过程确认及方法概述精选文档.ppt

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1、过程确程确认及方法概及方法概述述本讲稿第一页，共七十二页Agenda/Topics日程日程/主题主题主题主题 What is Process Validation?What is Process Validation?什么是过程确认？什么是过程确认？什么是过程确认？什么是过程确认？Brief history of validation Brief history of validation 确认的简要历史确认的简要历史确认的简要历史确认的简要历史 Who concerns about validation?Who concerns about validation?谁关心确认？谁关心确认？谁关

2、心确认？谁关心确认？Expectations Expectations 期望期望期望期望 Definitions/Compliance Definitions/Compliance 定义定义定义定义 /符合性符合性符合性符合性 Validation Economics Validation Economics 确认的经济意义确认的经济意义确认的经济意义确认的经济意义 Examples of Warning Letters Examples of Warning Letters 警告信的案例警告信的案例警告信的案例警告信的案例 Elements of Process ValidationElem

3、ents of Process Validation过程确认的要素过程确认的要素过程确认的要素过程确认的要素 When to Validate When to Validate 何时确认何时确认何时确认何时确认 Validation Master Plans Validation Master Plans 确认主计划确认主计划确认主计划确认主计划 What is Required to Be Outstanding in Process Validation?What is Required to Be Outstanding in Process Validation?确认中需要强调什么？确

4、认中需要强调什么？确认中需要强调什么？确认中需要强调什么？Steps to Validation of a Process Steps to Validation of a Process 过程确认的步骤过程确认的步骤过程确认的步骤过程确认的步骤 Protocol development Protocol development 方案编制方案编制方案编制方案编制 IQ IQ 安装鉴定安装鉴定安装鉴定安装鉴定 OQ OQ 操作鉴定操作鉴定操作鉴定操作鉴定 PQ PQ 性能鉴定性能鉴定性能鉴定性能鉴定 The Final Report The Final Report 最终报告最终报告最终报告最终

5、报告 RevalidationRevalidation再确认再确认再确认再确认 MonitoringMonitoring监控监控监控监控本讲稿第二页，共七十二页Why Are we discuss this?为什么我们要讨论？为什么我们要讨论？Validation may be new 也许确认对你来说是一个全新的概念You need a refresher 你需要更新知识You have specific questions你有一些具体的问题You may be under a 483(or worse,a warning letter!)也许你已经收到了483（或更糟，警告信！）本讲稿第三

6、页，共七十二页What is Process Validation(FDA)?什么是过程确认什么是过程确认(FDA)？Process validation is establishing Process validation is establishing documented evidencedocumented evidence which which provides a provides a high degree of assurancehigh degree of assurance that a specific that a specific process will cons

7、istently produce a product meeting its process will consistently produce a product meeting its predetermined specifications and quality predetermined specifications and quality characteristicscharacteristics 过程确认就是建立一套能证明特定的过程可以以高度的过程确认就是建立一套能证明特定的过程可以以高度的信心持续地生产出满足预定规格和质量特性的产品的书信心持续地生产出满足预定规格和质量特性的

8、产品的书面证据。面证据。Guidelines on General Principle of ProcessGuidelines on General Principle of Process Validation,GMP Manual,May 1987 Validation,GMP Manual,May 1987过程确认总原则指导，过程确认总原则指导，19871987年年5 5月，月，GMPGMP手册，手册，本讲稿第四页，共七十二页What is Process Validation(GHTF)?什么是过程确认什么是过程确认什么是过程确认什么是过程确认(GHTF)?(GHTF)?Proces

9、s validation:Process validation:establishing by objective evidence establishing by objective evidence that a process consistently produces a result or that a process consistently produces a result or product meeting its product meeting its predeterminedpredetermined requirements.requirements.过程确认：有客

