【精品】PALL过滤器-完整性检测原理

滤芯完整性检测,GMP 对完整性检测的要求,“过滤工艺要经过严格验证确认在生产过程替换同型滤芯能完成同样的过滤任务实现这一目标的途径就是关联滤芯完整性数据与过滤性能。 FDA Guidelines on Aseptic Processing 摘自：FDA无菌制剂指南,完整性定义,完好的完全的未受损坏的,完整性检测试验的目的是确定滤芯是否完好,不是测量孔径,完整性检测目的,滤芯制造商认证生产质量控制滤芯用户确认滤芯级别确认滤芯正确安装确认滤芯未受损坏确认滤芯符合制造规格确认此滤芯和那些经制造商认证的滤芯一样工艺认证文件批次记录文件,滤芯完整性检测试验类型,颗粒挑战,细菌挑战,细菌截留试验对除菌能力是最灵敏的完整性检测试验。非破坏性的完整性试验是和细菌挑战试验关联的替代性试验,前进流,泡点,压力保持,水浸入,非破坏性,破坏性,完整性检测告诉我们什么?,滤芯符合规范滤芯没有在下列环节受到损伤 搬运安装蒸汽消毒、高压灭菌滤芯安装正确,完整性试验检测的滤芯种类?,精度 107/cm2的假单胞细菌挑战,关于除菌滤膜的一些神话,滤膜就是一层薄膜细菌都是被滤膜表面的小孔截住的0.2 m滤膜的意思就是膜的孔径都小于等于 0.2 m,SEM of Nylon66 Membrane,Surface View,Challenged with 5 x 108 B.diminuta per cm2Osumi (1991),SEM of Nylon66 Membrane,Section View,Challenged with 5 x 108 B.diminuta per cm2Osumi (1991),除菌滤芯完整性检测指标,Forward Flow test前进流Bubble Point test泡点,前进流,气体从浸润的滤膜微孔扩散,上游,下游,高压,低压,滤膜,大体积气流通过破损孔道,检测压力,大气压力,上游,下游,滤膜,滤膜的微观结构,前进流检测的理论模型,J：前进流ml/minD：气体在溶液的扩散率 cm2/minH：气体在溶液中的溶解度 ml/psiP：压差psiA：膜面积cm2L：液膜厚度cm ：空隙体积,前进流特点,直接检测的流量值恒定温和的检测压力可检测超大面积滤膜能反映滤膜厚度和使用状态可连续检测可反映滤膜材质、工艺的变化,手动检测前进流,仪器检测前进流,进,出,仪器,气源,阀,润湿滤芯,压力表,外接至大气,前进流检测碰到的问题,主要提示信息,Flow within limits限值内Flow outside limits限值外Line pressure too low气源压力过低Flow too low流量过低Flow too high流量过高Unable to stabilise无法稳定Flow measurement unstable不稳定,“Flow Outside Limits” - FF Test,滤芯浸润不彻底？滤壳、气管泄漏？低表面张力液体？滤芯安装不正确？O型圈破损？滤芯破损？,泡点检测,泡点原理,高压,低压,上游,下游,滤膜,大压力下击穿微孔水膜,泡点原理,基于毛细孔模型液体表面张力和膜孔润湿接触角度决定膜孔润湿程度润湿的膜孔阻碍了气流在一定的气体压力下，液膜被冲开，最初的气体流量和相应的孔径之间存在比例关系第一个微米级过滤器非破坏性完整性检测方法*滤芯用润湿溶液润湿，缓慢加压(空气或氮气) 至大量气体从下游流出大流量出现时的最低压力 * David B. Pall, U.S. 专利 # 3,007,334 Filed Nov. 30, 1956,滤膜泡点检测演示,泡点法理论公式,P：泡点压力：粘度 dynes/cm：润湿角度D：孔径F：滤膜迷宫管路校正系数,泡点法特定,检测滤膜最大开孔的直径和滤膜开孔率、厚度、使用状况无关非直接测量值，需要通过前进流数据推导难以区别滤膜材质的变化,泡点值-有效体积,泡点值-最大孔径,BP0.45m1?mbar0.2m 3?mbar0.1m 5?mbar,手动泡点检测,气源,阀,浸润滤芯,压力表,观察泡点,如何确定泡点?,泡点的确定依赖于检测方法、操作人员以及设备,盘式滤膜、小滤芯的完整性检测对泡点值的判断上存在主观成分在较高的压力和较大的膜面积时，灵敏 度降低,泡点检测的优缺点,仪器检测泡点值的原理,自动泡点试验提供更准确的BP值吗?,排除了操作者因素.提供可重复的数值, 但是.程序预设的公式？仅为数学推算公式泡点判定的标准？不同厂商间存在差别背景扩散的影响？灵敏度随膜面积增大而降低,泡点检测常见问题,Bubble point within limits限值内Bubble point outside limits限值外Bubble point not obtainable无法达到泡点Line pressure too low气源压力不足,“BP Outside Limits”,滤芯润湿不充分？ 滤壳、气管泄漏？浸润液体表面张力过低？,“BP Outside Limits”,安装不正确？O型圈损坏？滤芯损坏？上游体积/滤芯体积比例过大？,When / Why / How 进行完整性检测?,“除菌滤芯的完整性检测必须在使用前、使用后立即进行” E.C. GMP Guide,GMP 对完整性检测的要求,When?,在线还是离线?使用前后?灭菌前后?,疏水滤芯的完整性检测,完整性检测,前进流泡点 水侵入,完整性检测 亲水滤芯 疏水滤芯,前进流、泡点法检测疏水滤芯,需要完全浸润 需要低表面张力液体检测完后需要清洗关系到有毒、易燃易爆等安全问题,气体滤芯完整性检测的指导文件,水侵入法,水侵入机理,疏水滤膜,气压,水,水侵入机理,疏水滤膜,气压,水,水侵入检测系统,空气,压缩空气,设备,水,阀,外接至大气,流速和压力的关系,固定压力下流速和时间关系,流速与温度关系,水侵入数据与细菌挑战实验的关联,0.50.40.30.20.10,流量 (ml/min),水侵入常见问题,WIT Test,Flow within limits限值内Flow outside limits超限值Line pressure too low气源压力过低Flow too low流速过低Flow too high流速过高Unable to stabilise无法稳定Flow measurement unstable检测不稳,“Flow Outside Limits” - WIT test,滤壳、气管斜路？水位不够？ 含有酒精？滤芯安装不正确？O型圈破损？滤芯破损？