过滤膜完整性测试理论过滤/完整性测试培训课程为什么要对除菌滤器进行完整性测试？完整性测试的方法有哪些？为什么可以用起泡点的方法代替细菌挑战试验？什么时候进行完整性检测？起泡点测试原理是什么？扩散流测试原理是什么？下游污染下游没有污染物Common Sense通常理解Filtrtion is often the most criticl step in n opertion过滤通常是操作的关键步骤Confirmtion of mnufcturers specifictions确认制造规格Detecting leks due to o-rings, gskets, sels检测O形环,垫圈,密封垫的泄漏ssuring the correct pore size filter确认正确的过滤孔经ssuring integrity before steriliztion确认灭菌前完整性ssuring integrity fter steming or utoclving确认蒸汽和消毒锅灭菌后完整性Business Prctice商业惯例Government Guidelines & Regultions法规要求Prt of corporte stndrd operting procedure公司标准操作规程uditing requirementXX需要FD Guideline指南(20XX)–Whtever filter or combintion of filters is used, vlidtion should include microbiologicl chllenges to simulte worst-cse 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 nnex 1 to EC Guide to GMP for sterile medicinl 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 nd should be confirmed immeditely fter use by n ppropritemethod such s bubble point, diffusive flow or pressure hold test”–除菌过滤膜应该在使用前及使用后马上采取合适的方法确认其完整性,可以采纳泡点,扩散流或压力保持的方法.FD Guideline on Sterile Drug Products Produced by septic Processing (1987) FD对于无菌操作生产的无菌药品的要求(1987版)–“Normlly, integrity testing of the filter is performed fter the filter unit is ssembled nd 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PD Technicl Report # 26PD技术报告26版–“It generlly is regrded s cGMP requirement tht filters or filter systems routinely be integrity tested both prior to nd fter 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WHEN TO DO IT?什么时候做? Before steriliztion 灭菌前Before use使用前fter use使用后DETECTS WHT?检查什么?Fulty housings外壳的问题Out-of-the box filures包装以外的问题Steriliztion induced filures 灭菌的影响Stress induced filures压力的影响破坏性细菌挑战测试制造商以及客户进行验证时进行非破坏性起泡点测试，扩散测试制造商出厂时及使用者现场进行Regultory & qulity orgniztions need dt fromboth to ssure relible nd predictble filterperformnce法规和质量治理需要数据确保可靠和预知过滤器性能关联Regultory requirement法规需要FD septic GuidelinesFD无菌指南Vlidtion justifiction for theuse of test测试应用的验证理由Bubble point cn hve direct correltion起泡点有直接的关联Diffusion & other tests cn hve n "go -no go" correltion扩散和其它测试有”通过,不通过”关连Smples Retentive 246810 12 14 16 18 20 22 2426Corrtest水压法Diffusive bsed tests基于扩散测试Diffusion 扩散Forwrd Flow 前向流Pressure hold / decy压力保持/衰减P1P2irWterdsq fBubble point is the pressure t which gsBubble point indictes the mgnitude 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MembrneP ct > P Bpt完整膜上游压力小于泡点值没有大量气流出现上游压力小于泡点值孔保持力低,导致低于泡点即被吹干出现气流The bubble point isBP = -----------------dwhere这里k = shpe correction fctor 形状校正因子γ= surfce tension 表面张力θ= contct ngle 接触角d = pore dimeter 孔径P1PirWterdσθDepends on cpillry forces依赖毛细管力membrne mteril, surfce tension,contct ngle, effective dimeter,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T emperture温度minimum pressure最小压力Solid / liquid interction固/液相互作用Chnging the wetting fluidchnges the bubble point改变湿润液体会改变起泡点pplies todifferent wetting fluid不同的湿润液体different surfcechemistries不同的表面化学性pre-use vs. post-usecomprison使用前和使用后比较Must know the effects of the chnges, perform flushing or conduct product bubble point qulifiction必须知道变化的影响,进行冲洗或用产品泡点确认Two sterilizing grde filters with identicl bcteril retention clims nd performnce hve the following minimum bubble point specifictions:两种无菌过滤膜有同样的细菌截留率，有下列最小的起泡点规格:–Durpore?PVDF CVGL>=50 psig–Chrged Durpore?PVDF CCGL>=40 psigsterilizing grde filter hs is the following minimum bubble point specifictions:一种无菌过滤膜有下列最小的起泡点规格:–Wter>=50 psig–70/30 IP>=18.5 psigHigher bubble point test vlues do not men better filters高起泡点值并不是意味好的过滤膜–Check the filter mnufcturer's vlidtion guide for the destructive / non-destructive integrity test correltion, integrity testing technique nd bcterilchllenge 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Useful for qulified mnul testing of filters less thn pproximtely 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 utomtic integrity testers for filters with gs flow rtes of up to 100 ml/min or limit of the utomtic testers qulifictions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Flush with wter冲洗pply ir pressure加压增加压力直到起泡点在下游出现亲水滤芯起泡点测试内的液体中P1> P2 pressure differentil will give different gs concentrtion cross thefilter.