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Guidance for Industry-----------翻译人：Julia 行业指南 CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports 应在年报中记载的CMC已批准生产变更 U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) March 2014 CMC OMB Control Number 0910-0758 Expiration Date: 01/31/2017 有效期至：2017年1月31日 (Expiration date will be updated periodically.) （效期将周期性更新） See additional PRA statement in section VI of this guidance. 参见本指南第六部分附加PRA申明
Guidance for Industry 行业指南 CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports 应在年报中记载的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.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) March 2014 CMC
TABLE OF CONTENTS I. INTRODUCTION. 介绍 II. BACKGROUND.背景 III. DISCUSSION 讨论 IV. CONTENTS OF ANNUAL REPORT NOTIFICATION.年报通知的内容 V. RESOURCES 资源 VI. PAPERWORK REDUCTION ACT OF 1995 无纸化法案1995年 APPENDIX A: EXAMPLES OF CMC POSTAPROVAL MANUFACTURING CHANGES TO BE DOCUMENTED IN ANNUAL REPORTS IF THEY HAVE A MINIMAL POTENTIAL TO HAVE AN ADVERSE EFFECT ON PRODUCT QUALITY APPENDIX B: EXAMPLES OF CHANGES TO BE DOCUMENTED IN AN ANNUAL REPORT FROM FDA’S SUPAC-IR, SUPAC-MR, SUPAC-SS, AND CHANGES TO AN APPROVED NDA OR ANDA GUIDANCES 目录 I． 介绍 II． 背景 III． 讨论 IV． 年报通知的内容 V． 资源 VI． 1995无纸化法案 附录A：应在年报中记载的批准后CMC生产变更举例，如果对产品质量有很小的负面影响 附录B：应在年报中记载的变更举例，变更来自SUPAC-IR, SUPAC-MR, SUPAC-SS，以及对已批准NDA或ANDA变更等指南
Guidance for Industry[1] 行业指南 CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports 应在年报中记载的CMC已批准生产变更 This guidance represents 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. 本指南代表的是FDA目前对这一专题的态度。它并未建立或赋予任何个人任何权利，并不与FDA或公众有任何绑定。你可以使用任何一种替代方法，只要所用的方法满足成文的法规要求。如果你想要讨论一个替代方法，请与FDA负责实施本指南的相关人员联系。如果你无法识别要联系的人，可以拨打本指南首页所列的相应的电话号。 |
I. INTRODUCTION 介绍 This guidance provides recommendations to holders of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) regarding the types of changes to be documented in annual reports. Specifically, the guidance describes chemistry, manufacturing, and controls (CMC) postapproval manufacturing changes that we have determined will likely have a minimal potential to have an adverse effect on product quality[2] and, therefore, should be documented by applicants in an annual report.[3][4] 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，因此应由申请人在年度报告中进行记载。 Appendix A lists examples of CMC postapproval manufacturing changes previously submitted under manufacturing supplements that we have determined generally to be of low risk to product quality. 附录A列出了CMC已批准生产变更，这些变更我们认为一般来说对产品质量影响较低，但之前要求在生产增补中提交的变更。 Appendix B provides examples of minor changes to be documented in an annual report that were previously published in FDA’s Scale-up and Postapproval Changes (SUPAC) guidances and other postapproval change CMC guidances (see Section V. Resources for a list of those guidances). 附录B提供了在年报中应记载的轻微变更的例子，之前是包括在FDA的放大生产和批准后变更（SUPAC）指南中，及其它批准后变更CMC指南中（参见第五部分，其它指南资源清单）。 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 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) (FD&C Act), which was added by section 116 of the Food and Drug Administration Modernization Act[5], and 21 CFR 314.70. Section 506A of the FD&C 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 variations provided for 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 supplemental application to the NDA or ANDA before the product made with the manufacturing change is distributed (also known as a prior approval supplement (PAS)). If a change is considered to be moderate, an applicant must submit a supplement at least 30 days before the product is distributed (CBE-30 supplement) or, in some cases, submit a supplement at the time of distribution (CBE-0 supplement). 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 on product quality through appropriate studies. 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)[6]. 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对NDA或ANDA的批准后才能将变更后工艺生产的产品用于销售（也称为预批准增补PAS）。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（CBE-30增补），或在某些情况下，在销售同时提交变更申请（CBE-0增补）。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，申请人均必须通过适当的研究来评价变更对产品质量的影响。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）。 