下载文档原格式
EUROPEAN COMMISSION 欧盟委员会ENTERPRISE AND INDUSTRY DIRECTORATE-GENERAL 企业与工业管理局Consumer goods 消费品Pharmaceuticals 药品Brussels, 03 February 2010 布鲁塞尔2010.02.03ENTR/F/2/AM/an D(2010) 3374EudraLex（European Union Law On drug regulatory affairs）欧盟药品法规The Rules Governing Medicinal Products in the European Union欧盟医药产品管理规则Volume 4卷4Good Manufacturing Practice良好生产规范Medicinal Products for Human and Veterinary Use人用和兽用医药产品Part II: Basic Requirements for Active Substances used as Starting Materials 第二部分：作为起始物料的原料药的基本要求Table of Contents目录1 Introduction1简介1.1 Objective1.1目的1.2 Regulatory Applicability1.2法规适用性1.3 Scope1.3范围2 Quality Management2质量管理2.1 Principles2.1原则2.2 Quality Risk Management2.2质量风险管理2.3 Responsibilities of the Quality Unit(s) 2.3质量部门的职责2.4 Responsibility for Production Activities 2.4生产活动的职责2.5 Internal Audits (Self-Inspection)2.5内部审计（自检）2.6 Product Quality Review2.6产品质量回顾3 Personnel3 人员3.1 Personnel Qualifications3.1 人员资质3.2 Personnel Hygiene3.2 人员卫生3.3 Consultants3.3 顾问4 Buildings and Facilities4 厂房设施4.1 Design and Construction4.1 设计和建造4.2 Utilities4.2 公用工程4.3 Water4.3 水4.4 Containment4.4 限制4.5 Lighting4.5 照明4.6 Sewage and Refuse4.6 废水废物4.7 Sanitation and Maintenance4.7 公共卫生及保养5 Process Equipment5 工艺设备5.1 Design and Construction5.1 设计和建造5.2 Equipment Maintenance and Cleaning5.2 设备的保养和清洁5.3 Calibration5.3 校验5.4 Computerized Systems5.4 计算机系统6 Documentation and Records6 文件和记录6.1 Documentation System and Specifications6.1 文件系统与规格标准6.2 Equipment Cleaning and Use Record6.2 设备清洁和使用记录6.3 Records of Raw Materials, Intermediates, API Labelling and Packaging Materials 6.3 原料、中间产品、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 生产指令（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 Records6.6 实验室控制记录（批检验记录）6.7 Batch Production Record Review6.7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 接受和待检7.3 Sampling and Testing of Incoming Production Materials7.3 到货物料的取样和检测7.4 Storage7.4 贮存7.5 Re-evaluation7.5 再评估8 Production and In-Process Controls8 生产和过程控制8.1 Production Operations8.1 生产操作8.2 Time Limits8.2 时间限制8.3 In-process Sampling and Controls8.3 中控取样和控制8.4 Blending Batches of Intermediates or APIs8.4 中间产品和原料药的混批8.5 Contamination Control8.5 污染控制9 Packaging and Identification Labelling of APIs and Intermediates 9 中间产品和原料药的包装和贴签9.1 General9.1 总则9.2 Packaging Materials9.2 包装材料9.3 Label Issuance and Control9.3 标签放行和控制9.4 Packaging and Labelling Operations9.4 包装和贴签操作10 Storage and Distribution10 贮存和销售10.1 Warehousing Procedures10.1 入库程序10.2 Distribution Procedures10.2 销售程序11 Laboratory Controls11 实验室控制11.1 General Controls11.1 控制通则11.2 Testing of Intermediates and APIs11.2 中间产品和原料药的检测11.3 Validation of Analytical Procedures11.3 分析方法的验证11.4 Certificates of Analysis11.4 分析报告11.5 Stability Monitoring of APIs11.5 原料药的稳定性监测11.6 Expiry and Retest Dating11.6 失效和复检日期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 Process Validation12.4 工艺验证方法12.5 Process Validation Program12.5 工艺验证计划12.6 Periodic Review of Validated Systems12.6 验证系统的定期审核12.7 Cleaning Validation12.7 清洁验证12.8 Validation of Analytical Methods12.8 分析方法验证13 Change Control13 变更控制14 Rejection and Reuse of Materials14 物料的拒收和再利用14.1 Rejection14.1 拒收14.2 Reprocessing14.2 返工14.3 Reworking14.3 重新加工14.4 Recovery of Materials and Solvents14.4 物料和溶剂的回收利用14.5 Returns14.5 退回15 Complaints and Recalls15 投诉和召回16 Contract Manufacturers (including Laboratories)16 合同生产企业（包含实验室）17 Agents, Brokers, Traders, Distributors, Repackers, and Relabellers 17 代理商、经纪商、贸易商、经销商、重新包装商和重新贴签商17.1 Applicability17.1 适用性17.2 Traceability of Distributed APIs and Intermediates17.2 已销售中间产品和原料药的追踪17.3 Quality Management17.3 质量管理17.4 Repackaging, Relabelling and Holding of APIs and Intermediates 17.4 中间产品和原料药的重新包装、重新贴签和处理17.5 Stability17.5 稳定性17.6 Transfer of Information17.6 信息的传输17.7 Handling of Complaints and Recalls17.7 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 用于细胞培养/发酵而得原料药的特殊指南18.1 General18.1 总则18.2 Cell Bank Maintenance and Recordkeeping18.2 细胞库的维护和记录保存18.3 Cell Culture/Fermentation18.3 细胞培养/发酵18.4 Harvesting, Isolation, and Purification18.4 收获、分离和精制18.5 Viral Removal/Inactivation Steps18.5 病毒除去/灭火步骤19 APIs for Use in Clinical Trials19 用于临床试验的原料药19.1 General19.1 总则19.2 Quality19.2 质量19.3 Equipment and Facilities19.3 设备设施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 词汇表1 Introduction1 介绍This guideline was published in November 2000 as Annex 18 to the GMP Guide reflecting the EU’s agreement to ICH Q7A and has been used by manufacturers and GMP inspectorates on a voluntary basis. Article 46 (f) of Directive 2001/83/EC and Article 50 (f) of Directive 2001/82/EC; as amended by Directives 2004/27/EC and 2004/28/EC respectively, place new obligations on manufacturing authorisation holders to use only active substances that have been manufactured in accordance with Good Manufacturing Practice for starting materials. The directives go on to say that the principles of Good Manufacturing Practice for active substances are to be adopted as detailed guidelines. Member States have agreed that the text of former Annex 18 should form the basis of the detailed guidelines to create Part II of the GMP Guide.本指南已经在2000年11月以GMP指南附录18的形式公布过，它反应了欧盟对ICH Q7A的认可以，该指南已经被生产商和GMP检查员在自愿的原则下所使用。
![欧盟 GMP中英文对照[优质PPT]](https://img.taocdn.com/s1/m/80497bd1172ded630b1cb6cc.png)
欧盟G M P中英文对照(总66页)-CAL-FENGHAI.-(YICAI)-Company One1-CAL-本页仅作为文档封面，使用请直接删除European Union药品生产质量管理规范GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS目录第一章质量管理CHAPTER 1: QUALITY MANAGEMENT原则............................................................ ............. ........................................ ............ ...................... ..5 Principle................................................................... ............................................................................ (5)质量保证................................................................... ...... ........ . (5)Quality Assurance................................................................... (5)药品生产质量管理规范(GMP)...................................................................... (7)Good Manufacturing Practice for Medicinal Products.................................................................... . (7)质量控制(QC) ...................................................................... . (9)QualityControl....................... ............................................. . (9)产品质量回顾....................... ....................... .......................... . (10)第二章人员CHAPTER 2: PERSONNEL................................................................... ................... .. (11)原则............................................................................ . (11)Principle................................................................... (11)通则............................................................................ . (12)General..................................................................... ................................................. . (12)关键人员.......................................................................... ......................................... . (12)Key Personnel................................................................... (12)培训.......................................................................... ............................................................................ . (12)Training.................................................................... ................................................. . (15)人员卫生.......................................................................... . (16)Personnel Hygiene..................................................................... .. (16)第三章厂房和设备CHAPTER 3: PREMISES AND EQUIPMENT................................................................ .. (18)原则.......................................................................... .. (18)Principle................................................................... .. (18)厂房.......................................................................... (18)Premises.................................................................... . (18)通则.......................................................................... (18)General..................................................................... .. (18)生产区.......................................................................... . (19)Production Area........................................................................ ................................................19贮存区.......................................................................... . (21)Storage Area........................................................................ .. (21)质量控制区.......................................................................... (22)Quality Control Area........................................................................ . (22)附助区.......................................................................... . (22)Ancillary Areas....................................................................... .. (22)设备.......................................................................... (23)Equipment................................................................... .. (23)第四章文件CHAPTER 4: DOCUMENTATION............................................................... . (24)原则.......................................................................... (24)Principle................................................................... .. (24)通则.......................................................................... (25)General..................................................................... .. (25)文件要求.......................................................................... (27)Documents Required.................................................................... (27)Specifications.............................................................. (27)Specifications for starting and packaging materials (27)Specifications for Intermediate and Bulk Products (27)Specifications for Finished Products.................................................................... (28)Manufacturing Formulae and Processing Instructions (28)Packaging Instructions................................................................ .. (30)Batch Processing Records..................................................................... . (31)Batch PackagingRecords. ................................................................... .. (32)Procedures and Records..................................................................... ................... .. (33)Receipt..................................................................... . (34)Sampling.................................................................... .. (34)Testing..................................................................... . (35)Other....................................................................... .. (35)第五章生产CHAPTER 5: PRODUCTION......................................... ........ (36)原则........................................ . (36)Principle (36)通则........................................ . (36)General (36)生产过程中对交叉污染的预防 (39)Prevention of Cross-contamination in Production (39)验证........................................ . (40)Validation................................. . (40)原料........................................ . (41)Starting Materials..................... . (41)生产操作：中间产品和待包装产品 (42)Processing Operations: Intermediate and Bulk Products (42)Packaging Materials.......................... . (43)包装操作........................................ . (44)Packaging Operations........................ . (44)成品........................................ . (46)Finished Products..................... . (46)不合格、回收料和退货物料 (46)Rejected, Recovered and Returned Materials (46)第六章质量控制CHAPTER 6: QUALITY CONTROL (48)原则........................................ . (48)Principle................................... . (48)通则........................................ . (48)General... .. (48)质量控制实验室规范 (49)Good Quality Control Laboratory Practice (49)Documentation (49)Sampling................................... (50)Testing... .. (52)销售产品的稳定性考察 (54)第七章委托生产与委托检验CHAPTER 7: CONTRACT MANUFACTURE AND ANALYSIS (55)原则........................................ . (55)Principle................................... . (55)通则........................................ . (56)General..................................... . (56)委托方.................................... . (56)The Contract Giver.................... .. (56)受托方.................................... (57)The Contract Acceptor.............. (57)合同........................................ . (58)The Contract............................. (58)第八章投诉与召回CHAPTER 8: COMPLAINTS AND PRODUCT RECALL (59)原则........................................ . (59)Principle.................................... . (59)Complaints................................ . (59)召回 (60)Recalls (60)第九章自查CHAPTER 9: SELF INSPECTION (61)原则 (61)Principle (61)附件8 原辅料和包装材料的取样ANNEX8 SAMPLING OF STARTING AND PACKAGING MATERIALS (63)原则 (63)Principle (63)人员 (63)Personnel (63)原辅料 (63)Starting materials (64)包装材料 (65)Packaging material (65)第一章质量管理CHAPTER 1 QUALITY MANAGEMENTPrinciple原则生产许可证持有厂家只能生产医药产品，以确保药品符合其预期的使用目的，符合销售许可证的要求，并不因药品安全性、质量或药效方面的问题而给患者带来风险。
国际组织ISO（International Organization for Standardization）：国际标准化组织日常办事机构是中央秘书处，设在瑞士日内瓦WHO（World Health Organization）：世界卫生组织是联合国属下的专门机构，国际最大的公共卫生组织，总部设于瑞士日内瓦PIC/S（Pharmaceutical Inspection Convention/Pharmaceutical Inspection Cooperation Scheme）：国际医药品稽查协约组织由欧洲自由贸易区（EFTA）组建ICH（International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human U se）：人用药物注册技术要求国际协调会由欧盟（EU）、欧洲制药工业协会联合会（EFPIA）、日本厚生省（MHW）、日本制药工业协会（JPMA）、美国FDA、美国药物研究生产联合会（PRMA）等机构组成WHO、EFTA、加拿大卫生保健局（CHPB）为观察员ISPE（International Society for Pharmaceutical Engineering）：国际制药工程协会是致力于培训制药领域专家并提升制药行业水准的世界最大的非盈利性组织之一，在美国坦帕州设有全球总部，在布鲁塞尔设有欧洲总部，亚洲总部在新加坡HHS（United States Department of Health and Human Services）：美国卫生及公共服务部（美国卫生部）FDA（Food and Drug Administration）：美国食品药品监督管理局（HHS下属机构） PDA（Parenteral Drug Association）：美国注射剂协会 EPA（Environmental Protection Agency）：美国国家环境保护局CDER（Center for Drug Evaluation and Research）：FDA药物评价与研究中心EMEA（The European Agency for the Evaluation of Medicinal Products）：欧洲药物评审组织MHW（Ministry of Health and Welfare）：日本厚生省，现改为厚生劳动省MHLW （Ministry of Health, Labor and Welfare），负责医疗卫生和社会保障的主要部门 D&B（Dun & Bradstreet）：邓白氏公司DUNS（DataUniversal Numbering System）：邓白氏公司提供的唯一的公司代号，用于信用评级等在SMF文件中会用到ATCC（American Type Culture Collection）：美国模式培养物集存库 ASTM（American Society for Testing Materials）：美国材料与试验协会法规GMP（Good Manufacturing Practice）：药品良好生产规范cGMP（Current Good Manufacture Practices）：动态药品生产管理规范，即现行的 GLP（Good Laboratory Practice）：药物非临床研究质量管理规范，及优良实验室规范 GSP（Good Supplying Practice）：药品经营质量管理规范，及良好的药品供应规范 GAP（Good Agricultural Practice for Chinese Crude Drugs）：中药材生产质量管理规范 GDP （Good Documentation Practice）：良好文件管理 GEP（Good Engineering Practice）：工程设计规范GAMP（Good Automated Manufacturing Practice）：优良自动化生产规范 USP（united states pharmacopeia）：美国药典 EP（European Pharmacopeia）：欧洲药典 JP（Japanese Pharmacopoeia）：日本药典 CFR（Code of Federal Regulations）：美国联邦法律CFR 21 Part 11（Code of Federal Registry Part11）：联邦法规法律标题21第11部分 CEP/COS （Certificate of Suitability to the monographs of European Pharmacopoeia）：欧洲药典适应性认证证书CEP认证，COS 证书CTD（Common Technical Document）：国际注册用常规技术文件CTD文件是国际公认的文件编写格式，用来制作一个向药品注册机构递交的结构完善的注册申请文件 EHS（Environment、Health、Safety）：环境-健康-安全管理体系HACCP（Hazard Analysis and Critical Control Point）：（保健食品）危害分析和关键控制点 REACH （REGULATION concerning the Registration, Evaluation, Authorization and Restriction of Chemicals）：欧盟规章《化学品注册、评估、许可和限制》，欧盟建立的，并于2007年6月1日起实施的化学品监管体系ICH法规ICH-Q1A：新原料药和制剂的稳定性试验ICH-Q1B：稳定性试验：新原料药和制剂的光稳定性试验ICH-Q1C：稳定性试验：新剂型的要求ICH-Q1D：新原料药和制剂的稳定性试验的括号法和矩阵法设计ICH-Q1E：稳定性数据的评价ICH-Q1F：气候带Ⅲ和Ⅳ注册申请的稳定性数据ICH-Q2A：分析步骤验证：正文ICH-Q2B：分析步骤验证：方法学ICH-Q3A：原料药中的杂质ICH-Q3B：新制剂中的杂质ICH-Q3C：杂质；残留溶剂的指导原则ICH-Q4：药典ICH-Q4A：药典的同一化ICH-Q4B：各地区使用的药典正文评估和建议ICH-Q5A：来源于人或动物细胞系的生物技术产品的病毒安全性评价ICH-Q5B：生物技术产品的质量：rDNA衍生蛋白质产品生产细胞的表达构建体分析ICH-Q5C：生物技术产品的质量：生物制品生物技术产品的稳定性试验ICH-Q5D：用于生物技术产品及生物制品生产的细胞基质的来源和鉴定ICH-Q5E：生物技术产品生物制品在工艺变更时的可比性ICH-Q6A：质量标准新原料药和制剂的检测以及可接受标准：化学物质ICH-Q6B：质量标准：生物技术产品及生物制品的检测方法和可接受标准ICH-Q7：原料药良好制造规范(ICH-Q7A的新版)ICH-Q7A：原料药的GMP规范ICH-Q8：药物研发指南ICH-Q9：质量风险管理ICH- Q10（PQS）：药物质量体系ICH-Q11：原料药研发与生产常见术语QA（Quality Assurance）：质量保证QC（Quality Control）：质量控制CQA（Critical Quality Attribute）：关键质量属性QRM（Quality Risk Management）：质量风险管理IPC（InproceicsQuality Control）：制程品质控制/中控OOS（Out of Specification）：检验结果超标OOT（Out of Trend）：超趋势结果OOL（Out of Limit）：超出极限的结果，如温湿度等OOE（Out of Expectation）：超期望结果SOP（Standard Operation Procedure）：标准操作规程DMF（Drug Master File）：药品主文件SMF（Site Master File）：工厂主文件URS（User Requirement Specification）：用户需求标准FAT（Factory Acceptance Test）：工厂验收测试SAT（Site Acceptance Test）：现场验收测试FS（Functional Specification）：功能标准DS（Design Specification）：设计标准DQ（Design Qualification）：设计确认IQ（Installation Qualification）：安装确认OQ（Operational Qualification）：运行确认PQ（Performance Qualification）：性能确认RQ（Requalification）：再确认CAPA（Corrective Action & Preventive Action）：纠正预防系统，Q10的四大要素之一QbD（Quality byDesign）：质量源于设计PMC（Product Material Control）：生产物料控制PC生产控制；MC物料控制CMC（Chemistry and manufacture control）：生产和化学控制APR（Annual Products Review）：年度质量回顾CNC（Controlled Non-Classified Area）：受控非洁净区应用技术APS（Aseptic Processing Simulation）：培养基模拟灌装CIP（Cleaning