膜压差造成跨膜气体浓度差Results in gs flow through theliquid dissolved in the filter pores.结果使膜孔溶解的气体流出完整膜上游压力80%泡点值下游气流小于规定值上游压力80%泡点值孔会扩散更多气体使得下游气流大于规定值where:K = Diffusivity / Solubility coefficient 扩散因子P1, P2 = Pressure difference cross the system系统两边的压力ρ= Membrne porosity 膜开孔率L = Effective pth length 有效膜孔长度= Membrne re 膜面积Gs flow rte mesured downstremt pressures below the bubble point,diffusion lwys occurs在低于起泡点压力,扩散发生Diffusion testing does not indictepore size扩散测试不显示膜孔径t 2.8 br (40 psig), 0.22 nd0.1 um rted filters will hve the“sme”diffusionl flowrtes在2.8Br,0.22和0.1um空径膜具有相同的扩散速率得困难Need s much informtion bout the filter s possible需要尽可能多关于膜的信息Use diffusion testing incombintion with bubblepoint testing使用起泡点与扩散测试相结合GsFlowDifferentil Pressure1m20.1m2For filters with gs flowrte of >100 ml/min过滤器扩散流速大于100ml/minhigh surfce re filters大表面积过滤器thin membrnes薄的膜orgnic solvent wetted filters有机溶剂湿润的过滤器Diffusionl flow specifictions (nd the S.O.P.) should include;扩散速率说明(包括SOP)应当包括filter type过滤器类型wetting liquid湿润液体test gs测试气体Temperture温度mximum cceptble flow rte最大接受流速Orgnic solvents hve high diffusion flowrtes有机溶剂有较高的扩散流速Gs气体Crbon dioxide hs higher gs flow thn ir or nitrogen二氧化碳比空气或氮气有较高的扩散流速Temperture温度Poor Venting Proper Venting 80% higher flowrte t 60 degrees在６０摄氏度流速高80%Polypropylene crtridge tested with nitrogen t 18.8 psig (1.3 br )聚丙烯过滤器用氮气(18.8psig)测试–cetone<390 ml/min–IP<120 ml/minMESSGE:Chnging solvents chnges diffusionl flowPure orgnic solvents hve high diffusionl flow改变溶剂可改变扩散流速,纯溶剂有较高的流速–Cn msk bubble points–可能与起泡点相混Hydrophilic filter is tested with both nitrogen nd compressed ir t 2.8 br (40psi)–Nitrogen<8 ml/min–Compressed ir<10 ml/minMESSGE:Chnging the test gs cn give flse diffusionl flowrte改变测试气体可以给错误的扩散流速Wht is the mximum diffusionl flow for 5x30" pleted crtridge filter system?–10" element<13.3 ml/min–30" element<39.9 ml/min–5x30" elements<199.5 ml/minMESSGE:For the sme device, diffusion is directly proportionl to surfce re相同的过滤器，扩散与膜面积成正比Diffusion testing mesures gs flow扩散测试测量气体流速t bubble point, gs flows rpidly through the lrgest pore(s)在起泡点，气体则快速通过最大的孔Downstrem gs flow (or upstrem pressure loss) cn come from both diffusion through the wetted pores PLUS the gs flow through the“dry”pores which hve reched their bubble point下游气流（或上游压力损失）可以由扩散流和达到起泡点时流出“干”孔的气流两者引起Forwrd Flow前向流Mrketing term for diffusionl flow.只是扩散的不同说法Pressure Decy压力衰减Mesures the mximum loss of upstrem gs pressure with time (typiclly 10 minutes) on the upstrem side of filter.在过滤器上游测试10分钟上游气体压力的最大损失Needs sensitive nd ccurte pressure mesuring device 需要敏感和精确的压力测试装置Is dependent on upstrem volume与上游体积相关Cn be converted to "diffusionl" flow rte using n eqution能够使用算式换算成扩散流速Useful s "go" or "no-go" test for gross testing only仅适合做一些粗的是或不是的测试Mnul bubble point手动起泡点Minor effect dependent minly on surfcetension表面张力有小影响pproximtely 15% chnge from 20 -60 oC从20-60摄氏度15%的改变Minor effect on mnul test t normlmbient rnge dependent on gs solubilitynd diffusivity与气体溶解度和扩散率相关pproximtely 80% chnge from 20 -60 oC从20-60摄氏度80%的改变s temperture rises, diffusionl flow rterises温度升高，扩散流速增加utomtic test自动测试Mjor effect with temperture chngeduring the test on diffusionlflowrte主要影响测试时的扩散流速Bubble point nd Diffusion (or “Forwrd flow”) re BOTH vlid integrity tests s per regultory gencies.起泡点, 扩散流（或前向流）是符合法规的完整性测试方法The choice of n integrity test depends on the testing equipment, the filter mnufcturer, the compny‘s philosophy nd the testing environment完整性测试的选择倚赖测试装置，过滤器制造商，公司体系和测试环境Bubble point provides direct correltion to bcteril retention, the criticl performnce chrcteristic起泡点提供与细菌截留的直接关联，重要的性能特性Diffusion testing provides sensitive wy to determine integrity for lrger re filters扩散测试提供一个敏感方法来测试大面积过滤器。