In our September 2004 final report, Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century – A Risk-Based Approach (Pharmaceutical Product Quality Initiative), the Agency 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, the Agency 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 FD&C Act and 21 CFR 314.70, applicants are required to comply with other applicable laws and regulations, including the Current Good Manufacturing Practice for Finished Pharmaceuticals (CGMP) regulations in 21 CFR Parts 210 and 211. 除了食品药品法案第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 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 our risk-based evaluation, we developed a list (see Appendix A) to provide additional current recommendations to companies regarding some postapproval manufacturing changes for NDAs and ANDAs that may be considered to have a minimal potential to have an adverse effect on product quality, and, therefore, may be classified as a change to be documented in the next annual report (i.e., notification of a change after implementation) rather than in a supplement. 基于最近的评价，我们列出了一个清单（见附录A），向公司提供更多的现行建议，对于一些可以认为对药品质量只有非常小的潜在负面影响的已批准的NDA和ANDA生产变更，可以归类为下年度年报需记载的变更（即实施后通知类型），而不需要提交增补。 The changes listed in Appendix A are categorized according to the type of manufacturing change. These changes are either additions or revisions to the CMC changes recommended for documentation in an annual report that were previously published in the guidance for industry on Changes to an Approved NDA or ANDA, the SUPAC guidances, and other related guidances (see Section V. Resources). Thus, before you submit a supplement based on recommendations provided in these previously published guidances, you also should refer to the list of risk-based recommendations that are provided in Appendix A of this guidance. These recommendations clarify whether submission of a supplement or documentation of the change in an annual report may be appropriate. 在附录A中列出的变更是根据生产变更所进行的分类清单。这些变更是对之前出版的行业指南“已批准NDA或ANDA变更”，SUPAC指南及其它相关指南（参见第五部分，资讯）中推荐记载在年报中CMC变更的补充或修订。因此，在你基于之前出版的这些推荐准备提交增补之前，你还应该参照一下本指南附录A中提供的基于风险的建议清单。这些建议申明了将一个增补或变更文件列入年报或许是合适的。 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 product quality. When a risk-based evaluation shows that the proposed change would have a minimal potential to have an adverse effect on product quality, the change can be documented in the next annual report. An NDA or ANDA holder may, based on their specific circumstances, decide that a change described in Appendices A and B would more appropriately be submitted as a supplement rather than in an annual report. In such cases, changes should be reported to the Agency according to the results of the risk-based evaluation and 21 CFR 314.70. Accordingly, we consider this guidance to provide recommendations for changes that are appropriately documented in an annual report rather than to establish a requirement to document 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进行的变更进行评价，根据其具体的环境来决定提议的变更是否对药品的质量只有非常小的潜在负面影响。如果基于风险的评估显示所提议的变更对药品质量只有非常小的潜在负面影响时，可以将变更记载在下一次年报中。NDA或ANDA持有人可以，基于其特定的情况，决定在附录A和B中所描述的变更采用增补方式提交比在年报中记载更合适。在此情况下，应该根据基于风险评估的结果和21CFR 314.70将变更向当局报告。基于上述原因，我们认为本指南只是对那些适于在年报中记载的变更提供建议，而不是根据21CFR 314.70(a)(3)对这些变更是否记载在年报中提出要求。 To the extent that a recommendation in this guidance to document a single change in an annual report is found to be inconsistent with previously published FDA guidances, the reporting category recommended in this guidance would apply, assuming that the applicant’s proposed change would present a minimal potential to have an adverse effect on product quality. For changes not addressed in this guidance, or for multiple related changes implemented simultaneously, applicants should refer to other CDER guidances (see Section V. Resources), as well as Appendix B, to determine the appropriate reporting categories (i.e., PAS, CBE-30, CBE-0, or annual report) for notifying the Agency of the changes. 对同一个变更，如果本指南建议记载在年报中，与FDA之前出版的指南不一致，那么只要申请人所提议的变更对产品质量仅有很小的潜在负面影响，则适用本指南中的报告分类建议。对于本指南中未说明的变更，或者是多个相关变更同时实施，申请应参照CDER指南（参见第五部分，资讯），以及附录B，来决定以适当的报告类型将变更通知官方（例如PAS，CBE-30，CBE-0或年报）。 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 (August 2001). 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 establishing and following appropriate written procedures reviewed and approved by the quality unit, qualifying equipment as suitable for its intended use, using validated test methods, scientifically establishing the commercial manufacturing process, and ensuring the manufacturing process’s ongoing state of control (which may include additional process validation and stability studies depending on the nature of the change).