艺的收集液体量或子批次批量进行变更。
3.3 Replacement of equipment with that of the same design and operating principle that does not affect the proce methodology or in-proce control limits, with the exception of equipment used in aseptic proceing(e.g., new filling line, new lyophilizer).更换设备，设备设计和操作原理相同，不影响工艺操作方法或过程控制限度，无菌工艺设备除外（例如新的充填线、新的冻干器）
3.4 Addition of a duplicate proce chain or unit proce in the drug substance and drug product manufacturing proce with no change in in-proce control limits or product specifications.原料药和制剂生产中增加一套同样的工艺设备或单元，对过程控制限度或产品质量标准不进行变更。
3.5 Addition of, deletion of, or change in a reproceing protocol for refiltrations to control bioburden because of integrity test failures.由于整体检测失败，增加、删除或变更控制微生物的过滤工艺
3.6 Reduction of open handling steps if there is an improvement with no change to the proce(e.g., implementation of aseptic connection devices to replace flame protection procedures).不改变工艺无改进意义情况下减少敞开操作步骤（例如，采用无菌连接设备替换防火保护操作程序）
3.7 Changes to filtration proce parameters(such as flow rate, preure, time, or volume, but not filter materials or pore size)that are within currently validated parameters and therefore would not warrant new validation studies for the new parameters.在验证过的参数范围内，对过滤工艺参数进行变更（例如流速、压力、时间或容量，但不变更过滤材质或孔径），但不对新的参数进行新的验证。
3.8 For sterile drug products, change from a qualified sterilization chamber(ethylene oxide(EtO), autoclave)to another of the same design and operating principle for container/closure preparation when the new chamber and load configurations are validated to operate within the previously validated parameters.This does not include situations that change the validation parameters.无菌原料药的包装/容器制备灭菌用具，从验证过的灭菌器（环氧乙烷EtO自动灭菌器）改为相同设计相同操作原理的设备，且新的灭菌器参数经过验证，在原验证过的参数下可以操作的。这里不包括验证参数变更的情况。Specifications 质量标准
4.1 Addition of a specification for existing excipients.增加已有辅料的质量标准
4.2 Change to a drug substance or drug product to comply with the official compendia can be reported in an annual report if it is: 变更原料药或药品的质量标准，使符合官方药典，符合下列情形时可在年报中报告
4.2.1 A change to tighten an existing acceptance criterion;or 该变更加严已有的可接受标准，或
4.2.2 Other changes, except for changes to aays, impurities, product-related substances, or biological activities in approved NDAs and ANDAs.其它变更，变更不涉及已批准的NDA或ANDA的含量、杂质、产品有关物质或生物活性
4.3 Change in the approved analytical procedure if the revised method maintains basic test methodology and provides equivalent or increased aurance that the drug substance or drug product will have the characteristics of identity, strength, quality, purity, or potency that it claims to have or is represented to poe and the acceptance criteria remain unchanged(e.g., change in the flow rate or sample preparation for a high performance liquid chromatography(HPLC)method).已批准的检验方法变更，修订后的检验方法保持相同的方法，具有等效性或更好保证原料药或药品所申明的鉴别、剂量、质量、纯度或效价方面的特性，或其可接受标准保持不变（例如，改变HPLC方法的流速或样品溶液配制）
4.4 Replacement of a nonspecific identity test with a discriminating identity test that includes a change in acceptance criteria(e.g., replacing SDS-PAGE[11] with peptide map).采用一个有专属性的鉴别取代一个非专属性的鉴别，导致可接受标准变更（例如，用肽图替代SDS-PAGE，见注11）4.5 Addition of an in-proce test.增加中控检验
4.6 Replacement of blend uniformity and in-proce homogeneity tests with other appropriate testing that aures adequacy of mix.采用另一适当的，可以保证混合充分性的检测，替代现有混合均一性和中控均一性检测。
4.7 Revision of tablet hardne if there is no significant change in the diolution profile.不显著改变溶出度结果的情况下，改变片剂硬度
4.8 Elimination of an in-proce disintegration test where a diolution test is required for release.放行包括溶出度检测的情况下，取消中控的崩解测试
4.9 Deletion of the homogeneity test as a routine test from the application, provided the applicant has proce controls in place to demonstrate the product’s homogeneity.申请者有过程控制证明产品均一性时，删除包括在注册资料中日常均一性检测
4.10 Addition of a test for packaging material to provide increased aurance of quality.对包装材料增加检测，以提高质量保证
