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过滤完整性测试培训课程

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过滤完整性测试培训课程 Integrity Testing Theory 完整性测试理论完整性测试理论 过滤/完整性测试培训课程 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?‹扩散流测试原理是什么? ‹自动完整性测试仪 什么是滤膜完整性? 完整滤膜 非完整滤膜完整滤膜 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 下游污染下游没有污...

过滤完整性测试培训课程
Integrity Testing Theory 完整性测试理论完整性测试理论 过滤/完整性测试培训课程 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?‹扩散流测试原理是什么? ‹自动完整性测试仪 什么是滤膜完整性? 完整滤膜 非完整滤膜完整滤膜 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 下游污染下游没有污染物 Why Integrity Test? 为什么做完整性测试?为什么做完整性测试? 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„ 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„ Assuring 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„ 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 excel标准偏差excel标准偏差函数exl标准差函数国标检验抽样标准表免费下载红头文件格式标准下载 操作规程Part of corporate standard operating procedure公司标准操作规程 „ Auditing requirement审计需要 法规中对完整性测试的规定 FDA Guideline指南 (2003)FDA Guideline指南 (2003) – Whatever filter or combination of filters is used, validation should include microbiological challenges to simulate worst-s ou d c ude c ob o og ca c a e ges to s u ate o st 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。 法规中对完整性测试的规定 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 (199 版)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 flow or pressure hold test”p , p – 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)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,灭菌后使用前进行完 性 试 常在 安 , 菌后使 前 行 PDA Technical Report # 26 PDA技术 报告 软件系统测试报告下载sgs报告如何下载关于路面塌陷情况报告535n,sgs报告怎么下载竣工报告下载 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 Where & When Do We Integrity Test? 何时和何地做完整性测试?何时和何地做完整性测试? WHEN TO 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 What Are The Integrity Testing Choices? 完整性测试的选择?完整性测试的选择? 分类 测试名称 测试实施者金标准分类 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 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 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 Destructive vs. Non-destructive Testing 破坏性和非破坏性测试破坏性和非破坏性测试 There must be a correlation between a destructive and a be wee a des uc ve a d 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„ 法规需要 z FDA Aseptic Guidelines z FDA无菌指南 V lid ti j tifi ti f th„ Validation justification for the use of a test „ 测试应用的验证理由测试应用的验证理由 Integrity Testing Correlations 完整性测试关联完整性测试关联 Specification # of Retentive Non- R t tiSamples Retentive B bbl i t h di t 2 4 6 8 10 12 14 16 18 20 22 24 26 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”关起泡点有直接的关联 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?何种非破坏性测试合适? Capillary based tests 基于毛细管测试基于毛细管测试 „ Bubble Point起泡点 „ HydroCorr 挤水法 P1 P2 Air Water d s q fy „ Corrtest水压法 Diff i b d t t Waterq f Diffusive based tests 基于扩散测试 Diff i 扩散„ Diffusion扩散 „ Forward Flow前向流 „ Pressure hold / decay压力保持/y压力保持/ 衰减 Bubble Point Introduction 起泡点介绍 Bubble point is the pressure at which gas 起泡点介绍 Bubble point is the pressure at which gas displaces liquid from 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 Air Pact < PBpt 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 Membrane The oldest non-destructive integrity test 最传统的非破坏性测试 Pact > PBpt 泡点测试 完整膜 非完整膜完整膜 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 孔保持力低,导 Largest Pore 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 流流 Bubble Point Equation 起泡点等式起泡点等式 The bubble point is expressed 泡点可表达为as:泡点可表达为 4 . k . γ . cos θ   BP = P1 P2σBP = ----------------- d where 这里 P1 Air Water d σ θ k = shape correction factor 形状校正因子 = surface tension 表面张力γ = surface tension 表面张力 θ = contact angle 接触角 d = pore diameter 孔径p 孔径 泡点的影响因素 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 关于××同志的政审材料调查表环保先进个人材料国家普通话测试材料农民专业合作社注销四查四问剖析材料 ,表面张力,接触角,有效孔径 起泡点说明(包括SOP)应当包 括括 „ filter type过滤器类型 „ wetting liquid湿润液体„ wetting liquid湿润液体 „ Temperature温度 „ minimum pressure最小压力 接触角的影响 Solid / liquid interactionSolid / liquid interaction 固/液相互作用 „ Changing the wetting fluid h h b bbl ichanges the bubble point „ 改变湿润液体会改变起泡点 Applies to 不同的湿润液体„ different wetting fluid不同的湿润液体 „ different surface chemistries不同的表面化学性 pre use vs post use„ pre-use vs. post-use comparison使用前和使用后比较 Must know the effects f th h fof the changes, perform flushing 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 Examples of the Effect of Contact Angle and Surface Tension on Bubble Point Values 接触角和表面张力对起泡点值的影响实例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 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– Durapore® PVDF CVGL >= 50 psig – Charged Durapore® PVDF CCGL >= 40 psig A sterilizing grade filter has is the following minimum bubble point specifications: 种无菌过滤膜有下列最小的起泡点规格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 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 manufacturer's validation guide for the destructive / non- destructive integrity test correlation integrity testing technique and bacterialdestructive 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 Bubble Point Test Applicability 起泡点测试适用性起泡点测试适用性 Useful for qualified manual testing of filters less than approximately 2000 cm^2 ( 2 sq 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 testersrates 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 实验室-小面积起泡点测试实 Flush with water冲洗 Apply air pressure加压 Increase presssure until bubblesIncrease presssure until bubbles are seen downstream 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 0 22 PVDF Millidi k 亲水滤芯起0.22um PVDF Millidisk 亲水滤芯起 泡点测试 Diffusion Testing Introduction 扩散流测试介绍扩散流测试介绍 下游气体 上游 缩„ Gas dissolves in liquid held in the pores of a fully wetted b filt 气体溶解在完全 下游气体 P2 压缩 气体 P1membrane filter.