GMP验证过程介绍ppt课件.ppt

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1、Introduction to Process Validation过程验证简介,Course Contents 课程内容Explain what validation is and why we do it 验证的定义及进行验证的原因Review what processes need to be validated 检查什么样的过程需要验证Describe an effective process validation 描述一个有效的过程验证Describe how to manage process validation 描述如何管理过程验证Sterilization Validatio

2、n Brief Introduction 灭菌验证简介,FIRST SECTION第一部分,Definitions of Validation 验证的定义Significance of a Validation 验证的意义,What is Validation FDA DefinitionFDA对验证的定义,Established documented evidence which provide a high degree of assurance that a specific process will consistently produce a product meeting its

3、predetermined specification and quality attributes. 建立提供高度保证的书面证据，确保特定过程将持续生产满足既定参数和质量属性的产品。,What is Validation ISO Definition ISO对验证的定义,Confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use are fulfilled.,通过测试和提供客观证据，确认达到特定预期用途的

4、特殊要求是否得到满足。,27.12.2022,5,Validation Training,What is Validation Baxters Definition百特公司对验证的定义,“Confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use are consistently fulfilled.” “通过测试和提供客观证据，确认达到特定预期用途的特殊要求是否得到持续满足。”,Why do we val

5、idate? 为什么我们要进行验证？1.To control the assessment and implementation of equipment and processes, which might impact product safety, quality or efficacy 为了控制那些可能影响产品安全性, 质量或功效的过程的评估和实施.Fulfill regulatory requirement满足法规的要求,Validation Learning Curve验证学习曲线,Benefits of Validation验证的好处,Quality Benefits质量方面的好

6、处End User Benefits用户方面的好处Business Benefits商业方面的好处,Improve Customer Satisfaction/ Reduce Cost提高客户满意度/降低成本,Reduce defects, scrap and rework 减少瑕疵品，废品和返工Reduce complaints and field corrective actions 减少投诉和区域纠正措施Reduce development time 缩短准备周期Faster time to market 加快进入市场的步伐,Regulatory Requirements法规方面的要求,

7、Regulatory Agencies require validation: -US FDA via Drug/Device GMPs -EU CE Mark via the MDD/ISO -Japan via the GMPs -Australia via the TGA 法规机构要求验证： -美国FDA的药品及医疗器械的GMP认证 -欧洲CE标志的MDD及ISO认证 -日本的GMP认证 -澳大利亚的TGA认证,1998版中国GMP,第七章的第五十七条至第六十条提出了“验证“的要求：验证包括哪些方面，什么情况下要验证，验证的实施，验证的归档。,SECOND SECTION第二部分,Wha

8、t Processes need to be Validated 什么样的过程需要验证？,What Process Require Validation 什么样的过程需要验证,“ All processes that affect quality must be validated ” “所有影响质量的过程都必须验证。”,Types of Processes that required validation 需要验证的过程的类型,Critical System, e g. Water, air, steam 关键性系统，如水，空气，蒸汽系统等Product Manufacturing Proc

9、esses 产品制造过程Product Design Changes 产品设计变更New or modified equipment 新的或改良的设备Computer Software 计算机软件Sterilization 灭菌Analytical Test Methods 分析测试方法Cleaning Methods 清洁方法,THIRD SECTION第三部分,Describe an effective Process Validation 描述有效的过程验证,What are the implication of not effectively validation 无效验证的含义,Ex

10、tended Development Times 准备时间过长For Unreleased Product 对于未出售的产品 -Elevated scrap 废品量增加 -Products holds 产品滞留 For Released Products对于已出售的产品 -Litigation 诉讼 -Customer complaints 客户投诉 -Recalls 召回 -Patient safety concerns 病人安全问题,Validation System Model验证系统模式,Validation- Process Operation -Re-validation验证 &

11、Monitoring 再验证 过程操作和监控,Validation Management验证管理,Validation does not begin or end with the protocol, it is a continuous improvement process验证并不会随验证方案的开始或结束而开始或结束, 它是持续改进的一个闭合循环活动,First Step in Validation验证的第一步,Establish a Team 建立一个团队 -One of the most important things you can do to assure a successfu