in Place）：原位清洗（全自动，如针剂配制系统）WIP（Washing in Place）：在线清洁（半自动，需要手动的拆卸，如流化床）SIP（Sterilization in Place）：在线灭菌BFS（Blowing Filling and Sealing）：吹-灌-封PA T（Process Analytical Technology）：过程分析技术PLC（Programmable Logic Controller）：可编程逻辑控制EDI（Electrodeionization）：一种制备纯化水的离子交换技术MAC（Minimum Acceptable Cycle）：最低可接受程序SAM（Steam-Air Mixture）：蒸汽空气混合气体灭菌程序WIT（Water IntrusionTest）：水侵入测试（东富龙疏水性滤器的在线进行完整性测试的方法） BP（Bubble Point Test）：起跑点试验FF（Forward Flow/Diffusive Flow）：前进流、扩散流试验HPLC（High Performance Liquid Chromatography）：高效液相色谱GC（Gas Chromatography）：气相色谱FTIR（Fourier Transform Infrared spectroscopy）：傅氏转换红外线光谱分析仪MS（Mass Spectroscopy）：质谱LC/MS：液质联用GC/MS：气质联用TOC（Total Organic Carbon）：总有机碳NVR（NonvolatileResidue）：不挥发残留物RFS（Ready for Sterilization）：免洗胶塞RFU（Ready for Use）：即用胶塞物品名称SVP（Small V olume Parenteral）：小容量注射剂 LVP（Large Volume Parenteral）：大容量注射剂 APA （Aseptic Processing Area）：无菌区P&ID（Piping and Instrument Diagram）：工艺管道仪表流程图 PFD（Process Flow Diagram）：工艺流程图 UFD （Utility Flow Diagram）：公用工程流程图HV AC（Heating Ventilation Air Conditioning）：供热空气调节净化系统 HEPA（High Efficiency Particulate Air Filter）：高效过滤器 FFU（Fan Filter Units）：风机滤器单元 AHU（Air Handling Unit）：空气处理单元COA（Certificate of Analysis）：分析证书/检验报告书/检验报告单 BPR（Batch Production Record）：批生产记录API（Active Pharmaceutical Ingredients）：药物活性成分，通常指的原料药 WFI（Water for Injection）：注射用水DOP：为邻苯二甲酸二辛酯，HEPA检漏用的气溶胶 PAO：聚-α-烯烃，HEPA检漏用的气溶胶 IBC （IntermediateBulkContainer）：中型散装容器 FBD（Fluid Bed Dryer）：流化床IRTD（IntelligentResistance Temperature Detector）：智能热电阻温度探头，标准温度探头 SV（Solenoid Valve）：电磁阀FV：气动阀P/HG（Porous/Hard Goods Loads）：多孔/坚硬装载，包括过滤器、胶塞、软管、拖把、工作服、塞子、清洁器具或设备的更换部件。
欧盟GMP中英文对照EU GMP (Good Manufacturing Practice) is a set of standards and guidelines that govern the manufacturing of drugs and medicinal products within the European Union. These guidelines are designed to ensure that these products are of high quality and are safe for use by patients.欧盟GMP是一组标准和指南，用于监管欧洲联盟内的药品和医疗产品的生产。
这些准则旨在确保这些产品具有高质量，并且对患者使用安全。
Introduction引言：The European Union has a comprehensive set of guidelines and regulations in place to ensure that drugs and medicinal products manufactured within the EU are of high quality and meet the safety standards required for patient use. These regulations are designed to ensure that the pharmaceutical industry operates at the highest possible level of quality.欧盟已经实施了一套全面的指导方针和法规，以确保在欧盟内制造的药品和医疗产品具有高质量，并符合患者使用所需的安全标准。
这些法规旨在确保制药工业运营在最高水平的质量。
The EU GMP guidelines form the basis for the quality assurance in the manufacture and control of medicinal products within the EU and have been laid down by the European Commission. Theseguidelines are based on the principles of Good Manufacturing Practice and cover all aspects of the production and control of medicinal products, including raw materials, manufacturing premises, equipment, personnel and quality management systems.欧盟GMP指南是欧盟内药品生产和控制质量保证的基础，并由欧洲委员会制定。
European Union欧阳家百（2021.03.07）药品生产质量管理规范GUIDE TO GOOD MANUFACTURING PRACTICE FORMEDICINAL PRODUCTS目录第一章质量管理CHAPTER 1: QUALITYMANAGEMENT原则............................................................................................................... .. (5)Principle..................................................................................................... (5)质量保证............................................................................................................... . (5)Quality Assurance................................................................................................... . (5)药品生产质量管理规范(GMP) (7)Good Manufacturing Practice for Medicinal Products (7)质量控制(QC)........................................................................................................... (9)Quality Control....................................................................................................... .. (9)产品质量回顾............................................................................................................... . (10)第二章人员CHAPTER 2:PERSONNEL............................................................................................ ..11 ........................................................................................................................ .. (11)Principle..................................................................................................... .. (11)........................................................................................................................ .. (12)General....................................................................................................... . (12)关键人员............................................................................................................... .. (12)Key Personnel................................................................................................... . (12)培训............................................................................................................... . (12)Training..................................................................................................... .. (15)人员卫生............................................................................................................... (16)Personnel Hygiene...................................................................................................... .. (16)第三章厂房和设备CHAPTER 3: PREMISES AND EQUIPMENT (18)原则............................................................................................................... . (18)Principle..................................................................................................... . (18)厂房............................................................................................................... .. (18)Premises..................................................................................................... . (18)通则............................................................................................................... .. (18)General....................................................................................................... . (18)生产区............................................................................................................... (19)Production Area........................................................................................................... .............19贮存区............................................................................................................... (21)Storage Area........................................................................................................... (21)质量控制区............................................................................................................... .. (22)Quality Control Area........................................................................................................... ..22附助区............................................................................................................... (22)Ancillary Areas.......................................................................................................... (22)设备............................................................................................................... .. (23)Equipment.................................................................................................. . (23)第四章文件CHAPTER 4: DOCUMENTATION................................................................................ .. (24)原则............................................................................................................... .. (24)Principle..................................................................................................... . (24)通则............................................................................................................... .. (25)General....................................................................................................... . (25)文件要求............................................................................................................... .. (27)Documents Required..................................................................................................... (27)Specifications............................................................................................. .. (27)Specifications for starting and packaging materials (27)Specifications for Intermediate and Bulk Products (27)Specifications for Finished Products (28)Manufacturing Formulae and Processing Instructions (28)Packaging Instructions................................................................................................ (30)Batch Processing Records...................................................................................................... .31Batch Packaging Records...................................................................................................... .32Procedures and Records...................................................................................................... ...33 Receipt....................................................................................................... (34)Sampling.................................................................................................... (34)Testing....................................................................................................... (35)Other.......................................................................................................... (35)第五章生产CHAPTER 5: PRODUCTION......................................................................................... .. (36)原则............................................................................................................... .. (36)Principle..................................................................................................... (36)通则........................................ ...................................................................... (36)General....................................................................................................... (36)生产过程中对交叉污染的预防 (39)Prevention of Cross-contamination in Production (39)验证............................................................................................................... .. (40)Validation.................................................................................................. .. (40)原料............................................................................................................... .. (41)Starting Materials.................................................................................................... (41)生产操作：中间产品和待包装产品 (42)Processing Operations: Intermediate and Bulk Products (42)包装材料............................................................................................................... .. (43)PackagingMaterials.................................................................................................... .. (43)包装操作............................................................................................................... .. (44)Packaging Operations.................................................................................................. .. (44)成品............................................................................................................... .. (46)Finished Products..................................................................................................... .. (46)不合格、回收料和退货物料 (46)Rejected, Recovered and Returned Materials (46)第六章质量控制CHAPTER 6: QUALITY CONTROL (48)原则............................................................................................................... .. (48)Principle..................................................................................................... . (48)通则............................................................................................................... .. (48)General....................................................................................................... . (48)质量控制实验室规范 (49)Good Quality Control Laboratory Practice (49)Documentation........................................................................................... .. (49)Sampling.................................................................................................... . (50)Testing....................................................................................................... (52)销售产品的稳定性考察 (54)第七章委托生产与委托检验CHAPTER 7: CONTRACT MANUFACTURE AND ANALYSIS (55)原则............................................................................................................... .. (55)Principle..................................................................................................... . (55)通则............................................................................................................... .. (56)General....................................................................................................... . (56)委托方............................................................................................................... . (56)The Contract Giver.......................................................................................................... (56)受托方............................................................................................................... (57)The Contract Acceptor..................................................................................................... (57)合同............................................................................................................... .. (58)The Contract..................................................................................................... (58)第八章投诉与召回CHAPTER 8: COMPLAINTS AND PRODUCT RECALL (59)原则............................................................................................................... .. (59) (59)投诉............................................................................................................... .. (59)Complaints................................................................................................. .. (59)召回............................................................................................................... . (60)Recalls....................................................................................................... . (60)第九章自查CHAPTER 9: SELF INSPECTION (61)原则............................................................................................................... (61)Principle..................................................................................................... .. (61)附件8 原辅料和包装材料的取样ANNEX8 SAMPLING OF STARTING AND PACKAGING MATERIALS (63)原则............................................................................................................... (63)Principle..................................................................................................... .. (63)人员............................................................................................................... (63)Personnel................................................................................................... (63)原辅料............................................................................................................... .. (63)Starting materials..................................................................................................... . (64)包装材 (65)Packaging material...................................................................................................... . (65)第一章质量管理CHAPTER 1 QUALITY MANAGEMENTPrinciple原则生产许可证持有厂家只能生产医药产品，以确保药品符合其预期的使用目的，符合销售许可证的要求，并不因药品安全性、质量或药效方面的问题而给患者带来风险。
ISO（International Organization for Standardization）：国际标准化组织日常办事机构是中央秘书处，设在瑞士日内瓦WHO（World Health Organization）：世界卫生组织是联合国属下的专门机构，国际最大的公共卫生组织，总部设于瑞士日内瓦PIC/S（Pharmaceutical Inspection Convention/Pharmaceutical Inspection Cooperation Scheme）：国际医药品稽查协约组织由欧洲自由贸易区（EFTA）组建ICH（International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use）：人用药物注册技术要求国际协调会由欧盟（EU）、欧洲制药工业协会联合会（EFPIA）、日本厚生省（MHW）、日本制药工业协会（JPMA）、美国FDA、美国药物研究生产联合会（PRMA）等机构组成WHO、EFTA、加拿大卫生保健局（CHPB）为观察员ISPE（International Society for Pharmaceutical Engineering）：国际制药工程协会是致力于培训制药领域专家并提升制药行业水准的世界最大的非盈利性组织之一，在美国坦帕州设有全球总部，在布鲁塞尔设有欧洲总部，亚洲总部在新加坡HHS（United States Department of Health and Human Services）：美国卫生及公共服务部（美国卫生部）FDA（Food and Drug Administration）：美国食品药品监督管理局（HHS下属机构）PDA（Parenteral Drug Association）：美国注射剂协会EPA（Environmental Protection Agency）：美国国家环境保护局CDER（Center for Drug Evaluation and Research）：FDA药物评价与研究中心EMEA（The European Agency for the Evaluation of Medicinal Products）：欧洲药物评审组织MHW（Ministry of Health and Welfare）：日本厚生省，现改为厚生劳动省MHLW （Ministry of Health, Labor and Welfare），负责医疗卫生和社会保障的主要部门D&B（Dun & Bradstreet）：邓白氏公司DUNS（Data Universal Numbering System）：邓白氏公司提供的唯一的公司代号，用于信用评级等在SMF文件中会用到GMP（Good Manufacturing Practice）：药品良好生产规范cGMP（Current Good Manufacture Practices）：动态药品生产管理规范，即现行的GLP（Good Laboratory Practice）：药物非临床研究质量管理规范，及优良实验室规范GSP（Good Supplying Practice）：药品经营质量管理规范，及良好的药品供应规范GAP（Good Agricultural Practice for Chinese Crude Drugs）：中药材生产质量管理规范GDP（Good Documentation Practice）：良好文件管理GEP（Good Engineering Practice）：工程设计规范GAMP（Good Automated Manufacturing Practice）：优良自动化生产规范USP（united states pharmacopeia）：美国药典EP（European