制程认可管理方案.ppt

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,FIRST SECTION第一部分

2、,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 attr

3、ibutes. 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 Va

4、lidation 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 impl

5、ementation 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质量方面的好处 End User Benefits用户方面的好处 Business Benefits商业方面的好处,

6、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

7、 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

8、？,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

9、 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

10、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 such conditions have become widely kn

11、own 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 retrievable 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 ite

12、m 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. 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

13、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 Protocol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 accompl

14、ished 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 Scope范围 *Clearly define equipment or process to be validated, i.e. Description, asset tag, or other unique

15、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,Installation Qualification,Operational Qualification,Performance Qualification,安装确认,运行确认,性能确认,Protocol Phas

16、es 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的结合.,VALIDATION 验证,PROTOCOL 验证方案,QUALIFICATION 确认,Installation Qualification-IQ 安装确认,“ Documented

17、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 considered.” “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

18、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. ) 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

19、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,Operational Qualification-OQ 运行确认,“ Establishment of process parameters which will produce pro

20、duct 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/RegulatoryGMP/法规的符合性 Training Requirements/Documentation培训要求/文件 Programmable Controller/Microcompu

21、ter 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 Evaluation化学评估 Microbiological Evaluation微生物评估 Storage/Distribution贮存/运输 SOP/Specification R

22、evision 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 ( Statistically Design Experiment ) 优化过程参数（统计上的设计实验 ） C. Evaluate process stability

23、(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 Paper 热封带) Parameter: 参数 (Temp.,Time, Pressure) Environment: 环境 (Room Temp., Hum

24、idity),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 confirmation of operating parameters 在确认操作参数时考虑最坏情况的条件 For heat sealing,

25、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).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,

26、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.,Evaluate process stability (standard deviation - sigma & average) & capa

27、bility (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,

28、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,The calculation of Cpk:Cpk 的计算： Determine specification limit - USL & LSL 确定规范限度 Calculate average (X) and st

29、andard 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

30、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

31、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 und

32、er 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

33、） 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

34、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

35、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 mo

36、dified 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

37、 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 sof

38、tware 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

39、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

40、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

41、 (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 Asse

42、ssment 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:

43、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

44、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

45、 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

46、 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 ins

47、pection of an area after OQ testing to assure that no experimental materials/OQ samples remain. 在OQ测试完成后进行在线清场以保证没有实验用的物料/样品遗留在场.,Run Validation 进行验证,Prepare Final Report 准备总结报告,Contents 内容 Executive summary执行情况 Data analysis数据分析 Final report needs to address each acceptance criteria 总结报告需要陈述每条接受标准

48、State conclusion 陈述结论 Original Data 原始资料 Other referenced documents, I.e. specification, drawings, forms, etc. 其他参考文件，如质量标准，图纸，表格等 Final review and approval 最终审核和批准,File Final Report 将总结报告归档,Retrievable 可检索 Protected from damage 避免受损,At a minimum, once every five years ensure the validation status o

49、f each appropriate process (there is another specific period for sterilization validation) is formally validated and documented. The five-year cycle begins after the initial validation of a process, a formal revalidation of the entire process or a formal verification of the validation status. 至少每五年确

50、保每一适当的过程(灭菌验证另有规定)都已被正式验证，并有文件记录。五年周期从初始的过程验证、正式的整个过程的再验证或者正式的验证状态确认后开始。,Revalidation 再验证,Revalidation is required for: 以下情形要求再验证 Changes in the process 过程变更 Changes in Quality Indicator Trends 质量指标趋势的变化 Changes in the product or customer usage 产品或客户用途变更 Time, when it could have an impact 时间，如果它可能有影

51、响 Product Transfers (A process is transferred from one plant to another) 产品转换（过程由一家工厂转到另一家工厂）,Revalidation再验证,Fourth Section第四部分,Describe how to Manage Process Validation 描述如何管理过程验证,Validation ManagementNeed Procedures that Address:验证管理需要程序说明：,Validation system 验证系统 Protocol format & Master protocol

52、s 验证方案格式和主验证方案 Final Report Contents and Organization. 总结报告的内容和组织 Final Report review and approval 总结报告的审核和批准 Filing/Tracking system for Final Report 总结报告的归档/跟踪系统,SOP-QM-55,Validation System Procedure验证系统程序,Define what processes require validation 说明什么样的过程需要验证 Define require activities 说明要求的活动 Define responsibilities and approvals 说明职责和批准人员 Scope and thoroughness of validation should be commensurate with risk and complexity of the process. 验证的范围和程度应与过程的风险和复杂性相称。,SOP-QM-55,Protocol Format Procedure验证方案格式程序,Check List检查清单,Prot