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Q7a（中英文对照）FDA原料药GMP指南Table of Contents 目录1. INTRODUCTION 1. 简介1.1 Objective 1.1目的1.2 Regulatory Applicability 1.2法规的适用性1.3 Scope 1.3范围2. QUALITY MANAGEMENT 2.质量管理2.1 Principles 2.1总则2.2 Responsibilities of the Quality Unit(s) 2.2质量部门的责任2.3 Responsibility for Production Activities 2.3生产作业的职责2.4 Internal Audits (Self Inspection) 2.4内部审计（自检）2.5 Product Quality Review 2.5产品质量审核3. PERSONNEL 3. 人员3.1 Personnel Qualifications 3.人员的资质3.2 Personnel Hygiene 3.2 人员卫生3.3 Consultants 3.3 顾问4. BUILDINGS AND FACILITIES 4. 建筑和设施4.1 Design and Construction 4.1 设计和结构4.2 Utilities 4.2 公用设施4.3 Water 4.3 水4.4 Containment 4.4 限制4.5 Lighting 4.5 照明4.6 Sewage and Refuse 4.6 排污和垃圾4.7 Sanitation and Maintenance 4.7 卫生和保养5. PROCESS EQUIPMENT 5. 工艺设备5.1 Design and Construction 5.1 设计和结构5.2 Equipment Maintenance and Cleaning 5.2 设备保养和清洁5.3 Calibration 5.3 校验5.4 Computerized Systems 5.4 计算机控制系统6. DOCUMENTATION AND RECORDS 6. 文件和记录6.1 Documentation System andSpecifications6.1 文件系统和质量标准6.2 Equipment cleaning and Use Record 6.2 设备的清洁和使用记录6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials 6.3 原料、中间体、原料药的标签和包装材料的记录6.4 Master Production Instructions (MasterProduction and Control Records)6.4 生产工艺规程（主生产和控制记录）6.5 Batch Production Records (BatchProduction and Control Records)6.5 批生产记录（批生产和控制记录）6.6 Laboratory Control Records 6.6 实验室控制记录6.7 Batch Production Record Review 6.7批生产记录审核7. MATERIALS MANAGEMENT 7. 物料管理7.1 General Controls 7.1 控制通则7.2 Receipt and Quarantine 7.2接收和待验7.3 Sampling and Testing of IncomingProduction Materials7.3 进厂物料的取样与测试7.4 Storage 7.4储存7.5 Re-evaluation 7.5复验8. PRODUCTION AND IN-PROCESSCONTROLS8. 生产和过程控制8.1 Production Operations 8.1 生产操作8.2 Time Limits 8.2 时限8.3 In-process Sampling and Controls 8.3 工序取样和控制8.4 Blending Batches of Intermediates orAPIs8.4 中间体或原料药的混批8.5 Contamination Control 8.5 污染控制9. PACKAGING AND IDENTIFICATIONLABELING OF APIs ANDINTERMEDIATES9. 原料药和中间体的包装和贴签9.1 General 9.1 总则9.2 Packaging Materials 9.2 包装材料9.3 Label Issuance and Control 9.3 标签发放与控制9.4 Packaging and Labeling Operations 9.4 包装和贴签操作10. STORAGE AND DISTRIBUTION 10.储存和分发10.1 Warehousing Procedures 10.1 入库程序10.2 Distribution Procedures 10.2 分发程序11. LABORATORY CONTROLS 11.实验室控制11.1 General Controls 11.1 控制通则11.2 Testing of Intermediates and APIs 11.2 中间体和原料药的测试11.3 Validation of Analytical Procedures 11.3 分析方法的验证11.4 Certificates of Analysis 11.4 分析报告单11.5 Stability Monitoring of APIs 11.5 原料药的稳定性监测11.6 Expiry and Retest Dating 11.6 有效期和复验期11.7 Reserve/Retention Samples 11.7 留样12. V ALIDATION 12.验证12.1 Validation Policy 12.1 验证方针12.2 Validation Documentation 12.2 验证文件12.3 Qualification 12.3 确认12.4 Approaches to Process Validation 12.4 工艺验证的方法12.5 Process Validation Program 12.5 工艺验证的程序12.6 Periodic Review of Validated Systems 12.6验证系统的定期审核12.7 Cleaning Validation 12.7 清洗验证12.8 Validation of Analytical Methods 12.8 分析方法的验证13. CHANGE CONTROL 13.变更的控制14. REJECTION AND RE-USE OFMATERIALS14.拒收和物料的再利用14.1 Rejection 14.1 拒收14.2 Reprocessing 14.2 返工14.3 Reworking 14.3 重新加工14.4 Recovery of Materials and Solvents 14.4 物料与溶剂的回收14.5 Returns 14.5 退货15. COMPLAINTS AND RECALLS 15.投诉与召回16. CONTRACT MANUFACTURERS(INCLUDING LABORATORIES)16.协议生产商（包括实验室）17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS 17.代理商、经纪人、贸易商、经销商、重新包装者和重新贴签者17.1 Applicability 17.1适用性17.2 Traceability of Distributed APIs andIntermediates17.2已分发的原料药和中间体的可追溯性17.3 Quality Management 17.3质量管理17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates 17.4原料药和中间体的重新包装、重新贴签和待检17.5 Stability 17.5稳定性17.6 Transfer of Information 17.6 信息的传达17.7 Handling of Complaints and Recalls 17.7 投诉和召回的处理17.8 Handling of Returns 17.8 退货的处理18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 18. 用细胞繁殖/发酵生产的原料药的特殊指南18.1 General 18.1 总则18.2 Cell Bank Maintenance and RecordKeeping18.2细胞库的维护和记录的保存18.3 Cell Culture/Fermentation 18.3细胞繁殖/发酵18.4 Harvesting, Isolation and Purification 18.4收取、分离和精制18.5 Viral Removal/Inactivation steps 18.5 病毒的去除/灭活步骤19.APIs for Use in Clinical Trials 19.用于临床研究的原料药19.1 General 19.1 总则19.2 Quality 19.2 质量19.3 Equipment and Facilities 19.3 设备和设施19.4 Control of Raw Materials 19.4 原料的控制19.5 Production 19.5 生产19.6 Validation 19.6 验证19.7 Changes 19.7 变更19.8 Laboratory Controls 19.8 实验室控制19.9 Documentation 19.9 文件20. Glossary 20. 术语Q7a GMP Guidance for APIs Q7a原料药的GMP指南1. INTRODUCTION 1. 简介1.1 Objective 1.1目的This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess. 本文件旨在为在合适的质量管理体系下制造活性药用成分（以下称原料药）提供有关优良药品生产管理规范（GMP）提供指南。
