美国FDA分析方法验证指南中文译稿[1]

201507FDA行业指南：分析方法验证（中英文）（下）VII. STATISTICAL ANALYSIS AND MODELS 统计学分析和模型A. Statistics 统计学Statistical analysis of validation data can be used to evaluate validation characteristics against predetermined acceptance criteria. All statistical procedures and parameters used in the analysis of the data should be based on sound principles and appropriate for the intended evaluation. Several statistical methods are useful for assessing validation characteristics, for example, an analysis of variance (ANOVA) to assess regression analysis R (correlation coefficient) and R squared (coefficient of determination) or linear regression to measure linearity. Many statistical methods used for assessing validation characteristics rely on population normality, and it is important to determine whether or not to reject this assumption. There are many techniques, such as histograms, normality tests, and probability plots that can be used to evaluate the observed distribution. It may be appropriate to transform the data to better fit the normal distribution or apply distribution-free (nonparametric) approaches when the observed data are not normally distributed. Appropriate literature or text should be consulted for information on statistical procedures to use when developing new test methods, evaluating existing test methods or evaluating measurement system performance, as well as other general information on the interpretation and treatment of analytical data[18].The data analysis should be assured either by using appropriately validated software or independent verification for correctness.验证数据的统计学分析可以用于评估验证的属性是否符合预定的可接受标准。

（中英对照）美国FDA 分析方法验证指南目 录1.绪论 (4)II.背景 (5)III.分析方法的类型 (7)A. 法定分析方法 (7)B. 替代分析方法 (7)C. 稳定性指示分析 (8)IV 标准品 (8)A．标准品的类型 (8)B．分析报告单 (9)C．标准品的界定 (9)V．IND中的分析方法验证 (11)VI．NDA，ANDA，BLA和PLA中分析方法的内容和格式 (12)A．基本方法 (12)B．取样 (12)C．仪器和仪器参数 (12)D．试剂 (13)E．系统适应性实验 (13)F．标准品的制备 (14)H．操作过程 (14)J．计算 (14)K.结果报告 (14)VII.NDA，ANDA，BLA和PLA中的分析方法验证 (16)A．非药典分析方法 (16)1)验证项目 (16)2)其它分析方法验证信息 (17)a.耐用性 (18)b.强降解实验 (19)c.仪器输出/原始资料 (19)3)各类检测的推荐验证项目 (21)B.药典分析方法 (24)VIII.统计分析 (25)A．基本原则 (25)B.对比研究 (25)C.统计 (25)IX．再验证 (26)X．分析方法验证资料：内容和数据处理 (27)A．分析方法验证资料 (27)B.样品的选择和运输 (29)C.各方职责 (30)XI．方法学 (32)A.高效液相色谱(HPLC) (32)B.气相色谱(GC) (35)C.分光光度法，光谱法和相关的物理方法 (37)D.毛细管电泳(CE) (37)E.旋光度 (39)F.粒径分析相关的分析方法 (40)G.溶出度 (41)H.其它仪器分析方法 (43)附录A NDA, ANDA, BLA 和PLA申请的内容 (44)附录B 析方法验证的问题和延误 (45)参考文献 (46)术语表 (48)I. INTRODUCTIONThis guidance provides recommendations to applicants on submitting analytical procedures, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products.1.绪论本指南旨在为申请者提供建议，以帮助其提交分析方法，方法验证资料和样品用于支持原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。

201507FDA行业指南：分析方法验证（中英文）（上）Analytical Procedures and Methods Validation for Drugs and Biologics药品和生物制品分析方法验证Guidance for Industry行业指南U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)July 2015Pharmaceutical Quality/CMCAnalytical Procedures and Methods Validation for Drugs and BiologicsGuidance for IndustryAdditional copies are available from:Office of Communications, Division of Drug InformationCenter for Drug Evaluation and ResearchFood and Drug Administration10001 New Hampshire Ave., Hillandale Bldg., 4th FloorSilver Spring, MD 20993Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email:****************.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidan ces/default.htmand/orOffice of Communication, Outreach and DevelopmentCenter for Biologics Evaluation and ResearchFood and Drug Administration10903 New Hampshire Ave., Bldg. 71, Room 3128Silver Spring, MD 20993Phone: 800-835-4709 or 240-402-7800Email:************.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInf ormation/Guidances/default.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)July 2015Pharmaceutical Quality/CMCAnalytical Procedures and Methods Validation for Drugs and Biologics药物和生物制品分析方法验证Guidance for Industry[1]行业指南This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not create any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.本指南代表了FDA对本专题的当前想法。

