计算机化系统验证要点分析

1、1/89目录 Table of Contents 3.新建及遗留计算机化系统验证示例分析 Case Study for Validation of New and Legacy Computerized Systems2.新建计算机化系统验证流程介绍 Introduction to Validation Process of New Computerized SystemTable of Contents 1.计算机化系统相关法规 Computerized System Related Regulations 计算机化系统验证要点分析Key-Point Analysis of Computer

2、ized System ValidationAnwar奥星设备与工艺系统事业部 验证总监3/89计算机化系统相关法规 Computerized System Related Regulations第一部分 Part 14/89相关法规和指南总览 Relevant Regulations and Guidelines (US FDA) 21CFR Part11 美国联邦法规21篇第11部分电子记录与电子签名 (US FDA) 21CFR Part11: Electronic record and electronic signature (US FDA)工业指南 11部分 电子记录与电子签名-范

3、围和应用 (US FDA) Guidance for Industry, Part11 Electronic record and electronic signature scope and application (US FDA) 联邦法规第21篇第210 211部分，成品药的现行生产质量管理规范 (US FDA) 21CFR Part 210 and 211, cGMP for finished pharmaceuticals (ISPE) 良好自动化生产实践指南，遵从GxP计算机化系统监管的风险管理方法 (ISPE) GAMP, A risk-based approach to a G

4、xP compliant Computerized system (ISPE)GAMP GPG 良好实践指南，GAMP架构下的系列良好实践指南 (ISPE)GAMP GPG , GPG under the framework of GAMP (EU)欧盟药事法规第4卷GMP，附录11计算机化系统 EU Guidelines to Good Manufacturing Practice: (Volume 4), annex 11 Computerized System (PIC/S)GMP指南，药用产品良好生产实践指南 (TGA)GMP，药用产品良好生产实践指南(PIC/S)在“GxP”监管环境

5、下的计算机化系统良好实践（检查官指南） PIC/S Computerized system good practices under GxP regulation( Inspector guideline) (WHO) GMP 2003, Annex 4 (WHO Technical Report Series, No. 908) (CFDA) 2010年版GMP 及征求意见稿计算机化系统 CFDA GMP-2010 and “ Computerized System”(draft for comment)(CFDA) GSP附录二附录三药品经营企业计算机系统温湿度自动监测 (CFDA) GS

6、P Annex 2 and Annex 3 “ Computerized System of Pharmaceutical Trading Enterprises” and “Automatic Temperature and Humidity Monitoring”5/89CFDA GMP及附录 CFDA GMP and Annexes第一百六十三条使用电子数据处理系统的，只有经授权的人员方可输入或更改数据，更改和删除情况应当有记录；应当使用密码或其他方式来控制系统的登录；关键数据输入后，应当由他人独立进行复核。用电子方法保存的批记录，应当采用磁带、缩微胶卷、纸质副本或其他方法进行备份，以确

7、保记录的安全，且数据资料在保存期内便于查阅。Article 163If an electronic data processing system is used, only authorized persons can input or change data, the change and deletion records shall be kept, the systems logging in shall be controlled by the way of inputting a password or other methods; after inputting key data,

8、 it shall be double checked by another person independently. The batch record stored electronically shall be backed up with a magnetic tape, a microfilm, a paper duplicate or other methods, to ensure the safety of the record and the convenience to review during the preservation period.附录1第七十条 采用自控和监

9、测系统的，应当经过验证，保证符合关键工艺的要求。 Article 70, Annex 1 Where automation and monitoring systems are used for these applications they should be validated to ensure that critical process requirements are met.6/89CFDA GMP征求意见稿计算机化系统CFDA Draft for comment “Computerized system”第四条 应使用科学的风险评估方法来决定计算机化系统验证的范围与程度。应当将验

10、证看作计算机化系统“生命周期”的一个组成部分。Article 4 Science based risk assessment approaches shall be used to determine the scope and extent of computerized system validation. The validation shall be considered as a part of the “ lifecycle” of a computerized system. 第七条 软件是计算机化系统的重要组成部分。软件的使用者应当根据风险评估的结果，对于所采用软件进行分级管理

11、（如针对软件供应商的审计），保证软件的编制过程符合质量保证系统的要求。Article 7 Software is an important part of a computerized system. Users of software shall perform differentiated management (such as for audits to software suppliers) to the software used based on the risk assessment results, to ensure the programming process of so