原料药出口DMF注册文件中的杂质研究中国是世界上原料药出口大国，而美国则是原料药进口大国，每年消耗各种原料药的费用约达40亿美元，占世界原料药市场的1/3。
因此，美国市场成为对中国众多原料药生产企业最具吸引力的市场。
美国食品与药品推行FDA认证。
FDA对原料药及制剂生产、销售的所有方面进行相应的法律监管，以确保这些产品符合联邦食品、药品、化妆品法案的要求。
FDA要求从国外进口的制剂药或原料药厂商必须向FDA当局申请DMF（drug master file）注册，递交涵盖药品生产全过程CMC（chemistry，manufacturing and control）的DMF文件。
美国原料药GMP标准采用人用药品注册技术要求国际协调会（ICH）于2000年公布的Q7A（good manufacturing practice guide for active pharmaceutical ingredients）标准，此标准由ICH 推荐欧洲共同体、日本和美国的药政部门共同采用，并很快被100多个国家和地区的制药行业所认可采用。
FDA认证的科学性和严谨性，使其已成为世界公认的标准，是目前国际上对质量要求很高的药品认证之一。
随着这几年我国药品GMP 的实施、发展和原料药企业对GMP认识的不断加深，在质量管理体系方面，特别是部分具有前瞻性的出口企业，一直在不断完善和规范企业自身的质量管理控制，以顺应国际市场质量管理规范的要求。
但是，大多数的原料药生产企业的质量管理体系还不是很规范，存在着诸多问题，因此在编写DMF文件时会出现许多不足之处，而DMF文件作为药品出口的敲门砖，如果没有通过审核，则会直接影响企业的原料药出口贸易。
本文以美国对进口原料药注册的标准为依据，就我国原料药生产企业在编写DMF文件中涉及的杂质相关问题进行探讨。
在DMF文件“原料药物特性确认”部分中，杂质是一个重要内容。
应该包括有关杂质的信息，包括杂质的分析方法、杂质的定性（化学结构、分子式等）、杂质限度（总杂质、单独杂质）等。
Guidance for Industry Controlled Correspondence Related to Generic DrugDevelopment行业指南：有关仿制药研发的书面咨询This guidance represents the current thinking of the Food and Drug Administration (FDA, or the Agency) on this topic. It does not establish 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.该指南代表了FDA对该主题目前的看法。
它并不会赋予任何人任何权利，也不会约束FDA或公众，如果有替代的方法能够满足法律法规的要求，可以使用替代的方法。
如果想探讨替代的方法，请联系该指南首页中FDA 负责执行该指南的工作人员。
I.INTRODUCTION 简介This guidance provides information regarding the process by which generic drug manufacturers and related industry can submit correspondence to FDA requesting information related to generic drug development. This guidance also describes the Agency’s process for providing communications related to such correspondence. FDA is issuing this guidance as part of its implementation of the Generic Drug User Fee Amendments of 2012 (Public Law 112-144, Title III), commonly referred to as GDUFA.该指南描述了仿制药生产商以及相关行业向FDA提交书面咨询，询问有关仿制药研发信息的过程，同时还描述了FDA针对这些书面咨询提供交流的过程。
Q7a（中英文对照）FDA原料药GMP指南Table of Contents 目录1. INTRODUCTION 1. 简介1.1 Objective 1.1目的1.2 Regulatory Applicability 1.2法规的适用性1.3 Scope 1.3范围2. QUALITY MANAGEMENT 2.质量管理2.1 Principles 2.1总则2.2质量部门的责任2.2 Responsibilities of theQuality Unit(s)2.3生产作业的职责2.3 Responsibility forProduction Activities2.4 Internal Audits (Self2.4内部审计（自检）Inspection)2.5 Product Quality Review 2.5产品质量审核3. PERSONNEL 3. 人员3.1 Personnel Qualifications 3.人员的资质3.2 Personnel Hygiene 3.2 人员卫生3.3 Consultants 3.3 顾问4. BUILDINGS AND FACILITIES 4. 建筑和设施4.1 Design and Construction 4.1 设计和结构4.2 Utilities 4.2 公用设施4.3 Water 4.3 水4.4 Containment 4.4 限制4.5 Lighting 4.5 照明4.6 Sewage and Refuse 4.6 排污和垃圾4.7 Sanitation and Maintenance 4.7 卫生和保养5. PROCESS EQUIPMENT 5. 工艺设备5.1 Design and Construction 5.1 设计和结构5.2 Equipment Maintenance and5.2 设备保养和清洁Cleaning5.3 Calibration 5.3 校验5.4 Computerized Systems 5.4 计算机控制系统6. DOCUMENTATION AND RECORDS 6. 文件和记录6.1 Documentation System andSpecifications6.1 文件系统和质量标准6.2 Equipment cleaning and UseRecord6.2 设备的清洁和使用记录6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials 6.3 原料、中间体、原料药的标签和包装材料的记录6.4 Master Production Instructions (Master Production and Control Records)6.4 生产工艺规程（主生产和控制记录）6.5 Batch Production Records (Batch Production and Control Records)6.5 批生产记录（批生产和控制记录）6.6 Laboratory Control Records 6.6 实验室控制记录6.7 Batch Production RecordReview6.7批生产记录审核7. MATERIALS MANAGEMENT7. 物料管理7.1 General Controls7.1 控制通则7.2 Receipt and Quarantine7.2接收和待验7.3 Sampling and Testing of7.3 进厂物料的取样与测试Incoming Production Materials7.4 Storage7.4储存7.5 Re-evaluation7.5复验8. 生产和过程控制8. PRODUCTION AND IN-PROCESSCONTROLS8.1 Production Operations8.1 生产操作8.2 Time Limits8.2 时限8.3 In-process Sampling and 8.3 工序取样和控制Controls8.4 中间体或原料药的混批8.4 Blending Batches ofIntermediates or APIs8.5 Contamination Control8.5 污染控制9. PACKAGING AND IDENTIFICATION9. 原料药和中间体的包装和贴签LABELING OF APIs ANDINTERMEDIATES9.1 General9.1 总则9.2 Packaging Materials9.2 包装材料9.3 Label Issuance and Control9.3 标签发放与控制9.4 包装和贴签操作9.4 Packaging and LabelingOperations10. STORAGE AND DISTRIBUTION10.