FDA工艺验证指南新旧版透彻比较解读【整理者提醒】1-左侧文本为2011年1月最新修订版本，右侧文本为2008年11月草案版本。

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9-欢迎各位朋友提出宝贵建议，联系邮箱zhulikou431@.Guidance for IndustryProcess Validation: General Principles and PracticesFinal Version January 2011 Draft 2008I. INTRODUCTIONI. INTRODUCTION简介This guidance outlines the general principlesand approaches that FDA considers appropriate elements of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients (APIs or drug substances), collectively referred to in thisguidance as drugs or products. This guidanceincorporates principles and approaches thatall manufacturers can use to validate manufacturing processes.本指南概括了一般的原则与方法，这些原则与方法是FDA 认为进行工艺验证的恰当要素，这些工艺被用于生产人用药、动物用药以及生物制品，包括活性药物成分(API 或药用物质)，在本指南中以上统称为药品或产品。

Guidance for Industry 行业指南Process Validation: General Principles and Practices工艺验证：一般原则与规范U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Center for Veterinary Medicine (CVM)January 2011Current Good Manufacturing Practices (CGMP)Revision 1美国卫生与人类服务部食品药品管理局药物评价和研究中心（CDER）生物制品评价和研究中心（CBER）兽药中心（CVM）2011年1月现行药品质量生产管理规范（CGMP）修订版1包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心info@ Guidance for Industry 行业指南Process Validation: General Principles and Practices工艺验证：一般原则与规范Additional copies are available from:Office of CommunicationsDivision of Drug Information, WO51, Room 220110903 New Hampshire Ave.Silver Spring, MD 20993Phone: 301-796-3400; Fax: 301-847-8714druginfo@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmand/orOffice of Communication, Outreach and Development, HFM-40Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike, Rockville, MD 20852-1448(Tel) 800-835-4709 or 301-827-1800/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/orCommunications Staff, HFV-12Center for Veterinary MedicineFood and Drug Administration7519 Standish Place,Rockville, MD 20855(Tel) 240-276-9300/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心info@另外的副本可从以下部门得到：马里兰州银泉市新罕布什尔大道10193号2201室药品信息处，对外信息办公室，邮政编码：20993电话：301-796-3400; 传真：301-847-8714druginfo@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm和/或马里兰州洛克维尔市洛克维尔大道1401号HFM-40 FDA生物制品评价和研究中心对外信息、外联与发展办公室邮政编码：20852-1448电话：800-835-4709 或301-827-1800/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm和/或马里兰州洛克维尔市Standish Place 7519号食品药品管理局兽药中心HFV-12通讯处，邮政编码：20885电话：240-276-9300/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Center for Veterinary Medicine (CVM)January 2011Current Good Manufacturing Practices (CGMP)Revision 1美国卫生与人类服务部食品药品管理局药物评估和研究中心（CDER）生物制品评估和研究中心（CBER）兽药中心（CVM）2011年1月现行药品质量生产管理规范（CGMP）修订版1包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心info@Table of Contents目录I. INTRODUCTION (1)一. 简介 (1)II. BACKGROUND (3)二. 背景 (3)A. Process Validation and Drug Quality (4)A. 工艺验证与药品质量 (4)B. Approach to Process Validation (5)B. 工艺验证方法 (5)III. STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS VALIDATION (7)三. 对工艺验证的法规和监管要求 (7)IV. RECOMMENDATIONS (9)四. 建议 (9)A. General Considerations for Process Validation (9)A. 对工艺验证的总体考虑 (9)B. Stage 1 - Process Design (10)B. 第一阶段- 工艺设计 (10)1. Building and Capturing Process Knowledge and Understanding (11)1. 建立和捕获工艺知识与理解 (11)2. Establishing a Strategy for Process Control (12)2. 建立工艺控制策略 (12)C. Stage 2 - Process Qualification (14)C. 第二阶段- 工艺确认 (14)1. Design of a Facility and Qualification of Utilities and Equipment (14)1. 厂房设施设计以及公用设施与设备确认 (14)2. Process Performance Qualification (16)2. 工艺性能确认 (16)3. PPQ Protocol (17)3. 工艺性能确认方案 (17)4. PPQ Protocol Execution and Report (19)4. 工艺性能确认执行与报告 (19)D. Stage 3 - Continued Process Verification (20)D. 第三阶段- 持续工艺验证 (20)V. CONCURRENT RELEASE OF PPQ BATCHES (22)五. 工艺性能确认批次的同时放行 (22)VI. DOCUMENTATION (24)六. 文件记录 (24)VII. ANALYTICAL METHODOLOGY (24)七. 分析方法 (24)GLOSSARY (26)术语表 (26)REFERENCES (28)参考资料 (28)包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心info@1Guidance for Industry1行业指南1Process Validation: General Principles and Practices工艺验证：一般原则与实施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 canuse an alternative approach if the approach satisfies the requirements of the applicable statutes andregulations. If you want to discuss an alternative approach, contact the FDA staff responsible forimplementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate numberlisted on the title page of this guidance.本指南体现了食品药品管理局（FDA）关于这一主题的最新见解。

