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1、VALIDATION & RISK ANALYSIS Steam Sterilization and Lyophilizzation 蒸汽灭菌和冻干的验证及风险管理,A route from process principles to a safe and compliant product. The awareness of a documented evidence. 药品安全、达标工艺原理的途径 对文件和记录证据的理解,Presented by Mr.Villani 2012-09 JN,CONTENT 内容,GMP and Validation GMP和验证 Qualification
2、 & Validation Lifecycle 确认及验证生命周期 Risk Management 风险管理 Case studies 案例讨论 FMEA of Sterilization Process 灭菌工艺FMEA FMEA of Lyophillization Process 冻干工艺FMEA FTA of Terminal Sterilized Product 最终灭菌产品故障树分析 Conclusions 结论,GMP及验证 Qualification & Validation lifecycle Risk Management Case studies FMEA of Ster
3、ilization Process FMEA of Lyophillization Process FTA of Terminal Sterilized Product Conclusions,CONTENT 内容,GMP 和验证,1972 DEVENPORT INCIDENT (UK) 英国德旺波特药难事件 Infusional solutions, produced at the Devemport Hospital, caused six patient deceases. 在英国德旺波特医院生产的输液，造成6个死亡病例 The ROSENHEIM Report found the ca
4、uses in a not correct sterilization treatment. 在ROSENHEIM报告中披露，原因是灭菌不完全,Extracted from the ROSENHEIM Report 罗森海姆报告有以下内容 The AIR was not properly removed from the chamber 没有适当去除空气 The drain of the chamber was blocked by pieces of glasses 排水管被玻璃堵塞 The lower section of the load did not reach the steril
5、ization temperature 低部位装载未达到灭菌温度 The temperature recorder showed this anomaly but people thought it was not working properly 温度记录有异常，以为是仪表问题 Sterility tests were carried out only on the upper layers of the load 无菌检查只取了上部的样品,GMP 和验证,Engineering Equipment Implications 工程设计-设备方面,Chapter 3 of EU-GMP (Pr
6、emises and Equipment) 欧盟GMP第3章 （厂房及设备） 21 CFR part 211.63, 211.65, 211.67 (Equipment) 联邦法规211.63, 211.65, 211.67 （设备）,Annex 11 UE GMP (Computerised systems) 欧盟附录11计算机系统 21 CFR part 211.68 (Automatic, mechanical and electronic equipment) （自动化、机械及电气设备） 21 CFR part 11 (Electronic records Electronic Sig
7、natures) 联邦法规 21 第11部分（电子记录-电子签名） GAMP (Good Automated Manufacturing Practice) GAMP= 优良自动化生产规范,21 CFR parts 210-211 (211.100, 211.110, 211.213) 联邦法规210-211 (211.100, 211.110, 211.213) 21 CFR part 820 (820.75) 联邦法规820 (820.75) EU GMP (Cap. 5.21 5.24) 欧盟-GMP (Cap. 5.21 5.24) EU GMP Annex 15: (Qualific
8、ation and Validation) 欧盟-GMP (Cap. 5.21 5.24) 确认与验证 Compliance Policy Guide Sec. 490.100 (Process Validation Requirements for Drug Products Subject to Pre-Market Approval) 达标方针指南 490.100 节 （药品批准前工艺验证要求）,验证,EU GMP 5.21: Validation studies should reinforce Good Manufacturing Practice and be conducted
9、in accordance with defined procedures. Results and conclusions should be recorded. 验证试验应强化GMP并按规程进行。应有记录和结论 Annex 15 EU GMP Principle: 欧盟GMP原则 It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular operations
10、. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, should be validated. A risk assessment approach should be used to determine the scope and extent of validation. GMP要求生产企业鉴别需要验证的内容，以证明特殊操作的关键点受控。影响产品质量的厂房、设备及工艺的重要变更均应验证。应通过风险评估确定验证
11、的范围。,验证,验证,What has to be validated? 应验证的内容 A process ? 工艺 A product ? 产品 A piece of equipment ? 设备 Lets consider the definition of “validation” 我们来考虑“验证”的定义,Validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a p
12、roduct meeting its pre-determined specifications and quality characteristics (FDA Guideline on General Principles of Validation, 1987) _ Validation is a defined strategy of inter-related practices and procedures which in combination with routine production methods and quality control techniques prov
