制程认可管理方案.ppt

按一下此處編輯母片標題樣式,按一下此處編輯母片樣式,階層 2,階層 3,階層 4,階層 5,階層 6,階層 7,階層 8,*,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,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 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特殊要求是否得到满足。,6,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 validate?,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,Numbers of system errors,系统错误数量,Begin validation开始验证,Begin,Production开始生产,Begin,Production,开始生产,End validation,结束验证,Savings 节省$,Without validation,没有验证,With validation,有验证,Time 时间,Begin Process,Development,开始过程准备,Benefits of Validation验证的好处,Quality Benefits质量方面的好处,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,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,What 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 Processes 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,Extended 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&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 successful 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 officer,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,Develop,Protocol 准备验证方案,Run,Validation 进行验证,Prepare,Final Report 准备总结报告,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,Validation Waiver 验证豁免,Low Risk 低风险,Define Requirements说明要求,Define product and process characteristics 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 in 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,DESIGN INPUT,设计输入,3.1.1,All design inputs must be 99.35%reliable with 95%confidence value unless otherwise stated.,所有的设计输入必须在,95%,的可信度上达到,99.35%,的可靠性。,Ensure all verification testing demonstrates performance to a high level of reliability with a high degree of confidence,保证在高可信度的情况下所有的验证测试证明结果具有高水平的可靠性。,RATIONALE,基本原理,Define Requirements说明要求,Design Inputs设计输入,3.2,Package Product Characteristics,DESIGN INPUT,设计输入,3.2.1,3.2.2,Packaging materials must not degrade from exposure to PVI.,包装材料必须能在聚维酮碘暴露的环境下不会降解。,The pouch,must provide a sanitary environment in which the cap is contained until the patient is ready to use,the cap.,包装袋必须给碘伏帽提供卫生的环境,，直至病人使用。,Must maintain a neat appearance for the customer.,使客户在使用产品时仍保持整洁的外观。,Needed to provide ease of use for the customer.,客户用起来放心，安全。,RATIONALE,基本原理,Failure Modes and Effects Analysis(FMEA):,An FMEA is systematic analysis of the potential failure modes.It includes the 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 Analysis,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.,Requirements,Definition,Prior to Build,Fix During,Validation,May Be Much More,Recalls,Regulatory Action,Complaints,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/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,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-Occurrence,Rating:,1=1/100K 表示发生的可能性约十万分之一,2=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-Severity,Rating: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 additional 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 reduction 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-Detection,Rating:,1=1/MCompletely mistake proof.Current controls ensure failure prevention/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 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 of 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 RPN 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,LSL,USL,A Stable&Capable Process 稳定的和有能力的过程,Grand standard deviation and average are both almost the same as that of sub-group.Far away from the limit all the time.,总体的标准偏差及平均值与小组的标准偏差及平均值几乎一致.而且总是离限度很远.,The calculation of Cpk:Cpk 的计算：,Determine specification limit-USL&LSL 确定规范限度,Calculate average(X)and standard deviation(,)计算平均值和标准偏差,Calculate Cpk计算Cpk,Formula is:计算公式：,Cpk=(USL X)/3,or(X-LSL)/3,(the min.result is Cpk),Cpk=（上限平均值）个标准偏差,或（平均值下限）个标准偏差,取最小的结果作为Cpk。,Operational Qualification 运行确认,OQ Items 运行确认考虑因素,There are many tools for helping to achieve stable and capable processes:,有许多工具用于优化参数达到稳定和有能力的过程,Control Charts 控制图,Multi-variant Charts多变量图,Analysis of Mean均值分析,Component Swapping Studies成分交换研究,Scatter Diagrams离散图,Response Surface Studies表面响应研究,Taguchi Methods田口方法,Variation Transmission Analysis变异转移分析,Operational Qualification 运行确认,OQ Items 运行确认考虑因素,Performance Qualification-PQ 性能确认,“Documented evidence that the process,under all anticipated conditions,consistently produces a product which meets all predetermined requirements.”,“过程在所有预期条件下，持续生产符合所有既定要求的产品的书面证据。”