储存和分发10.1 Warehousing Procedures10.1 入库程序10.2 Distribution Procedures10.2 分发程序11. LABORATORY CONTROLS11.实验室控制11.1 General Controls11.1 控制通则11.2 Testing of Intermediates11.2 中间体和原料药的测试and APIs11.3 分析方法的验证11.3 Validation of AnalyticalProcedures11.4 Certificates of Analysis11.4 分析报告单11.5 原料药的稳定性监测11.5 Stability Monitoring ofAPIs11.6 Expiry and Retest Dating11.6 有效期和复验期11.7 Reserve/Retention Samples11.7 留样12. VALIDATION12.验证12.1 Validation Policy12.1 验证方针12.2 Validation Documentation12.2 验证文件12.3 Qualification12.3 确认12.4 Approaches to Process12.4 工艺验证的方法Validation12.5 Process Validation Program12.5 工艺验证的程序12.6 Periodic Review of12.6验证系统的定期审核Validated Systems12.7 Cleaning Validation12.7 清洗验证12.8 Validation of Analytical12.8 分析方法的验证Methods13. CHANGE CONTROL13.变更的控制14.拒收和物料的再利用14. REJECTION AND RE-USE OFMATERIALS14.1 Rejection14.1 拒收14.2 Reprocessing14.2 返工14.3 Reworking14.3 重新加工14.4 物料与溶剂的回收14.4 Recovery of Materials andSolvents14.5 Returns14.5 退货15. COMPLAINTS AND RECALLS15.投诉与召回16. CONTRACT MANUFACTURERS16.协议生产商（包括实验室）(INCLUDING LABORATORIES)17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS 17.代理商、经纪人、贸易商、经销商、重新包装者和重新贴签者17.1 Applicability17.1适用性17.2 Traceability of Distributed APIs and Intermediates 17.2已分发的原料药和中间体的可追溯性17.3 Quality Management17.3质量管理17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates 17.4原料药和中间体的重新包装、重新贴签和待检17.5 Stability17.5稳定性17.6 Transfer of Information17.6 信息的传达17.7 Handling of Complaints andRecalls17.7 投诉和召回的处理17.8 Handling of Returns17.8 退货的处理18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 18. 用细胞繁殖/发酵生产的原料药的特殊指南18.1 General18.1 总则18.2 Cell Bank Maintenance andRecord Keeping18.2细胞库的维护和记录的保存18.3 Cell Culture/Fermentation18.3细胞繁殖/发酵18.4 Harvesting, Isolation andPurification18.4收取、分离和精制18.5 Viral Removal/Inactivationsteps18.5 病毒的去除/灭活步骤19. APIs for Use in ClinicalTrials19.用于临床研究的原料药19.1 General19.1 总则19.2 Quality19.2 质量19.3 Equipment and Facilities19.3 设备和设施19.4 Control of Raw Materials19.4 原料的控制19.5 Production19.5 生产19.6 Validation19.6 验证19.7 Changes19.7 变更19.8 Laboratory Controls19.8 实验室控制19.9 Documentation19.9 文件20. Glossary20. 术语Q7a GMP Guidance for APIsQ7a原料药的GMP指南1. INTRODUCTION 1. 简介1.1 Objective 1.1目的This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess.本文件旨在为在合适的质量管理体系下制造活性药用成分（以下称原料药）提供有关优良药品生产管理规范（GMP）提供指南。
发布日期20060228栏目化药药物评价>>化药质量控制标题FDA关于仿制药申请中原料药杂质研究的指导原则（讨论稿）介绍作者史继峰部门正文内容审评七室史继峰摘要：本文主要介绍了FDA关于仿制药杂质研究的最新指导原则。
该指导原则对1999年版的同名指导原则进行了修订，文中对仿制药的杂质研究及限度控制进行了详细阐述。
介绍该指导原则，希对我国仿制药研制有一些提示。
关键字：FDA 仿制药杂质研究指导原则仿制药申请：原料药杂质研究指导原则（讨论稿）于2005年1月28日在FDA网站发布。
FDA对1999年版同名指导原则进行修订是基于以下两点考虑：其一，为了与2003年ICH修订的Q3A（R）“新药原料药杂质研究指导原则”相一致，对仿制药申请（ANDAs）同名指导原则中的“杂质列表、可接受的标准及杂质的合理控制（限度与方法）内容进行更新。
其二，删除1999年版指导原则中与Q3A（R）叙述重复的部分（如杂质分类、分析过程及方法等等）。
限于篇幅，本文仅对其最重要部分“杂质的合理控制（QUALIFICATIONS OF IMPURITIES）”（原文第四部分）作介绍。
杂质的合理控制（QUALIFICATIONS OF IMPURITIES）A 质控限度的考虑ICH Q3A (R)中推荐的“质控限度”是根据原料药每日剂量来制订的。
如果所制订的限度超过该限度值，就必须提供所订限度的合理性依据。
某些情况下，“质控限度”可调高或降低。
比如，当有证据表明某药物中的杂质与副作用相关，就很有必要降低该杂质限度。
相反，如果杂质与安全性无多大关联，杂质限度值可以设定高一些。
FDA会根据患者人群、药物分类及历史数据等因素考虑申请者对杂质限度的调整。
B 杂质限度的研究方法如果杂质水平超过了ICH Q3A(R)中推荐的“质控限度”，那么可以参考附录1中的决策树来制订杂质的合理限度。
一般情况下，与其提供额外的论证资料还不如把杂质水平控制在限度值以下更为简便。
Q7a（中英文对照）FDA原料药GMP指南Table of Contents 目录1. INTRODUCTION 1. 简介1.1 Objective 1.1目的1.2 Regulatory Applicability 1.2法规的适用性1.3 Scope 1.3范围2. QUALITY MANAGEMENT 2.质量管理2.1 Principles 2.1总则2.2 Responsibilities of the Quality Unit(s) 2.2质量部门的责任2.3 Responsibility for Production Activities 2.3生产作业的职责2.4 Internal Audits (Self Inspection) 2.4内部审计（自检）2.5 Product Quality Review 2.5产品质量审核3. PERSONNEL 3. 人员3.1 Personnel Qualifications 3.人员的资质3.2 Personnel Hygiene 3.2 人员卫生3.3 Consultants 3.3 顾问4. BUILDINGS AND FACILITIES 4. 建筑和设施4.1 Design and Construction 4.1 设计和结构4.2 Utilities 4.2 公用设施4.3 Water 4.3 水4.4 Containment 4.4 限制4.5 Lighting 4.5 照明4.6 Sewage and Refuse 4.6 排污和垃圾4.7 Sanitation and Maintenance 4.7 卫生和保养5. PROCESS EQUIPMENT 5. 工艺设备5.1 Design and Construction 5.1 设计和结构5.2 Equipment Maintenance and Cleaning 5.2 设备保养和清洁5.3 Calibration 5.3 校验5.4 Computerized Systems 5.4 计算机控制系统6. DOCUMENTATION AND RECORDS 6. 