13、ides documented assurance that a system is performing repetitively as intended and/or that a product conforms to its pre-determined specifications (PDA TM#1 revised, Glossary),验证,验证是建立文件证据，确保一个特定的工艺肯定能始终如一生产出预定质量特性及质量标准的产品 (FDA 验证总则指南, 1987) _ 验证是有管理程序与运行操作相关的一种策略，它将常规生产方法和质量控制技术相结合，以文件的形式保证一个系统能良好重
14、复地按预期性能运行，和/或一个产品能符合预期的质量标准 (PDA TM#1 revised, Glossary),验证定义,Common items: 常见项目 - Specify 阐述 - Document 文件 - Verify the effectiveness 检查标准 - Verify the reproducibility 检查重现性 The scope of validation is the process or the product 工艺可产品验证的范围 The new PDA definition considers validation as a “ongoing pr
15、ocess” (maintaining the validated status) FDA新的指南将验证看作一个持续不断的过程（保持经验证的状态）,验证,验证,Main concepts 主要概念,Personnel 人员 Equipment 设备 Process/Products 工艺/产品 Instruments 仪器仪表 Documents and SOP 文件及SOP,Qualified, trained 培训、确认资质 To be qualified (IQ, OQ, PQ) 确认 To be validated 验证 Suitable, calibration has to be
16、planned and documented 适当，校准有计划/文件 Up-to date, distributed, maintained under control 更新，分发，保持受控,Process 工艺,Product 产品,Equipment Rules and standards,Characteristics 特性 Handling 处理 Stoppering 上胶塞 Terminally sterilized 最终灭菌,Sterilization 灭菌 ? Lyophillization 冻干? Sterilization method 灭菌方法?,验证,设备 法规及标准,G
17、MP及验证 Qualification & Validation lifecycle Risk Management Case studies FMEA of Sterilization Process FMEA of Lyophillization Process FTA of Terminal Sterilized Product Conclusions,CONTENT 内容,确认及验证生命周期,Stages of the qualification of a piece of equipment should include DQ, IQ, OQ and PQ.,User Require
18、ments Specifications,Functional Specifications,Design Specifications,Project execution,Installation Qualification,Operational Qualification,Performance Qualification,Related to,Related to,Related to,Design Qualification,VALIDATION LIFECYCLE,一项设备的确认应包括的阶段： DQ, IQ, OQ and PQ.,用户需求标准,功能标准,设计标准,项目的实施,安装
19、确认,运行确认,性能确认,相关联,相关联,相关联,设计确认,验证的生命周期,DESIGN QUALIFICATION,设计确认 The documents of the projects at disposal specify in an exhaustive way the equipment, the systems, and the installations that compose that project 一个要处理项目详细阐述其设备、系统以及设施的文件 The documents related to the user requirements specifications, t
20、o the basic design (or functional) and to the detail design (or executive) are clearly identified 它是对用户技术要求、基础（或功能）设计以及详细设计相关文件作详细鉴别/审查的文件,DESIGN QUALIFICATION,The project documents are correctly approved by the competent functions upon what established in the quality plan of the project 根据项目所定的质量计划
21、的要求，由主管功能部门批准项目文件 The functional specs (basic design) and the engineering documents (detail design) of the system under exam are based on the needs of the user (user requirements) 根据用户技术要求，对系统的基础设计及详细设计进行审查 The design has been carried out considering a compliance to the cGMPs and eventual applicable
22、 guidelines 设计过程中已考虑了cGMP及相关指南的要求,“Installation Qualification is an essential step preceding the Process Validation exercise. It is normally executed by the Engineering group. The installation of equipment, piping, services and instrumentation is undertaken and checked to engineering drawings Piping
23、 & Instrument Drawings, (P&I.Ds) and Plant Functional Specifications developed during the project planning stage. During the project planning stage, Installation Qualification should involve the identification of all system elements, service conduits and gauges and the preparation of a documented re
24、cord that all installed equipment satisfies the planned requirements.” “安装确认是进行工艺验证的重要组成部分。它通常由工程设计组人员完成。相关的设备、管路、公用系统、仪表要按管路及仪表设计图(P&I.Ds)以及项目计划阶段工厂的功能要求核对/审查。在项目的计划阶段，安装确认应对所有系统的组成部分，公用管路、仪表以及文件记录的准备进行鉴别/审查（文件应能够表明所有安装的设备满足计划的要求）。”,Recommendations on Validation Master Plan, Installation and Operat