美国FDA 分析方法验证指南目录表I.绪论 (1)I I.背景 (2)I I I. 分析方法的类型 (3)A.法定分析方法 (3)B.可选择分析方法 (3)C.稳定性指示分析 (3)I V.对照品 (4)A.对照品的类型 (4)B.分析报告单 (4)C.对照品的界定 (4)V.I N D中的分析方法验证 (6)V I. N D A,AN D A,B LA和P L A 中分析方法验证的内容和格式 (6)A.原则 (6)B.取样 (7)C.仪器和仪器参数 (7)D.试剂 (7)E.系统适应性实验 (7)F.对照品的制备 (7)G.样品的制备 (8)H.分析方法 (8)L.计算 (8)J.结果报告 (8)V I I. N D A，A N DA,BL A和P L A 中的分析方法验证 (9)A．非法定分析方法 (9)1．验证项目 (9)2.其它分析方法验证信息 (10)a.耐用性 (11)b.强降解实验 (11)c.仪器输出/原始资料 (11)3．各类检测的建议验证项目 (13)B．法定分析方法 (15)VIII. 统计分析 (15)A.总则 (15)B.比较研究 (16)C.统计 (16)I X.再验证 (16)X.分析方法验证技术包：内容和过程 (17)A.分析方法验证技术包 (17)B.样品的选择和运输 (18)C.各方责任 (19)X I.方法 (20)A.高效液相色谱(H P L C) (20)B.气相色谱(G C) (22)C.分光光度法，光谱学，光谱法和相关的物理方法 (23)D.毛细管电泳 (23)E.旋光度 (24)F.粒径相关的分析方法 (25)G.溶出度 (26)H.其它仪器分析方法 (27)附件 A：NDA，ANDA，BLA和PLA 申请的内容 (28)附件 B：分析方法验证的问题和延误 (29)参考文献 (30)术语表 (32)I. 绪论本指南旨在为申请者提供建议，以帮助其提交分析方法，方法验证资料和样品用于支持原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。

FDA 行业指南中英对照待完成Guidance for IndustryContainer Closure Systems for Packaging Human Drugs and BiologicsChemistry, Manufacturing and Controls Documentation行业指南人用药品及生物制品的包装容器和封装系统：化学，生产和控制文件指南发布者：美国FDA下属的CDER及CBER 发布日期：May 1999TABLE OF CONTENTS目录I. II.INTRODUCTION 介绍 BACKGROUND 背景 A. B. C.III.Definitions 定义CGMP, CPSC and USP Requirements on Containers and Closures. CGMP, CPSC和USP对容器和密封的要求Additional Considerations 其他需要考虑的事项QUALIFICATION AND QUALITY CONTROL OF PACKAGING COMPONENTS 包装组件的合格要求以及质量控制 A. B. C. D. E. F. G. H.IV. V.Introduction 介绍General Considerations 通常要求Information That Should Be Submitted in Support of an Original Application for Any Drug Product 为支持任何药品的原始申请所必须提供的信息 Inhalation Drug Products 吸入性药品Drug Products for Injection and Ophthalmic Drug Products 注射剂和眼科用药Liquid-Based Oral and Topical Drug Products and Topical Delivery Systems 液体口服和外用药品和外用给药系统Solid Oral Dosage Forms and Powders for Reconstitution 口服固体剂型和待重新溶解的粉末Other Dosage Forms 其他剂型POSTAPPROVAL PACKAGING CHANGES 批准后的包装变更 TYPE III DRUG MASTER FILES 药品主文件第III类 A. B.VI.A. B.General Comments 总体评述Information in a Type III DMF 第III类DMF中包括的信息 Containers for Bulk Drug Substances 用于原料药的容器 Containers for Bulk Drug Products 用于散装药品的容器BULK CONTAINERS 大包装容器ATTACHMENT A 附件AREGULATORY REQUIREMENTS 药政要求ATTACHMENT B 附件BCOMPLIANCE POLICY GUIDES THAT CONCERN PACKAGING 关于包装，所适用的政策指南ATTACHMENT C 附件CEXTRACTION STUDIES “提取性”研究 ATTACHMENT D 附件DABBREVIATIONS 缩略语ATTACHMENT E 附件EREFERENCES 参考文献GUIDANCE FOR INDUSTRY1Container Closure Systems for Packaging Human Drugs and BiologicsChemistry, Manufacturing and Controls DocumentationThis guidance document represents the Agency's current thinking on container closure systems for the packaging of human drugs and biological products. It does not create or confer any rights for or on any person anddoes not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both.本指南代表了FDA目前对于人用药品和生物制品包装的容器/封装系统方面的看法。

