过滤完整性测试培训课程

1、MILLIPORE过滤/完整性测试培训课程Integrity Testing Theory完整性测试理论MILLIPORE内容提要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MILLIPORE完整滤膜非完整滤膜MILLIPOREMILLIPORE比膜孔大的污染物比膜孔大的污染物o ° o ° °O 匸 C ° O00%°o°o o ° ° o ° oMILLIPO

2、REMILLIPORE下游没有污染物MILLIPOREWhy Integrity Test?MILLIPORE为存么做完墓性测试？Common Sense通常理解 Filti'ation is often tlie most critical step in an operation过滤通常是操作的关键步骤 Confinnation of manufacturers specifications确认制造规格 Detecting leaks due to o-nngs, gaskets, seals检测0形环，垫圈，密封垫的泄漏 Assiumg tlie coiTect pore siz

3、e filter确认正确的过滤孔径 Assuring integrity before sterilization确认灭菌前完整性 Assiumg integrity after steammg or autoclavmg确认蒸汽和消毒锅灭菌后完整性Bus mess Practice 商业惯例 Government Guideluies & Regulations法规要求 Part of coiporate staiidaid operatuig piocedure公 司 标准操作规程Auditing Tequirement审彳十需要MILLIPOREGuidance for Indu

4、strySterile Drug ProductsProduced by Aseptic Processing Current Good Manufacturing Practice'炉mF /'FI< Ar ifSF皿 O出.Wk ET法规中对完整性测试的规定FDA Guideline指南(2003)一 Whatever filter or combination of filters is used, validation should include microbiological challenges to simulate worstcase productio

5、n conditions”对于由一个或多个滤器组成的过泯 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。MILLIPOREI、IK pmrin of Ikaltte 4inl llv«4n Srrkc% nl ！ 1衍成< <Mer 仏I ndb i< l>l R>< cure2d小Rccv“h“Tll Ri<lllkc ttcxukiltir%l<*H Srplcno»<r ilKMPli4riii»c<tttiil ( S、ll%MILUPORE法规中对完整性测试的规定Revision

6、 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)一 “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 flow or pressure hold test55-

7、除菌过滤膜应该在使川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)一 “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P

8、DA Technical Report # 26PDA技术报告26版一 “It generally is regarded as a cGMP requirement that filters or filter systems routinely be integrity tested both prior to and after use.55-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？DETECTS WHAT? 检查什么？

9、Before sterilization灭菌前Faulty housings 外壳岛问题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What Are The Integrity Testing Choices? 完整性测试的选择？ 分类测试名标准测试实施者破坏性细菌挑战测徐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 & quali

10、ty 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MILLIPOREDestructive vs. Non-destructive Testing 破坏性和非破坏性测试There must be a correlation between a destructive and a non-destructive integrity test 破坏性和非破坏性测试两鸟必须有 关联 Regulatory requiremen

11、t法规需要 FDA Aseptic Guidelines FDA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MILLIPOREMILLIPORE3m<> NOE弓OC Oo-JUJCDomwBUBBLE POINT (in psi)MILLIPOREMILLIPOREBubble point can have a direct correlation起泡点有直接的关联Diffusion & other tests can h

12、ave an ngo no gon correlation扩散和其它测试有汀通过，不通过汀关 连MILLIPOREWhat Nou-Destructive Integrity Tests are AvailablM1 LL|PORE 何种非破坏性测试合适？®Capillary based tests 基于毛监管测试 Bubble Point起泡点 HydroCorr 挤水法 Corrtest水压法Diffusive based tests基于扩散测试 Difiusion 扩散 Forward Flow前向流 Pressure hold / decay压力保持/ 衰减Bubble Po

13、int Introduction 起泡点介绍MembraneBubble point is the pressure at which gas displaces liquid fi om tlie largest set of filter pores and flows rapidly tlnough 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 tlie magnitude of tlie forces holding liquid in the filter stmctiue 起泡点显示过滤结构内保持液体的力的

14、大小The oldest non-destmctive integrity test 最传统的非破坏性测试MILLIPORE泡点测试全润湿的膜闽没有大量气 流出现Lareest破损出现的大 孔保持力低，导 致低于泡点即 被吹干出现气 流上游压力 小于 泡点值非完整膜MILLIPOREBubble Point Equation 起泡点等式UlThe bubble point is expressedas:泡点可表达为4 . k . y. cos 9BP=dwhere这里k = shape correction factor 形状校正因子y = surface tension 表面张力0 = co

15、ntact angle 接触角d = pore diameter 孑0径泡点的影响因素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，有效孔召起泡点说明（包括SOP）应当包 括 filter type过滤器类型 wetting liquid湿润液体 TemperatuTe 温度minimum pressuw最小压力MILLIPORE接触角的影响Solid / liquid interaction固/液相互作

16、用 Changing the wetting fluid changes the bubble point改变湿润液体会改变起泡点Applies to different wetting fluid不同的湿润液体 different swfacechemistries不同的表面化学性 pre-use vs. post-use comparison使用前和使用后比较Must know the effectsMore Hvd<O0hMicenrttCosine0出of the changes, performflushing or conduct product bubble point q

17、ualification必须知道变化的影响，进行冲洗或用 产品泡点确认Conkcl- Ancle (degrees!Effect of Contact Ang e on i1fsO.R75 30 85 SOExamples of the Effect of Contact Angle and Surface Tension也jjpore Bubble Point Values接触角和表面张力对起泡点值的影响实例Two sterilizing grade filters with identical bacterial retention claims and performanee have

