过滤技术及应用

1、质保处质保处2016.04 过滤知识及原理过滤知识及原理 过滤器的使用及维护过滤器的使用及维护 完整性测试完整性测试 自动完整性测试仪自动完整性测试仪 Important differences in the types of filters used in Bioprocesses. 生物制药中使用的不同类型过滤器及生物制药中使用的不同类型过滤器及其特性其特性 Why we use membrane filters for critical application 关键应用中为什么使用膜过滤器关键应用中为什么使用膜过滤器 How to recognize filtration problem

2、s and perform basictroubleshooting 怎样理解过滤中的问题和解决简单故障怎样理解过滤中的问题和解决简单故障 Size Exclusion大小排除大小排除 Particles are too large to pass through the “pore” 基于大小来分离基于大小来分离 Examples are termed entrapment,sieving, surface capture 例如拦截例如拦截,筛分筛分,表面捕获表面捕获 Adsorption吸附吸附 Particles stick to the filter bychemical / elec

3、trical attraction 颗粒由于化学颗粒由于化学/电荷作用粘附在滤器上电荷作用粘附在滤器上 Mechanisms can be affected by: 截流机制可以被以下因素影响：截流机制可以被以下因素影响： Fluid characteristics 流体特性流体特性 Operating conditions 操作条件操作条件 Particle type 颗粒类型颗粒类型 Filter type 过滤膜类型过滤膜类型 Viscosity粘度粘度 Chemical / Ionic content 化学化学/离子成分离子成分 Comments Slow flow allows mo

4、re contact较慢流速有较多接触较慢流速有较多接触 Mixing/Contact time can be critical混合混合/接触时间有较大影接触时间有较大影响响 Only affect adsorptive retention 只影响吸附截留只影响吸附截留 - NOT size exclusion 不影响大小排除不影响大小排除 Particle speed / velocity 颗粒速度颗粒速度 Applied pressure过滤压力过滤压力 Comments建议建议 Slow flow is good选择低流速选择低流速 better retention at slower

5、flow越低的流速越低的流速,越好的截留越好的截留 Matrix movement is bad结构移动是不利的结构移动是不利的 particles and fibers can bereleased from depth filters 颗粒和纤维能从深层过滤器析出颗粒和纤维能从深层过滤器析出 Velocity/Differential Pressure can have a major effect on adsorptive retention - Little to no effect on size exclusion 速度速度/压差对吸附截留有压差对吸附截留有重要影响重要影响,对大

6、小排除影响相当小对大小排除影响相当小 Deformable (soft)可变形颗粒可变形颗粒 Non-deformable (hard)不可变形颗粒不可变形颗粒 Comments建议建议 Under pressure soft particles canintrude into the filter structurecausing more effective filter blinding 在压力下软性颗粒会进入过滤膜内并导致更多的过滤堵在压力下软性颗粒会进入过滤膜内并导致更多的过滤堵塞塞 例如例如:凝胶凝胶 Hard particles form open cakes 硬颗粒形成一层饼例

7、如硬颗粒形成一层饼例如:沙子沙子 Pore rating孔径孔径 Structure结构结构 Rigid or movable刚性或可移动刚性或可移动 Comments Sterilizing filter common rating (legal definition)除菌过滤除菌过滤-公共孔径公共孔径(法规定义法规定义) Prefilters have nominal ratings - each manufacturer has their own standards and methods 预过滤预过滤-额定孔径额定孔径,每一个制造商有自己的定义和方法每一个制造商有自己的定义和方法0.

8、22 um Durapore Surface (3,000 x)0.22 um Durapore Cross-section (600 x) “Water Loving”亲水亲水 Wet spontaneously (or with little effort) with water Cellulosic materials(i.e. Regenerated cellulose, mixed cellulose ester, etc.)纤维素纤维素材料材料 Polycarbonate with additives (i.e. PVPP), Modified polysulfone, Nylon

9、, Modified polyvinylidenefluoride (PVDF)聚碳化合物聚碳化合物 Applications应用应用 Filtration and sterile filtration of aqueous or aqueous / organic solutions水或水水或水/有机溶液混合的过滤和除菌过滤有机溶液混合的过滤和除菌过滤 “Water hating”疏水疏水 Not spontaneously wetwith water. Water can remain or be “tricked”to enter filter水被截流或巧妙进入膜水被截流或巧妙进入膜 P