[8] 申请人要注意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”（2001年8月）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要求包括建立并遵守适当的书面程序，并经过质量部门审核和批准，确认设备适用于其既定用途，采用验证过的检验方法，科学建立商业生产工艺，以及保证生产工艺进行状态的控制（根据变更的情况，这可能包括附加工艺验证和稳定性试验）。 If you have specific questions associated with whether or not the change should be submitted to the Agency in a supplement or documented in an annual report, we recommend that you contact the appropriate CDER review division in the Office of New Drug Quality Assessment, the Office of Generic Drugs, or OPS’s New Drug Microbiology Staff. 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 document changes 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: 为使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 l A list of each change and the date each change was implemented; and l 变更清单，各变更实施的日期 l Relevant summary of data from studies and tests performed to assess the effects of each change on product quality, including (where applicable) a list of cross-references to change control and change validation protocols and standard operating procedures (SOPs) that were used to assess or demonstrate the effect of the change. l 用以评价变更对产品质量影响的研究和检测数据总结，包括（适用时）用于评估或证明变更影响的变更控制、变更验证方案和标准操作程序的交叉引用清单， The description also should include: 描述还要包括 l The name(s) of one or more drug products affected or involved in the change (e.g., different label strengths/product presentations); or l 所有受影响或变更涉及的产品名称（例如，不同标示剂量/产品说明），或 l Reference to any previously approved grouped supplements if the change affected multiple products. l 如果变更影响多个产品，对之前已批准的一组增补的引用 Executed batch records, SOPs, and data from studies and tests performed to assess the effects of each change should be kept on file and made available to the Agency on request (e.g., during an inspection). The applicant should describe each change in an annual report in enough detail to allow the Agency to efficiently determine whether the appropriate reporting category has been used. If the submitted change is inappropriate for documentation in an annual report, the applicant will be notified of the correct category and additional information may be requested. 要保留实施的批生产记录、SOP，用于评估每个变更影响而实施的研究和测试的数据，在官方索要时提供（例如，在现场检查过程中）。申请人应在年报中对各变更进行详细描述，以使官方能充分判断所采用的报告方式是否适当。如果年报中所提交的文件不适用于该变更，则官方会通知申请人更正其分类，可能会要求增补文件。 V. RESOURCES 资讯 Provided below are other FDA guidances that discuss reporting of CMC postapproval changes. They should be referred to in addition to this guidance. 以下提供了FDA的其它关于CMC已批准变更报告讨论相关的指南。在使用本指南时同时应参照这些指南。 ? FDA guidances applicable to the CMC section of a drug application:http://www.fda.gov/Drugs/Guidanc ... ances/ucm064979.htm In prior CMC postapproval changes guidance documents, recommendations are provided for changes in components and composition, manufacturing sites, manufacturing process, specifications, container/closure system, labeling, miscellaneous changes, and multiple related changes. 在CMC已批准变更指南文件之前，还有一些关于组件、生产场所、生产工艺、质量标准、容器/密闭系统、标签、其它变更和多个相关变更的指南。 ? PAC-ATLS: Postapproval Changes – Analytical Testing Laboratory Sites, dated April 28, 1998,http://www.fda.gov/downloads/Dru ... nces/UCM070582.pdf. ? SUPAC-IR: Immediate Release Solid Oral Dosage Forms: Scale-up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation, dated November 1995,http://www.fda.gov/downloads/Dru ... nces/UCM070636.pdf. ? SUPAC-IR Questions and Answers about SUPAC-IR Guidance, dated February 18, 1997,http://www.fda.gov/Drugs/Guidanc ... nces/ucm124826.htm. ? SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms Manufacturing Equipment Addendum, dated January 1999,http://www.fda.gov/downloads/Dru ... nces/UCM070637.pdf. ? SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale-up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation, dated September 1997,http://www.fda.gov/downloads/Dru ... nces/UCM070640.pdf. ? SUPAC-SS: Nonsterile Semisolid Dosage Forms; Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation,dated May 1997,http://www.fda.gov/downloads/Dru ... nces/UCM070930.pdf. ? SUPAC-SS: Nonsterile Semisolid Dosage Forms Manufacturing Equipment Addendum, dated December 1998,http://www.fda.gov/downloads/Dru ... nces/UCM070928.pdf. ? Changes to an Approved NDA or ANDA: Questions and Answers, dated January 2001,http://www.fda.gov/downloads/Dru ... nces/UCM122871.pdf. ? Changes to an Approved NDA or ANDA, Revision 1, dated April 2004,http://www.fda.gov/downloads/Dru ... nces/UCM077097.pdf. ? Changes to an Approved NDA or ANDA; Specifications – Use of Enforcement Discretion for Compendial Changes, dated November 2004,http://www.fda.gov/downloads/Dru ... nces/UCM070544.pdf. VI. PAPERWORK REDUCTION ACT OF 1995 无纸化法案1995年 This guidance contains information collection provisions that are subject to review by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The expiration of the OMB control number will be updated periodically. 