12、l validation is to form a multi-functional team to oversee the validation activities -保证验证成功的最重要事情之一是，组建一个多功能的团队来监督验证活动,First Step in Validation验证的第一步,The team members 团队成员 -Chemist, Microbiologist, Quality Engineer, Project Engineer, Sterility Assurance Engineer, Production Supervisor, Regulation o

13、fficer, IT -化学师, 微生物师, 质量工程师, 无菌保证工程师, 生产主管, 法规专员, 信息技术人员,Validation Following Steps 验证后续步骤,Define Requirements 说明要求,Approve & File Final Report 批准并将总结报告归档,FMEA / Quality Risk Analysis 失效模式和影响分析(FMEA)/ 质量风险分析,High/Mid Risk 高中风险,Low Risk 低风险,Define Requirements说明要求,Define product and process characte

14、ristics that could be affected by whats being validated. 说明会受验证内容影响的产品和过程的特征 These requirements include:这些要求包括： -Those defined in specifications 质量标准说明的内容 -Appropriate reference standards, i.e. GMP, ISO, ANSI, USP, MDD, etc. 适当的参考标准，如：GMP, ISO, ANSI, USP, MDD 等 -Additional requirements not covered i

15、n specifications and standards质量标准和参考标准里未包括的附加要求,Define Requirements说明要求,Design inputs - To specify each requirements of product / process, it is including: 设计输入 - 说明产品或过程的每一项要求，它包括:- Reliability 可靠性- Characteristics 特征- Physical Requirements 物理要求- Functional Requirements功能要求- Safety Requirements 安全

16、要求- Packaging 包装要求- Regulatory 法规要求,Design Inputs,Design Inputs设计输入,3.1 Package Product Reliability,Define Requirements说明要求,Design Inputs设计输入,3.2 Package Product Characteristics,Failure Modes and Effects Analysis (FMEA): An FMEA is systematic analysis of the potential failure modes. It includes the

17、identification of possible failure modes, determination of the potential causes and consequences and an analysis of the associated risk. FMEA can be performed on both the product and the process. 失效模式和影响分析(FMEA)：FMEA是对潜在失败模式的系统分析。它包括可能的失效模式的鉴定，潜在的原因和推理，以及相关风险的判定。FMEA可适用于产品和过程。,FMEA / Quality Risk An

18、alysis 失效模式和影响分析(FMEA) / 质量风险分析,Risk Analysis: Prevention tool used to identify potential failure modes, its causes, and the impact on the system and final user. 风险分析: 识别潜在的失败模式, 以及它们的起因和对系统及使用者的影响的预防工具.,FMEA / Quality Risk Analysis 失效模式和影响分析(FMEA) / 质量风险分析,在之前说明要求,在验证中解决,也许更多的产品召回, 法规措施, 和投诉,FMEA /

19、 Quality Risk Analysis 失效模式和影响分析(FMEA) / 质量风险分析,O - Occurrence, rating from 1-5 points, rating 5 stands for highest probability O - 代表发生的可能性, 分1-5个等级, 等级5代表可能性最高S - Severity, rating from 1-5 points, rating 5 stands for most serious S - 代表严重程度, 分1-5个等级, 等级5代表程度最严重D - Detection, rating from 1-5 points

20、, rating 5 stands for most difficult to detect D - 代表被检测到的可能性, 分1-5个等级, 等级5代表最难检测到RPN- Risk Priority Number 风险等级 RPN=O*S*D 风险等级等于以上3个得分的成积,Risk Priority Number (RPN) 风险等级,FMEA / Quality Risk Analysis 失效模式和影响分析(FMEA) / 质量风险分析,Risk Priority Number (RPN) 风险等级,O - OccurrenceRating: 1 = 1/100K 表示发生的可能性约十

