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 appropriatemethod 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 # 26PDA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Regulatory & quality organizations need data fromboth to assure reliable and predictable filterperformance法规和质量管理需要数据确保可靠和预知过滤器性能关联Regulatory requirement法规需要FDA Aseptic GuidelinesFDA无菌指南Validation justification for theuse of a test测试应用的验证理由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Samples Retentive 246810 12 14 16 18 20 22 2426Corrtest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P1P2AirWaterdsq fBubble point is the pressure at which gasBubble 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MembraneP act > 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 = shape correction factor 形状校正因子γ= surface tension 表面张力θ= contact angle 接触角d = pore diameter 孔径P1PAirWaterdσθDepends 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T emperature温度minimum pressure最小压力Solid / liquid interaction固/液相互作用Changing the wetting fluidchanges the bubble point改变湿润液体会改变起泡点Applies todifferent wetting fluid不同的湿润液体different surfacechemistries不同的表面化学性pre-use vs. post-usecomparison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:两种无菌过滤膜有同样的细菌截留率，有下列最小的起泡点规格:–Durapore®PVDF CVGL>=50 psig–Charged Durapore®PVDF CCGL>=40 psigA 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 psigHigher 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 manufacturer's validation guide for the destructive / non-destructive integrity test correlation, integrity testing technique and bacterialchallenge 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 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Flush with water冲洗Apply air 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 A pressure differential will give adifferent gas concentration across thefilter.膜压差造成跨膜气体浓度差Results in gas 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 across the system系统两边的压力ρ= Membrane porosity 膜开孔率L = Effective path length 有效膜孔长度A = Membrane area 膜面积Gas flow rate measured downstreamAt pressures below the bubble point,diffusion always occurs在低于起泡点压力,扩散发生Diffusion testing does not indicatepore size扩散测试不显示膜孔径At 2.8 bar (40 psig), a 0.22 and0.1 um rated filters will have the“same”diffusional flowrates在2.8Bar,0.22和0.1um空径膜具有相同的扩散速率得困难Need as much information about the filter as possible需要尽可能多关于膜的信息 Use diffusion testing incombination with bubblepoint testing使用起泡点与扩散测试相结合GasFlowDifferential Pressure1m20.1m2For filters with gas flowrate of >100 ml/min过滤器扩散流速大于100ml/minhigh surface area filters大表面积过滤器thin membranes薄的膜organic solvent wetted filters有机溶剂湿润的过滤器Diffusional flow specifications (and 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 gas测试气体Temperature温度maximum acceptable flow rate最大接受流速Organic solvents have high diffusion flowrates有机溶剂有较高的扩散流速Gas气体Carbon dioxide has higher gas flow than air or nitrogen二氧化碳比空气或氮气有较高的扩散流速Temperature温度Poor Venting Proper Venting 80% higher flowrate at 60 degrees在６０摄氏度流速高80%Polypropylene cartridge tested with nitrogen at 18.8 psig (1.3 bar )聚丙烯过滤器用氮气(18.8psig)测试–Acetone<390 ml/min–IPA<120 ml/minMESSAGE:Changing solvents changes diffusional flowPure organic solvents have high diffusional flow改变溶剂可改变扩散流速,纯溶剂有较高的流速–Can mask bubble points–可能与起泡点相混Hydrophilic filter is tested with both nitrogen and compressed air at 2.8 bar (40psi)–Nitrogen<8 ml/min–Compressed air<10 ml/minMESSAGE:Changing the test gas can give a false diffusional flowrate改变测试气体可以给错误的扩散流速What is the maximum diffusional flow for a 5x30" pleated cartridge filter system?–10" element<13.3 ml/min–30" element<39.9 ml/min–5x30" elements<199.5 ml/minMESSAGE:For the same device, diffusion is directly proportional to surface area相同的过滤器，扩散与膜面积成正比Diffusion testing measures gas flow扩散测试测量气体流速At bubble point, gas flows rapidly through the largest pore(s)在起泡点，气体则快速通过最大的孔Downstream gas flow (or upstream pressure loss) can come from both diffusion through the wetted pores PLUS the gas flow through the“dry”pores which have reached 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Forward Flow前向流Marketing term for diffusional flow.只是扩散的不同说法Pressure Decay压力衰减Measures the maximum loss of upstream gas pressure with time (typically 10 minutes) on the upstream side of a filter.在过滤器上游测试10分钟上游气体压力的最大损失Needs a sensitive and accurate pressure measuring device需要敏感和精确的压力测试装置Is dependent on upstream volume与上游体积相关Can be converted to a "diffusional" flow rate using an equation能够使用算式换算成扩散流速Useful as a "go" or "no-go" test for gross testing only仅适合做一些粗的是或不是的测试Manual bubble point手动起泡点Minor effect dependent mainly on surfacetension表面张力有小影响Approximately 15% change from 20 -60 ºC从20-60摄氏度15%的改变Minor effect on manual test at normalambient range dependent on gas solubilityand diffusivity与气体溶解度和扩散率相关Approximately 80% change from 20 -60 ºC从20-60摄氏度80%的改变As temperature rises, diffusional flow raterises温度升高，扩散流速增加Automatic test自动测试Major effect with temperature changeduring the test on diffusionalflowrate主要影响测试时的扩散流速Bubble point and Diffusion (or “Forward flow”) are BOTH valid integrity tests as per regulatory agencies.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 an integrity test depends on the testing equipment, the filter manufacturer, the company‘s philosophy and 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 a direct correlation to bacterial retention, the critical performance characteristic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 a sensitive way to determine integrity for larger area filters扩散测试提供一个敏感方法来测试大面积过滤器。