本指南包含的信息收集条款需由预算管理办公室（OMB）根据1995年无纸化法案（44 U.S.C. 3501-3520）进行审核。OMB控制号的有效期将定期更新。 The total number of supplements submitted per year is estimated to reduce based on the recommendations in the guidance because certain changes submitted as supplements would now be documented in annual reports. Therefore, for such changes, the information collection with respect to the submission of supplements will be reduced. Because the number of supplements per year is estimated to reduce, the total number of hours for preparing supplements would correspondingly reduce. Send comments regarding this burden estimate or suggestions for reducing this burden to: 根据本指南中的建议，由于一些原来作为增补提交的变更现在会记载在年报中，因此预计每年提交的增补总数会下降。对于这类变更，与增补相关的信息收集会减少。因为每年增补的数量会减少，用于准备增补的时间总数会相应减少。请将关于此项负担预期评价或降低负担的建议提交： The Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 4178, Silver Spring, MD 20993-0002. FDA，CDER药物科学办公室，地址：10903 New Hampshire Ave., Bldg. 51, Rm. 4178, Silver Spring, MD 20993-0002. This guidance also refers to previously approved collections of information found in FDA regulations: (1) The submission of supplements to FDA for certain changes to an approved application in accordance with 21 CFR 314.70 and 314.71; (2) the submission of annual reports to FDA (Form FDA 2252) in accordance with § 314.81(b)(2); (3) the submission of supplements to an approved ANDA for changes that require FDA approval; and (4) other post-marketing reports for ANDAs in accordance with § 314.98(c), of which the estimate for annual reports is included under § 314.81(b)(2). FDA currently has OMB approval for these collections of information under OMB Control Number 0910-0001. 本指南还引用了之前批准的一些信息，可以在FDA法规上找到 （1） 根据21CFR314.70和314.71向FDA提交已批准的申请进行变更的增补 （2） 根据314.81(b)(2)向FDA提交年报（表格FDA2252） （3） 提交需要FDA批准的已批准ANDA变更的增补 （4） 根据314.98(c)提交的ANDA的其它上市后的报告，其中对年报的评估包括在314.81(b)(2)项下 FDA目前持有OMB对这些信息收集的批准，OMB控制号为0910-0001. An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB control number. The OMB control number for this information collection is 0910-0758 (expires 01/31/17). 如果没有现行有效的OMB控制号，官方可能不会执行或发起，也并不要求个人进行回应，对信息的收集。本信息收集的OMB控制号为0910-0758（有效期至2017年1月31日）。 |
APPENDIX A: EXAMPLES OF CMC POSTAPPROVAL MANUFACTURING CHANGES TO BE DOCUMENTED IN ANNUAL REPORTS IF THEY HAVE A MINIMAL POTENTIAL TO HAVE AN ADVERSE EFFECT ON PRODUCT QUALITY 附件A：如果对产品质量有很小的负面影响，应在年报中记载的批准后CMC生产变更举例 1 Components and Composition 成份和组成 1.1 Elimination or reduction of an overage from the drug product manufacturing batch formula that was previously used to compensate for manufacturing losses.
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。 1.2 Change in coating formulation for immediate-release solid dosage forms if the coating material and quantity have been approved for another similar product[9] and the change does not alter release of the drug, specification (i.e., tests, analytical procedures, and acceptance criteria for test results), or stability.
即释固体制剂包衣配方变更，且该变更后的包衣材料和数据已在另一产品中得到批准，且该变更不会改变药品的释放、质量标准（即，测试、检测方法、检测结果的可接受标准），或稳定性。 1.3 In instances where the supplier of an inactive ingredient was specified in an approved application, change to a new supplier of that inactive ingredient (e.g., change from one drug master file (DMF) holder to other DMF holder or change to a new qualified supplier). This is applicable only if the inactive ingredient’s specification remains unchanged.
在已批准的申请中指定了一个非活性成分的供应商，要变更至一个新的供应商（例如，从一个DMF持有人转至另一个DMF持有人，或转至一个新的合格供应商）。该条款仅适用于非活性成份的质量标准保持不变时。 2 Manufacturing Sites生产场所 2.1 Minor structural modifications made in the sterile product manufacturing facility approved in an application that do not affect a product manufacturing area or sterility assurance and do not change product quality or specification.
