使用一次性技术的单克隆抗体生产设施--Vice+President+(VP)+副总裁2012.4.17.ppt

CHINAANNUALCONFERENCE16th17thApril2012,Beijing,MAbSingleUseTechnologyFacilities使用一次性技术的单克隆抗体生产设施,NielsGuldagerSeniorTechnologyPartner,Biopharmaceuticals资深生物制药专家NielsUlrikHaxthausenVicePresident(VP)副总裁NNEPharmaplan恩宜珐玛,1,Outline概要,Biotech-trendsandchallenges生物技术-趋势和挑战TheMAbcase单克隆抗体案例FacilityoftheFuturebasedontheISPEguideline未来的生产设施基于ISPE准则3ManufaturingOperationsandActivities生产运营和活动4ProcessandEquipment工艺和设备5Processsupportandutilities工艺支持和公用工程6Facilitydesign厂房设计7Processcontrols+QualitybyDesign&ASTME2500工艺控制+质量源于设计&ASTME2500Howfarcanwestandardize?我们什么时候能达到标准化？,2,NielsGuldager,NielsisaseniorconsultforbioprocessandtechnologyatNNEPharmaplan.Hehas16yearsofexperiencewithoperationanddesignofbiopharmaceuticalprocesses.NielshasspearheadedtheimplementationanddevelopmentofnewconceptswithinsingleusetechnologyandwithintheapplicationofQualitybyDesignandASTME2500.Niels是恩宜珐玛公司生物工艺和技术领域的高级顾问。他在生物制药工艺的设计和运营领域有16年经验。他是实施和开发一次性使用技术，质量源于设计和ASTME2500应用的先驱。Nielsiscurrentlyengagedincollaborativewritingeffortsfortaskforceandbaselineguidegroups.HeholdstheCertifiedPharmaceuticalIndustryProfessionalcertificationfromISPE.目前他负责专案组和基准指南小组的协同写作工作。他持有ISPE认证的“制药行业专家”证书。,3,Biotechnology-challenges生物技术-挑战,ModernproductiontechnologiesandnewfacilitydesignphilosophieshavethepotentialtorevolutionizethebusinesscaseforBiopharmaceuticaldevelopment,launchandproductionfacilities.现代生产技术和新建生产设施设计理念具有改革生物制药开发，上市和生产设施的潜能。BringingBiopharmaceuticalproductsfromdevelopmenttoproductionintroducesconsiderationsaboutthelongtemfacilitylifecycleandhowapragmaticfutureorientedperspectivecanensureprojectsuccess.生物制药产品从开发到生产要考虑生产设施的长期生命周期和实际着眼于未来的能保证项目成功的因素。Thechallengeisnotonlyprocessandtechnologydrivenfactorslikequalitysystem,analyticalprogram,technologytransferandorganizationalcompetencesarealsopartofthesynthesisnecessaryforsuccessfulbridgingfromdevelopmenttocommercialproduction.所面临的挑战不仅是工艺和技术为导向-质量体系，分析程序，技术转让和组织能力等因素也是成功的从开发到商业化生产的综合必要因素。,4,MonoclonalAntibodies单克隆抗体,FacilityoftheFutureContinuedgrowthinMabbut:TheparadigmswillshiftThemarketwillbemuchmorefragmented单克隆抗体技术生产设施在未来的发展-但是模式将变化市场将会变得更加散乱无序,5,Solidtumours实体肿瘤:12Head/neckcancer头颈癌:3Leukemia白血病:17Lungcancer肺癌:15Pancreticcancer胰腺癌:9Colorectalcancer肠癌:10Kidneycancer肾癌:5Prostatecancer前列腺癌:5Sarcoma恶性毒瘤:4Cancer/chemotherapy癌症/化疗relatedconditions相关情况:2Unspecifiedcancers未定义的癌症:5*Drugsthathavepotentialforoneormoreofthementionedcancers*表示有可能治疗上述提到的一种或者几种癌症的药物,MAbsforcancertreatment-manyproducts,smallervolumes单克隆抗体用于癌症治疗-多种产品,小剂量,Braincancer脑癌:8Breastcancer乳腺癌:10Ovariancancer卵巢癌:7Livercancer肝癌:4Bladdercancer膀胱癌:1Stomachcancer胃癌:4Othercancers其他癌症:10Multiplemyeloma多发性骨髓瘤:7Lymphoma淋巴瘤:22Skincancer皮肤癌:3,Source:Nearly900MedicinesandVaccinesinTestingOfferHopeinthefighAgainstCancer,2011reportfromAmericasbiopharmaceuticalresearchcompanies),887newcancertreatmentproductsarecurrentlyindevelopment-approximately200ofthesearemonoclonalantibodies:目前正在研发的治疗癌症的新药有887种-其中大约200种是单克隆抗体,6,7,创新的生物制药可以治疗那些致命的或是十年前严重降低生活质量的疾病。