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1、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 te
2、st 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Filtrati
3、on 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
4、 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 i
5、nclude 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 sh
6、ould 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 test
7、ing 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
8、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
9、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
10、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 GuidelinesFDA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 correla
11、tion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 fr
12、om 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 po
13、int 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 qual
14、ified manual testing of filters less than approximately 2000 cm2(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,T
15、he bubble point is expressed as:泡点可表达为 4.k.cos BP=-dwhere 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
16、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 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-usecomp
17、arison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:两种无菌过滤膜用同一细菌截留有下列最小的
18、起泡点规格:Durapore PVDF CVGL=50 psigCharged Durapore PVDF CCGL=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 psig70/30 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 manufac
19、turers validation guide for the destructive/non-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
20、表面张力对起泡点值的影响实例,Diffusion Testing Introduction扩散流测试介绍,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 A pressure differential will give a different gas concentration across the filter.膜压差造成跨膜气体浓度差 Results in gas flow through the liquid dissolved in the
21、filter pores.结果使膜孔溶解的气体流出,下游气体,P2,上游压缩气体,P1,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 specific
22、ation破损出现的大孔会扩散更多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=-Lwhere: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,A Reason for Diffusion Testing什么情
23、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Use diffusion testing in combination with bubble point testing使用起泡点与扩散测试相结合,Diffusion Test Applicability扩散测试适用性,For filters with gas flowrate of 1
24、00 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,Factors Aff
25、ecting Diffusion Tests扩散测试的影响因素,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80%higher flowrate at 60 degre
26、es在摄氏度流速高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Acetone390 ml/minIPA120 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,Example of Changed
27、Diffusional Flow举例,Hydrophilic filter is tested with both nitrogen and compressed air at 2.8 bar(40psi)Nitrogen8 ml/minCompressed air10 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,Example of Changed Diffusional Flow举例,What is the maximum diffusional flow
28、 for a 5x30 pleated cartridge filter system?10 element13.3 ml/min30 element39.9 ml/min5x30 elements199.5 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,Example of Changed Diffusional Flow举例,“Diffusion Testing”Summary扩散测试总结,Diffusion testing measu
29、res 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
30、点时流出“干”孔的气流两者引起,Problems for hydrophobic filter integrity test with alcohol 疏水滤膜采用有机溶剂进行完整性测试的问题,Alcohol/Water mixtures are often used due to:酒精/水的混合物使用经常会导致Cost成本高Flammability有燃烧的危险high diffusion高的扩散流Secure areas and equipment needed需要可靠的区域及设备Can be difficult to perform in-situ很难在线操作Some concerns w
31、ith residual test solution remaining in filter holder/pipework after testing在测试后,测试液体会残存在过滤器/管路中Residual solution should be removed before filter sterilization灭菌前需要去除残存的液体,HydroCorr TestingHydrocorr测试,Force water under pressure onto the surface of the filter.把水灌在膜表面Applied pressure is integral filte
32、r intrusion pressure加压至小于膜的水浸入压The water pressure is maintained but not increased.压力维持但不再加压Pleated structure compacts折叠式结构进一步压缩If integral,the upstream pressure will not drop below a preset value.膜如果是完整的,上游的压力不会太快下降,Integrity Tester,HydroCorr TestResistance to water intrusion水浸入法测试,0,2.6,bar,0,10,20