10、TFE -Polytetrafluoroethylene, PVDF -Polyvinylidene fluoridePolypropylene, Polysulfone,Polycarbonate Applications应用应用 Solvent, acid, base, and chemical filtration溶剂溶剂,酸酸,碱和化学品过滤碱和化学品过滤 Tank/Equipment vents, process gas, fermentation inlet/exhaust filters 罐罐/设备呼吸器设备呼吸器,工艺用气工艺用气,发酵进气发酵进气/排气过滤排气过滤 深层过滤器

11、深层过滤器 表面过滤器特性表面过滤器特性 膜过滤器膜过滤器 Fibrous (can shed fibers)纤维纤维(有纤维脱落有纤维脱落) Difficult to give an accurate pore size rating不能给出一个确切的空径不能给出一个确切的空径 Thick (3 -30 mm) & often adsorptive厚度厚度(3-30毫米毫米),通常有吸附通常有吸附 Give a percentage (i.e. 30 -70%) particle reduction只能给出颗粒减少的比例只能给出颗粒减少的比例 Have the greatest ca

12、pacity较大的承污能较大的承污能力力 Examples -Microfiberglass, String-wound, pad filters例如例如-玻璃纤维玻璃纤维,线绕式线绕式,压压板式板式 Fibers locked together by heat or membrane coating纤维用热粘合或膜涂布纤维用热粘合或膜涂布 Given a nominal rating or rated by the filter it protects可以给出公称空径可以给出公称空径 Thin (1 mm or less) & Slightly Adsorptive较薄较薄(小于小于

13、1毫米毫米),较小吸附较小吸附 Give a percentage (90 -99.9%) particle reduction给出颗粒减少的比例给出颗粒减少的比例(90-99.9%) Examples -Cellulose ester coated cellulose or polyesterweb例如例如-纤维素酯纤维素酯涂纤维或聚酯片涂纤维或聚酯片 Strong, Rigid NOT brittle坚强坚强，硬不易碎，硬不易碎 Tortuous pathway曲折的通道曲折的通道 Not all the retention on top 不是都截流在膜表面不是都截流在膜表面 Very h

14、igh internal area 非常高的内表面积非常高的内表面积 65-75% porosity 65%-75%开孔率开孔率 Size exclusion particle retention does not change with flow or pressure 大小排除颗粒截流与流速和压力无关大小排除颗粒截流与流速和压力无关Sterilizing filters must have 99.99999% removal 无菌过滤器必须具有大于无菌过滤器必须具有大于99.99999%截流截流 Integrity testable (diffusion &/or bubble p

15、oint) 能做完整性测试能做完整性测试 Produced by Casting 铸造膜 Nylon, Cellulose (mixed ester, regenerated), PVDF, Polysulfone 尼龙,纤维素(混合酯, 改良),聚偏二氟乙烯,聚砜 Produced by Stretching 拉伸膜 PTFE 聚四氟乙烯 Mainly made by casting membrane 主要由铸造方式制造 Can be either hydrophilic orhydrophobic 可以是亲水和疏水 Rated on the size of the smallest par

16、ticleit retains 孔径是对最小的颗粒的截留 Very thin (100 - 260 um) 非常薄（100-260微米） Adsorption depends on materials 吸附与材料相关 Examples例如 Cellulose ester纤维素酯 Regenerated cellulose改良纤维素 Nylon尼龙 Polysulfones聚砜 PVDF聚偏二氟乙烯 Slot shaped pores 狭窄的孔道 Very thin 非常薄 Often bonded to a supportmaterial 常常与支撑结合 Can have high prote

17、inadsorption 有较高的蛋白吸附 Examples例如 PTFE - Teflon聚四氟乙烯 Naturally hydrophobic天然疏水 Most hydrophobic polymer澄清(Millistak+ orPolygard)预过滤(Milligard orPolysep-II)最终(Durapore 0.22 or0.45m）深层表面膜 孔径逐渐减小的过滤系列 Clarifying filter-澄清过滤 深层过滤 在过滤系列开始是最大的 过滤容量 Prefilter-预过滤 Prefilter-预过滤-表面过滤 中等截留，中等载量 Final filter-除菌

