PDA-TR15-切线流过滤-Tangential-Flow-Filtration-1992

IndustrialPerspectiveonValidationofTangentialFlowFiltrationinBiopharmaceuticalApplications对生物制药应用中切向流验证的工业透视PARENTERALDRUGASSOCIATION注射药物协会TableofContents目录PageI.Forward前言S3II.Introduction简介S3III.ValidationofGenericTFFEquipment验证一般TFF设备S4A.InitiatingValidationProjects开始验证项目S4B.OverallApproach整体法S4C.IQ安装确认S4D.OQ运行确认S6IV.GenericConceptsofProcessValidation工艺验证的一般概念S6A.Prospectivevs.ConcurrentValidation预期验证vs.同步验证S6B.WorstCaseConditions最坏情况条件S7C.NumberofReplications重复试验数量S7D.PrerequisitestoInitiatingProcessValidation开始工艺验证的先决条件S7E.DesignandExecutionofProcessValidation工艺验证的设计和执行S7V.CriticalElementsofTFFProcessValidationTFF工艺验证的关键要素S7A.Compatibility相容性S7B.Retention滞留S8C.Integrity完整性S9D.SystemandMembraneCleaning系统和膜清洗S9E.Sterilization/Sanitization灭菌/.消毒SI0F.MembraneRe-Use膜再使用SI0G.ProcessScaleChanges工艺规模变更SI0H.QualifyingAlternateVendors审核选择的供应商SI0I.MiscellaneousIssues其他问题S11VI.SpecificApplications具体应用S11A.EndotoxinRemoval内毒素去除S11B.ProteinConcentration/Diafiltration蛋白质浓度/过滤S11C.CellDebrisRemoval细胞碎片移除S12D.BacteriaHarvesting细菌捕获S12E.MammalianCellSeparation哺乳动物细胞分离S12VII.Summary总结S13VIII.References参考S13I.Foreword前言ThePurificationandScale-UpTaskForceofthePDA'sBiotechnologySub-committeehassoughttoaddresshowtheFDA's1987GuidelineonGeneralPrinciplesofProcessValidationmaybeappliedtothevalidationofspecificoperationsinthemanufacturingofparenteralproductsbytheBiotechnologyindustry.PDA生物技术委员会的净化和扩大规模工作小组已力求说明工艺验证一般原理的1987年FDA指南如何应用到生物技术工业的注射用药物生产的特定操作验证中。Twomajorcategoriesofseparationusedinpurificationanddownstreamprocessingarechromatographyandtangentialflowfiltration(TFF).Thisarticlefocusesonthevalidationoftangentialflowfiltrationprocessesasitrelatestothe1987FDAguidelines.Inpreparingthisdocument,weassumedthereaderwouldbefamiliarwiththetechnicalaspectsoftangentialflowfiltrationanditsapplicationinbiopharmaceuticalprocesses.WehavepositionedthisarticletoprovidetheknowledgeableusersomeinsightintotheprocessofvalidatingTFFapplications.ReadersseekingadditionalbackgroundinformationonTFFarereferredtothereferences(1-5)listedattheendofthearticle.用于提纯和下游工艺的两种主要分离方法是色谱分析和切向流过滤（TFF）。本文侧重于切向流过滤工艺的验证，因为它与1987年的FDA指南有关。在准备本文件时，我们假设读者都熟知切向流过滤的技术验证及其在生物制药工艺上的应用。我们将该文件定位于向有见识的用户提供一些验证TFF应用工艺的见解。探求有关TFF的附加背景知识，请读者参阅本文件末尾所列的参考文献（1-5）。II.Introduction简介Validationisestablishingdocumentedevidencewhichprovidesahighdegreeofassurancethataspecificprocesswillconsistentlyproduceaproductmeetingitspredeterminedspecificationsandqualityattributes(6).ProcessvalidationisarequirementoftheCurrentGoodManufacturingProcesses21CFRParts210and211wheretheendproductistobeusedinclinicaltrialsorforcommercialsale.Toassistthepharmaceuticalmanufacturerincomplyingwiththisrequirement,theFDAissuedaguidelinein1987(6)which“outlinesgeneralprinciples...consider(ed)tobeacceptableelementsofprocessvalidation...”.InthisdocumentwearegivinganindustrialperspectiveofthegeneralprinciplesoutlinedintheFDA'sguidelineasappliedtothespecificproblemofvalidatingaTangentialFlowFiltration(TFF)process.验证是“建立提供高度保证的文件证明，以保证某一特定工艺将持续生产满足其预先确定的说明和质量属性”（6）。工艺验证是现行良好生产工艺21CFR第210和211部分的要求，终端产品用于临床试验或商务销售。为了帮助制药生产商遵照要求，FDA在1987年发布了“概述一般原则...认为工艺验证原理可以接受”的指导方针。本文件我们给出了FDA指导方针所概述的一般原则的工业观点，该观点应用于验证切向流过滤（TFF）工艺的特定问题。Tangentialflowfiltration,atermsynonymouswithcrossflowfiltration,isfiltrationinwhichthedrivingforceforflow(transport)offluidacrossthefilter(membrane)isprovidedbyapressuresourcewhichisusuallyamechanicalpump.InTFFthepumpisalsousedtodrivefluidflowparallel(tangential)tothemembranesurfacewhichremovesmaterialsatthemembranesurfacetoreduceconcentrationpolarizationofthefilter(Fig.1).Onlyaportionofthefluidpassesthroughthemembraneasthefluidrecirculatesthroughthesystem.TheexactmechanismsandequationswhichdescribethepolarizationprocessandsubsequentlythemodeofactionofTFFhavebeenextensivelyresearchedanddiscussedinthechemicalengineeringliterature(7)andwillnotbediscussedinthisdocument.TFFisaversatiletechniquewhichhasproveneffectiveinawidevarietyofBiopharmaceuticalapplicationsincluding:removingorconcentratingwholecellsorinsolublelysedcellcomponents,concentrationofmacromolecules,bufferexchange,anddepyrogenation.术语切向流过滤和交叉流过滤同义，其中，压力源提供的驱动力使液体流（运输）穿过过滤器（薄膜），压力源通常是一个机械泵。在TFF中，该泵也用于推动液体流与薄膜表面相平行（相切），从而移除了膜表面的物质，以减少过滤器浓度的极化（图表1）。液体通过系统再循环时，只有部分液体穿过薄膜。精确的原理和方程式式描述了极化工艺，随后，TFF的运行模式已经过广泛研究并在化学工程文献中进行论述。TFF是一种多用途技术，多种生物制药的应用有效证明了这点，包括：移除或浓缩整个细胞或不可溶解的细胞成分、大分子浓缩液、缓冲液交换和去除热源。III.ValidationofGenericTFFEquipment一般TFF设备的验证A.InitiationofaValidationProject启动验证项目Thefirststepinanytaskistoassignresponsibilityforthedesign,planning,execution,andfinalapprovalfortheproject.Therolesperformedbygroupsandindividualsinvalidationprojectswillvaryamongorganizationsdependingontheorganization'soverallvalidationexperienceaswellasthespecificexpertiseexistingwithintheorganization'sgroupsatthetimetheprojectisinitiated.Typically,therewillbeavalidationmanagerwhodrawsuponappropriateexpertisefromEngineering,QualityControl,Regulatory,ProductionandProcessDevelopmenttoassistinthevariousphasesofavalidationprogram.Oftenvendorexpertiseisusedtocomplementin-houseexpertise