血液的體積和組成

血液旳體積及組成70公斤重旳成年男子具有5公升旳血量。含紅血球、白血球及血小板。成年人血漿(plasma)佔(zhàn)全身血液總量旳50~60%。血漿旳大部分是水，水重要作為溶劑。血漿呈淡黃色，其中具有數(shù)百種血漿蛋白，涉及白蛋白(albumin)、球蛋白(globulins)及纖維蛋白原(fibrinogen)。1第1頁人類血漿之特異性是一種非常豐富及複雜之生物來源物質(zhì)。含超過100~200種以上不同旳（醣）蛋白（涉及凝血因子，蛋白分解酵素克制劑，蛋白分解酵素，免疫球蛋白），白蛋白，peptide，生長因子….。約17~20種血漿成分已建立治療價(jià)值。是一人類治療所必需旳兵工廠。2第2頁血漿來源SourcePlasma(fromplasmapheresis)RecoveredPlasma(fromwholeblooddonations)3第3頁血液旳功能運(yùn)送細(xì)胞旳產(chǎn)物及廢物，並將養(yǎng)分及氧氣送到細(xì)胞。血液內(nèi)吞噬細(xì)胞旳功用除了如清道夫外，並且能抵御外來旳感染。為運(yùn)輸激素旳途徑。平衡穩(wěn)定體內(nèi)旳pH值。將體熱帶到皮膚發(fā)散以維持體溫恆定。4第4頁5第5頁6第6頁7第7頁Takeabreak!8第8頁9第9頁10第10頁11第11頁12第12頁Virusestransmissibleviabloodandplasmaproducts13第13頁HumanVirusesofConcern

WithRespecttoPlasmaDerivativesEnvelopedVirusesHumanImmuneDeficiencyVirus(HIV)HepatitisB(HBV)HepatitisC(HCV)Non-EnvelopedVirusesHumanParvovirusB19(B19)HepatitisA(HAV)NotSignificientRisksHumanT-lymphotrophicvirus(HTLVI&II)Cytomegalovirus(CMV)EpsteinBarrVirus(EBV)UnmeasurableRisksTransmissibleSpongioformEncephalopathies(TSE,esp.CJD)Unidentifiedand/oremergingagents14第14頁SignificanceofViralEnvelopeProteinnecessaryforattachmentandpenetrationofhostcellsareonthesurfacesofviruses.Non-envelopedvirusestendtobemoreresistanttophysico-chemicalconditions(heat,solvent-detergent).Thesmallestvirusesarenon-enveloped.15第15頁DonorScreeningforViralContamination16第16頁GeneralSafetyMeasuresScreeningdonorsMaintainingdonordeferralregistriestoeliminateunsuitabledonorsfromtherollsTestingbloodandplasmadonationsTestingpools,intermediates,and/orfinalcontainersViralclearancestepsinmanufacturingMonitoringandinvestigatingadverseincidentstoensurethatdeficienciesarecorrected17第17頁WhatisaPrion?proteinaceousinfectiousagentresiststreatmentsthatdestroynucleicacidsdestroyedbytreatmentsthatdegradeproteinderivedfromtheprionprotein(PrP)isoformofPrPc/subfractionofPrPscpartiallyresistanttoproteinases18第18頁19第19頁ViraleliminationtreatmentsofplasmaproductsSpecificNanofiltration:filtrationofaproteinthroughamembrane/hollowfiberwithanominalporesizeofafewnanometers(intherangeof15to40nm)inconditionswhereproteinsmigratethroughthenanofilterwhilevirusesareretainedNonspecific:Chromatography,PrecipitationUltrafiltration20第20頁MostfrequentlyusedspecificviralinactivationtreatmentsofplasmaproductsAcidpH(IgG)Incubationoftheproteinsolution(IgG)atpH4,withorwithoutthepresenceoftracesofpepsin,at37oCfor22hoursormore.21第21頁MostfrequentlyusedspecificviralinactivationtreatmentsofplasmaproductsSolvent-DetergentIncubationofanhomogeneousplasmaproteinsolutioninthepresenceofanorganicsolvent(trin-butylphosphate)andadetergent(Tween80;TritonX-100)for4-6hoursat25to35oC.22第22頁MostfrequentlyusedspecificviralinactivationtreatmentsofplasmaproductsDryHeatTreatmentHeat-treatmentofalyophilisedproteinproductorfraction(drystate)fromseveralminutestoseveraldaysattemperaturesfrom60to100oC23第23頁MostfrequentlyusedspecificviralinactivationtreatmentsofplasmaproductsPasteurizationHeat-treatmentofanhomogeneousproteinsolution(liquidstate)for10hoursat60oC,generallyinthepresenceofstabilizers(sugars,amino-acids,polyols,…..)24第24頁ViralClearanceClearance=Inactivationand/orRemovalIndividualmanufacturingsteps:

-specificallydesignedforviralclearance-intendedprimarilyforpurificationEachclearancestepisseparatelyvalidatedProductionmethodsandpracticesmustconformtovalidatedmethods25第25頁ViralClearanceValidationI:Scale-downNecessity:-Undesirabletointroducevirusesintoproductionfacilities;-Limitedabilitytoproducelargeamountsofhightiterviruspreparations;-Risktolaboratoryworkers.Requirements-Labprocessmimicsproductionscale(relativegeometries,volumes,flowrates,etc.)-Labprocessperformslikeproductionprocess(relativecapacity,yield,purification,etc.)26第26頁ViralClearanceValidationII:SelectionofrelevantandmodelvirusesTypically,severalvirusesareselectedtoencompasstheanticipatedrisks.Relevant=avirusthatmaybefoundinthebloodorplasma.Model=alaboratorystrainofavirusnotnecessarilyfoundinthebloodorplasma.27第27頁ClassificationforbiologicalproductsClassIProductsderivedfromhumantissuesorfluids:(plasmaderivatives,hormonesfromurine,placentalderivatives,etc.)Riskencountered:nospeciesbarrier,unknownviruses.Viralsafety:screeningofthedonorsandthecapacityoftheprocesstoeliminateand/orinactivateviruses.28第28頁ClassificationforbiologicalproductsClassIIViralvaccines:killed(inactivated)andliveattenuatedvaccinesRiskencountered:Presenceofresidualactivevirusinkilledvaccines(Cutterincident-1953);reversiontovirulenceoftheattenuatedstrainsorafailureinGMP.Viralsafety:Controloftheinactivationprocedureandgeneticstabilityoftheattenuatedviruses.29第29頁ClassificationforbiologicalproductsClassIII

Productsderivedfromanimaltissuesandfluids:collagen,heparins,animalimmunoglobulins,monoclonalantibodiesproducedinascites,etc.Riskencountered:Presenceofvirusesinthestartingmaterial;thescreeningforviralmarkersofthesourcematerialisnotfeasible.Viralsafety:Thereisthespeciesbarrier.Viralsafetyisbasedsolelyonthecapacityoftheprocesstoremoveand/orinactiveviruses.30第30頁ClassificationforbiologicalproductsClassIV

Productsderivedfromanimalcellcultures:proteinsobtainedbyrDNA,monoclonalantibodies,cytokines..Riskencountered:Presenc