过滤技术及应用ppt课件.ppt

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1、过滤技术原理及应用,质保处2009.05,主要内容,过滤知识及原理过滤器的使用及维护完整性测试自动完整性测试仪,Introduction to Filtration 过滤基本知识,主要内容,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,主要内容续,How to recognize filtration problems and per

2、form basictroubleshooting 怎样理解过滤中的问题和解决简单故障,什么是过滤？,How do Filters Work? 过滤机理,Size Exclusion大小排除Particles are too large to pass through the “pore”基于大小来分离Examples are termed entrapment,sieving, surface capture例如拦截,筛分,表面捕获Adsorption吸附Particles stick to the filter bychemical / electrical attraction颗粒由于化

3、学/电荷作用粘附在滤器上,Retention Mechanisms影响过滤的因素,Mechanisms can be affected by:截流机制可以被以下因素影响：Fluid characteristics流体特性Operating conditions操作条件Particle type颗粒类型Filter type过滤膜类型,影响过滤的因素(流体特性),Viscosity粘度Chemical / Ionic content化学/离子成分CommentsSlow flow allows more contact较慢流速有较多接触Mixing/Contact time can be cri

4、tical混合/接触时间有较大影响Only affect adsorptive retention只影响吸附截留- NOT size exclusion不影响大小排除,影响过滤的因素(操作条件),Particle speed / velocity 颗粒速度Applied pressure过滤压力Comments建议Slow flow is good选择低流速better retention at slower flow越低的流速,越好的截留Matrix movement is bad结构移动是不利的particles and fibers can bereleased from depth f

5、ilters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/压差对吸附截留有重要影响,对大小排除影响相当小,影响过滤的因素(颗粒类型),Deformable (soft)可变形颗粒Non-deformable (hard)不可变形颗粒Comments建议Under pressure soft particles canintrude into the filter stru

6、cturecausing 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塞例如:凝胶Hard particles form open cakes硬颗粒形成一层饼例如:沙子,影响过滤的因素(滤膜的影响),Pore rating孔径Structure结构Rigid or movable刚性或可移动CommentsSterilizing filter common rating (legal definition)除菌过滤-公共孔径(法规定义)Prefilters have nominal ratings - each manufactu

7、rer has their own standards and methods预过滤-额定孔径,每一个制造商有自己的定义和方法,0.22 um Durapore Surface (3,000 x),0.22 um Durapore Cross-section (600 x),Filter Materials Hydrophilic过滤材质亲水性,“Water Loving”亲水Wet spontaneously (or with little effort) with waterCellulosic materials(i.e. Regenerated cellulose, mixed cel

8、lulose ester, etc.)纤维素材料Polycarbonate with additives (i.e. PVPP), Modified polysulfone, Nylon, Modified polyvinylidenefluoride (PVDF)聚碳化合物Applications应用Filtration and sterile filtration of aqueous or aqueous / organic solutions水或水/有机溶液混合的过滤和除菌过滤,Filter Materials Hydrophobic过滤材质疏水性,“Water hating”疏水No

9、t spontaneously wetwith water.Water can remain or be “tricked”to enter filter水被截流或巧妙进入膜PTFE -Polytetrafluoroethylene, PVDF -Polyvinylidene fluoridePolypropylene, Polysulfone,PolycarbonateApplications应用Solvent, acid, base, andchemical filtration溶剂,酸,碱和化学品过滤Tank/Equipment vents, process gas, fermentat

10、ion inlet/exhaust filters罐/设备呼吸器,工艺用气,发酵进气/排气过滤,过滤器分类,深层过滤器表面过滤器特性膜过滤器,What do Depth Filters look like?深层过滤器,Fibrous (can shed fibers)纤维(有纤维脱落)Difficult to give an accurate pore size rating不能给出一个确切的空径Thick (3 -30 mm) & often adsorptive厚度(3-30毫米),通常有吸附Give a percentage (i.e. 30 -70%) particle reducti

11、on只能给出颗粒减少的比例Have the greatest capacity较大的承污能力Examples -Microfiberglass, String-wound, pad filters例如-玻璃纤维,线绕式,压板式,What do Surface Filters look like?表面过滤器,Fibers locked together by heat or membrane coating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Thin (1 mm or less) &

12、 Slightly Adsorptive较薄(小于1毫米),较小吸附Give a percentage (90 -99.9%) particle reduction给出颗粒减少的比例(90-99.9%)Examples -Cellulose ester coated cellulose or polyesterweb例如-纤维素酯涂纤维或聚酯片,Key Membrane Filter Characteristics膜过滤器的特性,Strong, Rigid NOT brittle坚强，硬不易碎Tortuous pathway曲折的通道Not all the retention on top不是

13、都截流在膜表面Very high internal area非常高的内表面积65-75% porosity65%-75%开孔率,Key Membrane Filter Characteristics膜过滤器的特性-续,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Sterilizing filters must have 99.99999% removal无菌过滤器必须具有大于99.99999%截流Integrity testable (diffusion &/or

