过滤芯完整性测试资料方案密理博中国有限公司.ppt

Filter Integrity test 过滤器完整性测试,,,密理博中国有限公司 生物制药工艺部,Content 讲座目录,Why we do integrity test for sterile filter? 为什么要对除菌滤器进行完整性测试？ Method for IT?完整性测试的方法有哪些？ Why bubble point could replace bacterial retention test? 为什么可以用起泡点的方法代替细菌挑战试验？ When should we do IT? 什么时候进行完整性检测？ Bubble point theory.起泡点测试原理是什么？ Diffusion test theory.扩散流测试原理是什么？ Automatic integrity tester自动完整性测试仪,What is filter integrity? 什么是滤膜完整性?,,Integral membrane 完整滤膜Contaminant 比膜孔大的污染物,Non-integral membrane非完整滤膜Contaminant比膜孔大的污染物,,,,,,,,,,,,,,,,,,,,,,Contaminant in downstream 下游污染,No contaminant in downstream 下游没有污染物,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Why Integrity Test? 为什么做完整性测试?,Common Sense通常理解 Filtration is often the most critical step in an operation 过滤通常是操作的关键步骤 Confirmation of manufacturers specifications 确认制造规格 Detecting leaks due to o-rings, gaskets, seals 检测O形环,垫圈,密封垫的泄漏 Assuring the correct pore size filter 确认正确的过滤孔经 Assuring integrity before sterilization 确认灭菌前完整性 Assuring integrity after steaming or autoclaving 确认蒸汽和消毒锅灭菌后完整性 Business Practice 商业惯例 Government Guidelines & Regulations法规要求 Part of corporate standard operating procedure公司标准操作规程 Auditing requirement审计需要,Regulations about integrity test 法规中对完整性测试的规定,FDA Guideline指南 (2003) Whatever filter or combination of filters is used, validation should include microbiological challenges to simulate worst-case production conditions…”对于由一个或多个滤器组成的过滤系统，对它的验证都应该包括在最差条件下进行的微生物挑战试验。

Revision of annex 1 to EC Guide to GMP for sterile medicinal products (1997) 欧盟对于无菌药品GMP指南的附件一(1997版) “The integrity of the sterilized filter should be verified before use and should be confirmed immediately after use by an appropriate method such as a bubble point, diffusive flow or pressure hold test” 除菌过滤膜应该在使用前及使用后立即采取合适的方法确认其完整性,可以采用泡点,扩散流或压力保持的方法. FDA Guideline on Sterile Drug Products Produced by Aseptic Processing (1987) FDA对于无菌操作生产的无菌药品的要求(1987版) “Normally, integrity testing of the filter is performed after the filter unit is assembled and sterilized prior to use.” 完整性测试通常在过滤器安装,灭菌后使用前进行 PDA Technical Report # 26 PDA技术报告26版 “It generally is regarded as a cGMP requirement that filters or filter systems routinely be integrity tested both prior to and after use.” 现行的GMP要求过滤器及过滤系统在使用前及使用后均需要进行完整性测试,Regulations about integrity test 法规中对完整性测试的规定,Where & When Do We Integrity Test? 何时和何地做完整性测试?,WHEN TO DO IT? 什么时候做?Before sterilization 灭菌前 Before use 使用前 After use 使用后,DETECTS WHAT? 检查什么?Faulty housings 外壳的问题Out-of-the box failures 包装以外的问题Sterilization induced failures 灭菌的影响 Stress induced failures压力的影响,金标准,What Are The Integrity Testing Choices? 完整性测试的选择?,Regulatory & quality organizations need data from both to assure reliable and predictable filter performance法规和质量管理需要数据确保可靠和预知过滤器性能,Destructive vs. Non-destructive Testing 破坏性和非破坏性测试,There must be a correlation between a destructive and a non-destructive integrity test 破坏性和非破坏性测试两者必须有关联 Regulatory requirement 法规需要 FDA Aseptic Guidelines FDA无菌指南 Validation justification for the use of a test 测试应用的验证理由,Integrity Testing Correlations 完整性测试关联,Bubble point can have a direct correlation 起泡点有直接的关联,Diffusion & other tests can have an “go - no go“ correlation 扩散和其它测试有”通过,不通过”关连,What Non-Destructive Integrity Tests are Available? 何种非破坏性测试合适?,Capillary based tests 基于毛细管测试 Bubble Point起泡点 HydroCorr 挤水法(水侵入法) Corrtest水压法 Diffusive based tests 基于扩散测试 Diffusion扩散 Forward Flow前向流 Pressure hold / decay压力保持/衰减,Bubble point is the pressure at which gas displaces liquid from the largest set of filter pores and flows rapidly through the filter 起泡点是气体从湿润的最大膜孔挤出液体快速流出时的压力Bubble point indicates the magnitude of the forces holding liquid in the filter structure 起泡点显示过滤结构内保持液体的力的大小The oldest non-destructive integrity test 最传统的非破坏性测试,Bubble Point Introduction 起泡点介绍,Bubble point test 泡点测试,,,,Integral 完整膜,,Non-Integral 非完整膜,Fully wetting 完全润湿的膜,,,Pressure less than bubble point上游压力小于泡点值,No mass gas fluid observed 没有大量气流出现,Pressure less than bubble point上游压力小于泡点值,mass gas fluid observed 破损出现的大孔保持力低,导致低于泡点即被吹干出现气流,,Largest Pore,Bubble Point Test Applicability 起泡点测试适用性,Useful for qualified manual testing of filters less than approximately 2000 cm^2 (~2 sq.ft.) 手动测试通常适用于过滤器面积小于2000平方厘米Useful for automatic integrity testers for filters with gas flow rates of up to 100 ml/min or limit of the automatic testers qualifications 自动完整性测试仪适用于气体流速超过100毫升/分钟或自动测试仪的限定,Bubble Point Equation起泡点等式,The bubble point is expressed as:泡点可表达为4 . k . γ . cos   BP = -----------------d where 这里 k = shape correction factor 形状校正因子  = surface tension 表面张力  = contact angle 接触角 d = pore diameter 孔径,Effect on bubble point test 泡点的影响因素,Depends on capillary forces; 依赖毛细管力 membrane material, surface tension, contact angle, effective diameter, 膜材料,表面张力,接触角,有效孔径起泡点说明(包括SOP)应当包括 filter type过滤器类型 wetting liquid湿润液体 Temperature温度 minimum pressure最小压力,Contact angle 接触角的影响,Solid / liquid interaction 固/液相互作用 Changing the wetting fluid changes the bubble point 改变湿润液体会改变起泡点 Applies to different wetting fluid不同的湿润液体 different surface chemistries不同的表面化学性 pre-use vs. post-use comparison使用前和使用后比较 Must know the effects of the changes, perform flushing or conduct product bubble point qualification 必须知道变化的影响,进行冲洗或用产品泡点确认,。