21、万分之一 2 = 1/10K表示发生的可能性约万分之一 3 = 1/1K 表示发生的可能性约千分之一 4 = 1/100 表示发生的可能性约百分之一 5 = 1/10表示发生的可能性约十分之一,S - SeverityRating: 1 = Minor Failure (Unlikely to be noticed in the next process)轻微失败（未必在以后能察觉） 2 = Minor Failure (Downstream annoyance complaints. Causes minor work-arounds in the next process, or addi

22、tional testing by another department轻微失败（下游的投诉。引起下一工序的额外工作或其他部门的额外测试） 3 = Moderate failure (Downstream reduction in performance & throughput. Causes delays, rework, or capacity reductions in the next process step)中等失败（下游的生产能力和表现下降。引起延迟、返工或下一工序的生产能力的下降） 4 = Major Failure (System inoperable or major r

23、eduction in performance. Causes loss of product.)主要失败（系统不能工作或表现明显下降。导致产品损失） 5 = Safety and/or regulatory issue. (Causes a non-conformance in product efficacy, purity, and/or potency that may not be captured downstream. Causes the process to occur outside approved parameters.)安全和或法规方面的后果（导致产品的功效，纯度，和

24、或潜在的影响不能在下游发现。导致过程超出了规定的参数范围）,FMEA / Quality Risk Analysis 失效模式和影响分析(FMEA) / 质量风险分析,Risk Priority Number (RPN) 风险等级,FMEA / Quality Risk Analysis 失效模式和影响分析(FMEA) / 质量风险分析,Risk Priority Number (RPN) 风险等级,D - DetectionRating: 1 =1/MCompletely mistake proof. Current controls ensure failure prevention /

25、detection prior to passing on to the next step)检测不到的可能性为百万分之一，完全能防止错误。目前的控制手段能保证防止或发现失败进入下一步。2 =1/10KFailure obvious. (Pre-run or in process quality checks look for possibility of the failure mode)检测不到的可能性为万分之一，失败是显而易见的。（试运转或过程检查能发现这一失败）3 =1/1KFailure likely to be detected. (Quality check dont look

26、specifically for this failure mode, but may likely catch them.)检测不到的可能性为千分之一，失败有可能被发现。（质量控制的检查并不是特定用来发现这一失败，但有可能发现到它） 4 =1/100Failure not obvious. (Quality checks are statically based, or not performed for every run.)检测不到的可能性为百分之一，失败不明显。（质量检查是静态进行的，或并不是每次运作时都有质量检查） 5 =1/10No detection plan, chance o

27、f missing failure. (No Quality checks in place)检测不到的可能性为十分之一，没有探测方案，极有可能放过这一失败。,FMEA / Quality Risk Analysis 失效模式和影响分析(FMEA) / 质量风险分析,Risk level:风险水平: - Low Risk RPN15, Validation can be waived低风险 - RPN 小于15, 验证豁免 - Medium Risk RPN:15-27, Requires test and nominal level operation performed by corres

28、ponding SOP. Worse-case challenge not required中风险 - RPN 介于15 和 27 之间, 只要根据已定义步骤的程序和顺序进行运作, 不需要在最坏情况下进行挑战性试验. - High Risk Test should include a challenge of the items operation/performance under worse-case scenarios高风险 - RPN 大于 27, 应在最坏情况下进行该条款的运行或性能确认的挑战性试验,FMEA,FMEA 例子,FMEA / Quality Risk Analysis

29、失效模式和影响分析(FMEA) / 质量风险分析,3,4,5,60,27高风险,进行验证，找出最优化的操作参数，并确保过程的CPK值大于1.33,Validation Waiver验证豁免,A validation waiver is performed to justify implementing a process or change without additional testing验证豁免是用于证明执行一个过程或改变不需要额外的测试A waiver will have four main sections: 验证豁免包含4个主要部分:Background背景Risk Rationa

30、le风险的基本原理Justification for Not Testing豁免的原因Full Management Approval 管理层的一致批准,Validation Waiver,Validation Following Steps 验证后续步骤,Define Requirements 说明要求,Approve & File Final Report 批准并将总结报告归档,FMEA / Quality Risk Analysis 失效模式和影响分析(FMEA)/ 质量风险分析,High/Mid Risk 高中风险,Low Risk 低风险,Protocol Definition 验证