对在申报中已批准的无菌产品生产场所进行结构性改造，且不影响生产区域或无菌保证，对产品质量或质量标准不进行变更。 2.2 In the manufacturing of sterile products, the addition of barriers within a conventional fill area to prevent routine in-process human intervention in an existing filling or compounding area that is qualified and validated by established procedures.
无菌产品生产过程中，在传统充填区域增加隔断，以防止日常生产中人员对正在进行的充填或配方区域产生干扰，并根据已有程序进行了确认和验证。 3 Manufacturing Process, Batch Size, and Equipment 生产工艺、批量和设备 3.1 The following process changes: 以下工艺变更 3.1.1 Addition of a sieving step(s) for aggregates 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 blending powders, granules) for immediate-release solid oral dosage forms and solution products.[10]
Changes in mixing times for immediate-release solid oral dosage forms and for solution products.
即释固体口服制剂和液体产品混合时间（粉末混合、颗粒混合）变更 3.1.3 Changes in drying times for immediate-release solid oral dosage forms.
即释固体口服制剂干燥时间变更 3.2 Manufacturing batch size or scale change that results from combining previously separated batches (or lots) of in-process material to perform the next step in the manufacturing process if all combined batches meet the approved in-process control limits, the next step remains unaffected, and appropriate traceability is maintained.
由于将之前不同批次中间体进行合并进行下一步生产而导致的生产批量或数量变更，且所有批准在合并前均符合已批准的IPC限度，下一步不受影响，并有适当的追溯。 3.3 For equipment used in aseptic manufacturing processes (e.g., new filling line, new lyophilizer), replacement of equipment with that of the same design and operating principle, when there is no change in the approved process methodology or in-process control limits.
采用具有相同设计和操作原理替换原有无菌生产工艺的设备（例如新的充填线，新的冻干机），且不变更已批准的工艺方法或IPC限度。 3.4 Addition of identical processing lines that operate parallel to each other in the drug substance and drug product manufacturing process with no change in in-process control limits or product specification.
原料药和制剂增加同样的生产线，采用同样工艺，与原有生产线进行平行生产，且IPC限度和产品质量标准均无变更。 3.5 For sterile drug products, addition of, deletion of, or change in a reprocessing protocol for refiltrations to control bioburden because of filter integrity test failures.
无菌制剂增加、取消或变更再过滤返工方案，以控制由于过滤器完整性测试失败时的生物负载。 3.6 Decrease in the number of open handling steps or manual operation procedures, when it reduces risk to product and there is no other change to the process (e.g., implementation of aseptic connection devices to replace flame protection procedures).
减少开放操作或手工操作程序步骤，降低产品风险，且工艺没有其它变更（例如，采用无菌连接设备替换防火程序）。 3.7 For sterile drug products, changes to the ranges of filtration process parameters (such as flow rate, pressure, time, or volume, but not pore size) that are within currently validated parameters ranges and therefore would not warrant new validation studies for the new ranges.
无菌制剂过滤工艺参数范围变更（例如，流速、压力、时间或体积，但不变更孔径），但仍在目前经过验证的参数范围内，因此不需要对新的范围进行新的验证研究。 3.8 In the manufacture of sterile drug products, change from a qualified sterilization chamber (ethylene oxide (EtO), autoclave) to another of the same design and operating principle for the preparation of container/closure systems, sterilization of “change parts” for processing equipment, and terminal sterilization of product, 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.
无菌制剂生产从已确认的灭菌箱（环氧乙烷、灭菌器）变更为另一个同样设计和操作原理的容器/密闭系统制备，工艺设备“变更部件”灭菌，产品最终灭菌的灭菌箱，且新的箱子及装载参数经过验证，在之前已验证的参数内操作。本变更不包括对验证参数进行变更的情形。 4 Specifications 质量标准 4.1 Addition of a new test to the specification for an excipient
辅料增加新质量标准检测项目 4.2 Change to the specification for a drug substance, drug product, or pharmacopeial excipient that is made to comply with the official compendia if it is a change that does not relax an acceptance criterion or delete a test.
变更原料药、制剂或药典辅料的质量标准，使其符合官方药典要求，且该变更不放宽可接受标准，也不取消检测项目。
Specification changes not suitable for documentation in an annual report include changes to an assay, tests for impurities, degradation products, product-related substances, or biological activities that are approved in NDAs and ANDAs. Such changes should be submitted in a supplement.
如果质量标准变更包括对NDA和ANDA已批准的含量、杂质测试、降解物、有关物质或生物活性变更时，不适用上述范围，这类变更要在增补中提交。
4.3 Change in the approved analytical procedure if the revised method maintains the original test methodology and provides equivalent or increased assurance 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 possess and the acceptance criteria remain unchanged (e.g., change in the flow rate or sample preparation for a high performance liquid chromatography (HPLC) method).
