过程确认及方法概述PPT幻灯片

1、1,Process Validation the interlock of the cap into the tube was changed to improve the pull strength testing; and short caps were added to accommodate different size syringes. Verifications and/or validations, design reviews, design releases, and design approvals were not performed for any of these

2、changes. .对于这些变更没有实施确认和/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 performed at the maximum sterilization dose. 特别是，没有记录可以表明批号为31255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 CF

3、R 820.75. 你们没有按照21 CFR 820.75的要求进行验证/确认过程偏差。,21,Some FDA Compliance Officer CommentsFDA符合官员的一些评论,“Specifications need to be developed before you get to the validation stage.” “进行确认之前，需要制订技术规范。” “Manufacturers sometimes miss the step of completing adequate protocols before proceeding with validation

4、activities.” “制造商有时会忘记在开始确认之前完成充分的方案。” “Manufacturers sometimes fail to revisit the validation process when modifications are made 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。”,22,So Why Dont Companies Just Do It?为什么我们不能马上进行过程确认呢？,Misunderstanding of the regulation 对法规的误解 Lack of knowled

5、ge in execution 缺乏实施的知识 Lack of resources to execute 缺乏实施的资源 Fear of failure 害怕失败 Lack of management support 缺乏管理层支持 Fear of delay to market 担心延误了上市 Inhibits process change 隐藏了过程变化,23,过程确认的要素,确认,安装鉴定,操作鉴定,性能鉴定,开发,24,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,25,Processes Which Sho

6、uld Be Validated需要确认的过程,Sterilization 灭菌 Clean room ambient conditions 净化室周围的环境 Aseptic filling processes 无菌填充过程 Sterile packaging sealing processes 无菌包装密封过程 Lyophilization process （低压）冻干过程 Heat treating processes 热处理过程 Plastic injection molding process 注塑成型过程 2004 GHTF,26,Processes That May Be Veri

7、fied可以验证的过程,Manual cutting processes 手动切割过程 Testing for color, turbidity, total pH for solutions 测试溶液的颜色，混浊度，总的pH值 Visual inspection of printed circuit boards 印制电路板的目视检验 Manufacturing and testing of wiring harnesses 电缆线束的制造和测试 2004 GHTF,27,What is a Validation Master Plan?什么是确认主计划（VMP）,A master vali

8、dation plan identifies those processes to be validated, the schedule for validations, interrelationships between processes requiring validation and timing for revalidations. Once these have been established, and the purpose and scope for validations are clearly stated and known, protocol development

9、 can commence 确认主计划用以明确哪些过程要确认，确认（过程）的进度表，要求确认的过程和再确认（过程）时间选定上的相互关系。一旦确定了上述内容、清楚地规定确认的目的和范围并对外告知，方案的编制便可以着手进行了。 It documents specifically the validation of equipment, processes, software, facilities, etc . 它记录了要被确认的设备、过程、软件、设施等。 Its a map of the process validation process for the team to follow. 它是团

10、队要遵守的过程确认主线图。 A VMP is an index that FDA can follow in understanding your validations. 确认主计划是FDA 用来理解你的确认的索引,28,Why Use a Validation Master Plan?为什么要用确认主计划,Although these are not required by the FDA regulations it is one of the first things that an auditor may ask for during an inspection. 尽管这不是FDA法

11、规所要求的，但是它是审核员在检查过程中所要求的首要东西之一。 If a company holds true to its VMP and its documented evidence, credibility is established and FDA will have more confidence in ones outcomes. 如果公司能够按照VMP做并且记录了证据，信任就建立起来了，FDA对其结果就会更有信心。,29,Why Use a Validation Master Plan?为什么要用确认主计划,Allows one to be proactive rather t

12、han reactive. 考虑前瞻性而不是事后反应 Provides definition, scope creep, and commitment to responsibilities. 提供了定义、范围以及对职责的承诺 It provides a map or guide to the auditor defining how the company is tying their concept to reality in order to successfully achieve user requirements. 它为审核员提供了公司为了成功的满足用户的要求而如何将公司的观念和实