18、the following minimum bubble point specifications:两种无菌过龜膜有同样的细菌截菌率，有下列最小的起泡点规格：-Durapore® PVDF CVGL>= 50 psigbubble point specifications:50 psig18.5 psig-Charged Durapore® PVDF CCGL >= 40 psigA sterilizing grade filter has is the following minimum 一种无菌过蒲膜有下列最小的起泡点规格：-Water>=-70/30

19、 IPA>=nt test values do not mean better filters 意味好的过滤膜Higher b 哥起泡点-Check the filter manufacturer's validation guide for the destructive / nondestructive integrity test correlation, integrity testing technique and bacterial challenge method完整性测试关连的验证文本，完整性测试技-楂查垃薩月竟初造商 术和细菌挑战理论MILLIPOREBubbl

20、e Point Test Applicability 起泡点测试适用性Useful for qualified manual testing of filters less than approximately 2000 cmA2 （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

21、体流速超过100毫升/分钟或自 动测试仪的限定实验室-小面积起泡点测试MILLIPOREMILLIPOREFlush with water冲洗Apply air pressure加压MILLIPOREIncrease presssure until bubbles are seen down stream增加压力直到起泡点在下游出现试验安排-手工起泡点测试S60.22um PVDF Millidisk 亲水滤芯起 泡点测试Diffusion Testing IntroductionMILLIPORE扩散流测试介绍下游气体P2 Gas dissolves in liquidheld in the

22、 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 thefilter.膜压差造成跨膜气体浓度差上游 压缩' 气体Pl 扩散流(u-dv-uz £sso_u.SeoGas PressurePl > P2 Results in gas flow through the liquid dissolved in the filter pores.结果 使膜孔

23、溶解的气体流出MILLIPORE扩散流测试上游压力80%泡点 值下游气流小 于顶定值非完整破损出现的大 孔会扩散更多 气体使得下游 气流大于规定 值上游压力80%泡点值MILLIPOREDiffusion Testing Equation 扩散测试方程Regulated compressed gasK.(P1 -P2).A.pDiffusio n =Upstream Pressurizedwhere:K = Diffiisivity / Solubility coefficient扩散因子Pl, P2 = Pressiue differenceacrossthe system系统两边的压力p

24、= Membrane porosity开孑b率L = Effective path length有效膜孔长度A = Membrane area 面积i is % iA<<<<< 卜Gas flow rate measured dow nstreamMILLIPOREDiffusion Test 扩散测试At pressures below the bubble point, diffusion always occurs在 低于起泡点压力，扩嵌发生Diffusion testing does not indicate pore size扩散测试不显i 示膜孔径1

25、At 2.8 bar (40 psig), a 0.22 and0.1 um rated filters will have the usameJ, diffusional flowrates在2.8Bar,0.22和0.1 um空径膜具有相同的扩散速率MILLIPOREGas FlowA Reason for Diffusion Testing 什么情况下采用扩散测试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 th

26、e 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 >100 ml/min 过滤器扩散流速大于lOOml/min high 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

27、滤器Diffusional flow specifications （and the S.O.PJ 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 Tate最大接受 流速Factors Affecting Diffusion Tests 扩散测试的影响因素Vetting湿润度 Lower or inconsistent film thickness increases diffusion Q低的和不均匀

28、的薄厚会增加扩散JlFluid 流体 Organic solvents have high diffusion flowratesII w I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| ."emperatu re 温度Proper VentingPoor Venting 80% higher flowrate at 60 degrees 在6 0摄氏度流速咼80%MILLIPOREExample of Changed Diffusi

29、onal Flow举例psig (1.3 bar)Polypropylene cartridge tested with nitrogen at 18. 聚丙烯过滤器用氮气(188psig)测试-Acetone<390 ml/min-I PA<120 ml/minMESSAGE:Changing solvents changes diffusional flow Pure 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 o

30、f Changed Diffusional Flow举例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MILLIPOREWhat is the maximum system?-10n element-30

31、” element-5x30" elementsExample of Changed Diffusional Flow举例diffusional flow for a 5x30” pleated cartridge filter<13.3 ml/minv 39.9 ml/minv 199.5 ml/minMESSAGE:For the same device, diffusion is directly proportional to surface area扌目同 的过滤器，扩散与膜面积成正比MILLIPORE“Diffusion Testing” Summary 扩散测试总

32、结Diffusion testing measwres 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 "dr/ pores which have reached their b

33、ubble 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Manual Test手动测试Diffusion / Bubble Point ProcedureHydrophilic 0 2 micron filterTime (minutes)(一sd)Enssai:How to Measure Gns30WZ-EszmGasOther Integrity Testing Terms 其它完整性测试Forward Flow前 向流 Marketing term for diffusional flow. 只是扩散的不同说法亠Pressure Decay

34、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&q

35、uot; flow rate using an equation能够使用算式换算成扩散流速 Useful as a "gon or"no-go" test for gross testing only-仅适合做一些粗的是或不是的测试Overview of Temperature EffectsMILLIPORE温度的影响Manual bubble point于动起泡点 Minor effect dependent mainly on surface tension表面张另有小影响 Approximately 15% change from 20 - 60 QC 从20