对已批准的分析方法进行变更，修订的方法保持原有检测原理，且对原料药或制剂所声称其应具有的鉴别、剂量、质量、纯度或效价具有等同或更高的保证性，且可接受标准保持不变（例如，对HPLC方法中的流速或样品制备进行变更）。 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).
采用具有识别性的鉴别测试代替原有的非专属鉴别测试，并变更可接受标准（例如，采用肽谱替代SDS-PAGE11方法）。 4.5 Addition of an in-process test.
增加中控测试。 4.6 Replacement of blend uniformity and in-process homogeneity tests with other appropriate testing that ensures adequacy of mix.
采用其它适当的测试替代混合均一性和中控均一性测试，保证充分的混合。 4.7 Revision of tablet hardness (e.g., acceptance criterion for test result or change to a different analytical procedure and its associated acceptance criterion for test result) if there is no change in the approved dissolution analytical procedure, criteria, or associated dissolution profile.
片剂硬度修订（例如，检测结果的可接受标准或变更成不同的分析方法及相应的检测结果可接受标准），不变更已批准的溶出度分析方法、标准或相关的溶出度概况。 4.8 Addition of a test for packaging material to provide increased assurance of quality.
增加对包材的测试，以对质量提供更高的保证。 4.9 Tightening of an approved acceptance criterion for a drug substance, a drug product, drug product formulation components, and in-process material.
加严原料药、制剂、制剂组份、中控物料已批准的可接受标准。 5 Container/Closure System 容器/密闭系统 5.1 A change in the container/closure system for the storage of a nonsterile drug substance (solid, semisolid, or liquid) when the proposed container/closure system has no increased risk of leachable substances in the extractable profile (for semisolids and liquids) and equivalent protection properties for the packaged material.
对无菌原料药（固体、半固体或液体）用于存贮的密闭/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 or transfer to a contract manufacturing organization (CMO) for the washing, drying, or/and siliconization of a drug product stopper or any part of a container closure system, provided the applicant certifies that the CMO’s processes have been validated and the CMO’s site has been audited and found CGMP compliant by the applicant (or by another party sponsored by the applicant).
采用或变更一个合同生产组织（CMO）清洗、干燥，或/和硅化制剂用塞或容器密闭系统的任何部件，申请人证明该CMO的工艺已经过验证，CMO场所由申请人（或由申请人指定的另一方）审计并认为符合GMP。 5.3 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 5.3.1 Change in type of desiccant to another desiccant that was previously used in another approved product and is suitable for its intended use.
改用另一种干燥剂，该干燥剂之前已用于另一个已获得批准的产品，且适用于其用途。 5.3.2 Elimination of a bottle filler, such as a fibrous material (e.g., suitable type of cotton, rayon, polyester, etc.) that is used to fill empty or void space in the finished product container.
去除用于填充制剂容器中空隙的瓶充填物，如纤维材料（例如，适当类型的棉、人造纤维、涤纶等）。 5.4 For parenteral drug products, a change in glass supplier without a change in glass type or coating and without a change in container/closure dimensions.
注射剂玻璃供应商变更，但不改变玻璃类型或覆膜，也不改变容器/密闭尺寸。 5.5 Changes to a crimp cap (ferrule and flip cap/overseal), provided that there are no changes to the color and that the container and closure integrity have been demonstrated using a validated test method. Note, however, that a change in the flip cap/overseal color to make it consistent with an established color coding system for that class of drug products is to be documented in an annual report.
对卷边帽（金属环和翻盖/顶封）进行变更，不改变颜色，已采用经过验证的检验方法证明了容器和密闭完整性。注意，即使这样，为使其与已有颜色代码系统保持一致而对翻盖/顶封颜色进行的变更还是要记载在年报中。 5.6 Change to delete the company trademark or other markings on the crimp cap (ferrule and flip cap/overseal) to comply with the official compendium.
去除卷边帽上（金属环和翻盖/顶封）上的公司商标或其它标识，以符合官方要求。 6 Labeling Changes 标签变更 6.1 Revision in drug product labeling to reflect the qualitative change in inactive ingredient(s) of coating formulation, as recommended in 1.2 above. The final Structured Product Labeling (SPL) reflecting the qualitative change should be submitted to the Agency when implementing this change to allow for maintenance of the current product information in eLIST.[12] This will help ensure the safe and effective use of the drug product.