文件和记录6.1 Documentation System andSpecifications6.1 文件系统和质量标准6.2 Equipment cleaning and Use Record 6.2 设备的清洁和使用记录6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials 6.3 原料、中间体、原料药的标签和包装材料的记录6.4 Master Production Instructions (MasterProduction and Control Records)6.4 生产工艺规程（主生产和控制记录）6.5 Batch Production Records (BatchProduction and Control Records)6.5 批生产记录（批生产和控制记录）6.6 Laboratory Control Records 6.6 实验室控制记录6.7 Batch Production Record Review 6.7批生产记录审核7. MATERIALS MANAGEMENT 7. 物料管理7.1 General Controls 7.1 控制通则7.2 Receipt and Quarantine 7.2接收和待验7.3 Sampling and Testing of IncomingProduction Materials7.3 进厂物料的取样与测试7.4 Storage 7.4储存7.5 Re-evaluation 7.5复验8. PRODUCTION AND IN-PROCESSCONTROLS8. 生产和过程控制8.1 Production Operations 8.1 生产操作8.2 Time Limits 8.2 时限8.3 In-process Sampling and Controls 8.3 工序取样和控制8.4 Blending Batches of Intermediates orAPIs8.4 中间体或原料药的混批8.5 Contamination Control 8.5 污染控制9. PACKAGING AND IDENTIFICATIONLABELING OF APIs ANDINTERMEDIATES9. 原料药和中间体的包装和贴签9.1 General 9.1 总则9.2 Packaging Materials 9.2 包装材料9.3 Label Issuance and Control 9.3 标签发放与控制9.4 Packaging and Labeling Operations 9.4 包装和贴签操作10. STORAGE AND DISTRIBUTION 10.储存和分发10.1 Warehousing Procedures 10.1 入库程序10.2 Distribution Procedures 10.2 分发程序11. LABORATORY CONTROLS 11.实验室控制11.1 General Controls 11.1 控制通则11.2 Testing of Intermediates and APIs 11.2 中间体和原料药的测试11.3 Validation of Analytical Procedures 11.3 分析方法的验证11.4 Certificates of Analysis 11.4 分析报告单11.5 Stability Monitoring of APIs 11.5 原料药的稳定性监测11.6 Expiry and Retest Dating 11.6 有效期和复验期11.7 Reserve/Retention Samples 11.7 留样12. V ALIDATION 12.验证12.1 Validation Policy 12.1 验证方针12.2 Validation Documentation 12.2 验证文件12.3 Qualification 12.3 确认12.4 Approaches to Process Validation 12.4 工艺验证的方法12.5 Process Validation Program 12.5 工艺验证的程序12.6 Periodic Review of Validated Systems 12.6验证系统的定期审核12.7 Cleaning Validation 12.7 清洗验证12.8 Validation of Analytical Methods 12.8 分析方法的验证13. CHANGE CONTROL 13.变更的控制14. REJECTION AND RE-USE OFMATERIALS14.拒收和物料的再利用14.1 Rejection 14.1 拒收14.2 Reprocessing 14.2 返工14.3 Reworking 14.3 重新加工14.4 Recovery of Materials and Solvents 14.4 物料与溶剂的回收14.5 Returns 14.5 退货15. COMPLAINTS AND RECALLS 15.投诉与召回16. CONTRACT MANUFACTURERS(INCLUDING LABORATORIES)16.协议生产商（包括实验室）17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS 17.代理商、经纪人、贸易商、经销商、重新包装者和重新贴签者17.1 Applicability 17.1适用性17.2 Traceability of Distributed APIs andIntermediates17.2已分发的原料药和中间体的可追溯性17.3 Quality Management 17.3质量管理17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates 17.4原料药和中间体的重新包装、重新贴签和待检17.5 Stability 17.5稳定性17.6 Transfer of Information 17.6 信息的传达17.7 Handling of Complaints and Recalls 17.7 投诉和召回的处理17.8 Handling of Returns 17.8 退货的处理18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 18. 用细胞繁殖/发酵生产的原料药的特殊指南18.1 General 18.1 总则18.2 Cell Bank Maintenance and RecordKeeping18.2细胞库的维护和记录的保存18.3 Cell Culture/Fermentation 18.3细胞繁殖/发酵18.4 Harvesting, Isolation and Purification 18.4收取、分离和精制18.5 Viral Removal/Inactivation steps 18.5 病毒的去除/灭活步骤19.APIs for Use in Clinical Trials 19.用于临床研究的原料药19.1 General 19.1 总则19.2 Quality 19.2 质量19.3 Equipment and Facilities 19.3 设备和设施19.4 Control of Raw Materials 19.4 原料的控制19.5 Production 19.5 生产19.6 Validation 19.6 验证19.7 Changes 19.7 变更19.8 Laboratory Controls 19.8 实验室控制19.9 Documentation 19.9 文件20. Glossary 20. 术语Q7a GMP Guidance for APIs Q7a原料药的GMP指南1. INTRODUCTION 1. 简介1.1 Objective 1.1目的This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess. 本文件旨在为在合适的质量管理体系下制造活性药用成分（以下称原料药）提供有关优良药品生产管理规范（GMP）提供指南。
全文：美国FDA对原料药杂质的看法第六图书馆美国FDA原料药杂质医药月刊高注质不详1991第六图书馆品（ＦＥＢＲＵＡＲＹ，１９１９１）ＵＳＭＥＦＥＮＡＭＩＡＣＩＲＥＦＥＲＥＮ—ＰＣＤＳＴＡＮＲＤＵＳ反铂标准品（ＵＮＥ１，ＰＪ１９）９１ＣＥＳＴＡＮＤＡＲＤＰ甲灭酸标准品（ＵＳＭ—ＡＲＣＨ１，１９９１）ＵＳＤＩＰＬＵＴＥＤＩＮＴＲＯＧＬＹＣＥＲＩＲ—Ｎ我们知道，目前在国内尚未普遍收到第３、第４增补版，我们把内容作简要的介绍，希望同行对有关产品的检测要求引起重视，特别是对一些外销的产品更应及时对ＥＦＥＲＥＮＣＥＳＴＡＮＤＡＲＤＰ稀释硝ＵＳ酸甘油标准品（ＪＵＮＥ１．１９９１）ＵＳＰＴＲＡＮＳｐＬＡＴＩＮＲＥＦＥＲＥＮＣＥ照，采取措施，达到标准。
美国ＦＡ对原料药杂质的看法Ｄ高注质在过去几年里，美国ＦＤＡ日益重视原料药中出现的杂质及其鉴定和限量，这是有许会有很大差异。
通常每一合成方法是与特定的杂质有关的，所以对现有生产工艺进行改动或者用不同的生产工艺就必须要有相应的多理由的。
理由之一：杂质的鉴定和定量方法的改进和提高使加紧控制成为可能，大多数企业都能利用色谱方法（特别是高压液相色谱方法）把原料药中的杂质分开，而且，具有高度的准确性、精密性、灵敏性和线性。
此外，ＦＤＡ特别重视药物的安全性，所以对具有致畸、致癌的杂质更为关注。
不论是合成带来的，还是降解产生的，只有少数方法来控制和检测可能会形成的杂质。
这一要求对新化合物和巳收载的药物是同样适用的。