Pharmacopeia）：欧洲药典JP（Japanese Pharmacopoeia）：日本药典CFR（Code of Federal Regulations）：美国联邦法律CFR 21 Part 11（Code of Federal Registry Part11）：联邦法规法律标题21第11部分CEP/COS（C ertificate o f S uitability to the monographs of E uropean P harmacopoeia）：欧洲药典适应性认证证书CEP认证，COS证书CTD（Common Technical Document）：国际注册用常规技术文件CTD文件是国际公认的文件编写格式，用来制作一个向药品注册机构递交的结构完善的注册申请文件EHS（Environment、Health、Safety）：环境-健康-安全管理体系HACCP（Hazard Analysis and Critical Control Point）：（保健食品）危害分析和关键控制点REACH（REGULATION concerning the Registration, Evaluation, Authorization and Restriction of Chemicals）：欧盟规章《化学品注册、评估、许可和限制》，欧盟建立的，并于2007年6月1日起实施的化学品监管体系ICH-Q1A：新原料药和制剂的稳定性试验ICH-Q1B：稳定性试验：新原料药和制剂的光稳定性试验ICH-Q1C：稳定性试验：新剂型的要求ICH-Q1D：新原料药和制剂的稳定性试验的括号法和矩阵法设计ICH-Q1E：稳定性数据的评价ICH-Q1F：气候带Ⅲ和Ⅳ注册申请的稳定性数据ICH-Q2A：分析步骤验证：正文ICH-Q2B：分析步骤验证：方法学ICH-Q3A：原料药中的杂质ICH-Q3B：新制剂中的杂质ICH-Q3C：杂质；残留溶剂的指导原则ICH-Q4：药典ICH-Q4A：药典的同一化ICH-Q4B：各地区使用的药典正文评估和建议ICH-Q5A：来源于人或动物细胞系的生物技术产品的病毒安全性评价ICH-Q5B：生物技术产品的质量：rDNA衍生蛋白质产品生产细胞的表达构建体分析ICH-Q5C：生物技术产品的质量：生物制品/生物技术产品的稳定性试验ICH-Q5D：用于生物技术产品及生物制品生产的细胞基质的来源和鉴定ICH-Q5E：生物技术产品/生物制品在工艺变更时的可比性ICH-Q6A：质量标准新原料药和制剂的检测以及可接受标准：化学物质ICH-Q6B：质量标准：生物技术产品及生物制品的检测方法和可接受标准ICH-Q7：原料药良好制造规范(ICH-Q7A的新版)ICH-Q7A：原料药的GMP规范ICH-Q8：药物研发指南ICH-Q9：质量风险管理ICH- Q10（PQS）：药物质量体系QA（Quality Assurance）：质量保证QC（Quality Control）：质量控制QRM（Quality Risk Management）：质量风险管理IPC（Inproceics Quality Control）：制程品质控制/中控OOS（Out of Specification）：检验结果超标OOT（Out of Trend）：超趋势结果OOL（Out of Limit）：超出极限的结果，如温湿度等OOE（Out of Expectation）：超期望结果SAL（Sterility Assurance Level）：无菌保证水平灭菌后微生物的存活概率的负−lgN0对数，要求≥6SAL=−lg存活率=F0DD值：杀灭90%的微生物所需要的时间，D值越大，微生物死亡越难，D值与细菌的耐热性成正比Z值：指灭菌时间减少到原来的10%所需要升高的温度或是相同的灭菌时间内杀死99%的微生物所需要提高的温度F值：为一定温度下，给定Z值所产生的灭局效果与参比温度T0下给定Z值所产生的灭菌效果相同时所相当的时间F值用于干热灭菌F0值：为一定温度下，Z值为10℃产生的灭菌效果与120℃，Z值为10℃时产生的灭菌效果相当的时间，t分钟内的灭菌效果相当于120℃下灭菌F0分钟的效果F0被称为标准灭菌时间，用于热压灭菌LRV：除菌过滤的对数下降值LRV=lgN0-lgNSOP（Standard Operation Procedure）：标准操作规程DMF（Drug Master File）：药品主文件SMF（Site Master File）：工厂主文件URS（User Requirement Specification）：用户需求标准FS（Functional Specification）：功能标准DS（Design Specification）：设计标准DQ（Design Qualification）：设计确认IQ（Installation Qualification）：安装确认OQ（Operational Qualification）：运行确认PQ（Performance Qualification）：性能确认RQ（Requalification）：再确认CAPA（Corrective Action & Preventive Action）：纠正预防系统，Q10的四大要素之一QbD（Quality by Design）：质量源于设计COA（Certificate of Analysis）：分析证书/检验报告书/检验报告单BPR（Batch Production Record）：批生产记录API（Active Pharmaceutical Ingredients）：药物活性成分，通常指的原料药PMC（Product Material Control）：生产物料控制PC生产控制；MC物料控制CMC（Chemistry and manufacture control）：生产和化学控制APR（Annual Products Review）：年度质量回顾KPI（Key Performance Indicators）：关键业绩指标P&ID（Piping and Instrument Diagram）：工艺管道仪表流程图PFD（Process Flow Diagram）：工艺流程图UFD（Utility Flow Diagram）：公用工程流程图CIP（Cleaning in Place）：原位清洗（全自动，如针剂配制系统）WIP（Washing in Place）：在线清洁（半自动，需要手动的拆卸，如流化床）SIP（Sterilization in Place）：在线灭菌WFI（Water for Injection）：注射用水HVAC（Heating Ventilation Air Conditioning）：供热空气调节净化系统HEPA（High Efficiency Particulate Air Filter）：高效过滤器DOP：为邻苯二甲酸二辛酯，HEPA检漏用的气溶胶PAO：聚-α-烯烃，HEPA检漏用的气溶胶IBC（I ntermediate Bulk Container）：中型散装容器BFS（Blowing Filling and Sealing）：吹-灌-封PAT（Process Analytical Technology）：过程分析技术PLC（Programmable Logic Controller）：可编程逻辑控制CPP（Critical Process Parameters）：关键工艺参数FBD（Fluid Bed Dryer）：流化床AHU（Air Handling Unit）：空气处理单元SAT（Site Acceptance Test）：现场验收测试FAT（Factory Acceptance Test）：工厂验收测试。
欧盟GMP（中英⽂对照）（The words that are in the green background are new standards）(绿⾊背景下的内容为新标准)ANNEX 1MANUFACTURE OF STERILE MEDICINAL PRODUCTS附录1 ⽆菌医药产品的⽣产Principle总则The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspects must not be placed on any terminal process or finished product test.⽆菌药品的⽣产，必须符合⼀些特殊的要求，以防⽌微⽣物、微粒和热源的污染。
这很⼤程度上依赖与⼯作⼈员的技术⽔平、培训和⼯作态度。
在这⽅⾯质量保证显得特别重要，这种类型的⽣产，必须严格按照完善的和经过验证的⽣产⽅法和⼯作程序。
欧盟GMP中英文对照( +30 )药品生产质量管理规范GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS第一章质量管理CHAPTER 1: QUALITY MANAGEMENT原则 (5)Principle (5)质量保证. (5)Quality Assurance (5)药品生产质量管理规范(GMP) (7)Good Manufacturing Practice for Medicinal Products (7)质量控制(QC) (9)Quality Control (9)产品质量回顾 (10)第二章人员CHAPTER 2: PERSONNEL........................ .. (11)原则 (11)Principle (11)通则 (12)General...................................................... . (12)关键人员 (12)Key Personnel (12)培训 (12)Training..................... . (15)人员卫生 (16)Personnel Hygiene (16)第三章厂房和设备CHAPTER 3: PREMISES AND EQUIPMENT (18)原则 (18)Principle (18)厂房 (18)Premises (18)通则 (18)General (18)生产区 (19)Production Area (19)贮存区 (21)Storage Area (21)质量控制区 (22)Quality Control Area (22)附助区 (22)Ancillary Areas (22)设备 (23)Equipment (23)第四章文件CHAPTER 4: DOCUMENTATION (24)原则 (24)Principle (24)通则 (25)General (25)文件要求 (27)Documents Required (27)Specifications (27)Specifications for starting and packaging materials (27)Specifications for Intermediate and Bulk Products (27)Specifications for Finished Products (28)Manufacturing Formulae and Processing Instructions (28)Packaging Instructions (30)Batch Processing Records (31)Batch Packaging Records. (32)Procedures and Records (33)Receipt (34)Sampling (34)Testing (35)Other (35)第五章生产CHAPTER 5: PRODUCTION (36)原则 (36)Principle (36)通则 (36)General (36)生产过程中对交叉污染的预防 (39)Prevention of Cross-contamination in Production (39)验证 (40)Validation (40)原料 (41)Starting Materials (41)生产操作：中间产品和待包装产品 (42)Processing Operations: Intermediate and Bulk Products (42)包装材料 (43)Packaging Materials (43)包装操作 (44)Packaging Operations (44)成品 (46)Finished Products (46)不合格、回收料和退货物料 (46)Rejected, Recovered and Returned Materials (46)第六章质量控制CHAPTER 6: QUALITY CONTROL (48)原则 (48)Principle (48)通则 (48)General... . (48)质量控制实验室规范 (49)Good Quality Control Laboratory Practice (49)Documentation (49)Sampling (50)Testing... (52)销售产品的稳定性考察 (54)第七章委托生产与委托检验CHAPTER 7: CONTRACT MANUFACTURE AND ANALYSIS (55)原则 (55)Principle (55)通则 (56)General (56)委托方 (56)The Contract Giver (56)受托方 (57)The Contract Acceptor (57)合同 (58)The Contract (58)第八章投诉与召回CHAPTER 8: COMPLAINTS AND PRODUCT RECALL (59)原则 (59)Principle (59)投诉 (59)Complaints (59)召回 (60)Recalls (60)第九章自查CHAPTER 9: SELF INSPECTION (61)原则 (61)Principle (61)附件8 原辅料和包装材料的取样ANNEX8 SAMPLING OF STARTING AND PACKAGING MATERIALS (63)原则 (63)Principle (63)人员 (63)Personnel (63)原辅料 (63)Startingmaterials (64)包装材料 (65)Packaging material (65)欧盟GMP中英文对照02第一章质量管理CHAPTER 1 QUALITY MANAGEMENTPrinciple原则生产许可证持有厂家只能生产医药产品，以确保药品符合其预期的使用目的，符合销售许可证的要求，并不因药品安全性、质量或药效方面的问题而给患者带来风险。
EUROPEAN COMMISSIONENTERPRISE AND INDUSTRY DIRECTORATE-GENERALConsumer goodsPharmaceuticalsBrussels, 14 February 2008EudraLexThe Rules Governing Medicinal Products in the European UnionVolume 4EU Guidelines toGood Manufacturing PracticeMedicinal Products for Human and Veterinary UseAnnex 20Quality Risk ManagementDocument HistoryAdoption as ICH Q9 guideline Step 4 November 2005 Deadline for coming into operation 01 March 2008 Commission Européenne, B-1049 Bruxelles / Europese Commissie, B-1049 Brussel – Belgium. Telephone: (32-2) 299 11 11Table of ContentsForeword & Scope of Application (3)1Introduction (4)2Scope (5)3Principles of Quality Risk Management (5)4General Quality Risk Management Process (5)4.1 Responsibilities (6)4.2 Initiating a Quality Risk Management Process (6)Assessment (7)4.3 RiskControl (8)4.4 Risk4.5 RiskCommunication (8)Review (9)4.6 Risk5Risk Management Methodology (9)6Integration of Quality Risk Management into Industry and Operations107Definitions (11)8References (12)Annex I: Risk Management Methods and Tools (14)Management Facilitation Methods (14)I.1 BasicRiskI.2 Failure Mode Effects Analysis (FMEA) (14)I.3 Failure Mode, Effects and Criticality Analysis (FMECA) (15)I.4 Fault Tree Analysis (FTA) (15)I.5 Hazard Analysis and Critical Control Points (HACCP) (15)I.6 Hazard Operability Analysis (HAZOP) (16)I.7 Preliminary Hazard Analysis (PHA) (16)I.8 Risk Ranking and Filtering (17)StatisticalTools (17)I.9 SupportingAnnex II: Potential Applications for Quality Risk Management (19)II.1 Quality Risk Management as Part of Integrated Quality Management (19)II.2 Quality Risk Management as Part of Regulatory Operations (21)II.3 Quality Risk Management as Part of Development (21)II.4 Quality Risk Management for Facilities, Equipment and Utilities (22)II.5 Quality Risk Management as Part of Materials Management (23)II.6 Quality Risk Management as Part of Production (24)II.7 Quality Risk Management as Part of Laboratory Control and StabilityStudies (24)II.8 Quality Risk Management as Part of Packaging and Labelling (24)Foreword and Scope of ApplicationThe new GMP Annex 20 corresponds to ICH Q9 guideline on Quality Risk Management. It provides guidance on a systematic approach to quality risk management facilitating compliance with GMP and other quality requirements. It includes