33、,Time(min.),Install dry cartridge装上干的滤芯,Fill upstream w/water在上游充满水,apply pressureand hold加压并保持,Measure pressureDecay测量压力衰减,Pressure causes pleats to compact-resulting in apparent water flow压力导致折叠式滤膜进一步压缩现象是有一定的水流,HydroCorr Test Results测试结果,After initial stabilization,“apparent”water flow for an int
34、egral filter is very low在最初的稳定后,对于完整膜来说,水流是非常小的Specifications are correlated to bacterial challenge水流指标是与细菌挑战有关For integral filter there is no“actual”water flow实际上完整膜,没有实际的水流Filter remains dry and does not require drying between testing and use在测试与使用中,过滤膜维持干燥也不需要干燥,HydroCorr Test Considerations测试的注意
35、点,Must have a leak-free system必须在一密闭系统内进行Filters must be dry and clean过滤芯必须干燥且干净It is relatively easy to Hydrocorr test“very hydrophobic”membranes such as PTFE对于疏水性很强的滤芯,例PTFE材质的膜,水浸入法是相当容易Successfully testing“less hydrophobic”membranes such as PVDF requires ideal conditions that can be difficult to
36、 achieve in actual biopharmaceutical processes在实际的生物制药工艺中,测试一些疏水性不强的滤膜,例PVDF膜是比较困难的Temperature changes should be minimized尽量减少温度的变化Reference testing is important相关的参考比较重要Must have a complete validation package必须有一完整的验证文本Values must be comprehensively correlated to microorganism challenge数据必须与细菌挑战相关,
37、Trouble shooting Decision Tree for Integrity Test完整性测试失败处理措施(英文）,替换过滤柱并且退回膜去分析,Trouble shooting Decision Tree for Integrity Test完整性测试失败处理措施(中文）,Repeat wetting 再湿润 Use longer wetting 使用更长的时间湿润 Use higher pressure 使用更高的压力湿润 Use higher temperature 使用更高的温度湿润 Wet with an Alcohol 用酒精湿润 Replace static soak
38、 with dynamic flush 用动态的冲洗取代静态的浸透,Wetting Suggestions湿润建议,Summary总结,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）和HydroCorr是法规认可的完整性测试方法 The choice of an integrity test depends on the testing equipment,the filter manufacturer,the
39、companys 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
40、试提供一个敏感方法来测试大面积过滤器,Automated Integrity Testers自动完整性测试仪,Why Do People Use Automatic Testers为何用户会选用自动测试仪,Ability to perform test without risk to downstream sterility可以在排除下游无菌状态受到影响的情况下操作Post SIP testing可以在蒸气灭菌后操作Hard copy printout有打印文本Eliminate operator subjectivity排除操作人员的主观因素Validatable可验证的,Post SIP
41、Integrity TestingSIP后的完整性测试,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
42、 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
43、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,Automated Integrity Testing自动完整性测试,A.During integrity testing gas molecule
44、s leave the system due to diffusion or bulk flow在完整性测试中,气体流失的原因是扩散及穿孔后的流失B.Fewer gas molecules upstream results in lowerpressure.上游气体分子越少压力越低C.All else being constant,the change in pressure canbe used to determine the gas flow rate在其它参数保持稳定的状况下,压力的改变可以确定气体的流速,Ideal Gas Law理想气体定律,PV=nRTWhere其中:P=pres
45、sure 压力V=volume 体积n=number of gas molecules气体分子数R=gas constant 气体常数T=temperature温度Key Point-The pressure in a closed system is directly related to the number of gas molecules in the system.关键点:在密闭系统内,压力直接与气体的分子数有关,Relating Pressure Decay to Gas Flow Rate压力衰减与气体流速的关系,Gas flow rate calculation 气体流速计算W
46、here其中 N=Gas flow rate 气体流速P=Pressure decay压力衰减ttest=time(min)时间Patm=atmospheric pressure大气压Vu=housing volume(cc)外壳体积,How Automatic Testers Determine Integrity完整性测试仪如何工作,Dependent on upstream volume依据上游体积Dependent on gas flow curve properties of the filter依据过滤器的气体流量曲线Diffusion is gas flow measuremen
47、t at a single pressure 扩散是在单一压力下测量的气体流Bubble point is a determined by measuring gas flow multiple times at increasing pressures泡点是在不断加压的情况下多次测量气体流的情况下而得的.,Gas Flow Curve气体流量曲线,Diffusion and Bubble point together make up a gas flow curve“扩散及泡点共同组成了一个”气体流量曲线”If flow is due to diffusion,it will increas
48、e linearly vs.delta P如果气体流量是由扩散而造成,流速与压降成正比If flow is a combination of diffusion and bulk flow,it will increase exponentially vs.delta P如果气体流量由扩散流及穿孔流共同组成,流速与压差成指数关系,Temperature CHANGES during a pressure decay test will have MAJOR impact on test results.在压力衰减测试中,温度变化对结果的影响是非常大的.Ideal Gas Law-PV=nRT
49、理想气体定律As Temperature increases Pressure increases温度上升时压力上升As Temperature decreases Pressure decreases温度下降时压力下降If the temperature changes even 1oC.during the test,the pressure change WILL NOT be solely due to gas flow在测试中,温度变化哪怕仅1度,压力的变化将不在仅归于气流Additional pressure loss or pressure gain are test error
50、额外的压力损失或增加会发生测试错误,Effect of Temperature on Automated Testing温度对自动测试的影响,Temperature Changes温度变化因素,Temperature changes can be due to:温度变化是由以下因素引起Inadequate stabilization after steaming灭菌后,冷却时间不够Touching the housing碰到了外壳Heating the automated tester加热了自动完整性测试仪Environmental changes during testing在测试中,环境温