Guidance for Industry Investigating Out-of-Specification (OOS)Test Results forPharmaceutical ProductionU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)October 2006Pharmaceutical CGMPs Contains Nonbinding RecommendationsGuidance for Industry Investigating Out-of-Specification (OOS)Test Results forPharmaceutical ProductionAdditional copies are available from: 本文件可自以下途径得到Office of Training and Communication 培训和交流办公室Division of Drug Information HFD-240 药品信息分部Center for Drug Evaluation and Research 药品审评中心Food and Drug Administration 食品药品管理局5600 Fishers LaneRockville, MD 20857(Tel) 301-827-4573/cder/guidance/index.htmU.S. Department of Health and Human Services 美国卫生和福利部Food and Drug Administration 食品药品管理局Center for Drug Evaluation and Research (CDER) 药品审评中心October 2006Pharmaceutical CGMPs Contains Nonbinding RecommendationsTABLE OF CONTENTSInvestigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production (4)I. INTRODUCTION 介绍 (4)II. BACKGROUND 背景 (5)III. IDENTIFYING AND ASSESSING OOS TEST RESULTS界定和评价OOS检验结果— PHASE I: LABORATORY INVESTIGATION第一步：化验室调查 (6)A. Responsibility of the Analyst 化验员职责 (7)B. Responsibilities of the Laboratory Supervisor化验室主管职责 (8)IV. INVESTIGATING OOS TEST RESULTS 对OOS结果的调查— PHASE II: FULL-SCALE OOS INVESTIGATION 第二步：全面OOS调查 (10)A. Review of Production 生产情况审核 (10)B. Additional Laboratory Testing 附加化验室测试 (11)C. Reporting Testing Results 报告测试结果 (14)V. CONCLUDING THE INVESTIGATION 调查结论 (17)A. Interpretation of Investigation Results 调查结果解释 (18)B. Cautions 注意事项 (19)C. Field Alert Reports (20)GUIDANCE FOR INDUSTRY1行业指南Investigating Out-of-Specification (OOS) Test Results forPharmaceutical Production药物生产中不合格结果的调查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FDA对本专题现行的想法。

（中英对照）美国FDA 分析方法验证指南目 录1.绪论 (4)II.背景 (5)III.分析方法的类型 (7)A. 法定分析方法 (7)B. 替代分析方法 (7)C. 稳定性指示分析 (8)IV 标准品 (8)A．标准品的类型 (8)B．分析报告单 (9)C．标准品的界定 (9)V．IND中的分析方法验证 (11)VI．NDA，ANDA，BLA和PLA中分析方法的内容和格式 (12)A．基本方法 (12)B．取样 (12)C．仪器和仪器参数 (12)D．试剂 (13)E．系统适应性实验 (13)F．标准品的制备 (14)H．操作过程 (14)J．计算 (14)K.结果报告 (14)VII.NDA，ANDA，BLA和PLA中的分析方法验证 (16)A．非药典分析方法 (16)1)验证项目 (16)2)其它分析方法验证信息 (17)a.耐用性 (18)b.强降解实验 (19)c.仪器输出/原始资料 (19)3)各类检测的推荐验证项目 (21)B.药典分析方法 (24)VIII.统计分析 (25)A．基本原则 (25)B.对比研究 (25)C.统计 (25)IX．再验证 (26)X．分析方法验证资料：内容和数据处理 (27)A．分析方法验证资料 (27)B.样品的选择和运输 (29)C.各方职责 (30)XI．方法学 (32)A.高效液相色谱(HPLC) (32)B.气相色谱(GC) (35)C.分光光度法，光谱法和相关的物理方法 (37)D.毛细管电泳(CE) (37)E.旋光度 (39)F.粒径分析相关的分析方法 (40)G.溶出度 (41)H.其它仪器分析方法 (43)附录A NDA, ANDA, BLA 和PLA申请的内容 (44)附录B 析方法验证的问题和延误 (45)参考文献 (46)术语表 (48)I. INTRODUCTIONThis guidance provides recommendations to applicants on submitting analytical procedures, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products.1.绪论本指南旨在为申请者提供建议，以帮助其提交分析方法，方法验证资料和样品用于支持原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。