大家知道，法定方法（别是非专一性的特滴定法）能检测不出在新合成方法中产生可的杂质。
实上，国药典在“注意事项事美总（ＧｅｅａｔｃｓｎｒｌＮｏｉｅ）中巳提到，在考虑产品的杂质时，不能兼顾到每一合成方法可能几个杂质会造成药物的毒副反应，特别是杂质的浓度为百万分之几时更是如比。
然而，也确有几个记录在案的例子，如地昔帕明盐酸盐（ＤｅｉｒｍｉｅＨｙｒｃ１ｒｄ）其中ｓｐａｎｄ０ｈ０ｉｅ，有一个杂质是有致畸性和致癌性的。
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USEICH H ARMONISED T RIPARTITE G UIDELINEI MPURITIES I N N EW D RUG S UBSTANCESQ3A(R2)Current Step 4 versiondated 25 October 2006This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA.Q3A(R2) Document HistoryCurrent Step 4 versionI MPURITIES I N N EW D RUG S UBSTANCESICH Harmonised Tripartite GuidelineHaving reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 7 February 2002, this guideline is recommended foradoption to the three regulatory parties to ICH.Attachment 2 has been revised on 25 October 2006.TABLE OF CONTENTSNo table of contents entries found.I MPURITIES I N N EW D RUG S UBSTANCES新原料药中的杂质1. PREAMBLE 序言This document is intended to provide guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state. It is not intended to apply to new drug substances used during the clinical research stage of development. The following types of drug substances are not covered in this guideline: biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation product and semi-synthetic products derived therefrom, herbal products, and crude products of animal or plant origin.本文件旨在为化学合成的新原料药（这些新原料药尚未在任何地区或成员国注册）在注册申请时，对其杂质的含量和界定的申报提供指导。
ANDAs: Impurities in DrugSubstancesU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)June 2009Office of Generic DrugsRevision 1ANDAs: Impurities in DrugSubstancesAdditional copies are available from:Office of CommunicationDivision of Drug Information, WO51, Room 2201Center for Drug Evaluation and ResearchFood and Drug Administration10903 New Hampshire Ave.Silver Spring, MD 20993-0002Phone: 301-796-3400; Fax: 301-847-8715druginfo@U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)June 2009Office of Generic DrugsRevision 1TABLE OF CONTENTSI.INTRODUCTION (1)II.BACKGROUND (2)III.LISTING IMPURITIES AND SETTING ACCEPTANCE CRITERIA FOR IMPURITIES IN DRUG SUBSTANCE SPECIFICATIONS (2)A. Listing Impurities in Drug Substance Specifications (2)B. Setting Acceptance Criteria for Impurities (3)IV.QUALIFICATION OF IMPURITIES (4)A. Qualification Thresholds (5)B. Qualification Procedures (5)1. Comparative Analytical Studies (5)2. Scientific Literature and Significant Metabolites (5)3. Toxicity Studies (5)ATTACHMENT: IDENTIFICATION AND QUALIFICATION OF IMPURITIES IN DRUG SUBSTANCES (7)Guidance for Industry1ANDAs: Impurities in Drug SubstancesThis 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.I. INTRODUCTIONThis guidance provides revised recommendations on what chemistry, manufacturing, and controls (CMC) information to include regarding the reporting, identification, and qualification of impurities in drug substances produced by chemical synthesis when submitting2: • Original abbreviated new drug applications (ANDAs)• Drug master files (DMFs) including type II DMFs• ANDA supplements for changes in the synthesis or processing of a drug substanceThe guidance also provides recommendations for establishing acceptance criteria for impurities in drug substances.The following types of drug substances are not covered in this guidance:• Biological/biotechnological• Peptide• Oligonucleotide• Radiopharmaceutical• Fermentation products• Semisynthetic products derived from fermentation products• Herbal products• Crude products of animal or plant originFDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should1 This guidance was prepared by the Office of Generic Drugs, Office of Pharmaceutical Science, in the Center for Drug Evaluation and Research at the Food and Drug Administration.2 See 21 CFR 314.94(a)(9).