12、ftware conforms to the requirements of the quality assurance system.第十条数据的输入或修改只能由经许可的人员进行。杜绝未经许可的人员输入数据的手段有：使用钥匙、密码卡、个人密码和限制对计算机终端的访问。Article 10 Only an authorized person is allowed to input or change data. Means to prevent unauthorized personnel from inputting data includes: key, cipher card, pers

13、onal password and restriction to access to computer terminals.7/89EU GMP Annex11计算机化系统4.6定制计算机系统的验证，应有一个适当的过程保证在系统所有生命周期的阶段进行正式的评估和质量和性能测试的报告。4.6 For the validation of customized computerized systems there should be a step in place that ensures the formal assessment and reporting of quality and perf

14、ormance measures for all the life-cycle stages of the system9.审计跟踪 Audit Trails9. 应该基于风险评估来考虑给系统加入一种可以生成记录的功能，来记录所有与GMP相关的变更和删除（系统生成的“审计跟踪”）。Consideration should be given, based on risk assessment, to building into the system a function for the creation of a record of all GMP-relevant changes and de

15、letions (an audit trail generated by the system).12.1应该使用物理和/或逻辑控制来严格控制计算机系统的权限，其权限只给经过授权的人。12.1 Physical and/or logical controls should be in place to restrict the access to a computerized system only to authorized persons.8/89US 21 CFR Part21121168自动化设备、机械化设备和电子设备应对计算机或有关系统采取适当控制，以确保生产及控制主记录或其它记录由

16、授权人员制定变更内容。配方、其它记录或数据在计算机或有关系统输入和输出时，应核查其准确性。21168 Automation equipment, mechanical equipment and electronic equipmentAppropriate controls shall be used for a computer or the related systems to assure that changes in the master production and control records or other records are instituted only by a

17、uthorized personnel. Input to and output from the computer or the related system of formulas or other records or data shall be checked for accuracy.9/89US 21 CFR Part11Sub B/11.10/a 系统的验证以保证准确、可靠、稳定地预期性能，有能力识别无效的和被改变的记录。 Sub B/11.10/a Validation of systems to ensure accuracy, reliability, consistent

18、 intended performance, and the ability to discern invalid or altered records.Sub B/11.10/e使用安全的、计算机产生的、时间印记的审计跟踪以便独立地记录操作者登录和建立、修改、或删除电子记录的行为的日期和时间。 ) Sub B/11.10/e Use of secure, computer-generated, time-stamped audit trails to independently record the date and time of operator entries and actions

19、that create, modify, or delete electronic records. Record changes shall not obscure previously recorded information.Sub B/11.10/g使用验证检查以保证只有被授权用户才可以使用系统，以电子方式签署记录，使用操作或计算机系统的输入输出设备，改变记录或手工执行操作。Sub B/11.10/g Use of authority checks to ensure that only authorized individuals can use the system, electr

20、onically sign a record, access the operation or computer system input or output device, alter a record, or perform the operation at hand.10/89WHO GMP15.9使用电子数据处理系统的，只有经授权的人员方可输入或更改数据，更改和删除情况应当有记录；应当使用密码或其他方式来控制系统的登录；关键数据输入后，应当由他人独立进行复核。用电子方法保存的批记录，应当采用磁带、缩微胶卷、纸质副本或其他方法进行备份，以确保记录的安全，且数据资料在保存期内便于查阅。15

21、.9 If electric data processing system is used, only authorized person could input or change data, the change and deletion records shall be kept; the systems logging in shall be controlled by the way of inputting password or other methods; after inputting key data, it shall be double examined by othe

22、r person independently. The batch record stored in electronic method shall be backed up with magnetic tape, microfilm, paper duplicate or other methods, to ensure the safety of the record and it is convenient to review data during the preservation period.11/89ISPE GAMPGAMP5（ Good Automated Manufactu

23、ring Practice -Rev5）GAMP是由国际制药工程协会主编的针对计算机化系统合规的实践指南。旨在提供一套基于现有行业规范的行之有效的方法，使计算机化系统符合预定用途并满足现有法规的要求。自90年代以来，不断改版的良好自动化生产实践指南已被广泛使用并得到国际监管部门的公认。它是计算机化系统验证的指导方针。GAMP5是目前的最新版本，于2008年2月发布。GAMP is practice guideline edited by ISPE aiming to regulatory compliance of computerized system. GAMP guidance aims