美国FDA分析⽅法验证指南中英⽂对照--6XI. METHODOLOGYSections II through IX provide general information on the submission of analytical procedures and methods validation information, including validation characteristics. Additional information on certain methodologies is provided below.XI．⽅法学II章到第IX章提供了分析⽅法和分析⽅法验证资料⽅⾯的基本信息，包括验证项⽬。

下⽂就⼀些具体的⽅法给出了说明：A. High-Pressure Liquid Chromatography (HPLC)The widespread use of HPLC analytical procedures and the multitude of commercial sources of columns and packings frequently have created problems in assessing comparability. Many of the following points may also apply to other chromatographic analytical procedures.⾊谱(HPLC)⾼效液相⾊谱A．⾼效液相HPLC分析⽅法的⼴泛应⽤及⾊谱柱和柱填充的众多来源都经常会给可⽐性评估带来很多问题。

如下这些要点中，很多都适⽤于其它⾊谱分析⽅法。

1. ColumnThe following characteristics are useful for defining a particular column and, if known, should be included in the analytical procedure description. If method development has indicated that columns from only one commercial source are suitable, this information should be included as part of the analytical procedure. If more than one column is suitable, a listing of columns found to be equivalent should be included.1.⾊谱柱在定义某⼀⾊谱柱时，如下这些性质是很有⽤的，也应当要包括在分析⽅法描述中。

201507 FDA行业指南：分析方法验证（中英文）（下）VII. STATISTICAL ANALYSIS AND MODELS 统计学分析和模型A. Statistics 统计学Statistical analysis of validation data can be used to evaluate validation characteristics against predetermined acceptance criteria. All statistical procedures and parameters used in the analysis of the data should be based on sound principles and appropriate for the intended evaluation. Several statistical methods are useful for assessing validation characteristics, for example, an analysis of variance (ANOVA) to assess regression analysis R (correlation coefficient) and R squared (coefficient of determination) or linear regression to measure linearity. Many statistical methods used for assessing validation characteristics rely on population normality, and it is important to determine whether or not to reject this assumption. There are many techniques, such as histograms, normality tests, and probability plots that can be used to evaluate the observed distribution. It may be appropriate to transform the data to better fit the normal distribution or apply distribution-free (nonparametric) approaches when the observed data are not normally distributed. Appropriateliterature or text should be consulted for information on statistical procedures to use when developing new test methods, evaluating existing test methods or evaluating measurement system performance, as well as other general information on the interpretation and treatment of analytical data[18].The data analysis should be assured either by using appropriately validated software or independent verification for correctness.验证数据的统计学分析可以用于评估验证的属性是否符合预定的可接受标准。

201507FDA行业指南：分析方法验证（中英文）（中）A. Principle/Scope 原理/范围A description of the basic principles of the analytical test/technology (i.e., separation, detection); target analyte(s) and sample(s) type (e.g., drug substance, drug product, impurities or compounds in biological fluids).分析测试/技术（即分离、检测）基本原因的描述；目标分析物和样品类型（例如，原料药、制剂、杂质或生物流体中的化合物）。

B. Apparatus/Equipment 仪器/设备All required qualified equipment and components (e.g., instrument type, detector, column type, dimensions, and alternative column, filter type).所有需要的确认过的仪器和组件（例如，仪器类型、检测器、柱子类型、尺寸和可替代的柱子、过滤器类型）。