制剂标签修订，以反映上述1.2中包衣配方中非活性成份性质变更。反映该性质变更的最终制剂标签SPL应在实施该变更时即提交给官方，以使电子清单中的产品信息得到即时更新。这会有助于保证药品的安全有效使用。 6.2 A change in the drug product labeling to revise information related to CMC changes discussed in this guidance. If the change involves associated revision of drug product labeling, 6.1 above would apply.
对制剂标签进行变更，以修订本指南中讨论的与CMC变更相关的信息。如果变更涉及相关制剂标识修订，则适用上述6.1规定。 7 Miscellaneous Changes 其它变更 7.1 Extension of the drug substance retest dating period or drug product expiration dating period based on real-time stability data from pilot-scale or larger/commercial-scale batches following an approved stability protocol.
基于按照已批准的稳定性试验方案，对中试规模或大生产/商业生产批次测试所得的实时稳定性数据，延长原料药复验期或制剂有效期。 7.2 For immediate release solid oral dosage forms, if a dissolution test is performed, elimination of a test for identity or hardness from an approved stability protocol.
已进行溶出度检测的即释固体口服制剂，在稳定性试验方案中取消鉴别或硬度测试项。 7.3 For changes in an application that are fully consistent in scope and requirements with changes previously approved in a grouped supplement (also defined as a Bundled Supplement), the same applicant can make the same change to similar drug products.[13]
如果一个变更在之前已通过组合增补获得批准，在变更范围和要求完全一致的情况下，申请人可以对类似的产品做出相同的变更。 APPENDIX B: EXAMPLES OF CHANGES TO BE DOCUMENTED IN AN ANNUAL REPORT FROM FDA’S SUPAC-IR, SUPAC-MR, SUPAC-SS, AND CHANGES TO AN APPROVED NDA OR ANDA GUIDANCES 附录B：应在年报中记载的变更举例，变更来自SUPAC-IR, SUPAC-MR, SUPAC-SS，以及对已批准NDA或ANDA变更等指南 1 Components and Composition 组份和组成 1.1 Any change made to comply with the official compendium, except relaxation of an acceptance criterion or deletion of a test (see 21 CFR 314.70(c)(2)(iii)).
所有为了符合官方要求而作出的变更，除了放宽可接受标准或删除测试项以外(参见 21 CFR 314.70(c)(2)(iii))。 1.2 Complete or partial deletion of an ingredient intended to affect only the color, flavor, or fragrance of the drug product without change in other approved specification. Note that a deletion or change in color, flavor, or fragrance also may affect the appearance and other noticeable organoleptic properties (visual appearance, taste, flavor, odor, or fragrance) of the dosage form. These changes may affect the “How the Drug Product is Supplied” section of labeling. In such cases, reporting of revision or change as described in Appendix A, 6. Labeling Changes, also would apply.
完全或部分去除一种仅对制剂色、味、气产生影响的成份，而不改变其它已批准的质量标准。注意，这种对色味气成分的去除或变更也可能影响制剂的外观和其它感官属性（目视外观、味道、口味、气味或香味）。这些变更可能会影响标签部分“制剂如何供应”。这种情况下，还需要根据附录A.6中“标签变更”的要求报告该修订或变更。 1.3 Change in nonrelease controlling excipients, expressed as percentage (w/w) of total formulation approved in the original application, less than or equal to the following percent ranges: Filler ± 5%, Disintegrant (Starch ±3%, Other ± 1%), Binder ±0.5%, Lubricant (Calcium or Magnesium Stearate ±0.25%, Other ± 1%), Glidant (Talc ±1%, Other ±0.1%), and Film Coat ±1%.
变更非释控辅料，在原始申报中表达为总配方的百分比（w/w），低于或等同于以下百分比范围：充填± 5%、崩解剂（淀粉±3%，其它± 1%），粘合剂±0.5%，润滑剂（硬酯酸钙或镁±0.25%，其它±1%），助流剂（滑石粉±1%，其它±0.1%），薄膜包衣±1%。 1.4 Change in the supplier of an excipient, where the technical grade and specification for the excipient remain the same.
变更辅料供应商，但保持辅料的级别和质量标准不变。 1.5 Changes in release controlling excipients less than or equal to 5% expressed as a percentage (w/w) of total release controlling excipients approved in the original application of a modified-release solid oral dosage form. After the change, the total weight of the dosage form and its specification would remain the same as originally approved.
