过滤完整性测试培训课程

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？自动完整性测试仪完整滤膜比膜孔大的污染物非完整滤膜比膜孔大的污染物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 filterAssuring the correct pore size filter确认正确的过滤孔径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 Part of corporate standard operating procedureAuditing requirement审计需要FDA Guideline指南(2003)FDA Guideline–Whatever filter or combination of filters is used, validation s ou d c ude c ob o og ca c a e ges to s u ate o stshould 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)指南的附件(199–“The integrity of the sterilized filter should be verified before use and should be confirmed immediately after use by an appropriatep,pmethod 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.”完性试常在安,菌后使前行–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.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WHENTO DO IT?DETECTS WHAT WHEN TO DO IT?什么时候做?Before sterilization DETECTS WHAT ?检查什么?Before sterilization 灭菌前Faulty housings 外壳的问题Before use 使用前Out-of-the box failures 包装以外的问题After use 使用后Sterilization induced failures灭菌的影响Stress induced failures压力的影响金标准分类测试名称测试实施者制造商以及客户进行验证时破坏性细菌挑战测试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 from both to assure reliable and predictable filterboth 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There must be a correlation be wee a des uc ve a d a 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z FDA Aseptic Guidelinesz FDA无菌指南V lid ti j tifi ti f thValidation justification for theuse of a test测试应用的验证理由Specification# of Retentive Non-R t tiSamples RetentiveB bbl i t h di t 246810 12 14 16 18 20 22 2426Bubble point can have a direct correlation Diffusion & other tests can have an "go -no go" correlation””起泡点有直接的关联扩散和其它测试有通过,不通过关连Capillary based tests基于毛细管测试Bubble Point 起泡点 HydroCorr 挤水法P 1P 2Airds yCorrtest 水压法Diff i b d t t WaterqfDiffusive based tests 基于扩散测试Diff i Diffusion 扩散Forward Flow 前向流Pressure hold / decay y 压力保持/衰减Bubble point is the pressure at which gasBubble point is the pressure at which gasdisplaces liquid from the largest set of filterpores 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 theAir P act < P Bpt 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Th ld t d t ti i t it t t MembraneThe oldest non-destructive integrity test最传统的非破坏性测试P act > P Bpt完整膜非完整膜完全润湿的膜上游压力没有大量气上游压力破损出现的大LargestPore小于泡点值流出现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 is expressed as:泡点可表达为4 . k . γ. cos θ　BP =P P 2BP = -----------------dwhere 这里1AirWaterdσθk = shape correction factor 形状校正因子=surface tension γ= surface tension 表面张力θ= contact angle 接触角d = pore diameter p 孔径Depends on capillary forces;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 wetting liquid 湿润液体 T emperature 温度minimum pressure 最小压力Solid / liquid interactionSolid/liquid interaction固/液相互作用Changing the wetting fluidchanges the bubble pointh h b bbl i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 usepre-use vs. post-usecomparison使用前和使用后比较Must know the effectsof the changes, performf th h fflushing or conduct product bubble point qualificationpoint 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:®PVDF CVGL50 psigDurapore PVDF CVGL>=50psig––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: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 bacterialdestructive 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 approximately2000cm^2(2sq ft)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 rates of up to100ml/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Increase presssure until bubblesIncrease presssure until bubblesare seen downstream增加压力直到起泡点在下游出现0.22um PVDF Millidisk 亲水滤芯起022PVDF Millidi k泡点测试上游缩 Gas dissolves in liquidheld in the pores of a fully wettedb filt 下游气体P2压缩气体membrane filter.气体溶解在完全湿润的滤器膜孔内的液体中A pressure differential willP1扩散流ZA pressure differential willgive a different gasconcentration across theP1> P2 filter.膜压差造成跨膜气体浓度差Results in gas flowthrough the liquiddissolved in the filter pores.结果使膜孔溶解的气体流出完整膜非完整膜完全润湿的膜上游压力下游气流小上游压力破损出现的大LargestPore80%泡点值于规定值80%泡点值孔会扩散更多气体使得下游气流大于规定值Upstream PressurizedUpstream PressurizedRegulated compressed gasK . (P1 -P2) . A . ρDiffusion = -------------------------Lwhere:K = Diffusivity / Solubilitycoefficient扩散因子P1, P2 = Pressure difference acrossthe system系统两边的压力ρ= Membrane porosity膜开孔率M b itL = Effective path length有效膜孔长度A = Membrane area膜面积Gas flow ratemeasureddownstreamAt pressures below the bubble At pressures below the bubble point, diffusion always occurs在低于起泡点压力,扩散发生Diffusion testing does not indicate pore size扩散测试不显indicate pore size示膜孔径At28bar(40psig)a022andAt 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 possibleGas Flow1m2需要尽可能多关于膜的信息 Use diffusion testing in combination with bubble Diff ti l P0.1m2combination with bubble point testing 使用起泡点与扩散测试相结合Differential Pressurefilters with gas flowrate of >100 ml/minFor filters with gas flowrate of>100ml/min过滤器扩散流速大于100ml/minhigh surface area filtershigh 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.) shouldinclude;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 gastest gas测试气体Temperature温度maximum acceptable flow rate最大接受流速W i Wetting湿润度 Lower or inconsistent film thickness increases diffusion低的和不均匀的薄厚会增加扩散Fluid 流体Organic solvents have high diffusion flowrates O ga c so ve ts ave g d us o ow ates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T t Temperature 温度80% higher flowrate at 60 degrees Poor VentingProper Venting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 flowChanging 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)(p)–Nitrogen<8 ml/minCompressed air10ml/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?y–10" element<13.3 ml/min30"element399ml/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For the same device diffusion is directly proportional to surface area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) 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 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 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Forward FlowMarketing term for diffusional flow.只是扩散的不同说法Pressure Decay压力衰减P DMeasures the maximum loss of upstream gas pressure with time (typically 10 minutes) on the upstream side of a filter.)p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g qCan 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仅适合做些粗的是或不是的测试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 surfaceMinor 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As temperature rises, bubble point falls温度升高，起泡点降低Manual diffusion test手动扩散测试Mi ff t l t t t lMinor effect on manual test at normalambient range dependent on gas solubilityand diffusivity与气体溶解度和扩散率相关Approximately80%change from20-60ºC Approximately 80% change from 20 -60 C从20-60摄氏度80%的改变As temperature rises, diffusional flow raterises温度升高，扩散流速增加度升高扩散增加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 validBubble 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, thep y p p y gfilter 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B bbl i t id di t l ti t b t i l t ti thBubble 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。