10、观证据支持，即过程将连续地产出符合预过程确认：有客观证据支持，即过程将连续地产出符合预定要求的结果或产品。定要求的结果或产品。2004 GHTF2004 GHTF 本讲稿第五页，共七十二页History of Validation确认的简要历史确认的简要历史 Before 1978Before 1978.no FDA regulations.no FDA regulations 19781978年之前年之前.没有没有FDAFDA法规法规 Current GMP became law in 1978Current GMP became law in 1978目前的目前的GMPGMP是在是在197

11、81978年成为法规的年成为法规的 19871987Global Harmonization Task Force released:Quality Management Global Harmonization Task Force released:Quality Management SystemsSystems Process Validation GuidanceProcess Validation Guidance19871987年年医疗器械全球协调行动组织发布：质量管理体系医疗器械全球协调行动组织发布：质量管理体系-过程确认指导过程确认指导 19871987FDA release

12、:Guideline on General Principles of Process ValidationFDA release:Guideline on General Principles of Process Validation19871987年年发布发布FDAFDA：过程确认总原则指导过程确认总原则指导 19991999Global Harmonization Task Force update:Quality Management Global Harmonization Task Force update:Quality Management SystemsSystems Pr

13、ocess Validation GuidanceProcess Validation Guidance 19991999年年医疗器械全球协调行动组织更新了：质量管理体系医疗器械全球协调行动组织更新了：质量管理体系-过程确认指导过程确认指导 20042004Global Harmonization Task Force update:Quality Management Global Harmonization Task Force update:Quality Management SystemsSystems Process Validation GuidanceProcess Valid

14、ation Guidance20042004年年医疗器械全球协调行动组织更新了：质量管理体系医疗器械全球协调行动组织更新了：质量管理体系-过程确认指导过程确认指导本讲稿第六页，共七十二页Who concerns about validation?Who concerns about validation?谁关心确认？Medical device manufacturing and quality management regulatoryMedical device manufacturing and quality management regulatory 医疗器械生产质量管理规范医疗器械

15、生产质量管理规范 FDA PreambleFDA Preamble FDA FDA导言导言 ISO13485ISO13485：20032003；YY0287YY0287：20032003 21 CFR 82021 CFR 820 FDA Regulation FDA Regulation 21 CFR 82021 CFR 820 FDAFDA法规法规 Global Harmonization Task ForceGlobal Harmonization Task Force 全球医疗器械协调行动组织全球医疗器械协调行动组织 Company who hopes to consistently p

16、roduce a product meeting its predetermined Company who hopes to consistently produce a product meeting its predetermined specifications and quality characteristicsspecifications and quality characteristics 希望能希望能持续地生产出满足预定规格和质量特性的产品的公司持续地生产出满足预定规格和质量特性的产品的公司 本讲稿第七页，共七十二页The Expectation The Expectati

17、on 期望期望 One of the principles on which the quality systems One of the principles on which the quality systems regulation is based is that all processes require some regulation is based is that all processes require some degree of qualification,verification,or validation,and degree of qualification,v

18、erification,or validation,and manufacturers should not rely solely on manufacturers should not rely solely on inspectioninspection and and testingtesting to ensure processes are adequate for their to ensure processes are adequate for their intended use.intended use.质量体系法规建立的基本原则之一是：所有的过程都要求进行一质量体系法规

19、建立的基本原则之一是：所有的过程都要求进行一定程度的认证、验证、或确认，制造商不应该仅仅依靠检验和测定程度的认证、验证、或确认，制造商不应该仅仅依靠检验和测试来确保其过程能充分地满足其预期要求。试来确保其过程能充分地满足其预期要求。PrePre amble#41,pg.52612 amble#41,pg.52612 本讲稿第八页，共七十二页Does Your Company Need to Do Process Validation?Does Your Company Need to Do Process Validation?你们公司需要做过程确认吗？你们公司需要做过程确认吗？你们公司需要做