18、过滤 除菌膜 最大的过滤截留率Performance ofFiltration Systems过滤系统性能Non-deformable types不可变形颗粒 Resin beads or fines树脂粒 Drug crystals药物晶体 Carbon fines炭粒 Diatomaceous Earth (D.E.)硅燥土 Form porous permeable cakes.在膜上形成可流通的饼Deformable types可变形颗粒 Proteins蛋白 Lipids脂 Sugar complexes糖复合物 Can move through the filter, breaku

19、p and compress into impermeablecakes.能穿过膜,破碎,压缩* Happens with hard particles 发生在硬颗粒* Particles build up on the surface of the filter 颗粒堆积在过滤膜的表面 Happens with deformable particles 发生在可变形颗粒 Particles completely block the pore“ 颗粒完全堵塞膜“孔” Happens with little prefiltration OR particles slightly larger t

20、han the pore size 发生在缺少预过滤或颗粒略大于孔径的情况 Happens with hard or deformable particles 发生在硬颗粒和可变形颗粒 Particles build up on the pore throat or opening 颗粒堆积在孔道或表面 Most common with biologicals 大多发生在生物化学颗粒 Gradual blockage most common 逐渐堵塞经常发生 Everything was going alright, then all of a sudden the filter blocke

21、d” 一切正常,然后突然过滤器堵 塞了 流速下降 可能低于要求的流速(如灌装速度) 压力上升 可能超过过滤系统承受的压差 过滤柱或管道/连接件 颗粒可能穿过过滤器 污染/堵塞下游过滤器 过滤成本改变 时间,产品和过滤器的成本 系统停止或更换过滤器 本道工序滤膜的选择，孔径，面积 操作条件（流速，温度，压力） 上道工序滤膜的选择 产品本身的变化 产品过滤前作压力流速实验 使用低的起始压差 1-2 psid or 0.1 bar 监测和调整压差 深层过滤:10-15PSID 表面过滤和膜过滤:30PSID 不超过制造商的规格 确保过滤在合时压力下进行 圆盘过滤器 13-293毫米直径 传统的滤器

22、可同时使用深层、表面滤膜 通常用于小批量过滤 成本低 分量重 安装困难 占地面积大Stacked Disk层叠式圆盘 Membrane bonded to both sides of a support disk 膜结合在圆盘支撑的两边 Support disks bonded together 圆盘支撑结合在一起 All filters work in parallel所有过滤器平行 Low hold-up volume残液低 Easy to use & compact使用方便紧凑 Either replacement filter (Millidisk) or disposable

23、 device (Millipak) 有可替换的和一次性使用的过滤器 Non-metallic非金属 Non-flexing structure不可变形构造 Low resistance to back pressure 承受反压低Pleated Cartridge折叠式 Membrane held between supportingmaterial膜在支撑材料间 Thermoplastic welding热熔 2-5 materials of construction 2-5种结构材料Good forward & reverse pressure resistance 较高的正/反

24、压承受能力 Large surface area大过滤面积Multiply steamable多次蒸气灭菌Variety of sizes, surface areas and o-ringconfigurations各种规格，表面积和形圈结构Can have prefilter / final filter in the samecartridge能将予过滤和除菌过滤膜结合在同一过滤芯内 湿润O型圈，易于安装 检查过滤外壳方向 inlet / outlet 不要过紧，合适的套筒不需要太大的力量 避免直接用手接触过滤器 使用前冲洗过滤器 灭菌次数： CVGL除菌滤芯： 30 SIP 30 mi

25、n 135 C; 30 高压灭菌60 min 126 C KVGL囊式除菌滤芯： 3 高压灭菌60 min 126 C; 不能在线灭菌 Millidisk除菌滤器： 5 SIP 60 min 135 C; 5 高压灭菌60 min 126 C 。 Aervent空气/有机溶剂除菌滤器：150（100正向/50反向） SIP 30 min 145 C; Express聚醚砜除菌过滤器： 25 次正向（或22次正向，3次反向） 30min135 C; 一定要预先阅读说明书-实际工艺使用次数需要确认 Preventative Maintenance 预防性维护Oxidation氧化Integrity