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.II.BACKGROUNDIn November 1999, FDA published the first version of this guidance. As a result of changes to recommendations on impurities in drug substances for new drug applications (NDAs), which the International Conference on Harmonisation (ICH) included in the guidance for industry on Q3A Impurities in New Drug Substances (Revision 1) (Q3A(R)) in 2003, we began an effort to revise this guidance for ANDAs.3 On January 31, 2005 (70 FR 4857), FDA announced the availability of a draft revision for public comment. The comment period closed on June 6, 2005. A number of comments were received, which the agency considered carefully as it began the process of finalizing the guidance.FDA believes that much of the content of the Q3A(R) guidance applies to ANDAs. See especially sections I through V and the Attachment, Thresholds.4III.LISTING IMPURITIES AND SETTING ACCEPTANCE CRITERIA FOR IMPURITIES IN DRUG SUBSTANCE SPECIFICATIONSApplicants submitting ANDAs, DMFs, including type II DMFs, and ANDA supplements for changes in the synthesis or processing of a drug substance are required to submit the specifications necessary to ensure the identity, strength, quality, and purity of the drug substance.5 Submissions should list impurities and set acceptance criteria for those impurities in the drug substance specifications.A. Listing Impurities in Drug Substance SpecificationsWe recommend that the specifications for a drug substance include a list of impurities. Stability studies, chemical development studies, and routine batch analyses can be used to predict those impurities likely to occur in the commercial product. It is important that the list of impurities for the drug substance specification be based on impurities found in the batch(es) manufactured by the proposed commercial process.3 CDER guidance documents can be found on the Internet at/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance Web site.4 Please note that in June 2008, FDA published a second revision of ICH Q3A(R) that updated an attachment that is not needed in the ANDA guidance.5 21 CFR 314.50(d)(1)(i).Applicants should also include in their submission a rationale for the inclusion or exclusion of impurities in the drug substance specification. It is important that the rationale include a discussion of the impurity profiles observed in the batch(es) under consideration, together with a consideration of the impurity profile of the batch(es) manufactured by the proposed commercial process.In this guidance, individual impurities with a specific acceptance criterion that are included in the specification for a drug substance are referred to as specified impurities. Specified impurities can be identified or unidentified. We recommend that specified identified impurities be included in the list of impurities along with specified unidentified impurities that are estimated to be present at a level greater than the identification threshold given in Q3A(R). For impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, we recommend that the quantitation and/or detection limit of the analytical procedures correspond to the level at which the impurities are expected to be controlled.When specified unidentified impurities are listed in the drug substance specification, we recommend that applicants also describe the identification efforts attempted and clearly state the procedure used and assumptions made in establishing the level of the impurity. It is important that specified unidentified impurities be referred to by an appropriate qualitative analytical descriptive label (e.g., unidentified A, unidentified with relative retention of 0.9). We recommend that you also include general acceptance criteria of not more than the identification threshold for any unspecified impurity and the acceptance criteria for total impurities (see Attachment 1, Q3A(R)).Where applicable, the drug substance specification should include a list of the following types of impurities:•Organic impurities− Each specified identified impurity− Each specified unidentified impurity− Any unspecified impurity with an acceptance criterion of not more than (≤) the identification threshold in Attachment 1, Q3A(R)− Total impurities• Residual solvents• Inorganic impuritiesB. Setting Acceptance Criteria for ImpuritiesIn establishing impurity acceptance criteria, the first critical consideration is whether an impurity is specified in the United States Pharmacopeia (USP). If there is a monograph in the USP that