对释控辅料进行变更，变化量小于或等于已批准的改释固体口服制剂原始申报量的5%（表达为总释控辅料的百分比w/w）。变更后，该剂型的总重量及其质量标准将与原始申报的保持相同。 2 Manufacturing Site 生产场所 2.1 When the new site has a satisfactory CGMP inspection status for the type of operation[14] involved, the following changes can be documented in an annual report:
如果新的场所对涉及的操作类型具有满意的CGMP检查状态，以下变更可以在年报中记载 2.1.1 A move to a different manufacturing site for secondary packaging, labeling, ink imprinting on a solid oral dosage form, and manufacture or processing of drug substance intermediates other than the final intermediate.
将外包、贴标、固体口服制剂上墨水打印、原料药中间体（但不是最后中间体）生产或加工移至一个不同的生产场所。 2.1.2 Change in location of manufacturing (including terminal sterilization of finished product) within the same facility or site for both company-owned and contract manufacturers that do not include any scale-up changes, changes in manufacturing process or equipment, or changes in components and composition of drug product. The standard operating procedures, personnel with suitable experience with the manufacturing processes, environmental conditions and controls, and manufacturing batch records will remain the same except for administrative information and the location within the same facility or site.
生产（包括制剂最终灭菌）位置变更，但仍在属原公司和合同生产商的同一厂房设施或场所内，对生产规模、生产工艺或设备、制剂组份和组成比例无变更。行政信息可以不同，位置仍在同一厂房或场所内，标准操作程序、具有适当生产工艺的人员、环境条件和控制、生产批记录保持相同。 3 Manufacturing Process 生产工艺 3.1 For drug products, change to equipment of the same design and operating principles, capacity, and/or batch size (increase or decrease), except for natural protein drug substances and natural protein drug products.
除天然蛋白原料药和天然蛋白制剂产品外，制剂设备变更为具有同样设计、操作原理、产能和/或批量（增加或减少）的设备。 3.2 Change in the order of addition of drug product components for solution dosage forms (except active pharmaceutical ingredients) or change in the order of ingredients added to solutions used in unit operations(e.g., granulation solutions).
改变溶液剂型中制剂成份加入顺序（除原料药），或改变单元操作（例如，制粒溶液）中向溶液中加入成分的顺序。 4 Specifications 质量标准 4.1 For drug substance and drug product, the addition or revision of an alternative analytical procedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application or deletion of an alternative analytical procedure.
增加或修订可替换的原料药和制剂分析方法，对被测物料在鉴别、剂量、质量、纯度或效价方面提供与原被批准申请中方法相同或更强的保证，或删除一个可替代的分析方法。 4.2 A change in an analytical procedure used for testing raw materials used in drug substance synthesis, starting materials introduced prior to the final drug substance intermediate, in-process materials prior to the final intermediate, or drug substance intermediates (excluding final intermediate) that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application.
变更用于原料、原料药合成、原料药最终中间体起始物料、最终中间体中控物料、及原料药中间体（最终中间体除外）的分析方法，变更后的方法对被测物料在鉴别、剂量、质量、纯度或效价方面提供与原被批准申请中方法相同或更强的保证。
[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] In this guidance, the term “product quality” refers to drug product identity, strength, quality, purity, or potency, as these factors may relate to the safety or effectiveness of the drug product.在本指南中，术语“产品质量”指制剂鉴别、剂量、质量、纯度或效价，因为这些因素可能与药品的安全性或有效性相关。 [3] See 21 CFR 314.70(d).
[4] This guidance excludes positron emission tomography (PET) drug products. See the guidance for industry, PET Drugs — Current Good Manufacturing Practice (CGMP), for information about PET drug products. CDER updates guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance web page atwww.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
[6] 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.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
[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 less burdensome notification of the change. In this guidance, we are asking applicants to use scientific data from appropriate studies and risk analysis to determine whether changes should be submitted in a PAS, CBE-30, CBE-0, or annual report. 根据21CFR 314.70(a)(3)，申请人应根据较少负担的法规或指南进行变更申请。在本指南中，我们要求申请人采用适当研究和风险分析，根据获得的科学数据来决定其变更是应该提交PAS, CBE-30, CBE-0或年报。
[8] See 21 CFR 314.81(b)(2)(i).
[10] Note the requirement for finished pharmaceuticals to establish and follow procedures regarding adequacy of mixing to assure uniformity and homogeneity for appropriate dosage forms per 21 CFR 211.110(a).
[11] SDS-PAGE stands for sodium dodecyl sulfate polyacrylamide gel electrophoresis.十二烷基硫酸鈉聚丙烯酰胺凝膠電泳
[14] See the guidance to industry, Changes to an Approved NDA or ANDA, Appendix B.参见行业指南“已批准NDA或ANDA的变更”附录B 参见行业指南“已批准NDA或ANDA的变更”附录B
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发表于 2014-4-18 21:33:16
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