13、际联系在一起的路线图或指导方向,30,Components of a Validation Master Plan?确认主计划的组成,Definition of the project 项目定义 Strategy or approach to the project 项目的策略或方法 Scope of the project 项目的范围 What processes will be validated? 将被确认的过程 What processes will be verified? 将被验证的过程 Responsibilities 职责,31,Components of a Validati

14、on Master Plan?确认主计划的组成,Are there any special considerations? 是否有任何特殊的考虑？ Key milestones 关键的里程碑 Validation protocol numbers 确认方案的编号 A VMP, per se, is not the same as a project plan!,32,What is in a Validation Master Plan?确认主计划是什么,33,What is Required to Be Outstanding in Process Validation?过程确认中需要强调什

15、么？,Planning 计划 Cross functional team THAT CAN WORK TOGETHER! 相关职能部门，一起合作 Profound process knowledge 渊博的过程知识 Having a long term commitment 长期的承诺 Roadmap reflecting regulatory guidelines 能反映法规指导的路标图 Metrics to map progress 进展的指标 Passion for excellence 追求卓越的激情,34,Steps to Validation of a Process过程确认的步骤

16、,Form a multi-disciplinary team 组建一个多功能小组 Plan the approach and define requirements 制定步骤并定义要求 Identify and describe the process 识别和描述过程 Specify process parameters and desired output 规定过程参数和希望的输出 Decide on verification and or validation 就验证和（或）确认做出决定 Create a Validation Master Plan 制定一个主要确认方案,35,Step

17、s to Validation of a Process,Select methods and tools for validations 选择确认的方法和工具 Create validation protocols 编制确认方案 Perform IQ, OQ, PQ and document results 执行IQ、OQ、PQ并将结果形成文件 Determine continuous process controls 确定连续的过程控制 Control the process continuously 连续地控制过程,36,Protocol development 方案编制,Process

18、 validation protocols should include the following elements: 过程确认方案应该包括如下元素： Complete description of the process 过程的完整描述 Identification of the process to be validated 要确认的过程标识 Select the worst case 选择最差条件（产品） Identification of device(s) to be manufactured using this process 在这个过程下产出的器械的标识 Objective

19、and measurable criteria for a successful validation 一个成功确认的目标和可测量的标准 Length and duration of the validation 确认的用时和有效期限 Shifts, operators, equipment to be used in the process 过程中采用的轮班制、操作人员和设备 Identification of utilities for the process equipment and quality of the utilities 过程设备中使用器具(utilities)的标识和质量

20、 Identification of operators and required operator qualification 操作员识别和要求的操作员资格（证）,37,Protocol development 方案编制,、 Relevant specifications that relate to the product, components, manufacturing materials, etc 产品、元件、生产材料等的相关规格 Any special controls or conditions to be placed on preceding processes durin

21、g the validation 在（过程）确认中，对先发生的过程所设置的任何特殊控制或条件 Process parameters to be monitored, and methods for controlling and monitoring 要监控的过程参数和监控方法 Product characteristics to be monitored and method for monitoring 监视的产品特性和方法 Any subjective criteria used to evaluate the product 用来评估产品的主观标准 Definition of what

22、 constitutes non-conformance for both measurable and subjective criteria 对于可测量标准和主观标准，定义什么是不合格 Statistical methods for data collection and analysis 数据收集和分析的统计方法 Consideration of maintenance and repairs of manufacturing equipment 生产设备保养和修理方面的考虑 IQ、OQ & PQ Criteria for revalidation 再确认标准,38,Protocol d

23、evelopment 方案编制,For all three phases, IQ, OQ, and PQ, based on product/process requirements: 对于三个阶段，IQ、OQ和PQ都要基于产品或过程的要求： Determine what to verify/measure 决定验证或测量什么 Determine how to verify/measure 决定如何验证或测量 Determine how many to verify/measure, i.e. statistical significance 决定验证或测量多少，如统计量 Determine