includes a limit for a specified impurity, we recommend that the acceptance criterion be set no higher than the official compendial limit.However, if the level of a specified impurity is above the level specified in the USP, we recommend qualification. Then, if appropriate qualification has been achieved, an applicant can petition the USP for revision of the acceptance criterion.If a limit for a specified impurity does not exist in the USP, we recommend that you qualify the impurity by comparing it to the observed amounts of the impurity in the reference listed drug product (RLD). Your acceptance criterion should be similar to the level observed in the RLD. Alternatively, the acceptance criterion may be set based on a qualified level that is justified by scientific literature, metabolite data, or toxicity studies.In some circumstances, the acceptance criterion may need to be set lower than the qualified level to ensure drug substance quality. For example, if the level of a metabolite impurity is too high, other quality attributes, like potency, could be seriously affected. In this case, we recommend that the impurity acceptance criterion be set lower than the qualified level.Acceptance criteria for unspecified impurities in ANDAs should be set not to exceed the identification threshold in Attachment 1, Q3A(R), even in the case when higher acceptance criteria for unspecified (other) impurities are listed in the USP monograph. If the acceptance criteria for unspecified (other) impurities in the USP monograph are lower than the identification threshold in Attachment 1, Q3A(R), the acceptance criteria for unspecified impurities should be set to the USP level.IV. QUALIFICATION OF IMPURITIESQualification is the process of acquiring and evaluating data that establish the biological safety of an individual impurity or a given impurity profile at the level(s) being considered. When appropriate, we recommend that applicants provide a rationale for establishing impurity acceptance criteria that includes safety considerations.An impurity is considered qualified when it meets one or more of the following conditions: •The observed level and proposed acceptance criterion for the impurity do not exceed the level observed in the reference listed drug product.•The impurity is a significant metabolite of the drug substance.•The observed level and the proposed acceptance criterion for the impurity are adequately justified by the scientific literature.•The observed level and proposed acceptance criterion for the impurity do not exceed the level that has been adequately evaluated in toxicity studies.Although Quantitative Structure Activity Relationships (QSAR) programs may be used for predicting the toxicity of an individual impurity or a given impurity profile, the results are not generally considered conclusive for qualification purposes.A. QualificationThresholdsRecommended qualification thresholds6 based on the maximum daily dose of the drug substance are provided in Q3A(R). When these qualification thresholds are exceeded, we recommend that impurity levels be qualified. In some cases, it may be appropriate to increase or decrease the threshold for qualifying impurities. For example, when there is evidence that an impurity in certain drug classes or therapeutic classes has previously been associated with adverse reactions in patients, it may be important to establish a lower qualification threshold. Conversely, a higher threshold for qualifying impurities may be appropriate when the concern for safety is low. Therefore, we will consider proposals for alternative qualification thresholds on a case-by-case basis after considering issues such as patient population, drug class effects, and historical safety data.ProceduresB. QualificationThe decision tree in the Attachment to this guidance describes what to consider for the qualification of an impurity when the usual qualification threshold recommended in Q3A(R) is exceeded. In some cases, decreasing the level of the impurity below the threshold rather than providing additional data can be the simplest course of action. Alternatively, adequate