14、bubble point)能做完整性测试,How are Membrane Filters Made?膜过滤是怎样制造的？,Produced by Casting铸造膜Nylon, Cellulose (mixedester, 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,What do Cast Filters look like?铸造方式制造的膜过滤器, Mainly made by casting membrane 主要由铸造方式制造 Can be ei

15、ther hydrophilic orhydrophobic 可以是亲水和疏水 Rated on the size of the smallest particleit 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,What do Stretched filt

16、ers look like?拉伸方式制造的膜过滤器, 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 proteinadsorption 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,过滤系统配置,澄清(Millistak+ orPolygard),预过滤(Milligard orPolysep-II),最终(Durapor

17、e 0.22 or0.45m）,深层,表面,膜,过滤系统配置, 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-除菌过滤 除菌膜 最大的过滤截留率,Performance ofFiltration Systems过滤系统性能,Types of Particles in Biological Fluids生物流体中颗粒类型,Non-deformable types不可变形颗粒 Resin beads or fines树脂粒

18、 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, breakup and compress into impermeablecakes.能穿过膜,破碎,压缩,Cake Formation 形成滤饼,* Happens with hard particles 发生在硬颗

19、粒* Particles build up on the surface of the filter 颗粒堆积在过滤膜的表面,Total Pore Blocking 完全堵塞,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 than the pore size发生在缺少预过滤或颗粒略大于孔径的情况,Gradual Pore Plugging逐渐堵

20、塞,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,How do Blocked Filters React?过滤器堵塞的现象,Gradual blockage most common逐渐堵塞经常发生Everything was going alright, then all of a sudden the filter blocked”一切

21、正常,然后突然过滤器堵 塞了,过滤器的堵塞现象,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,过滤器堵塞的原因,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,怎样最优化过滤过程？,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,Typical Filter Con

22、figurations 1典型过滤器配置-1,圆盘过滤器13-293毫米直径传统的滤器可同时使用深层、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,Typical Filter Configurations 2典型过滤器配置-2,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 Eas

23、y to use & compact使用方便紧凑 Either replacement filter (Millidisk) or disposable 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,Typical Filter Configurations 3典型过滤器配置-3,Pleated Cartridge折叠式 Membrane held between supportingmaterial膜在支撑材

24、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

25、膜结合在同一过滤芯内,Cartridge Installation Tips过滤器安装知识,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,最大灭菌次数,灭菌次数： CVGL除菌滤芯： 30 SIP 30 min 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（1

26、00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,Gas Filter Changeout Criteria气体过滤器更换标准,Preventative Maintenance 预防性维护Oxidation氧化Integrity 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 ye

27、ar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,Filtration Summary总结,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 are commonly used in biopharmaceuticalfiltration三类过滤器普遍使用在生物制药Depth, Surface, Membrane深层

28、,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Monitoring 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,内容目录,为什

29、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,Why Integrity Test?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 Detecting leaks due to o-rings, gasket

30、s, 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 & Regulations法规要求 Part of corporate standard operating procedure公司标准操作

31、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) 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 Guid

32、e 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 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

33、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,灭菌后使用前进行PDA Technical Report # 26PDA技术报

34、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,Where & When Do We Integrity Test?何时和何地做完整性测试?,WHEN TO DO IT? Detect what?什么时候做? 检查什么？Before sterilization faulty housing

35、s?灭菌前 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,What Are The Integrity Testing Choices?完整性测试方法的选择?,金标准,Regulatory & quality organizations need datafrom both to assure reliable and predictablefilter performance法规和

36、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 correlationbetween a destructive and anon-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 T

37、esting 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 Point Introduction 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

38、 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 non-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,泡点的影响因素,接触角的影响,Examples of the Effect of Contact Angle andSurfaceTension on Bubble Point Val

39、ues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 pores 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

40、 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,A Reason for Diffusion Testing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

41、 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,HydroCorr Test Resistance to water intrusion水浸入法测试,HydroCorr Test Results测试结果,HydroCorr Test Considerations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 relativel

42、y 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 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,例PVDF膜是比较困难的 Tempe

43、rature 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,完整性测试失败处理措施,润湿建议,Summary总结, Bubble point and Diffusion (or “Forward flow”) are BO

44、TH validintegrity 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 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 correlat

45、ion to bacterial retention, thecritical 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 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 Integri

46、ty Testing SIP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 flo

47、w 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

48、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 m

49、olecules 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 lower pressure.上游气体分子越少压力越低C. All else being constant, the change in pressure can be 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, PV = nRT Where其中: P = press

50、ure 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 directlyrelated 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,Ideal Gas Law理想气体定律,Relating Pressure Decay to Gas Flow Rate压力衰减与气体流速的关系