25、ional Qualification, Non-Sterile Process Validation, Cleaning Validation PI 006-2, 1 July 2004,INSTALLATION QUALIFICATION,The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 2001,“IQ should include, bu
26、t not limited to, the following: IQ包括，但不局限于以下各项： installation of equipment, piping, services and instrumentation checked to current engineering drawing and specifications; 设备、管路，公用管路以及仪表安装的检查符合竣工图及标准 collection and collation of supplier operating and working instruction, and maintenance requirements
27、; 收集供货商的运行操作指南及维修要求 calibration requirements; 校准文件 verification of materials of construction.” 对建造材料的检查,INSTALLATION QUALIFICATION,“OQ is an exercise oriented to the engineering function, generally referred to as commissioning. Studies on the critical variables (parameters) of the operation of the e
28、quipment or systems will define the critical characteristics for operation of the system or sub-system. All testing equipment should be identified and calibrated before use. Test methods should be authorized, implemented and resulting data collected and evaluated. OQ是试功能，通常指试车。对设备或系统的关键参数（变量）进行试验，确定
29、系统或子系统的关键特性。所有测试仪表均应在使用前校准。试验方法要经批准后实施，收集结果并进行评价。 It is important at this stage to assure all operational test data conform with pre-determined acceptance criteria for the studies undertaken.” 在此阶段，所有运行试验的数据应符合预定的合格标准。,Recommendations on Validation Master Plan, Installation and Operational Qualifica
30、tion, Non-Sterile Process Validation, Cleaning Validation PI 006-2, 1 July 2004,OPERATIONAL QUALIFICATION,“It is expected that during the Operational Qualification stage the manufacturer should develop draft standard operating procedures (SOPs) for the equipment and services operation, cleaning acti
31、vities, maintenance requirements and calibration schedules.” 在OQ阶段，通常要求生产企业制订SOP草案，包括设备、公用系统、清洁、维修要求及校准计划 “The completion of a successful Operational Qualification should allow the finalisation of operating procedures and operator instructions documentation for the equipment. This information should
32、 be used as the basis for training of operators in the requirements for satisfactory operation of the equipment.” OQ顺利完成应能完成设备的运行规程以及人员操作指南。这些信息应当用作培训员工的基础资料，以满足设备操作的要求。,Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Va
33、lidation PI 006-2, 1 July 2004,OPERATIONAL QUALIFICATION,OQ-运行确认,“OQ should include, but not limited to, the following: OQ包括，但不局限于以下各项： tests that have been developed from knowledge of process, systems and equipment; 根据有关工艺、系统和设备的知识所确定的试验 tests to include condition or set of conditions encompassing
34、upper and lower operating limits, sometimes referred to as “worst case” conditions.” 包括确定运行上下限的条件试验，有时称“最差条件”试验,The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 2001,OPERATIONAL QUALIFICATION,Docume
35、nted verification that the system is able to fulfill, in a constant and repetitive way, all the tasks indicated in the URS. 性能确认：有文件及记录确认，系统能始终如一并重复地实现、满足URS中所规定的目标,Usually they will be designed, to this aim, some challenges for the verification of the process parameters and of the operative conditi
36、ons, in the established intervals of variability, in compliance with the data reported in the official records. The conditions limit to the challenge, after the due considerations, can be different from the ones that represent the limit of the process. 为实现这个目标，通常PQ要设计一些试验，根据正式报告中的数据资料，在确定的变量范围以内，来挑战
37、工艺参数及运行条件，经适当考虑后的限度，可与工艺中所列的限度不同。,PERFORMANCE QUALIFICATION -性能确认,“PQ should include, but not limited to, the following: PQ包括，但不局限于以下各项： tests, using production material, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or