24、when to verify/measure 决定何时验证或测量 Define acceptance/rejection criteria 规定接受或拒绝的标准 Define required documentation 规定要求的文件 Remember: protocol must be reviewed and approved before execution 记住，在实施前，方案必须被评审和批准。,39,Protocol development 方案编制,Generally, protocol includes 4 sections: 一般来讲，方案可分为四大部分： The 1st s

25、ection: validation overview, including validation scope, process description, background, worst cases, length and duration of the validation, objective etc. 第一部分：确认概述部分，包含确认范围，过程描述，背景介绍，最差条件挑选，确认的用时和有效期限，目标 等等； The 2nd section: qualification readiness, including the requirements for man, machine, ma

26、terial, method, environment, test and label & traceability,PFMEA etc. 第二部分：鉴定准备阶段，包含所有的人、机、料、法、环、测及标志和追溯,PFMEA等要求和准备； The 3rd section: qualification (IQ,OQ&PQ), including qualification plan and deviation disposal etc. 第三部分：鉴定阶段(IQ,OQ&PQ)，包含鉴定计划及偏差处理等； The 4th section: document requirements，including

27、 the input and output documents required by this protocol. 第四部分：文件要求，包含本方案所需的文件及输出文件要求。,40,Qualification Types鉴定的类型,How do requirements apply? 怎样应用这些要求,41,The Importance of Gaging量具的重要性,Your measurement method is most important in determining your process parameters. 在确定你的过程参数的过程中，你的测量方法是最重要的。 Gages

28、 measure variation and provide signals for changes in variation. 量具用来测量变差并提供变差变化的信号。 Gages are the compass to help navigate through the validation process. 量具是整个确认过程中帮助我们导航的罗盘。,42,Installation Qualification (IQ)安装鉴定（IQ）,Establishing by objective evidence that all key aspects of the process equipment

29、 and ancillary system installation adhere to the manufacturers approved specification and that the 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 GHTF,43,Installation Qualification (IQ)安装鉴定（IQ）,“Is the eq

30、uipment installed correctly?” 设备已经正确的安装了吗？ IQ Goal： IQ目的 Verify and prove all key aspects of the process equipment and ancillary system installation adhere to the manufacturers approved specification and that the recommendations of the supplier of the equipment are suitably considered. 验证并证明所安装的过程设备

31、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。 The IQ reduces risk by reducing the number of root causes suspected when trouble occurs in the OQ and PQ. IQ通过消减在OQ和PQ过程中出现的麻烦的可疑原因数量来减少风险 Make sure equipments to meet intended use . 确保设备满足预期用途,44,Installation Qualification (IQ)安装鉴定（IQ）,45,Installation Qu

32、alification (IQ)安装鉴定（IQ）,Important considerations are: IQ考虑事项： Equipment design features (construction materials, cleanability) 设备设计特点（如清洁装置的结构材料等） Installation conditions (wiring, utilities) 安装条件（布线、实用性、功能性等） Calibration, Preventive Maintenance, cleaning schedules 校准、预防性保养、清洁计划 Safety 安全特性 Supplier

33、 documentation 供应商文件 Software documentation 软件文件 Spare parts list 零部件清单 Environmental conditions (temperature, humidity) 环境条件（如清洁室的要求、温度和湿度） 2004 GHTF,46,Acceptance Criteria接受标准,Considerations考虑点: Make them clear and objective 清晰、客观 Be descriptive 可描述的 Attributes should reference a standard when pos

34、sible. 可能时，定性参数应该作为参考标准 Specifications can be a tolerance, maximum or minimum 规格应该有公差，最大或最小 They must make sense， 必须能讲的清楚 They must keep the OQ and PQ in mind 必须一直把OQ和PQ记在心里 Acceptance criteria are created before the protocol is approved not afterward接受标准要在方案批准之前制定出来而不是之后制定出来,47,Installation Qualifi