24、 to achieve computerized systems that are fit for intended use and meet current regulatory requirements, by building upon existing industry good practice in an efficient and effective manner. Since 1990s, constantly revised GMAP has been widely used and recognized by international regulatory authori

25、ties. It is the guideline to computerized system validation. Since its issuance in February 2008, GMAP 5 is the latest version up to now. 五个关键概念 Five key concepts ：基于质量管理体系的生命周期方法 Life cycle approach within a QMS可增减的生命周期活动 Scaleable life cycle activities流程和产品的理解. Product and process understanding基于科

26、学的质量风险管理 Science based quality risk management充分利用供应商活动. Leveraging supplier involvement12/89法规、GMP、验证相关术语 Regulations, GMP , Validation related glossary 术语Abbr.名称NameCFDAChina Food and Drug Administration国家食品药品监督管理总局WHOWorld Health Organization世界卫生组织EUEuropean Union欧洲联盟（欧盟）PIC/SPharmaceutical Inspe

27、ction Convention and Pharmaceutical Inspection Co-operation Scheme药品检查合作计划 (药品检查协会）FDAU.S. Food and Drug Administration美国食品药品监督管理局ICHInternational Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use国际人用药品注册和医药技术协调会议ISPEInternational Society For Pha

28、rmaceutical Engineering国际制药工程协会RARisk Assessments 风险评估SIASystem Impact Assessment 系统影响性评估术语Abbr.名称NameCCAComponent Criticality Assessment 部件关键性评估FAT/SATFactory Acceptance Test /Site Acceptance Test 工厂/现场验收测试DQ/IQ/OQ/PQDesign / Installation / Operational / Performance Qualification 设计/安装/运行/性能确认CPPCr

29、itical Process Parameter 关键工艺参数CQACritical Quality Attribute关键质量属性ERESElectronic Record; Electronic Signature电子记录与电子签名13/89计算机化系统验证常见术语1 Common Glossary for Computerized System Validation 1名称 缩写英文 验证主计划 VMP Validation Master Plan 质量及项目计划QPPQuality and Project Plan用户需求说明 URS User Requirement Specific

30、ation 功能说明 FS Function Specification 硬件设计说明HDSHardware Design Specification软件设计说明SDSSoftware Design Specification软件模块说明SMSSoftware Module Specification设计确认 DQ Design Qualification 源代码审核SCR Source Code Review软件模块测试SMTSoftware Module Test工厂验收测试 FAT Factory Acceptance Test 现场验收测试 SAT Site Acceptance Te

31、st 安装确认IQInstallation Qualification运行确认OQOperation Qualification性能确认PQPerformance Qualification14/89计算机化系统验证常见术语 2Common Glossary for Computerized System Validation 12名称 缩写Abbr.英文 可追溯矩阵TMTraceability Matrix验证总结报告VSRValidation Summary Report国际制药工程协会ISPEInternational Society Of Pharmaceutical Engineer

32、ing良好自动化生产实践指南GAMPGood Automated Manufacturing Practice质量管理系统QMSQuality Management System可编程逻辑控制器PLCProgrammable Logic Controller集散控制系统DCSDistributed Control System数据采集与监视系统SCADASupervisory Control And Data Acquisition企业资源计划ERPEnterprise Resource Planning实验室信息管理系统LIMSLaboratory Information Managemen

33、t System生产执行系统MESManufacturing Execution Systems楼宇管理系统BMSBuilding Management System环境监视系统EMSEnvironment Monitoring System计算机系统验证CSVComputer System Validation不间断电源UPSUninterruptible Power Supply15/89新建计算机化系统验证流程介绍Introduction to Validation Process of New Computerized System 第二部分 Part 2CSV经典V-Model图及其

34、总流程 CSV classic V-Model and general flow chart 流程逐一步骤的良好实践 Good practices of process steps 16/89计算机化系统验证生命周期V-Model V-Model of computerized system validation lifecycle17/89验证生命周期文件架构 Lifecycle documentation framework 18/89计算机化系统验证总流程General flow of computerized system validation 确认计算机化系统 Computerize

35、d system definition初步系统评估确定系统影响，判定GxP系统 Perform initial system assessment and determine system impacts, and GxP system供应商评估确定其能力及参与评估点 Perform supplier assessment and determine their capacity and involvement assessment points软硬件分类评估确定其复杂性和新颖性 Perform hardware and software categorization assessment a