20、过程确认吗？你们公司需要做过程确认吗？Yes,if you are producing a medical device(it is the law!)Yes,if you are producing a medical device(it is the law!)是的，如果你们生产医疗器械，需要做过程确认（这是法是的，如果你们生产医疗器械，需要做过程确认（这是法规要求！）规要求！）What are classes of medical devices?What are classes of medical devices?医疗器械的类别医疗器械的类别 Class I Class I 一类一类

21、 Class II Class II 二类二类 Class III Class III 三类三类本讲稿第九页，共七十二页Does Your Company Need to Do Process Validation?Does Your Company Need to Do Process Validation?你们公司需要做过程确认吗？你们公司需要做过程确认吗？你们公司需要做过程确认吗？你们公司需要做过程确认吗？Are any classes of medical devices exempt?Are any classes of medical devices exempt?哪个类别的医疗器

22、械不需要做过程确认？哪个类别的医疗器械不需要做过程确认？No!Unless specifically stated in Medical Device No!Unless specifically stated in Medical Device Exemptions 510(k)and GMP RequirementsExemptions 510(k)and GMP Requirements没有！除非医疗器械豁免没有！除非医疗器械豁免510(k)510(k)和和GMPGMP要求中有特别声明。要求中有特别声明。http:/www.accessdata.fda.gov/scripts/cdrh/

23、cfdocs/cfpcd/315.http:/www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/315.c fm c fm 本讲稿第十页，共七十二页DefinitionsDefinitions定义定义 Understanding definitions is important in making sure we Understanding definitions is important in making sure we all are on the same page especially when it comes to all are

24、on the same page especially when it comes to talking with the FDA.talking with the FDA.理解定义对于确保我们有相同的理解是非常重要，尤其当我理解定义对于确保我们有相同的理解是非常重要，尤其当我们与们与FDAFDA讨论时。讨论时。Your definition of how a term is interpreted Your definition of how a term is interpreted is not as important as knowing how the FDA is not as

25、important as knowing how the FDA interprets it!interprets it!对于一个条款的解释，你个人的解释没有了解对于一个条款的解释，你个人的解释没有了解对于一个条款的解释，你个人的解释没有了解对于一个条款的解释，你个人的解释没有了解FDAFDA的解释重要。的解释重要。的解释重要。的解释重要。本讲稿第十一页，共七十二页Objective EvidenceObjective Evidence客观证据客观证据 Objective evidence is information that can be proved true,based on fact

26、s Objective evidence is information that can be proved true,based on facts through observation,measurement,test or other means.through observation,measurement,test or other means.客观证据是可以通过观察、测量、测试或其他方法被证实为真实的信息。客观证据是可以通过观察、测量、测试或其他方法被证实为真实的信息。ISO 8402 2.19ISO 8402 2.19As the old saying goes,As the o

27、ld saying goes,“If you didnIf you didn t document it,you didnt document it,you didn t do it!t do it!”正如老话所说正如老话所说“如果你没有做记录，就等于你什么也没做如果你没有做记录，就等于你什么也没做”。本讲稿第十二页，共七十二页Verification验证验证验证验证 Confirmation by examination and provision of objective evidence that Confirmation by examination and provision of

28、objective evidence that specified requirements have been fulfilled.specified requirements have been fulfilled.通过检查并提供客观证据来证实已经满足特定的要求。通过检查并提供客观证据来证实已经满足特定的要求。820.3(aa)820.3(aa)本讲稿第十三页，共七十二页Process Validation Protocol过程确认方案过程确认方案过程确认方案过程确认方案 A document stating how validation will be conducted,A docum

29、ent stating how validation will be conducted,including test parameters,product characteristics,including test parameters,product characteristics,manufacturing equipment,and decision points on what manufacturing equipment,and decision points on what constitutes acceptable test results.constitutes acc

30、eptable test results.说明如何实施确认的文件，包含了测试参数、产品特性、说明如何实施确认的文件，包含了测试参数、产品特性、生产设备和由什么构成可接受测试结果的判断要点。生产设备和由什么构成可接受测试结果的判断要点。2004 GHTF2004 GHTF Sometimes validation requires you start with Sometimes validation requires you start with the acceptance criteria and work backwards.the acceptance criteria and wor