,Palltronic Flowstar XC 完整性检测仪,Flowstar,The Principle of Direct Flow Measurement,Flow measured on the upstream side of the filterAt constant pressureFlow of air or water is measured by the amount of gas required to maintain a constant test pressure on the filter,Flow Measurement by Volume Dosing,Fixed chambers (2) of known calibrated volumesHigh accuracy 0.1% pressure transducers (2)Precision pressure controller/regulatorPurpose designed software,Flow Measurement by Volume Dosing,P1 measures volume pressure P2 measures system pressure Software determines volume dosing required to maintain constant pressure,Auto Stabilisation and Test Times,Total test times reduced by 50% or moreReal time continuous measurement of flow and flow stability mean that a safe and accurate result is always obtained,Auto Stabilisation,Once stable flow has been achieved the test phase beginsOn average takes 5 minutes,Auto Test Time,Algorithm fully described in the validation guideIs flow safely below the limit value?Is the flow stable?,Auto Test Time,75% of limit,120secs,Flow pass/fail limit,150secs - 80% 180secs - 85%,210secs - 90% 240secs - 95%,600secs FF 900secs WIT,Time,Flow,Auto Test Time,Test time automatically extended until stable flow detected,120secs,Time,Flow,Flow pass/fail limit,Prevents false pass due to closed valve or system not fully connected,“Flow Too Low” Safety Feature,Direct Flow Measurement Summary,Shorter and automatic test timesMore accurate test resultsReal time measurement and displayDetection of - unstable flow conditions- low flow due to closed valveEasier validation,How to Use The Palltronic Flowstar Instrument,Electrical Connections,Pneumatic Connections,External Vent Valve,During Testing,During Venting of Filter Housing,Test Result and Error Messages,Flow / BP within limitsFlow / BP outside limitsLine pressure too lowFlow too lowFlow too highUnable to stabiliseFlow measurement unstable,“Flow Outside Limits” - FF test,Check for leaks in the housing (valves and seals) and upstream tubingRewet the filter Low surface tension fluid contamination?Filter installed correctly?O-ring damage?Filter damage?,“Flow Outside Limits” - WIT test,Check for leaks in the housing (valves and seals) and upstream tubingWater level high enough? Alcohol contamination?Filter installed correctly?O-ring damage?Damaged filter?,Test Programmes Menu,Access limitedAllows supervisor to:Create Edit and delete test programmes,Test Results,Last 100 test results storedCan be redisplayed and reprintedStored by Type of testDate and time,System Menu,Limited accessAllows supervisor to:Change date and timeChange languageChange unitsInput/edit/delete user IDsAdjust touch screen,Calibration and Servicing,External vent valveInternal filter3 yearly serviceRecommended calibration period - one year maximumService and calibration on or off site,Air Clean,Have you used the remote vent valve?Might test liquid have entered the Flowstar?Periodic cleaning?,Air Clean,Connect compressed air to air inOpen air out valveConnect housing orMale Stubli,Flow Check Function,Plug-in flow check device