36、nd determine their complexity and novelty .结合供应商能力，系统复杂性和新颖性、GxP影响制定适宜V-Model Make an appropriate V-Model in conjunction with supplier capacity, system complexity and novelty and GxP impacts按照既定的V-Model实施确认 Perform verification as established in the V-Model19/89流程良好实践 1-1 Process Good Practices 通过网络

37、结构图，找到接口界面 “云图”的方式划分界定系统 Define systems through network structure chart, and interface “cloud picture 确认计算机化系统Computerized system definition20/89流程良好实践 1-2 Process Good Practices 1-2 确认计算机化系统Computerized system definitionWhen network architecture diagram is not available for no supplier performs sec

38、ondary development at the initial stage , the computerized system summary list is considered as the basis for defining systems.项目初期没有供应商二次开发无法得到网络架构图时，可考虑采用计算机化系统清单汇总作为界定划分系统的依据21/89流程良好实践 2 Process Good Practices 2 Select GxP critical systems through GxP risk assessment questions 通过GxP评估问题筛选出GxP关键系

39、统 Perform initial risk assessment and determine GxP critical systems初步风险评估判定GxP关键系统Does the system generate, manipulate or control data supporting regulatory safety and efficacy submissions?系统是否生成、处理或控制用于支持法规安全性和功效提交文件的数据？Does the system control critical parameters and data in preclinical, clinical,

40、 development, or manufacturing?系统是否控制临床前、临床、开发或生产相关关键参数和数据？Does the system control or provide data or information for product release?系统是否控制或提供有关产品放行的数据或信息？Does the system control data or information required in case of product recall?系统是否控制与产品召回相关要求的数据或信息？系Does the system control adverse event or c

41、ompliant recording or reporting?统是否控制不良事件或投诉的记录或报告？Does the system support pharmacovigilance? 系统是否支持药物安全监视？Critical systems are subject to validation, and non-critical systems are subject to GEP commissioning only. 关键系统做验证，非关键系统GEP调试即可22/89流程良好实践 3供应商评估确定其能力及参与平衡点对每一受GxP监管的计算机化系统和服务的供应商进行正式的评估，来确认计算

42、机系统能够以高标准满足他们的技术、商业及法规要求，同时确认能够充分利用供应商的知识、经验和文件。通过供应商审计来识别供应商QMS以及其能力水平方面的风险，被监管公司对计算机系统和服务供应商的质量和可靠性进行确认，要求有文件化的证据来证明该计算机系统能够如所预期的持续运行，并确保软件结构和功能的完整性。23/89Process Good Practices 3Perform supplier assessment and determine their capacity and involvement balance pointFormal assessment is performed to

43、each supplier of computerized system and service under the regulation of GxP, to verify that the computerized system can meet their technical, commercial and regulatory requirements, and at the same time make the best use of suppliers knowledge, experience and documents. Risks of suppliers QMS and c

44、apacity are identified through a supplier audit. The company under the regulation verify the quality and reliability of supplier of computerized system and services, and documented evidence is required to prove the computerized system can run continuously as intended, and ensure the integrity of sof

45、tware structure and function. 24/89流程良好实践 4-1软硬件分类评估确定其复杂性和新颖性硬件分2类 软件分4类通过识别软硬件类别来识别复杂性和新颖性带来的风险，从而确定出适宜的可增减周期策略25/89Process Good Practices 4-1Perform hardware and software categorization assessment and determine their complexity and novelty .Hardware is divided into two categories. Software is div

46、ided into four categories. Identify risks from complexity and novelty through identifying hardware and software categories, to determine proper extendable life cycle strategy. 26/89流程良好实践 4-2 硬件类别类别典型方法1, 标准硬件部件通过文件记录下生产厂家或供应商的详情、序列号和版本号确认正确的安装适用配置管理和变更控制2, 定制制造的硬件部件上述内容再加上：设计说明验收测试适用配置和变更控制27/89Pro

47、cess Good Practices 4-2 Hardware Categories CategoryCategoryTypical ApproachTypical Approach1. Standard Hardware 1. Standard Hardware ComponentsComponentsDocument manufacturer or supplier detail, serial number and Document manufacturer or supplier detail, serial number and version number version num

48、ber Correct installation to be verified Correct installation to be verified Configuration Management and Change control applyConfiguration Management and Change control apply2. Custom Built 2. Custom Built Hardware ComponentsHardware ComponentsThe above plus: The above plus: Design specificationDesi