data could be available in the scientific literature to qualify the impurity. The studies considered appropriate to qualify the impurity will depend on a number of factors, including the patient population, daily dose, and route and duration of drug administration. Such studies can be conducted on the drug substance containing the impurities to be controlled, although studies using isolated impurities can sometimes be appropriate. The following are descriptions of methods for qualifying impurities.1. Comparative Analytical StudiesAn impurity present in a drug substance covered by an ANDA can be qualified by comparing the analytical profiles of the drug substance with those in the RLD using the same validated, stability-indicating analytical procedure (e.g., comparative HPLC studies).A specified impurity present in the ANDA drug substance is considered qualified if the amount of the impurity in the ANDA drug substance is similar to the levels observed in the RLD.2. Scientific Literature and Significant MetabolitesIf the level of the specified identified impurity is adequately justified by the scientific literature, no further qualification is considered necessary. In addition, an impurity that is also a significant metabolite of the drug substance is generally considered qualified.Studies3. Toxicity6Qualification threshold is defined as a limit above (>) which an impurity should be qualified.Toxicity tests are the least preferred method to qualify impurities. We recommend the tests be used only when impurities cannot be qualified by either of the above procedures (section IV.B.1 or 2). The tests are designed to detect compounds that induce general toxic or genotoxic effects in experimental systems. If performed, such studies should be conducted on the drug product or drug substance containing the impurities to be controlled, although studies using isolated impurities may also be used.Is impurity greater than identification threshold a ?Yes No No actionAny Yes known human Yes identified? relevant risks b ? NoGreater than qualification Yes No further threshold a ?actionYes Reduce No to not more than (≤) qualification threshold a ? Yes Yes Is the impurity observed in the reference listed drug product at a similar level or is it adequately qualified by other acceptable approaches c ? NoConsider patient population and duration of use ATTACHMENT: IDENTIFICATION AND QUALIFICATION OF IMPURITIES INDRUG SUBSTANCES如果想要下载更多的资源请百度一下药智论坛Contains Nonbinding RecommendationsNotes on the Attachmenta Lower thresholds can be appropriate if the impurity is unusually toxic.b For example, do known safety data for this impurity or its structural class require no human exposure at the observed level?c A difference from Q3A(R), Attachment 3, is that an impurity is considered qualified for an ANDA when one or more of the following conditions are met:•The observed level and proposed acceptance criterion for the impurity do not exceed the level justified by the reference listed drug product.•The impurity is a significant metabolite of the drug substance.•The observed level and the proposed acceptance criterion for the impurity are adequately justified by the scientific literature.•The observed level and proposed acceptance criterion for the impurity do not exceed the level that has been adequately evaluated in toxicity studies.d If appropriate, a minimum screen (e.g., genotoxic potential) should be conducted. A study to detect point mutations and one to detect chromosomal aberrations, both in vitro, are considered an appropriate minimum screen.e If general toxicity studies are appropriate, one or more studies should be designed to allow comparison of unqualified to qualified material. The study duration should be based on available relevant information and performed in the species most likely to maximize the potential for detecting the toxicity of an impurity. On a case-by-case basis, single dose studies can be appropriate, especially for single dose drugs. In general, a minimum duration of 14 days and a maximum duration of 90 days would be considered appropriate.8本资料由药智论坛收集整理，仅供学习使用，任何单位或个人不得用于商业用途。