C. Operating Parameters 运行参数Qualified optimal settings and ranges (include allowed adjustments supported by compendial sources or development and/or validation studies) critical to the analysis (e.g., flow rate, components temperatures, run time, detector settings, gradient, head space sampler). A drawing with experimental configuration and integration parameters may be used, as applicable.确认过的优化的设置和范围（包括来自药典或研发和/或验证研究的允许调整），对于分析过程非常关键（例如，流速、部件温度、运行时间、检测器设置、梯度、顶空进样器）。

美国FDA分析方法验证指南中英文对照（二）上一篇/ 下一篇 2009-01-05 10:44:15 / 个人分类：GMP/GLP查看( 1076 ) / 评论( 2 ) / 评分( 0 / 0 ) III. TYPES OF ANALYTICAL PROCEDURESA. Regulatory A nalytical ProcedureA regulatory analy tical procedure is the analy tical procedure used to ev aluate a def ined characteristic of the drug substance or drug product. The analy tical procedures in the U.S. Pharmacopeia/National Formulary (USP/NF) are those legally recognized under section 501(b) of the Food, Drug, and Cosmetic Act (the Act) as the regulatory analytical procedures f or compendial items. For purpos es of determining compliance with the Act, the regulatory analytical procedure is used.III分析方法的类型A. 法定分析方法法定分析方法是被用来评估原料药或制剂的特定性质的。

USP/NF中的分析方法是法定的用于药典项目检测的分析方法。

为了确认符合法规，需使用法定分析方法。

B. A lternative A nalytical ProcedureAn alternativ e analy tical procedure is an analytical procedure proposed by the applicant f or use instead of the regulatory analy tical procedure. A v alidated alternativ e analy tical procedure should be submitted only if it is shown to perf orm. equal to or better than the regulatory analy tical procedure.B. 替代分析方法替代分析方法是申请者提出用于代替法定分析方法的分析方法。

Guidance for Industry 行业指南Process Validation: General Principles and Practices工艺验证：一般原则与规范U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Center for Veterinary Medicine (CVM)January 2011Current Good Manufacturing Practices (CGMP)Revision 1美国卫生与人类服务部食品药品管理局药物评价和研究中心（CDER）生物制品评价和研究中心（CBER）兽药中心（CVM）2011年1月现行药品质量生产管理规范（CGMP）修订版1包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心************** Guidance for Industry 行业指南Process Validation: General Principles and Practices工艺验证：一般原则与规范Additional copies are available from:Office of CommunicationsDivision of Drug Information, WO51, Room 220110903 New Hampshire Ave.Silver Spring, MD 20993Phone: 301-796-3400; Fax: 301-847-8714****************.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmand/orOffice of Communication, Outreach and Development, HFM-40Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike, Rockville, MD 20852-1448(Tel) 800-835-4709 or 301-827-1800/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/orCommunications Staff, HFV-12Center for Veterinary MedicineFood and Drug Administration7519 Standish Place,Rockville, MD 20855(Tel) 240-276-9300/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心**************另外的副本可从以下部门得到：马里兰州银泉市新罕布什尔大道10193号2201室药品信息处，对外信息办公室，邮政编码：20993电话：301-796-3400; 传真：301-847-8714****************.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm和/或马里兰州洛克维尔市洛克维尔大道1401号HFM-40 FDA生物制品评价和研究中心对外信息、外联与发展办公室邮政编码：20852-1448电话：800-835-4709 或301-827-1800/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm和/或马里兰州洛克维尔市Standish Place 7519号食品药品管理局兽药中心HFV-12通讯处，邮政编码：20885电话：240-276-9300/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Center for Veterinary Medicine (CVM)January 2011Current Good Manufacturing Practices (CGMP)Revision 1美国卫生与人类服务部食品药品管理局药物评估和研究中心（CDER）生物制品评估和研究中心（CBER）兽药中心（CVM）2011年1月现行药品质量生产管理规范（CGMP）修订版 1包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心**************Table of Contents目录I. INTRODUCTION (1)一. 简介 (1)II. BACKGROUND (3)二. 背景 (3)A. Process Validation and Drug Quality (4)A. 工艺验证与药品质量 (4)B. Approach to Process Validation (5)B. 工艺验证方法 (5)III. STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS VALIDATION (7)三. 对工艺验证的法规和监管要求 (7)IV. RECOMMENDATIONS (9)四. 建议 (9)A. General Considerations for Process Validation (9)A. 对工艺验证的总体考虑 (9)B. Stage 1 - Process Design (10)B. 第一阶段- 工艺设计 (10)1. Building and Capturing Process Knowledge and Understanding (11)1. 建立和捕获工艺知识与理解 (11)2. Establishing a Strategy for Process Control (12)2. 建立工艺控制策略 (12)C. Stage 2 - Process Qualification (14)C. 第二阶段- 工艺确认 (14)1. Design of a Facility and Qualification of Utilities and Equipment (14)1. 厂房设施设计以及公用设施与设备确认 (14)2. Process Performance Qualification (16)2. 工艺性能确认 (16)3. PPQ Protocol (17)3. 工艺性能确认方案 (17)4. PPQ Protocol Execution and Report (19)4. 工艺性能确认执行与报告 (19)D. Stage 3 - Continued Process Verification (20)D. 第三阶段- 持续工艺验证 (20)V. CONCURRENT RELEASE OF PPQ BATCHES (22)五. 工艺性能确认批次的同时放行 (22)VI. DOCUMENTATION (24)六. 文件记录 (24)VII. ANALYTICAL METHODOLOGY (24)七. 分析方法 (24)GLOSSARY (26)术语表 (26)REFERENCES (28)参考资料 (28)包含不具约束力的建议中文译稿：北京大学药物信息与工程研究中心**************1Guidance for Industry1行业指南1Process Validation: General Principles and Practices工艺验证：一般原则与实施This guidance represents the Food and Drug Administration’s (FDA’s) current thin king 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.本指南体现了食品药品管理局（FDA）关于这一主题的最新见解。