26、 failure完整性失败 Filter blockage过滤膜堵塞Too many sterilization cycles太多灭菌次数Filter changeout can vary; 1 week to 1 year过滤器更换时间范围很广(从1周到1年)Need documentation需要文本支持Increased scrutiny应不断进行检查There are two major retention mechanisms in liquids在流体过滤中有两类过滤机理 Adsorption, Size Exclusion吸附,大小排除Three types of filters

27、 are commonly used in biopharmaceuticalfiltration三类过滤器普遍使用在生物制药 Depth, Surface, Membrane深层,表面,膜过滤Filter materials are supplied as either过滤介质以下列形式提供 Disc, Stacked Disc, Pleated Cartridge圆盘,层叠式,柱式Filters block by either过滤堵塞可以是 Gradual, Total or Cake逐渐堵塞,完全堵塞Filtration problems can be solved过滤问题可以被解决 M

28、onitoring and optimizing are key techniques监测和优化是关键技术Integrity Testing Theory完整性测试理论 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 manufacturer

29、s 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 autoclaving 确认蒸汽和消毒锅灭菌后完整性Business Practice 商业惯例 Government Guidelines & Re

30、gulations法规要求 Part of corporate standard operating procedure公司标准操作规程 Auditing requirement审计需要 FDA Guideline指南(2003) Whatever filter or combination of filters is used, validation should 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

31、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 should be confirmed immediately after use by an appropriate method such as a bubble point, diffusive flow or pressure

32、 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.” 完整性测试通常在过滤器安装,

33、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 WHEN TO DO IT? Detect what? 什么时候做? 检查什么？ Before sterilization faulty housings? 灭菌前

34、 外壳的问题 Before use out-of-the box failures 使用前 包装以外的问题 After use sterilization induced failures 使用后 灭菌的影响 stress induced failures 压力的影响金标准Regulatory & quality organizations need datafrom both to assure reliable and predictablefilter 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 b

35、etween 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 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What Non-Destructive Integrity Tests are Available?何种非破坏性测试合适?Bubble Poi

36、nt Introduction 起泡点介绍起泡点介绍Bubble 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 ofthe forces holding liquid in the filterstructure起泡点显示过滤结构内保持液体的力的大小The oldest n

37、on-destructive integrity test最传统的非破坏性测试泡点测试Bubble Point Test Applicability起泡点测试适用性Bubble Point Equation起泡点等式起泡点等式泡点的影响因素接触角的影响Examples of the Effect of Contact Angle andSurfaceTension on Bubble Point Values接触角和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 liquidheld in the por

38、es of a fullywetted membrane filter.气体溶解在完全湿润的滤器膜孔内的液体中 A pressure differential willgive a different gasconcentration across thefilter.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扩散流测试Diffusion Testing Equation扩散测试方程扩散测试方程A Reason for Diffusion Testing

39、什么情况下采用扩散测试Diffusion Test Applicability扩散测试适用性Factors Affecting Diffusion Tests扩散测试的影响因素Example of Changed Diffusional Flow 举例Example of Changed Diffusional Flow 举例Example of Changed Diffusional Flow 举例“Diffusion Testing” Summary 扩散测试总结疏水滤膜采用有机溶剂进行完整性测试的问题HydroCorr Testing Hydrocorr测试测试HydroCorr Tes

40、t Resistance to water intrusion水浸入法测试水浸入法测试HydroCorr Test Results测试结果HydroCorr Test Considerations测试的注意点测试的注意点 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,例例PTFE材质的膜材质的膜,水

41、浸入法是相当容易水浸入法是相当容易 Successfully testing “less hydrophobic” membranes such as PVDF requires idealconditions that can be difficult to 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测试一些疏水性不强的滤膜,例例PVDF膜是比较困难膜是比较困难的的 Temperature changes should be minimized 尽量减少温度的变化 Reference testi

42、ng 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完整性测试失败处理措施润湿建议Summary总结总结 Bubble point and Diffusion (or “Forward flow”) are BOTH validintegrity tests as per regulatory agencies.起泡点, 扩散流（或前

43、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 companys philosophy and the testingenvironment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, thecritical performance characteri

44、stic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 forlarger area filters扩散测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Post SIP Integrity Testing SIP后的完整性测试后的完整性测试Revision of annex 1 to EC Guide to GM

45、P 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 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

46、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.” 完整性测试通常在过滤器安装,灭菌后使用前进行PDA Technical Report # 26 PDA技术报告技术报告26版版 “It generally is regarded as