principles to be used and options for processes, methods and tools which may be used when applying a formal quality risk management approach.To ensure coherence, GMP Part I, Chapter 1 on Quality Management, has been revised to include aspects of quality risk management within the quality system framework. A similar revision is planned for Part II of the Guide. Other sections of the GMP guide may be adjusted to include aspects of quality risk management in future broader revisions of those sections. With the revision of the chapters on quality management in GMP Parts I and II quality risk management becomes an integral part of a manufacturer’s quality system. Annex 20 itself is not intended, however, to create any new regulatory expectations; it provides an inventory of internationally acknowledged risk management methods and tools together with a list of potential applications at the discretion of manufacturers.It is understood that the ICH Q9 guideline was primarily developed for quality risk management of medicinal products for human use. With the implementation in Annex 20 benefits of the guideline, such as processes, methods and tools for quality risk management are also made available to the veterinary sector.While the GMP guide is primarily addressed to manufacturers, the ICH Q9 guideline, has relevance for other quality guidelines and includes specific sections for regulatory agencies. However, for reasons of coherence and completeness, the ICH Q9 guideline has been transferred completely into GMP Annex 20.Further consideration of regulatory aspects, such as with the revision of the "Compilation of Community Procedures on Inspections and Exchange of Information" and in some quality guidelines, as published by the EMEA, will follow in a step-by-step approach.1IntroductionRisk management principles are effectively utilized in many areas of business and government including finance, insurance, occupational safety, public health, pharmacovigilance, and by agencies regulating these industries. Although there are some examples of the use of quality risk management in the pharmaceutical industrytoday, they are limited and do not represent the full contributions that risk management has to offer. In addition, the importance of quality systems has been recognized in the pharmaceutical industry and it is becoming evident that quality riskmanagement is a valuable component of an effective quality system.It is commonly understood that risk is defined as the combination of the probabilityof occurrence of harm and the severity of that harm. However, achieving a shared understanding of the application of risk management among diverse stakeholders isdifficult because each stakeholder might perceive different potential harms, place a different probability on each harm occurring and attribute different severities to eachharm. In relation to pharmaceuticals, although there are a variety of stakeholders, including patients and medical practitioners as well as government and industry, theprotection of the patient by managing the risk to quality should be considered of prime importance.The manufacturing and use of a drug (medicinal) product, including its components,necessarily entail some degree of risk. The risk to its quality is just one component ofthe overall risk. It is important to understand that product quality should be maintained throughout the product lifecycle such that the attributes that are importantto the quality of the drug (medicinal) product remain consistent with those used in theclinical studies. An effective quality risk management approach can further ensure the high quality of the drug (medicinal) product to the patient by providing a proactive means to identify and control potential quality issues during development and manufacturing. Additionally, use of quality risk management can improve the decision making if a quality problem arises. Effective quality risk management can facilitate better and more informed decisions, can provide regulators with greater assurance of a company’s ability to deal with potential risks and can beneficially affect the extent and level of direct regulatory oversight.The purpose of this document is to offer a systematic approach to quality risk management. It serves as a foundation or resource document that is independent of, yet supports, other ICH Quality documents and complements existing quality practices, requirements, standards, and guidelines within the pharmaceutical industryand regulatory environment. It specifically provides guidance on the principles and some of the tools of quality risk management that can enable more effective and consistent risk based decisions, both by regulators and industry, regarding the qualityof drug substances and drug (medicinal) products across the product lifecycle. It is not intended to create any new expectations beyond the current regulatory requirements.It is neither always appropriate nor always necessary to use a formal risk management process (using recognized tools and/ or internal procedures e.g. standardoperating procedures). The use of informal risk management processes (using empirical tools and/ or internal procedures) can also be considered acceptable.Appropriate use of quality risk management can facilitate but does not obviateindustry’s obligation to comply with regulatory requirements and does not replaceappropriate communications between industry and regulators.2ScopeThis guideline provides principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality. These aspects include development, manufacturing, distribution, and the inspection and submission/review processes throughout the lifecycle of drug substances, drug (medicinal) products, biological and biotechnological products (including the use of raw materials, solvents, excipients, packaging and labeling materials in drug (medicinal) products, biological and biotechnological products).3Principles of Quality Risk ManagementTwo primary principles of quality risk management are:•The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient; and•The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk.4General Quality Risk Management ProcessQuality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle. A model for quality risk management is outlined in the diagram (Figure 1). Other models could be used. The emphasis on each component of the framework might differ from case to case but a robust process will incorporate consideration of all the elements at a level of detail that is commensurate with the specific risk.Figure 1: Overview of a typical quality risk management processDecision nodes are not shown in the diagram above because decisions can occur at any point in the process. These decisions might be to return to the previous step and seek further information, to adjust the risk models or even to terminate the risk management process based upon information that supports such a decision. Note: “unacceptable” in the flowchart does not only refer to statutory, legislative or regulatory requirements, but also to the need to revisit the risk assessment process.4.1ResponsibilitiesQuality risk management activities are usually, but not always, undertaken by interdisciplinary teams. When teams are formed, they should include experts from the appropriate areas (e.g. quality unit, business development, engineering, regulatory affairs, production operations, sales and marketing, legal, statistics and clinical) in addition to individuals who are knowledgeable about the quality risk management process.Decision makers should•take responsibility for coordinating quality risk management across various functions and departments of their organization; and•assure that a quality risk management process is defined, deployed and reviewed and that adequate resources are available.4.2Initiating a Quality Risk Management ProcessQuality risk management should include systematic processes designed to coordinate, facilitate and improve science-based decision making with respect to risk. Possiblesteps used to initiate and plan a quality risk management process might include the following:•Define the problem and/or risk question, including pertinent assumptions identifying the potential for risk•Assemble background information and/ or data on the potential hazard, harm or human health impact relevant to the risk assessment•Identify a leader and necessary resources•Specify a timeline, deliverables and appropriate level of decision making for the risk management process4.3Risk AssessmentRisk assessment consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards (as defined below).Quality risk assessments begin with a well-defined problem description or risk question. When the risk in question is well defined, an appropriate risk management tool (see examples in section 5) and the types of information needed to address the risk question will be more readily identifiable. As an aid to clearly defining the risk(s) for risk assessment purposes, three fundamental questions are often helpful:1.What might go wrong?2.What is the likelihood (probability) it will go wrong?3.What are the consequences (severity)?Risk identification is a systematic use of information to identify hazards referring to the risk question or problem description. Information can include historical data, theoretical analysis, informed opinions, and the concerns of stakeholders. Risk identification addresses the “What might go wrong?” question, including identifying the possible consequences. This provides the basis for further steps in the quality risk management process.Risk analysis is the estimation of the risk associated with the identified hazards. It is the qualitative or quantitative process of linking the likelihood of occurrence and severity of harms. In some risk management tools, the ability to detect the harm (detectability) also factors in the estimation of risk.Risk evaluation compares the identified and analyzed risk against given risk criteria.Risk evaluations consider the strength of evidence for all three of the fundamental questions.In doing an effective risk assessment, the robustness of the data set is important because it determines the quality of the output. Revealing assumptions and reasonable sources of uncertainty will enhance confidence in this output and/or help identify its limitations. Uncertainty is due to combination of incomplete knowledge about a process and its expected or unexpected variability. Typical sources of uncertainty include gaps in knowledge gaps in pharmaceutical science and process understanding, sources of harm (e.g., failure modes of a process, sources of variability), and probability of detection of problems.The output of a risk assessment is either a quantitative estimate of risk or a qualitative description of a range of risk. When risk is expressed quantitatively, a numerical probability is used. Alternatively, risk can be expressed using qualitative descriptors, such as “high”, “medium”, or “low”, which should be defined in as much detail as possible. Sometimes a "risk score" is used to further define descriptors in risk ranking.In quantitative risk assessments, a risk estimate provides the likelihood of a specific consequence, given a set of risk-generating circumstances. Thus, quantitative risk estimation is useful for one particular consequence at a time. Alternatively, some risk management tools use a relative risk measure to combine multiple levels of severity and probability into an overall estimate of relative risk. The intermediate steps withina scoring process can sometimes employ quantitative risk estimation.4.4Risk ControlRisk control includes decision making to reduce and/or accept risks. The purpose of risk control is to reduce the risk to an acceptable level. The amount of effort used for risk control should be proportional to the significance of the risk. Decision makers might use different processes, including benefit-cost analysis, for understanding the optimal level of risk control.Risk control might focus on the following questions:•Is the risk above an acceptable level?•What can be done to reduce or eliminate risks?•What is the appropriate balance among benefits, risks and resources?•Are new risks introduced as a result of the identified risks being controlled?Risk reduction focuses on processes for mitigation or avoidance of quality risk when it exceeds a specified (acceptable) level (see Fig. 1). Risk reduction might include actions taken to mitigate the severity and probability of harm. Processes that improve the detectability of hazards and quality risks might also be used as part of a risk control strategy. The implementation of risk reduction measures can introduce new risks into the system or increase the significance of other existing risks. Hence, it might be appropriate to revisit the risk assessment to identify and evaluate any possible change in risk after implementing a risk reduction process.Risk acceptance is a decision to accept risk. Risk acceptance can be a formal decision to accept the residual risk or it can be a passive decision in which residual risks are not specified. For some types of harms, even the best quality risk management practices might not entirely eliminate risk. In these circumstances, it might be agreed that an appropriate quality risk management strategy has been applied and that quality risk is reduced to a specified (acceptable) level. This (specified) acceptable level will depend on many parameters and should be decided on a case-by-case basis.4.5Risk CommunicationRisk communication is the sharing of information about risk and risk management between the decision makers and others. Parties can communicate at any stage of the risk management process (see Fig. 1: dashed arrows). The output/result of the quality risk management process should be appropriately communicated and documented (see Fig. 1: solid arrows). Communications might include those among interested parties;e.g., regulators and industry, industry and the patient, within a company, industry orregulatory authority, etc. The included information might relate to the existence, nature, form, probability, severity, acceptability, control, treatment, detectability or other aspects of risks to quality. Communication need not be carried out for each and every risk acceptance. Between the industry and regulatory authorities, communication concerning quality risk management decisions might be effected through existing channels as specified in regulations and guidances.4.6Risk ReviewRisk management should be an ongoing part of the quality management process. A mechanism to review or monitor events should be implemented.The output/results of the risk management process should be reviewed to take into account new knowledge and experience. Once a quality risk management process has been initiated, that process should continue to be utilized for events that might impact the original quality risk management decision, whether these events are planned (e.g.results of product review, inspections, audits, change control) or unplanned (e.g. root cause from failure investigations, recall). The frequency of any review should be based upon the level of risk. Risk review might include reconsideration of risk acceptance decisions (section 4.4).5Risk Management MethodologyQuality risk management supports a scientific and practical approach to decision-making. It provides documented, transparent and reproducible methods to accomplish steps of the quality risk management process based on current knowledge about assessing the probability, severity and sometimes detectability of the risk.Traditionally, risks to quality have been assessed and managed in a variety of informal ways (empirical and/ or internal procedures) based on, for example, compilation of observations, trends and other information. Such approaches continue to provide useful information that might support topics such as handling of complaints, quality defects, deviations and allocation of resources.Additionally, the pharmaceutical industry and regulators can assess and manage risk using recognized risk management tools and/ or internal procedures (e.g., standard operating procedures). Below is a non-exhaustive list of some of these tools (further details in Annex 1 and chapter 8):•Basic risk management facilitation methods(flowcharts, check sheets etc.)