31、k backwards.有时候，过程确认要求你首先从确定接受标准开有时候，过程确认要求你首先从确定接受标准开始，逆向实施确认。始，逆向实施确认。本讲稿第十四页，共七十二页Installation qualification(IQ)安装鉴定（IQ）Establishing by objective evidence that all key aspects of the process equipment and ancillary system installation adhere to the manufacturers approved specification and that th

32、e recommendations of the supplier of the equipment are suitably considered.用客观证据来支持证明，所安装的过程设备和辅助系统的关键安装方面，能满足制造商已批准的技术规范，且供应商的建议也被恰当的考虑了。2004 GHTF2004 GHTF本讲稿第十五页，共七十二页Operational qualification(OQ)操作鉴定（OQ）Establishing by objective evidence process control limits and action levels which result in pr

33、oduct that meets all predetermined requirements 用客观证据确定能够生产出满足所有预定要求的产品的过程控制极限和行动标准。2004 GHTF2004 GHTF 本讲稿第十六页，共七十二页Performance qualification(PQ)性能鉴定（PQ）establishing by objective evidence that the process,under anticipated conditions,consistently produces a product which meets all predetermined requ

34、irements.用客观证据确定，在预期条件下，过程能连续地产出符合所有预定要求的产品。2004 GHTF2004 GHTF本讲稿第十七页，共七十二页Validation EconomicsValidation Economics确认的经济意义确认的经济意义确认的经济意义确认的经济意义What is the cost of validating a process?What is the cost of validating a process?进行过程确认所付出的成本是什么？进行过程确认所付出的成本是什么？What is the cost of not validating a proces

35、s?What is the cost of not validating a process?不进行过程确认所付出的成本是什么？不进行过程确认所付出的成本是什么？本讲稿第十八页，共七十二页Validation Economics确认的经济意义确认的经济意义确认的经济意义确认的经济意义 Increased output(process velocity)Increased output(process velocity)产量提升（过程速度）产量提升（过程速度）Fewer product nonFewer product non conformancesconformances 更少的不合格产品更

36、少的不合格产品 Less scrap and rework Less scrap and rework 更少量的报废和重新加工更少量的报废和重新加工 Fewer complaints Fewer complaints 更少的投诉更少的投诉 The process becomes characterizedThe process becomes characterized 过程变得特征化过程变得特征化 Process becomes more predictableProcess becomes more predictable 过程变得更可预测过程变得更可预测 Less chance of r

37、ecallsLess chance of recalls 更少召回的可能性更少召回的可能性 Regulatory compliance Regulatory compliance 符合法规要求符合法规要求 本讲稿第十九页，共七十二页Examples from Warning Letters来自警告信中的案例来自警告信中的案例 This lot was not produced using the manufacturing process discussed in the This lot was not produced using the manufacturing process dis

38、cussed in the validation study protocol.validation study protocol.这批产品没有按照确认方案中讨论的制造过程生产。这批产品没有按照确认方案中讨论的制造过程生产。The molding operation was changed to improve the visibility of the biohazard The molding operation was changed to improve the visibility of the biohazard symbol on the cap;the interlock of

39、 the cap into the tube was changed to symbol on the cap;the interlock of the cap into the tube was changed to improve the pull strength testing;and short caps were added to accommodate improve the pull strength testing;and short caps were added to accommodate different size syringes.Verifications an

40、d/or validations,design reviews,different size syringes.Verifications and/or validations,design reviews,design releases,and design approvals were not performed for any of these design releases,and design approvals were not performed for any of these changes.changes.对于这些变更没有实施确认和对于这些变更没有实施确认和/或确认，设计评

41、审，设计发布，以及设计批准。或确认，设计评审，设计发布，以及设计批准。Specifically,records were not available to show that the burst test on lot 31255 was Specifically,records were not available to show that the burst test on lot 31255 was performed at the maximum sterilization dose.performed at the maximum sterilization dose.特别是，没有记