31、方案的定义,Develop Protocol 准备验证方案,Protocol is a validation documentation which specifies the procedures (and tests) to be conducted and the data to be collected. The purpose for which data are collected must be clear, the data must reflect facts and be collected carefully and accurately. 验证方案是说明将要进行的程序(

32、和测试)以及将要收集的数据. 对于收集数据的目的一定要清楚, 所收集的数据必须反映事实, 而且数据的收集必须是仔细和准确.The protocol should specify a sufficient number of replicate runs to demonstrate reproducibility and provide an accurate measure of variability among successive runs. The test conditions for these runs should encompass actual limits, which

33、 pose the greatest chance of process or product failure compared to ideal conditions; such conditions have become widely known as worst case conditions. 验证方案应说明能证明重现性的反复运作的足够次数, 而且要提供在成功的运作中的差异的准确的量度标准. 这些运作的实验条件应包括实际的相对于理想条件的可以造成过程或产品最大程度失效的限度, 这些条件成为公认的“最坏情况”的条件.,Protocol must be easily retrievabl

34、e 建立可检索性Protocol Tracking No. is GP-XX-YY-XXX according to SOP根据 SOP 定义验证方案的检索号为GP-XX-YY-XXX (Numbering according to item 11.0 in SOP-QM-55),Develop Protocol 准备验证方案,Protocol must be easily retrievable 建立可检索性,Develop Protocol 准备验证方案,Numbering: GP (Guangzhou Plant) + XX (classified code) + YY (Year No

35、. last two digital of the year) + XXX (Serial No., three digital).编码原则：GP( 广州工厂) + XX (分类号) + YY (年号，年号的后两位数) + XXX (系列号，三位数)。XX (Classified Code) include: XX (分类号)包括：MT-Material MT-物料MA-Manufacturing Process MA-生产工艺NP-New Product NP-新产品TM-Test Method TM-测试方法SY-System SY-系统OT-Other OT-其他,Develop Pro

36、tocol准备验证方案,Background and Scope 背景和范围Background背景*Briefly introduce purpose 简要地介绍验证的目的*What is to be accomplished 需要完成的内容*Description of current situation 描述目前状况*Summary of studies and validation relating to change相关的研究和验证的概述*Proposed change提出的变更,Develop Protocol准备验证方案,Background and Scope 背景和范围Sco

37、pe范围*Clearly define equipment or process to be validated, i.e. Description, asset tag, or other unique identification. 明确说明需要验证的设备或过程，如描述，资产标识，或其他独特的分辨特征。*What will it affect该验证将影响范围A plant一个工厂 An area一个区域 A particular product一种特定的产品,Develop Protocol 准备验证方案,IQ, OQ and PQ Phases IQ, OQ 和 PQ 阶段,Instal

38、lationQualification,OperationalQualification,PerformanceQualification,安装确认,运行确认,性能确认,Protocol Phases 方案的各个阶段,What is a Validation, a Protocol and a Qualification? 验证, 验证方案和确认三者的关系,A protocol is a document, qualification is an activity and validation is the complete package. 验证方案是文件, 确认是活动, 而验证是它们的完整

39、的结合.,VALIDATION 验证,PROTOCOL 验证方案,QUALIFICATION 确认,Installation Qualification-IQ 安装确认,“ Documented evidence that all key aspects of the process, process equipment and ancillary systems installation adhere to the approved design criteria, and that the recommendations of the manufacturer are suitably c

40、onsidered.” “证明过程, 过程设备和辅助系统安装的所有重要因素遵循经批准的设计标准, 及制造商的建议得到适当考虑的书面证据。”,Installation Qualification 安装确认 IQ Items 安装确认考虑因素,Verify equipment design features (i.e.materials of construction, cleanablity etc. ) 检查设备设计特征（如建筑材料，可清洁性等。）Verify installation correctness ( wiring, utilities, functionality, etc. )