气体溶解在完全 湿润的滤器膜孔内的液体中 „ A pressure differential will P1 扩散流 Z „ A pressure differential will give a different gas concentration across the P1 > P2 filter.膜压差造成跨膜气体浓度差 „ Results in gas flow through the liquid dissolved in the filter pores.结果 使膜孔溶解的气体流出使膜孔溶解的气体流出 扩散流测试 完整膜 非完整膜完整膜 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 孔会扩散更多 Largest Pore 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 值值 Diffusion Testing Equation 扩散测试方程扩散测试方程 Upstream PressurizedUpstream Pressurized Regulated compressed gas K . (P1 - P2) . A . ρ Diffusion = ------------------------- L where: K = Diffusivity / Solubility 扩散因子coefficient扩散因子 P1, P2 = Pressure difference across the system系统两边的压力 ρ M b it 膜开孔率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 downstreamdownstream Diffusion Test 扩散测试 At pressures below the bubbleAt pressures below the bubble point, diffusion always occurs在 低于起泡点压力 扩散发生低于起泡点压力,扩散发生 Diffusion testing does not indicate pore size扩散测试不显indicate pore size扩散测试不显 示膜孔径 At 2 8 bar (40 psig) a 0 22 and„ At 2.8 bar (40 psig), a 0.22 and 0.1 um rated filters will have the “same” diffusional flowrates在在 2.8Bar,0.22和0.1um空径膜具有相 同的扩散速率 A Reason for Diffusion Testing 什么情况下采用扩散测试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 得困难得困难 Need as much information about the filter as possible Gas Flow 1m 2 需要尽可能多关于膜的信息 „ Use diffusion testing in combination with bubble Diff ti l P 0.1m 2 combination with bubble point testing使用起泡点与 扩散测试相结合 Differential Pressure Diffusion Test Applicability 扩散测试适用性扩散测试适用性 For filters with gas flowrate of >100 ml/minFor filters with gas flowrate of >100 ml/min 过滤器扩散流速大于100ml/min „ high surface area filters大表面积过滤器„ 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 过滤器类型„ filter type过滤器类型 „ wetting liquid湿润液体 „ test gas测试气体„ test gas测试气体 „ Temperature温度 „ maximum acceptable flow rate最大接受流速 Factors Affecting Diffusion Tests 扩散测试的影响因素扩散测试的影响因素 W i 湿润度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„ 低的和不均匀的薄厚会增加扩散 Fluid流体 „ Organic solvents have high diffusion flowratesO 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 温度Temperature温度 „ 80% higher flowrate at 60 degrees „ 在60摄氏度流速高80% Poor Venting Proper Venting „ 在60摄氏度流速高80% Example of Changed Diffusional Flow举例 Polypropylene cartridge tested with nitrogen at 18.8 psig (1.3 bar ) 聚丙烯过滤器用氮气(18.8psig)测试聚丙烯过滤器用氮气(18.8psig)测试 – Acetone <390 ml/min – IPA <120 ml/min MESSAGE: Changing solvents changes diffusional flowChanging 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 Diffusional Flow举例 Hydrophilic filter is tested with both nitrogen and compressed air at 2.8 bar (40psi)( p ) – Nitrogen < 8 ml/min Compressed air < 10 ml/min– Compressed air < 10 ml/min MESSAGE: 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体可以给错误的扩散流速 Example of Changed Diffusional Flow举例 What is the maximum diffusional flow for a 5x30" pleated cartridge filter system?y – 10" element < 13.3 ml/min 30" element < 39 9 ml/min– 30" element < 39.9 ml/min – 5x30" elements < 199.5 ml/min MESSAGE: For the same device diffusion is directly proportional to surface area相同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” Summary 扩散测试 总结 初级经济法重点总结下载党员个人总结TXt高中句型全总结.doc高中句型全总结.doc理论力学知识点总结pdf 扩散测试总结 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 comeDownstream 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 bubbleflow 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 How to Measure Gas Flow 怎样测量气体流量怎样测量气体流量 Other Integrity Testing Terms 其它完整性测试其它完整性测试 Forward Flow前向流Forward Flow前向流 „ Marketing term for diffusional flow. 只是扩散的不同说法 P D 压力衰减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.) 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 „ Can be converted to a "diffusional" flow rate using an equationg q „ 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仅适合做 些粗的是或不是的测试 Overview of Temperature Effects 温度的影响温度的影响 Manual bubble point手动起泡点 „ Minor effect dependent mainly on surface„ Minor effect dependent mainly on surface tension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 l„ Minor effect on manual test at normal ambient range dependent on gas solubility and diffusivity与气体溶解度和扩散率相关 „ Approximately 80% change from 20 - 60 ºC„ Approximately 80% change from 20 - 60 C 从20-60摄氏度80%的改变 „ As temperature rises, diffusional flow rate rises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 change during the test on diffusional flowrate主要影响测试时的扩散流速 Summary 总结 Bubble point and Diffusion (or “Forward flow”) are BOTH valid„ 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 environmentp y p p y g 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 th„ 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
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