49、gn specificationAcceptance testingAcceptance testingConfiguration and Change control apply Configuration and Change control apply 28/89流程良好实践 4-3 硬件类别硬件类别第二类定制制造部件第一类标准部件29/89Process Good Practices 4-3 Hardware Categories Hardware CategoryCategory 2Custom Built Hardware ComponentsCategory 1Standard

50、Hardware Components30/89流程良好实践 4-4 软件类别31/89Process Good Practices 4-4 Software Categories TypeGAMP5GAMP51Operating systemInfrastructure SoftwareInfrastructure Software2Firmware Out of use3Standard software packageNon-configured4Configured software packageConfigured 5Custom(reserved)softwareCustom32

51、/89流程良好实践 4-5 软件类别类别说明典型示例典型方法1, 基础设施软件分层式软件用于管理操作环境的软件操作系统数据库引擎中间件编程语言电子制表软件版本控制给你工具网络监控工具记录版本号，按照所批准的安装规程验证正确的安装方式。3, 非配置软件可以输入并储存运行参数，但是并不能对软件进行配置以适合业务流程基于固件的应用程序COTS软件简化的生命周期法URS 用户需求说明基于风险的供应商审计/评估记录版本号，验证正确的安装方式基于风险进行测试有用于维持系统符合性的规程33/89Process Good Practices 4-5 Software Categories CategoryCa

52、tegoryDescriptionDescriptionTypical examplesTypical examplesTypical ApproachTypical Approach1. 1. Infrastructure Infrastructure SoftwareSoftwareLayered softwareLayered softwareSoftware used to Software used to manage the operating manage the operating environmentenvironmentOperating systemsOperating

53、 systemsDatabase enginesDatabase enginesMiddlewareMiddlewareProgramming languagesProgramming languagesSpreadsheetsSpreadsheetsVersion control toolsVersion control toolsNetwork monitoring toolsNetwork monitoring toolsRecord version number, verify correct Record version number, verify correct installa

54、tion by following approved installation by following approved installation procedureinstallation procedure3. Non-3. Non-configuredconfiguredRuntime parameters Runtime parameters maybe entered and maybe entered and stored, but the software stored, but the software can not be configured to can not be

55、configured to suit the business processsuit the business processFirmware based applications Firmware based applications COTs software COTSCOTs software COTSAbbreviated Life cycle approachAbbreviated Life cycle approachURSURSRisk based approach to supplier Risk based approach to supplier assessmentas

56、sessmentRecord version number, verify correct Record version number, verify correct installationinstallationRisk based testRisk based testProcedure in place for maintaining Procedure in place for maintaining compliancecompliance34/89流程良好实践 4-6 软件类别类别说明典型示例典型方法4, 可配置这种软件通常非常复杂，可以由用户来进行配置以满足用户具体业务流程的特

57、殊要求。这种软件的编码不能更改。SCADADCSBMSHMILIMSERPClinical trail monitoring生命周期法基于风险的供应商审计/评估供应商的质量管理系统记录版本号，验证正确的安装方式在测试环境中根据风险进行测试在业务流程中根据风险进行测试具有维持符合性的规程5, 定制定制设计和编码以适于业务流程的软件内部和外部开发的IT应用程序内部和外部开发的工艺控制应用程序定制功能逻辑定制固件电子制表软件（宏）与第4类相同，再加上更严格的公用设施评估，包括进行供应商审计完整的生命周期设计和源代码回顾35/89Process Good Practices 4-6 Software

58、Categories CategoryCategoryDescriptionDescriptionTypical examplesTypical examplesTypical ApproachTypical Approach4.4.Configured Configured Software, often Software, often very complex, very complex, that can be that can be configured by configured by the user to meet the user to meet the specific th

59、e specific needs of the needs of the users business users business process. process. Software code Software code is not altered.is not altered.DAQ systemsDAQ systemsSCADASCADADCSDCSBMSBMSHMIHMILIMSLIMSERPERPClinical trail monitoringClinical trail monitoringLife cycle approachLife cycle approachRisk

60、based approach to supplier assessmentRisk based approach to supplier assessmentSupplier QMSSupplier QMSRecord version number, verify correct installationRecord version number, verify correct installationRisk based testing in a test environmentRisk based testing in a test environmentRisk based testin