美国FDA分析方法验证指南美国FDA分析方法验证指南1. 绪论本指南旨在为申请者提供建议，以帮助其提交分析方法，方法验证资料和样品用于支持原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。

本指南旨在帮助申请者收集资料，递交样品并资料以支持分析方法。

这些建议适用于NDA，这些原则同样适用于二类DMF所涉及的原料药和制剂。

如果使用了其它方法，鼓励申请者事先和FDA药品评审中心的官员进行讨论，以免出现这种情况，那就是花了人力物力所准备起来的递交资料后来发现是不可用的。

本指南中所述的分析方法验证的原则适用于各种类型的分析方法。

但是，本指南中特定的建议可能不适用于有些产品所用的特殊分析方法，如生物药，生物技术药，植物药或放射性药物等。

比如说，许多生物分析是建立在动物挑战模式，免疫原性评估或其它有着独特特性的免疫分析基础上的，在递交分析方法和分析方法验证资料时需考虑这些独特的性质。

而且，许多原料药和制剂的界定和质量控制所需的生物和免疫化学检测并不在本指南的范围之内。

尽管本指南并不专门叙述原料，中间体，赋形剂，包装材料及原料药和制剂生产中所用的其它物料的分析方法及分析方法验证资料的递交，但是应该应用验证过的分析方法来分析检测这些物质。

对于本指南中未提及的关于分析方法验证和资料提交方面的问题，请向FDA相关的化学评审人员咨询。

本指南，一旦定稿，将取代FDA于1987年2月份发布的工业指南：分析方法验证所需提交的样品和分析资料。

II. 背景每个NDA和ANDA都必需包括必要的分析方法以确保原料药和制剂的认定，剂量，质量，纯度和效力，还包括制剂的生物利用度(21 CFR 314.50(d)(1) 和314.94(a)(9)(i))。

FDA验证文件现场备查，可以不与DMF一起交。

必须要有资料来论证所用的分析方法是符合一定的准确度和可靠性标准的。

分析方法验证是论证某一分析方法适用于其用途的过程。

分析方法的验证过程是从申请者有计划地系统性收集验证资料以支持分析方法开始的。

《美国FDA认证与申办指南》权威资讯系列《合成原料药DMF起草大纲》使用说明：1、本大纲是为了帮助我公司客户把握DMF的整体内容而准备的，由于DMF内容繁多，从整体上了解内容框架和组成部分，对于理解FDA对DMF的要求和意图非常有必要；2、根据FDA的要求，凡是本大纲提到的内容，原料药制造商均应该提供。