但是，现实是并不是所有人都能拥有这些创新药。,ContinuedGrowth-PatentExpiries持续增长-专利到期,Source:,Top10pharmaceutials2011andtheirpatentexpiries2011年前十位制药企业以及他们专利到期的时间,MAbsindicatedingrey灰色表示单克隆抗体,8,9,Mabs:YieldIncreasesChangesPerspectives单克隆抗体:提高产量改变前景,Case:CrucellPER.C6:案例:CrucellPER.C6-Humanorigincellline,human-glycosylationpattern人原代细胞系,人糖基化模式-Proteinproductionplatform:Therapeuticprotein,MAbs,virus蛋白质生产平台：治疗型蛋白质,单克隆抗体,病毒-6-8g/literfedbatch6-8克/升一组-ExtremeDensityprocess:15-27g/literatharvest高密度工艺:收获15-27克/升,Newcelllines新细胞生产线Mediaoptimizationandprocessunderstanding培养基优化和对工艺的理解MAbs:Frommgs/literto5-10-15-25g/literreported单克隆抗体:从毫克/升至5-10-15-25克/升的报告,Case:LONZAGSexpressionsystem:案例：LONZA谷氨酰胺合成酶表达系统：-Morethan100Xincreaseover1990scelllineyields细胞株系的产量比20世纪90年代增长了100倍,Convergingforcefield趋同的领域,1Manynewproductswillcompeteonsamemarket,sosmallervolumesneeded许多新产品在同一市场竞争，因而需要小剂量产品200+newMAbbasedproductsindevelopment超过200种单克隆抗体产品正在研发中Bio-similarlegislationindevelopmentorapprovedfromEU,JP,US,WHO生物仿制药的法规正在完善中或者已经获得欧盟,日本,美国和世卫组织批准Localproductioncapacitymayberequiredforentrytosomemarkets为了进入一些市场可能需要增强本地生产能力Investorsinemergingmarketseeahugeopportunityfor“quick”entryinbiotech新兴市场的投资者在快速进入生物科技行业中发现了巨大的机会Bioreactoryieldincreases生物反应器产量增加Singleusetechnologyandincreasedyieldsreducetheinvestmentlevelsdrastically一次性使用技术和增加的产量导致投资水平急剧下降Singleusetechnologygivesflexibilitytocovervariationsinplatformprocesses一次性技术为平台工艺的多样化提供了灵活性,10,ANewParadigm新的模式FromMegafacilitiestoSmall,SingleUseTechnologyUnits:从大规模设施到小规模,一次性使用技术单元,Duetoyieldincreases,thereisahugeovercapacityinthemarketsonovolumegrowthintheexistingfacilitiesinEU/US.由于产量增加，市场上产能过剩-所以欧盟和美国的现有设施没有增长的空间Theexistingfacilitiesaredesignedforlowyields(3g/l)几乎所有的新设施都追求一次性使用技术-追求更高的产量(3g/l)Theshifttobio-similar,andtomoreorlessprotectionistemergingmarketscreatesabigdiversification向仿制药的转换，而且对新兴市场或多或少的贸易保护造成了市场巨大的多元化Result:Anumberofsmallerunits.结果:一系列更小规模的单元,6years.1Bill$,1-2years50mill$,11,Tomorrowistoday明天源于今天,SingleUseMAb次性技术单克隆抗体,OthersingleuseBiotech其他一次性使用生物技术,12,2FacilityoftheFuture未来的生产设施,Impactofsingleusetechnology一次性使用技术的影响,13,14,ISPEBaselineGuidevolume6:ISPE基准指南第六卷BiopharmaceuticalManufacturingFacilities生物制药生产设施,June20041stedition.Scheduledforupdatesoon.2004年6月第一版，预计会在近期更新Jointeffortbetweenindustryandregulators行业和监管机构之间的共同努力Updated2ndeditionwillmuchmoreonclosedsystems,singleusetechnology更新的第二版将更多关注封闭系统和一次性使用技术Contents内容3ManufaturingOperationsandActivities生产运营和活动4ProcessandEquipment工艺和设备5Processsupportandutilities工艺支持和公用工程6Facilitydesign生产设施设计7Processcontrols工艺控制isnotalistoffinalanswers,butinputfor:这不是最终答案，但是是为了Careful,riskbasedapproach谨慎，基于风险的方法Regulatoryandqualityconcerns关注的法规和质量Safetyrequirements安全要求Pointstoconsider需要考虑的要点Regionaldifferencesinrequirements要求的区域差异,FacilityoftheFuture(1)未来的设施(1),Standard标准Processcoreisstandard-supportfunctionsareadaptableforlocalconditions工艺核心是标准-支持功能要能适用本地条件Equipment,documentationandproceduresbasedonplatformprocess设备,文件记录和规程都基于平台工艺Fast快速ReadyforPQwithin12-18monthsfromapprovedconcept基于批准的概念，12