FDA可在年度报告中提出的变更指南中英文对照

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Changes Reportable in Annual Reports可在年报中报告的CMC已批准生产变更DRAFT GUIDANCE指南草案This guidance document is being distributed for comment purposes only.本指南文件仅供征求意见。Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.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 301-796-2400U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)June 2010CMCGuidance 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 CommunicationsDivision of Drug Information, WO51, Room 2201 Center for Drug Evaluation and ResearchFood and Drug Administration10903 New Hampshire Ave.Silver Spring, MD 20993-0002Phone: 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)June 2010TABLE OF CONTENTSI. INTRODUCTION. 介绍.1II. BACKGROUND.背景.1III. DISCUSSION.讨论.2IV. CONTENTS OF ANNUAL REPORT NOTIFICATION.年报通知的内容.4APPENDIX 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for Industry1行业指南CMC Postapproval Manufacturing Changes Reportable in Annual Reports可在年报中报告的CMC已批准生产变更This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current thinking on this topic.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.23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 effectiveness 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。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 requirementsincluding 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,4and 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 assess 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 FDAs 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 FDAs 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 classified 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 classification 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.6In 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 regardless 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 FDAs 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 addressed in this guidance, and compliance with the CGMP regulations is required regardless 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 assure validated test methods and ongoing state of control of manufacturing processes, 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 associated with whether or not the change may be classified 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 Assessment (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 cross 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.9If 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1 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 losses. Note that this does not apply to loss 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 product10and 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。2 Manufacturing Sites 生产场所2.1 Modification of an approved manufacturing facility that does not affect a product manufacturing area or sterility assurance 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-process 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 processes 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。3 Manufacturing Process 生产工艺3.1 Process 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 process if all batches meet the approved in-process 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 process methodology or in-process control limits, with the exception of equipment used in aseptic processing (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 process chain or unit process in the drug substa