因此，客户务必依照规定提供尽可能详细的内容。

3、本大纲的内容和相关要求能够确保客户目前的运作达到FDA的cGMP标准，因此，准备DMF的过程，也使客户按照FDA的要求进行整改和提高的过程，这些都为FDA未来的现场检查打下良好基础；4、凡是本大纲中提到的非技术性具体内容要求，请参照本公司专有的与此大纲配套的相关DFM指导性文件，包括《FDA药物主文件指南》、《关于在药品递交中递交的有关原料药生产的支持文件的指南》、《药物申办中质量管理方面通用技术文件格式与内容要求》；5、凡是本大纲中提到的技术性具体内容要求，如杂质、稳定性、验证等具体技术要求，请参照本公司专有的FDA相关技术标准文件，包括《原料药认证指南》、《制剂认证指南》、《化学药物稳定性指南》、《化学药物杂质指南》、《化学药物化验与合格参数指南》、《化学药物验证指南》等；《合成原料药DMF起草大纲》一、公司和生产场地的基本描述1、第一类的DMF文件建议由位于美国之外的人提供，以帮助FDA对他们的生产设施进行现场检查。

DMF文件应描述生产场地、设备能力、生产流程图等。

A Type I DMF is recommended for a person outside of the United States to assist FDA in conducting on site inspections of their manufacturing facilities. The DMF should describe the manufacturing site, equipment capabilities, and operational layout.2、第一类的DMF文件对美国国内设施通常不需要，除非该设施没有登记并定期接受检查。

美国FDA 分析方法验证指南（中文）U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)August 2000目录一、结论………………………………………………………..…………………二、背景……………………………………………………………..……….…..三、分析方法的类型…………………………………………………………….A. 法定分析方法……………………………………………………………B. 替代分析方法……………………………………………………………C. 稳定性指示分析…………………………………………………………四、标准品……………………………………………………………………….. A．标准品的类型……………………………………………………………B．分析报告单………………………………………………………………C．标准品的界定……………………………………………………………五、IND 中的分析方法验证……………………………………………………..六、NDA、ANDA、BLA 和PLA 中分析方法的内容和格式…………………A．基本方法…………………………………………………………………B．取样………………………………………………………………………C．仪器和仪器参数…………………………………………………………. D．试剂………………………………………………………………………E．系统适应性实验…………………………………………………………. F．标准品的制备……………………………………………………………..G.操作过程…………………………………………………………………….H.操作程序……………………………………………………………………I．计算…………………………………………………………………………J.结果报告……………………………………………………………………. 1．通则……………………………………………………………………2．杂质分析规程…………………………………………………………七、NDA，ANDA，BLA 和PLA 中的分析方法验证………………………….. A．非药典分析方法…………………………………………………………1. 验证项目……………………………………………………………2. 其它验证资料……………………………………………………….(1) 讨论可能会形成的异构体并讨论异构体的控制…………………..a. 耐用性…………………………………………………….b. 强降解实验………………………………………………c.仪器输出/原始资料………………………………………i. 有机杂质……………………………………………ii. 原料药……………………………………………….iii. 制剂………………………………………………….(2) 各类检测的推荐验证项目…………………………………………..a. 鉴别………………………………………………………....b. 杂质………………………………………………………..c. 含量………………………………………………………..d. 特定实验…………………………………………………….B．药典分析方法(21CFR 211.194(a)(2))…………………………………..八. 统计分析…………………………………………………………………….A．基本原则………………………………………………………………B:对比研究…………………………………………………………………C:统计………………………………………………………………………九、再验证………………………………………………………………………十、分析方法验证资料：内容和数据处理…………………………………….A．分析方法验证资料…………………………………………………….B：样品的选择和运输…………………………………………………….C：各方职责……………………………………………………………….1.申请人……………………………………………………………….2.化学评审官………………………………………………………….3.FDA 实验室………………………………………………………….4.检查官……………………………………………………………….十一、方法学……………………………………………………………………A．高效液相色谱(HPLC)………………………………………………….1.色谱柱……………………………………………………………….2.系统适应性研究…………………………………………………….3.操作参数…………………………………………………………….B．气相色谱(GC)………………………………………………………….1.色谱柱……………………………………………………………….2.操作参数……………………………………………………………..3.系统适应性实验……………………………………………………..C：分光光度法，光谱法和相关的物理方法………………………………D：毛细管电泳(CE)…………………………………………………………E：旋光度……………………………………………………………………F：和粒径分析相关的分析方法……………………………………………G：溶出度…………………………………………………………………..H：其它仪器分析方法………………………………………………………附录A……………………………………………………………………………….. 附录B……………………………………………………………………………….. 术语表……………………………………………………………………………….一、绪论本指南旨在为申请者提供建议，以帮助其提交分析方法，方法验证资料和样品用于支持原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。