41、 检查安装的正确性（书写，有效性，功能等）Identify calibration, preventative maintenance and adjustments 确定校正，预防性维护和调整Verify all safety features 检查所有安全功能Review Supplier documentation, prints etc. 检查供应商文件，印刷件等。Review software documentation 检查软件文件Establish spare parts list 建立备件清单 Verify environmental conditions. 核实环境条件,Op

42、erational Qualification-OQ 运行确认,“ Establishment of process parameters which will produce product that meets all predetermined requirements.” “制定生产满足所有既定要求的产品的过程参数。”,Operating Parameters操作参数General/Preventative Maintenance Procedures常规/预防维护的建议Calibrations Requirements校正要求Conformance to GMP/Regulatory

43、GMP/法规的符合性Training Requirements/Documentation培训要求/文件Programmable Controller/Microcomputer Validation可编程控制器/微型计算机的验证,Operational Qualification 运行确认OQ Items 运行确认考虑因素,Operational Qualification 运行确认OQ Items 运行确认考虑因素,Prototype/Pilot Production小批量/试运行生产Functional Testing of Product产品功能测试Chemical Evaluatio

44、n化学评估Microbiological Evaluation微生物评估Storage/Distribution贮存/运输SOP/Specification Revision and Update 标准操作规程/标准的修改和更新,Operational Qualification 运行确认OQ Items 运行确认考虑因素,Operating Parameters 操作参数 A. Establish key process parameters ( Screening Experiment ) 建立关键过程参数（筛选实验） B. Optimize process parameters ( St

45、atistically Design Experiment ) 优化过程参数（统计上的设计实验 ） C. Evaluate process stability (average & standard deviation) & capability (Cpk) 评估过程的稳定性(标准偏差和平均值)和能力 (Cpk),Operational Qualification 运行确认OQ Items 运行确认考虑因素,Heat Sealing热封,OUTPUTS,INPUTS,Man: Operator 人员Machine: Sealer 机器Materials: 物料 (Film 膜 Seal Pap

46、er 热封带)Parameter: 参数 (Temp.,Time, Pressure)Environment: 环境 (Room Temp., Humidity),Seal Strength热封强度Seal Integrity热封完整性,The establishment of key operating parameters 建立关键操作参数,Optimize process parameters ( Statistically Design Experiment ) 优化过程参数（统计上的设计实验，如正交试验） Consider Worst case conditions during c

47、onfirmation of operating parameters在确认操作参数时考虑最坏情况的条件For heat sealing, use highest (highest temp.+ highest pressure + lowest speed) and lowest (lowest temp.+ lowest pressure + highest speed) setting challenge the sealing result (Over seal and no seal)对于热封, 用最高(最高的温度+最大的压力+最低的速度)和最低(最低的温度+最小的压力+最高的速度)

48、.参数来挑战封口的效果(过度热封和假封),Operational Qualification 运行确认OQ Items 运行确认考虑因素,Operational Qualification 运行确认OQ Items 运行确认考虑因素,Optimize process parameters (Statistically Design Experiment) 优化过程参数（统计上的设计实验，如正交试验） Final parameters must be equal to or lesser than the worst case limits.最终确定的参数必须等于或小于最坏情况的限度.,Eval

49、uate process stability (standard deviation - sigma & average) & capability (Cpk)评估过程的稳定性(标准偏差和平均值)和能力 (Cpk)- Data to provide stability and capability (Cpk) of the process 用数据提供过程稳定性和能力 (Cpk)的资料- Baxter requires a Cpk 1.33 for key process.百特公司要求关键过程的Cpk要大于1.33,Operational Qualification 运行确认OQ Items 运

50、行确认考虑因素,Operational Qualification 运行确认OQ Items 运行确认考虑因素,LSL,USL,An Unstable Process 不稳定的过程,Grand standard deviation and average are both quite different from that of sub-group.,总体的标准偏差及平均值与小组的标准偏差及平均值有较大差异.,Operational Qualification 运行确认OQ Items 运行确认考虑因素,A Stable but not Capable Process 稳定但没有能力的过程,U