35、cation (IQ)安装鉴定（IQ）,Protocol components: 方案构成 Purpose 目的 Equipment description 设备描述 Scope 范围 Process description 过程描述 Items to be verified in each installation category 在每个安装类别里所要验证的项目,48,Operational Qualification (OQ)操作鉴定（OQ）,Establishing by objective evidence process control limits and action leve

36、ls which result in product 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 GHTF,49,Operational Qualification (OQ)操作鉴定（OQ）,OQ Goal： OQ目的： The OQ is intended to create a process scope (limits) within which an operator controls the process. This will challenge the w

37、orst case(Limits) OQ用于创建过程范围(极限）,操作工可在此过程范围内控制过程。它将会挑战过程的最差条件按（极限）。 Using good science is essential to establishing reliable process parameters. 使用正确的科学知识是建立可靠地过程参数的基本条件。,50,Operational Qualification (OQ)操作鉴定（OQ）,Some time, limits can be gotten here from experience and other source in advance 有时，此处可

38、由经验或其他来源预先获得极限。,51,Operational Qualification (OQ)操作鉴定（OQ）,Important considerations are: 重要的考虑点： Process parameters control limits过程参数控制线 Define production runs batch qty / product qty and sequence for each group of parameters 确定每组参数的生产批次/产品的数量以及顺序 Acceptance criteria接受标准 Gaging or test methods测量或测试方

39、法 Raw materials原材料 Process change control过程变更控制 The limits and conditions established in the OQ will be the same limits and conditions used in the PQ. 在OQ中建立的极限和条件将是用在PQ中所使用的极限和条件相同的。,52,Operational Qualification (OQ)操作鉴定（OQ）,Important considerations: 重要的考虑点： Training 培训 Method for determining short

40、 term stability and capability of process 确定短期稳定性和过程能理的方法 Potential failure modes, action levels, and worst case conditions 可能的故障状态、作用程度和最坏情况条件 Use of statistical techniques to identify key process variables and DOE for optimization 统计学有效技术的使用来识别关键过程变差及用 DOE进行优化,53,Operational Qualification (OQ)操作鉴定

41、（OQ）,The OQ must test product at the worse case process conditions. OQ必须测试在最差过程条件中生产的产品 The worse case conditions must also include worse case product when more than one product is involved (i.e. a product family). 当涉及到不止一个产品时（比如一个产品族）最差条件也要包含最差条件的产品。 The process parameters established in the OQ wil

42、l establish the revalidation criteria. OQ中建立的过程参数要建立再确认标准。,54,Determination of Process Scope过程范围的确定,Conventional approach: Use best technical judgments to determine key parameters and operating scope 传统的方法：使用最好的技术判断来决定关键参数和操作范围。 Enhanced approach: Use Design of Experiments to determine operational s

43、cope 先进的方法：使用DOE来确定操作范围。,55,Additional OQ Considerations额外的OQ考虑点,This is the time to find the limits of your process 这是发现你们的过程极限的时间。 This is also the time to demonstrate you know how changes in inputs will effect your key process characteristics 这是证明你们知道当输入如何变化时会影响你们关键的过程特性的时间。 Remember: Once the ke

44、y process controls are established they cannot be violated by the operator or the engineer without revalidation! 记住：一旦建立了关键的过程控制，如果没有再确认，任何操作工或工程师都不能违背他们。,56,Performance Qualification (PQ)性能鉴定（PQ）,establishing by objective evidence that the process, under anticipated conditions, consistently produce

45、s a product which meets all predetermined requirements. 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 GHTF,57,Performance Qualification (PQ)性能鉴定（PQ）,PQ Goal： PQ目标： establishing by objective evidence that the process, under anticipated conditions, consistently produces a product which meets all predetermi

46、ned requirements. 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。 Normally , anticipated conditions are the best conditions (Nominal Parameters). 通常情况下，预期的条件就是最好的条件（名义参数）,58,Performance Qualification (PQ)性能鉴定（PQ）,In this phase the key objective is to demonstrate the process will consistently produce acceptable