-18个月内可完成性能确认之前的所有工作Singleusetechnologyreducesvalidationandinstallation一次性使用技术减少了验证和安装工作Flexible灵活Flexibilityandadaptabilityinherentinsingleusetechnologies灵活性和适应性依赖于一次性技术,15,Standardfacilityoutput标准设施产量,Annualoutput(bulkAPI)年产量Upto200kgMAbinstandardmode使用标准模式生产的单克隆抗体产量达到200公斤Upto400kgMAbinupgradedmode使用升级后的模式达到400公斤(attiter3g/L,70%overallyield,90%facilityutilization)(滴定量3g/L,总产率70%,设施利用率90%）Sufficienttomeetannualdemandforallbutbiggestsellingproductstoday现在除了大规模销售的药品，足够满足每年的需求,16,Capacity产能,Installedcapacity安装能力Initial初始阶段2SUBBioreactorgroupsof:1x50L+1x200L+2x1000L2个一次性生物反应器组：1x50L+1x200L+2x1000LTotalproductioncapacity:4x1000LSUBs全部产能：4x1000L一次性生物返应器Upgrade升级Upgradeableto4x2000LSUBsbysubstition可通过替换升级到4x2000L的一次性生物反应器(20L-100L-500L-2x2000L),17,18,19,ISPEBaselineGuidevolume6:ISPE基准指南第六卷3ManufacturingOperationsandActivities生产运营和活动,Concerns担忧：Processdesignistiedtofacilitydesign工艺设计与设施设计紧密结合Openprocessingplacesmorefocusonprocessesandpeople开放式操作区更多关注工艺和人员Hugedifferencebetweensingleproductandmultiproductfacility单一产品和多产品生产设施之间的巨大差异Viralclearance病毒清除,SingleUsetechnologydesignimpact一次性使用技术设计影响,Factorsdifferentfromtraditionaltechnology不同于传统技术的要素Operatorscomeclosetoprocessequipment,touchconnections操作人员接近工艺设备，直接接触设备Manualoperationstoinstall,makeconnectionsanddisassemble安装，链接和卸载的手动操作Transparencyvisualcontactdesirable(notcritical)透明度优良的虚拟式接触（不是关键因素）Limitationsinpressures,flows,massandheattransfer压力，流量，数量和传热的限制Transportvolumesanddistancesbecomecritical传输数量和距离成为关键Areafortransportandmaneuveringaround-pipelessplant(forprocess)传输区域和周围机动-无管式设施（工艺）Solidwasteincreased固态废弃增加Consumablesstoragespaceincreased消耗品存储空间增加,20,Flexibility灵活性,Singleusetechnologydecouplestheprocessfromthebuilding一次性技术分离工艺与建筑Thismeansthatflexibilitymainlytakestheformoflowclassificationfloorspace!这意味着灵活性主要采用低分类楼面空间的形式Nocomplexdistributionmatricesasconnectionsareflexible简单式分布矩阵作为链接是灵活的Mediaandbuffersupplyisconfiguredtothegivenprocess培养基和缓冲液供应被设置为特定工艺Canstartwithonlyeg.500Lbioreactortrainandexpandrapidly能够从只有500L的生物反应器开始培养和快速扩张2000Lfootprintisnotdrasticallylargerthan500Lfootprint2000L占地面积不大于500L的占地面积Alotofproductionpowerinasimplefacility在简单的生产设施里包含大量生产能力,21,22,ISPEBaselineGuidevolume6:ISPE基准指南第六卷4ProcessandEquipment工艺和设备,Concerns担忧Specificequipmentdesignconsiderations特定设备的设计考虑Controllingcriticalprocessparameters关键工艺参数控制Equipmentcleanability设备清洁性Equipmentshareduse设备共享使用Maintenanceoperationsimpactingproduction维护操作影响生产,NielsGuldager,nguMAbsingleusetechnologyfacilities,Chinapharm2011,23,Designfactors:设计要素Trend:HTSTmediatreatment趋势：HTST培养基处理Mediatowers培养基存储器Shelflife存储期限,23,NielsGuldager,nguMAbsingleusetechnologyfacilities,Chinapharm2011,24,Designfactors:设计要素Transportforharvestbag收获袋的传输Depthfiltersdismantled深度过滤器的拆除ConsiderincludingproAstep考虑包括proA步骤,24,ISPEBaselineGuidevolume6:ISPE基准指南第六卷6Facilitydesign设施设计,Concerns担忧Segregationandflowpatterns隔离和流向模式Layoutprinciples布局原则Areaclassifications区域分类Horizontalandverticalarrangements横向和纵向安排,25,NielsGuldager,nguMAbsingleusetechnologyfacilities,Chinapharm2011,26,Mediatowers培养基存储器,Bioreactors生物反应器,Buffertowers缓冲液存储器,Chromskids色谱板,Wastecontrol废弃物控制,Sideviewmedia/bufferprepprocessinterface侧视图培养基/缓冲液准备工艺接口,FacilitydesignFloorspaceforinspection,cleaning,transportHandlingsolidwasteincontrolledmannerExtrafloorspaceisflexibility(justaddmorebags)DaylightforintensiveoperationsProcessflowunidirectional,26,NielsGuldager,nguMAbsingleusetechnologyfacilities,Chinapharm2011,27,OverallResultingPhilosophy总体结果模式,Processsupportandutilities/FacilitydesignQuality:Flowfromdirty(powders)tocleaner(endproduct)Ergonomics:Flowfrombigtosmallvolumes/loads,27,28,ISPEBaselineGuidevolume6:ISPE基准指南第六卷5Processsupportandutilities工艺支持和公用工程,Concerns担忧WFIorpurifiedwater?注射用水或是纯净水？Riskofcontaminationfromsharedsystems来自共享系统的污染风险Designconsiderationsforcleanutilitysystems清洁公用工程系统的设计考虑Biowastehandling生物废料的处理,Localconditions当地条件,Classificationapproach:conservativeoraggressive洁净模式:保守还是激进Mediaandwateravailableaspreproduced可用的作为预生产的培养基和水Fill-finishy/n:灌装Warehouse:仓库Onsitey/n:现场Blackutilities非洁净公用工程QC-laboratoryQC实验室R&DlaboratoryR&D实验室PDpilotplantPD中试厂Clinicalpilotplant临床中试厂Administration,reception行政，前台Standardisadaptable:Siteinterfaces,buildinglevels标准化是具有灵活性的：现场接口，建筑层数,ProcesssupportandUtiltitiesSimplifysupplyinfrastructurebyplacingbiguserstogetherSeparatedispensingforgoodhousekeepingProvidestructuredwarehousearrangementSufficientlocalstorageforSUconsumables,29,ISPEBaselineGuidevolume6:ISPE基准指南第六卷7ProcessControls-QbDandASTME2500工艺控制质量源于设计和ASTME2500,Concerns担忧Identifythecriticalparametersbasedonscience&risk确定关键参数-基于科学和风险Knowyourproductspecificsbutleveragethecommonalities(startingpoint:theA-Mabstudy)知道你的产品细节-但是要利用共性（起点：一个单抗案例研究）Whatneedstobequalifiedinthefacilityandwhatisconsumables&operations生产设施里需要配备什么-什么是消耗品及营运Leachables&extractibles浸出和提取,30,RawMaterials&DisposablesSourcing原材料&废弃原料,Operationalknowhow操作技能,MarketKnowledge市场知识,Regulatoryfiling依法申报,Product&Processdevelopment产品/工艺研发,ClinicalMaterial临床材料,QualitySystems质量系统,GMP&QbDGMP&质量源于设计,Training培训,FacilityApproval设施批准,FacilityDesign生产设施设计,Construction施工,Validation验证,TheRoadtoCompliantproduction符合生产之路,31,Standard?YES&NO.是否要标准化？,AstandardfacilityforMabproductioncanbedefinedbut:可以定义单克隆产品的标准生产设施，但是Anumberoffactorswilldrivedifferentiationinincreasingimpactorder:许多因素将导致差异-以下因素按影响递增排序Sizematters尺寸因素Specificprocesses&specificyieldsmatters具体工艺&具体产量因素Countrymatters:国家因素Localregulations&practices当地法规Levelofregulatoryacceptance监管机构认可的水平Supplychain供应链Sitematters现场因素Availablefaciltitesclean&blackutilities,canteens,.可用的生产设施洁净和非洁净公用工程，食堂ExistingfunctionsQC,qualitysystems,maintenance,.现有的功能QC,质量体系，维修CompanyMattersVERYMUCH公司因素很多Start-uporglobaldeployment公司启动或是全球发展Existingcompanyknowhowandpractice现有的公司专有技术Internalregulationsandprocedures内部规范和流程Conservatismorrisk&changepreparedness做好保守主义或是冒险变革的准备Sowhatstaysstandard?那什么要保持标准化？,32,BiotechonDemand按需设计的生物科技设施,Fast,affordablestandardfacilities快速经济的标准设施Highpredictabalityinprice,timeandquality价格,时间和质量的可预测性Configurabletomeetlocaldemands,siteconditionsandreso