•Failure Mode Effects Analysis (FMEA)•Failure Mode, Effects and Criticality Analysis (FMECA)•Fault Tree Analysis (FTA)•Hazard Analysis and Critical Control Points (HACCP)•Hazard Operability Analysis (HAZOP)•Preliminary Hazard Analysis (PHA)•Risk ranking and filtering•Supporting statistical toolsIt might be appropriate to adapt these tools for use in specific areas pertaining to drug substance and drug (medicinal) product quality. Quality risk management methods and the supporting statistical tools can be used in combination (e.g. Probabilistic Risk Assessment). Combined use provides flexibility that can facilitate the application of quality risk management principles.The degree of rigor and formality of quality risk management should reflect available knowledge and be commensurate with the complexity and/ or criticality of the issue to be addressed.6Integration of Quality Risk Management into Industry and RegulatoryOperationsQuality risk management is a process that supports science-based and practical decisions when integrated into quality systems (see Annex II). As outlined in the introduction, appropriate use of quality risk management does not obviate industry’s obligation to comply with regulatory requirements. However, effective quality risk management can facilitate better and more informed decisions, can provide regulators with greater assurance of a company’s ability to deal with potential risks, and might affect the extent and level of direct regulatory oversight. In addition, quality risk management can facilitate better use of resources by all parties.Training of both industry and regulatory personnel in quality risk management processes provides for greater understanding of decision-making processes and builds confidence in quality risk management outcomes.Quality risk management should be integrated into existing operations and documented appropriately. Annex II provides examples of situations in which the use of the quality risk management process might provide information that could then be used in a variety of pharmaceutical operations. These examples are provided for illustrative purposes only and should not be considered a definitive or exhaustive list.These examples are not intended to create any new expectations beyond the requirements laid out in the current regulations.Examples for industry and regulatory operations (see Annex II):•Quality managementExamples for industry operations and activities (see Annex II):•Development•Facility, equipment and utilities•Materials management•Production•Laboratory control and stability testing•Packaging and labelingExamples for regulatory operations (see Annex II):•Inspection and assessment activitiesWhile regulatory decisions will continue to be taken on a regional basis, a common understanding and application of quality risk management principles could facilitate mutual confidence and promote more consistent decisions among regulators on the basis of the same information. This collaboration could be important in the development of policies and guidelines that integrate and support quality risk management practices.7DefinitionsDecision maker(s) – Person(s) with the competence and authority to make appropriate and timely quality risk management decisionsDetectability - the ability to discover or determine the existence, presence, or fact of a hazardHarm – damage to health, including the damage that can occur from loss of product quality or availabilityHazard - the potential source of harm (ISO/IEC Guide 51)Product Lifecycle – all phases in the life of the product from the initial development through marketing until the product’s discontinuationQuality – the degree to which a set of inherent properties of a product, system or process fulfills requirements (see ICH Q6a definition specifically for "quality" of drug substance and drug (medicinal) products.)Quality risk management – a systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycleQuality system – the sum of all aspects of a system that implements quality policy and ensures that quality objectives are metRequirements – the explicit or implicit needs or expectations of the patients or their surrogates (e.g. health care professionals, regulators and legislators). In this document, “requirements” refers not only to statutory, legislative, or regulatory requirements, but also to such needs and expectations.Risk – the combination of the probability of occurrence of harm and the severity of that harm (ISO/IEC Guide 51)Risk acceptance – the decision to accept risk (ISO Guide 73)Risk analysis – the estimation of the risk associated with the identified hazardsRisk assessment – a systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards.Risk communication – the sharing of information about risk and risk management between the decision maker and other stakeholdersRisk control – actions implementing risk management decisions (ISO Guide 73)Risk evaluation – the comparison of the estimated risk to given risk criteria using a quantitative or qualitative scale to determine the significance of the riskRisk identification – the systematic use of information to identify potential sources of harm (hazards) referring to the risk question or problem descriptionRisk management – the systematic application of quality management policies, procedures, and practices to the tasks of assessing, controlling, communicating and reviewing riskRisk reduction – actions taken to lessen the probability of occurrence of harm and the severity of that harmRisk review – review or monitoring of output/results of the risk management process considering (if appropriate) new knowledge and experience about the riskSeverity – a measure of the possible consequences of a hazardStakeholder – any individual, group or organization that can affect, be affected by, or perceive itself to be affected by a risk. Decision makers might also be stakeholders. For the purposes of this guideline, the primary stakeholders are the patient, healthcare professional, regulatory authority, and industryTrend – a statistical term referring to the direction or rate of change of a variable(s)8ReferencesICH Q8 Pharmaceutical developmentISO/IEC Guide 73:2002 - Risk Management - Vocabulary - Guidelines for use in StandardsISO/IEC Guide 51:1999 - Safety Aspects - Guideline for their inclusion in standardsProcess Mapping by the American Productivity & Quality Center 2002, ISBN 1928593739IEC 61025 - Fault Tree Analysis (FTA)IEC 60812 Analysis Techniques for system reliability—Procedures for failure mode and effects analysis (FMEA)Failure Mode and Effect Analysis, FMEA from Theory to Execution, 2nd Edition 2003, D. H. Stamatis, ISBN 0873895983Guidelines for Failure Modes and Effects Analysis (FMEA) for Medical Devices, 2003 Dyadem Press ISBN 0849319102The Basics of FMEA, Robin McDermott, Raymond J. Mikulak, Michael R.Beauregard 1996 ISBN 0527763209WHO Technical Report Series No 908, 2003 Annex 7 Application of Hazard Analysis and Critical Control Point (HACCP) methodology to pharmaceuticals.IEC 61882 - Hazard Operability Analysis (HAZOP)ISO 14971:2000 - Application of Risk Management to Medical DevicesISO 7870:1993 - Control ChartsISO 7871:1997 - Cumulative Sum ChartsISO 7966:1993 - Acceptance Control ChartsISO 8258:1991 - Shewhart Control ChartsWhat is Total Quality Control?; The Japanese Way, Kaoru Ishikawa (Translated by David J. Liu, 1985, ISBN 0139524339Annex I: Risk Management Methods and ToolsThe purpose of this annex is to provide a general overview of and references for some of the primary tools that might be used in quality risk management by industry and regulators. The references are included as an aid to gain more knowledge and detail about the particular tool. This is not an exhaustive list. It is important to note that no one tool or set of tools is applicable to every situation in which a quality risk management procedure is used.I.1 Basic Risk Management Facilitation MethodsSome of the simple techniques that are commonly used to structure riskmanagement by organizing data and facilitating decision-making are:•Flowcharts•Check Sheets•Process Mapping•Cause and Effect Diagrams (also called an Ishikawa diagram or fish bone diagram)I.2 Failure Mode Effects Analysis (FMEA)FMEA (see IEC 60812) provides for an evaluation of potential failure modesfor processes and their likely effect on outcomes and/or product performance.Once failure modes are established, risk reduction can be used to eliminate,contain, reduce or control the potential failures. FMEA relies on product andprocess understanding. FMEA methodically breaks down the analysis ofcomplex processes into manageable steps. It is a powerful tool forsummarizing the important modes of failure, factors causing these failures andthe likely effects of these failures.Potential Areas of Use(s)FMEA can be used to prioritize risks and monitor the effectiveness of riskcontrol activities.FMEA can be applied to equipment and facilities and might be used to analyzea manufacturing operation and its effect on product or process. It identifieselements/operations within the system that render it vulnerable. The output/results of FMEA can be used as a basis for design or further analysis or toguide resource deployment.。