,In this phase,the key objective is to demonstrate the process will consistently produce acceptable product under,normal operating conditions,.,在本阶段，关键目标是演示将在正常操作条件下持续生产合格产品的过程。,Performance Qualification 性能确认,PQ Items 性能确认考虑因素,Produce product using process parameters and procedures established in OQ.,使用在运行确认里建立的过程参数和程序来生产产品,Reconfirm acceptability of the products,(assure process capability),重新确认产品的可接受性（保证过程能力）,Demonstrate Process Repeatability (assure process stability,such as 3 trials),演示过程的重复性（保证过程的稳定性，如三次试验）,Product release requirements(generally to be released only after final report approval,unless the product quality can be qualified under certain specific procedure,e.g.100%inspection),产品放行的要求(通常只有在总结报告批准后才放行,除非产品的质量在某些特定的程序下得到保证,如有效的100%检查),Protocol Phases 方案的各个阶段,For all three phases IQ,OQ and PQ based on the product/process requirements:,对于基于产品/过程要求的安装确认，运行确认和性能确认：,-Determine,what,to verify/measure,确定检验/测量内容,-Determine,how,to verify/measure,确定检验/测量方式,-Determine,how many,to verify/measure,i.e.Statistical significance 确定检验/测量数量，如统计显著性,-Determine Acceptance/Rejection Criteria,确定接受/拒绝标准,-Determine required documentation 确定要求的文件,Determine,What,to verify/measure 确定检验/测量内容,For a carton using alternative texture,strength must be measured.,对于选用替代纸质的纸箱，必须测量其抗压强度,For modified solution bag,leak test must be conducted.,对于改良的溶液袋，必须进行泄漏测试,For Sub-Assy design change,drain time must be evaluated to be meet requirement or not.,对于附件设计的变更，必须评估排液时间是否还是符合要求,Determine,How,to Verify/Measure确定检验/测量方式,Utilize standard test methods such as ASTM,ANSI,ISO,USP,etc.When ever possible,尽可能利用标准测试法，如ASTM，ANSI，ISO，USP等,Test methods should replicate actual use conditions,测试方法必须再现实际使用条件,Assure test equipment is calibrated,保证测试设备经校正,Assure test method is validated,保证测试方法经验证,Utilize Statistically Valid Techniques,利用有效的统计技术,-Sampling Plan for validation,验证取样计划,Utilize WinSSD software 1.5 version to determine the sample size during OQ/PQ based on the classification of defect and confidence(95%for OQ and 90%for PQ).,在运行和性能确认阶段基于缺陷的分类和所要求的可信度(对于OQ选用95%,对于PQ选用90%),应用WinSSD软件来确定样品量.,Determine,How Many,to Verify/Measure确定检验/测量数量,Define Acceptance/Rejection Criteria说明接受/拒绝标准,Address all product and process requirements,陈述所有产品和过程要求,Establish specific criteria for each requirement,upper and lower limits,为每个要求建立特别标准，高限度和低限度,-Based on product specifications 以产品质量标准为基础,-Based on established standards 以已建立标准为基础,-Assure limits will result in a robust process.i.e.Cpk,确保限度在满足要求的前提下能使过程顺利进行，如Cpk,Define Acceptance/Rejection Criteria说明接受/拒绝标准,Acceptance Criteria 接受标准,What to,Measure,测量内容,How to,Measure,测量方法,How,Many,数量,Acceptance,Criteria,接受标准,Drain Time Timer n=50 X+3 SD within 10 mins,排液时间 计时器 平均值加 3个标准偏差在,10 分钟内,(Variable),Visual Defects Visual n=298 None allowed,(AQL=1.0%),可见缺陷 目测 不允许有,Leak Test Squeeze Tester n=4607 No leak allowed,(AQL=0.065%),泄漏测试 挤压机 不允许有泄漏,(Attribute),Summarize of the Validation Process验证过程小结,Steps(before running)步骤（运行前）,1.Form a Multifunctional Team 组织一个多功能团队,2.Define Requirements,for Product and Process,说明产品和过程的要求,3.Risk Assessment 风险分析,4.Prepare Validation Process 准备验证过程,-IQ,OQ and PQ 安装、操作和性能确认,5.Define What,How,How Many to do,Acceptance Criteria,and required documentation for each Phase,说明每个阶段应有的检测内容、方式和数量，接受标准及要求的文件,Run Validation 进行验证,The people executing the validation should be trained on:执行验证的人员应接受以下的培训:,GMPGMP,GDP(Good Documentation Practices),良好的文件规范,Protocol 验证方案,Equipment Safety设备安全,Operation 操作,Measurement 测量,Run Validation 进行验证,Be sure to 确保以下内容,Review the validation with those who will perform the testing,与进行测试的人员审阅验证,2 Retain all defects for root cause analysis,保留所有缺陷样本以便作根本原因分析,3.Document any unusual situation,用文件记录任何异常情况,4.Review all documentation for clarity&completeness,审阅所有文件的清晰性和完整性,Run Validation 进行验证,Be sure to 确保以下内容,All materials/samples used/made in OQ should be considered to be experimental materials.所有用于OQ的物料或OQ造的样品应考虑为只作实验用.,-Storage:储存:,Experimental material must be stored in a quarantine area.,实验用物料必须储存在隔离区域.,-Labeling:标识:,A.Describe materials to be used in the validation document.,描述物料用于哪个验证,B.Label experimental materials with“Experimental goods for test&evaluation only”and“Not for Human Use”labels.,用“仅作测试和评估用的实验物品”和“不能使用”的标签标识实验用物料,Be sure to 确保以下内容,All materials/samples used/made in OQ should be considered to be experimental materials.,所有用于OQ的物料或OQ造的样品应考虑为只作实验用.,-Testing control:测试控制:,A.Tests are performed in specific and controlled areas like quality laboratories,quarantined areas.,测试应在特定和受控的区域进行,如实验室,隔离区等.,B.Perform a line clearance inspection of an area