4.11 Tightening of an existing acceptance criterion.加严格已有的可接受标准 Container/Closure System 密封/包装系统
5.1 A change in the container/closure system for the storage of a nonsterile drug substance when the proposed container/closure system has no increased risk of leachable substances in the extractable profile(for liquids)and equivalent protection properties.对无菌原料药用于存贮的密封/包装系统进行变更，提出的变更不增加浸出物风险，没有新增可萃取物质，具有相等的保护特性。
5.2 Use of a contract manufacturing organization(CMO)for the washing of a drug product stopper, provided the applicant certifies that the CMO’s washing proce has been validated and the CMO’s site has been audited by the applicant(or by another party sponsored by the applicant)and found CGMP compliant.采用一个合同生产组织（CMO）清洗药品瓶塞，已提供申请人执照，CMO的清洁过程已经过验证，CMO的工厂已经过申请人（或由申请人指定的另一方）审计，确认符合CGMP要求。
5.3 For solid oral dosage forms: 对于固体口服制剂
5.3.1 Elimination of bottle dunnage.去除瓶上手提装置 5.3.2 Change in type of desiccant to another equivalent desiccant that was previously used in another approved product.将干燥剂改为在另一已批准的产品中使用的另一同等能力的干燥剂
5.4 For parenteral drug products, a change in gla supplier without a change in gla type or coating and without a change in container/closure dimensions.对于非口服药品，在不改变玻璃瓶种类和涂层及尺寸的情况下变更供应商。
5.5 Changes to a crimp cap(ferrule and cap/overseal), provided that there are no changes to the labeling or the color and that container and closure integrity have been demonstrated using a validated test method.对密封盖（套金属和盖/密封），如果标识方式无变化，颜色、整体密封包装形式经验证过的检验方法证明无变化。Miscellaneous Changes 其它变更
6.1 Extension of expiry based on real-time stability data from pilot scale batches following an approved stability protocol.根据已批准的稳定性试验方案，基于中试规模进行的实时稳定性试验数据延长有效期
6.2 Reduction of expiration dating for a drug product for reasons other than stability failures.由于非稳定性失败的原因缩短药品有效期
6.3 If a diolution test is performed, elimination of a nonstability indicating test for identity or hardne from an approved stability protocol.在进行溶出度试验前提下，将鉴别或硬度非稳定性指示试验从已批准的稳定性试验方案中删除
6.4 For changes in an application that are fully consistent in scope and requirements with changes previously approved in a bundled supplement, the same applicant can add similar drug products.(See MAPP 5015.6, “Review of the Same Supplemental Change to More than One NDA or ANDA in More Than One Review Division”
在对一个与之前已批准的组合增补的范围和要求完全一致的申请进行变更时，同一申请人可以增加类似的药品（见MAPP 5015.6“对需多部门审核的多个NDA或ANDA的相同增补的审核”）
[1] This guidance has been prepared by the Office of Pharmaceutical Science(OPS)in the Center for Drug Evaluation and Research(CDER)at the Food and Drug Administration.[2] See 21 CFR 314.70(d).[3] This guidance excludes positron emiion tomography(PET)drug products.See the guidance for industry, PET Drugs — Current Good Manufacturing Practice(CGMP).[4] Public Law 105-115.[5] CDER updates guidances periodically.To make sure you have the most recent version of a guidance, check the FDA Drugs guidance web page at www.daodoc.complianceRegulatoryInformation/Guidances/default.htm.[6] Note that the guidance, Changes to an Approved NDA or ANDA, will be revised to reflect these recommendations.注意该指南“已批准的NDA或ANDA的变更”将进行修订以反映这些建议。[7] Under 21 CFR 314.70(a)(3), an applicant is required to make a change in accordance with a regulation or guidance that provides for a le burdensome notification of the change, but in this guidance we are asking sponsors to use judgment in determining which changes should be submitted in a prior approval supplement.根据21CFR 314.70(a)(3)，申请人应根据较少繁杂的法规或指南进行变更，但在本指南中，我们要求申请人进行判定，哪一种变更需要进行预批准增补。
[8] See 21 CFR 210 and 211.[9] See 21 CFR 314.81(b)(2)(i).[10] See the Inactive Ingredient Guide, available on FDA’s web site at 参见活性成分指南，可以以下网站找到www.accedata.fda.gov/scripts/cder/iig/index.cfm.[11] SDS-PAGE stands for sodium dodecyl sulphate polyacrylamide gel electrophoresis.
