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1、密理博中国有密理博中国有 限公司限公司 生物制药工艺生物制药工艺 部部 Content 讲座目录 uWhy we do integrity test for sterile filter? u为什么要对除菌滤器进行完整性测试？ uMethod for IT?完整性测试的方法有哪些？ uWhy bubble point could replace bacterial retention test? u为什么可以用起泡点的方法代替细菌挑战试验？ uWhen should we do IT? u什么时候进行完整性检测？ uBubble point theory.起泡点测试原理是什么？ uDiffus
2、ion test theory.扩散流测试原理是什么？ uAutomatic 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 Se
3、nse通常理解 nFiltration is often the most critical step in an operation n过滤通常是操作的关键步骤 nConfirmation of manufacturers specifications n确认制造规格 nDetecting leaks due to o-rings, gaskets, seals n检测O形环,垫圈,密封垫的泄漏 nAssuring the correct pore size filter n确认正确的过滤孔经 nAssuring integrity before sterilization n确认灭菌前完整
4、性 nAssuring integrity after steaming or autoclaving n确认蒸汽和消毒锅灭菌后完整性 Business Practice 商业惯例 nGovernment Guidelines 依赖毛细管力 nmembrane 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 nfilter type过滤器类型 nwetting liquid湿润液体 nTemperature温度 nminimum pressure
5、最小压力 Contact angle 接触角的影响 Solid / liquid interaction 固/液相互作用 nChanging the wetting fluid changes the bubble point n改变湿润液体会改变起泡点 Applies to ndifferent wetting fluid不同的湿润液体 ndifferent surface chemistries不同的表面化学性 npre-use vs. post-use comparison使用前和使用后比较 Must know the effects of the changes, perform fl
6、ushing 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 Two sterilizing grade filters with identical bacterial retention claims and performance have the following minimum bubble point specifications: 两种无菌过滤膜用同一细菌截留有下列最小的起泡点规格: Durapore PVDF CVGL = 50 psig Charged Durapore PVDF C
7、CGL=40 psig A sterilizing grade filter has is the following minimum bubble point specifications: 一种无菌过滤膜有下列最小的起泡点规格: Water =50 psig 70/30 IPA =18.5 psig Higher bubble point test values do not mean better filters 高起泡点值并不是意味好的过滤膜 Check the filter manufacturers validation guide for the destructive / no
8、n-destructive integrity test correlation, integrity testing technique and bacterial challenge method 检查过滤膜制造商对破坏性/非破坏性完整性测试关连的验证文 本,完整性测试技术和细菌挑战理论 膜没有洗干净可能影响到接触角而导致完整性测试失败 Examples of the Effect of Contact Angle and Surface Tension on Bubble Point Values 接触角和表面张力对起泡点值的影响实例 Diffusion Testing Introduc
9、tion 扩散流测试介绍 n Gas dissolves in liquid held in the pores of a fully wetted membrane filter.气体溶 解在完全湿润的滤器膜孔内的 液体中 n A pressure differential will give a different gas concentration across the filter.膜压差造成跨膜气体浓度 差 n Results in gas flow through the liquid dissolved in the filter pores.结 果使膜孔溶解的气体流出 下游气体
10、 P 2 上游 压缩 气体 P 1 扩散流Z P1 P2 Diffusion test 扩散流测试 Integral 完整膜 Non-Integral 非完整膜 Fully wetting 完全润湿的膜 Pressure equal 80% BP上游 压力80%泡点 值 Down stream gas flow rate is less than specification 下游气流小 于规定值 Pressure equal 80% BP上游压力 80% 泡点值 Down stream gas flow rate is more than specification破 损出现的大孔 会扩散更多
11、气 体使得下游气 流大于规定值 Largest Pore Diffusion Testing Equation扩散 测试方程 K . (P1 - P2) . A . Diffusion = - L where: K = Diffusivity / Solubility coefficient扩散因子 P1, P2 = Pressure difference across the system系统两边的压力 = Membrane porosity膜开孔率 L = Effective path length有效膜孔长 度 A = Membrane area膜面积 Upstream Pressuri
12、zed Regulated compressed gas Gas flow rate measured downstream A Reason for Diffusion Testing 什么情况下采用扩散测试 Bubble Point detection becomes harder as membrane area increases 随着膜面积增加起泡点检测 变得困难 Need as much information about the filter as possible 需要尽可能多关于膜的信息 nUse diffusion testing in combination with bubble point testing使用起泡点 与扩散测试相结合 Gas Flow Differential Pressure 1m 2 0.1m 2