42、录可以表明批号为特别是，没有记录可以表明批号为3125531255的产品按照最大灭菌剂量进行了爆裂测试。的产品按照最大灭菌剂量进行了爆裂测试。Your firm failed to verify/validate several process deviations as required by 21 CFR Your firm failed to verify/validate several process deviations as required by 21 CFR 820.75.820.75.你们没有按照你们没有按照21 CFR 820.7521 CFR 820.75的要求进行验证

43、的要求进行验证/确认过程偏差。确认过程偏差。本讲稿第二十页，共七十二页Some FDA Compliance Officer CommentsSome FDA Compliance Officer CommentsFDAFDA符合官员的一些评论符合官员的一些评论 “Specifications need to be developed Specifications need to be developed beforebefore you get to the validation you get to the validation stage.stage.”“进行确认之前，需要制订技术规范。

44、进行确认之前，需要制订技术规范。”“Manufacturers sometimes miss the step of completing adequate Manufacturers sometimes miss the step of completing adequate protocols protocols beforebefore proceeding with validation activities.proceeding with validation activities.”“制造商有时会忘记在开始确认之前完成充分的方案。制造商有时会忘记在开始确认之前完成充分的方案。”“M

45、anufacturers sometimes fail to revisit the validation process Manufacturers sometimes fail to revisit the validation process when modifications are madewhen modifications are made in products or processes.in products or processes.”“当发生产品或过程变更时，制造商有时没有重新进行过程确认。当发生产品或过程变更时，制造商有时没有重新进行过程确认。”本讲稿第二十一页，共七

46、十二页So Why Dont Companies Just Do It?为什么我们不能马上进行过程确认呢？为什么我们不能马上进行过程确认呢？为什么我们不能马上进行过程确认呢？为什么我们不能马上进行过程确认呢？Misunderstanding of the regulationMisunderstanding of the regulation对法规的误解对法规的误解 Lack of knowledge in execution Lack of knowledge in execution 缺乏实施的知识缺乏实施的知识 Lack of resources to executeLack of re

47、sources to execute 缺乏实施的资源缺乏实施的资源 Fear of failureFear of failure 害怕失败害怕失败 Lack of management supportLack of management support 缺乏管理层支持缺乏管理层支持 Fear of delay to marketFear of delay to market 担心延误了上市担心延误了上市 Inhibits process changeInhibits process change 隐藏了过程变化隐藏了过程变化本讲稿第二十二页，共七十二页过程确认的要素过程确认的要素确认确认安装鉴

48、定安装鉴定操作鉴定操作鉴定性能鉴定性能鉴定开发开发本讲稿第二十三页，共七十二页何时确认何时确认A过程输出可验证吗？B验证是充分及成本可接受吗？C验证并控制过程D确认E重新设计产品和/或过程本讲稿第二十四页，共七十二页Processes Which Should Be ValidatedProcesses Which Should Be Validated需要确认的过程需要确认的过程 SterilizationSterilization灭菌灭菌 Clean room ambient conditionsClean room ambient conditions净化室周围的环境净化室周围的环境 A

49、septic filling processesAseptic filling processes 无菌填充过程无菌填充过程 Sterile packaging sealing processesSterile packaging sealing processes无菌包装密封过程无菌包装密封过程 Lyophilization process Lyophilization process （低压）冻干过程（低压）冻干过程 Heat treating processesHeat treating processes热处理过程热处理过程 Plastic injection molding proc

50、essPlastic injection molding process 注塑成型过程注塑成型过程 2004 GHTF 2004 GHTF 本讲稿第二十五页，共七十二页Processes That May Be VerifiedProcesses That May Be Verified可以验证的过程可以验证的过程 Manual cutting processesManual cutting processes手动切割过程手动切割过程 Testing for color,turbidity,total pH for solutionsTesting for color,turbidity,to