38、 equipment; 根据厂房、系统或设备所积累的工艺知识，采用生产物料，符合要求的替代品或模拟产品进行试验。 tests to include a condition or set of conditions encompassing upper and lower operating limits.”要包括上下限运行限度的试验,The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification a
39、nd Validation July 2001,PERFORMANCE QUALIFICATION,“Documentation” A report that cross-references the qualification and/or validation protocol should be prepared, summarising the results obtained, commenting on any deviations observed, and drawing the necessary conclusions including recommending chan
40、ges necessary to correct deficiencies. Any changes to the plan as defined in the protocol should be documented with appropriate justification.” “文件” 应写出有确认/验证方案交叉索引的报告，将获得的结果进行汇总，对观察到的偏差进行说明，图及对图的说明，包括纠正缺陷所需变更的建议。对方案中确定计划的任何变更，应有记录并说明理由。,The Rules Governing Medicinal Products in the European Union “
41、Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 2001,Validation & Qualification Report (Summary) 验证和确认小结,The Rules Governing Medicinal Products in the European Union “Good manufacturing practices” Annex # 15 Final Version Qualification and Validation July 200
42、1,“Documentation” After completion of a satisfactory qualification, a formal release for the next step in qualification and validation should be made as a written authorization” “文件” 在完成一项确认后，正式放行至下一步的确认及验证，应有书面的批准文件。,Validation & Qualification Report,“The following items should be included in the v
43、alidation report: 验证报告应包括以下内容： A description of the process Batch/Packaging Document, including details of critical steps, 对工艺的阐述包括关键步骤的批/包装文件 A detailed summary of results obtained from in-process and final testing, including data from failed tests. When raw data are not included reference should b
44、e made to the sources used and where it can be found, 对中间控制及最终检验结果（包括失败试验）的详细总结。如报告中不列原始数据，则应有资料索引，说明资料的存放点。,Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation PI 006-2, 1 July 2004,Validation & Qualification Rep
45、ort,Process Control System 工艺控制系统,What should it do? 系统的用处,Control and monitor the manufacturing process 控制及监测生产工艺 Guarantee a safe use of the equipment 保证设备安全使用 Comply with applicable standards and rules 符合适用的标准及规定 Generate a complete and accurate process documentation 获得完整及准确的工艺文件/记录 Integrate wit
46、h external systems for collecting or processing data 将收集或处理数据的外部系统有机组合/集成 Exchange information with external systems in general 与外部的通用系统交换数据,The criticality of these systems has to be referred to their role in pharmaceutical production 必须阐明这些系统在药品生产中的重要性,In 2003 ISPE issued a Good Practice Guide on
47、the validation of PCS 2003年，ISPE公布了一个工艺控制系统指南 controlling the manufacturing processes and having a direct impact on the product 控制生产及对产品有直接影响的工艺过程 processing, transferring or storing process information in electronic format 处理，转换或贮存电子模块的工艺信息,Process Control System工艺控制系统,Versione 5 - Drivers 第5版的动力,G
48、AMP guideline 优良自动化指南,Vers 5 Overview 第5版总览,GAMP guideline,Vers 5 Overview 第5版总览,GAMP guideline,药品开发,药品生产,药品上市及分销,用户,对产品及工艺的理解,一质量管理系统中生命周期的方法 可放大生命周期活动 基于质量风险管理科学,影响供货商财政的杠杆,供货商 （计算机系统及服务）,药品开发 及服务,提供产品及服务,保持及支持产品与服务,Computerized System Lifecycle 计算机系统生命周期,项目阶段,变更,退役,概念,项目,运行,退役,保留-搬迁-损坏的可能,供货商 参与,
49、风险管理，设计审查，变更及配置管理，可追溯性，文件管理,支持过程,计划,报告,技术要求,检查确认,配置/编码,GMP及验证 Qualification & Validation lifecycle Risk Management Case studies FMEA of Sterilization Process FMEA of Lyophillization Process FTA of Terminal Sterilized Product Conclusions,CONTENT 内容,质量风险管理（ICH Q9）,欧洲药品管理局,Quality Risk Management 质量风险管理,1. Introduction 引言 2. Scope 范围 3. Principles of Quality Risk Management (QRM) QRM的原则 4. General Quality Risk Manage