47、product under normal operating conditions. 在此阶段，要用关键的目标来证明在正常的操作条件下过程能持续的生产出可接受的产品。 2004 GHTF The PQ must be performed by the operator! PQ必须要由操作工来执行！,59,Performance Qualification (PQ)性能鉴定（PQ）,While FDA believes that three production runs during process validation is the accepted standard, FDA recogn

48、izes that all processes may not be defined in terms of lots or batches. The number three is, however, currently considered to be the acceptable standard. FDA相信在过程确认中三个生产循环是可接受的标准，FDA认识到所有的过程不可能根据批次来进行定义的。然而，三这个数字当前被认为是可接受的标准。 FDA Preamble,60,Performance Qualification (PQ)性能鉴定（PQ）,61,PQ consideration

49、s include: PQ应该考虑： Actual product and process parameters and procedures established in OQ OQ阶段的真实产品、过程参数和建立的程序 Acceptability of the product 产品的可接受性 Assurance of process capability as established in OQ 就像OQ阶段那样建立的对过程能力的保证 Process repeatability, long term process stability 过程的重复能力和长期过程的稳定能力,Performanc

50、e Qualification (PQ)性能鉴定（PQ）,62,PQ ExecutionPQ实施,1. Manufacture the predetermined number of lots. 生产预先确定批次数量的产品 2. Collect data on each lot. 收集每一批的数据 3. Analyze the data applying the proper statistical technique. 使用恰当的统计方法分析数据 4. Document all findings. 记录所有的发现 5. Disposition the protocol. 方案处理 Note:

51、 All lots must pass to consider the process validated! 注意：所有的批次必须通过将要被确认的过程！,63,The Final Report最终报告,Prepare at end of validation activities 在确认活动的最后准备 Summarize the findings and any deviations to the protocol. 总结发现和任何对方案的偏离 Include all attachments risen from protocol. 包含由方案所引起的所有附件 Consider whether

52、 the OQ is still valid. 考虑是否OQ仍然有效 Derive conclusions regarding the validation status of the process. 应得出关于过程确认状态的结论 Obtain final approval signatures. 获得最终的批准签字 Release process to manufacturing. 将过程放行给生产过程,64,Failed Study失效研究,Summarize the report. 总结报告 Investigate and document the root causes. 调查并记录

53、根本原因 Determine whether the OQ parameters are the root cause. 确定是否OQ参数是根本原因 Determine whether the OQ needs to be re-run. 决定是否要重新进行OQ Determine whether the PQ will be run again. 决定是否再进行PQ,65,Failed Study失效研究,Deviations from the protocol 对方案的偏离 Deviations can be acceptable. 偏离是否是可接受的 State the deviatio

54、n. 陈述偏离 State how it does not affect the protocol 陈述偏离不影响方案 Have the deviation approved. 让偏离获得批准,66,Discussion Questions问题讨论,What happens if two out of three lots fail due to operator error? Can each lot be dispositioned one at a time? Can different products be run in-between each validation lot? Wh

55、at happens if the parameters need to be temporarily changed due to a raw material change? Does a new operator require the process to be revalidated? When equipment is moved to a new location does the process need to be revalidated? Does new gauging or measurement method require the process to be rev

56、alidated?,67,Revalidation再确认,As long as the process operates in a state of control and no changes have been made to the process or output product, the process does not have to be revalidated. 一旦过程在受控状态内操作且没有对过程或输出的产品没有变更，过程不需要再确认。 FDA Conditions for revalidation should be clearly defined and documen

57、ted. 必须清楚地定义出再确认的条件并文件化。,68,When is Revalidation appropriate or required?什么时候要求再确认,change(s) in the actual process that may affect quality or its validation status 可能影响质量或其确认状态的真实过程的改变 negative trend(s) in quality indicators 质量指示器的负面动向 change(s) in the product design which affects the process 对过程有影响的产品设计上的改变 transfer of processes from one facility to another 从一台装置到另一台装置的过程转换 change of the application of the process 过程应用的改变 2004 GHTF,69,When is Revalidation appropriate or r