制药用水系统介绍

•PharmaceuticalWaterSystems制药用水系统©AlfaLavalSlide2Waterstorageanddistributionsystem水的贮存和分配系统•Themostcommonandwellknownsysteminthepharmaceuticalindustry.是最常规的•Still,manyconfusionsonhowtoselectthemostsuitable,hygienicandcosteffectivesolution然而，在怎么选择最合适、卫生和成本、效能方面最困惑•Thekeyistounderstandthebasicprinciple关键是要懂得基本的原理©AlfaLavalSlide3FeedwaterReverseosmosisElectro-deionisationTankDistillationsystemTankWaterpurification&distributionloop纯化和分配PurificationprocessDistributionloop©AlfaLavalSlide4Definitions定义ISPEdifferentiatebetweenthreetypesofwater:ISPE区分三种水：•USPPurifiedWater(PW)美国药典的纯化水（PW）•USPWaterforInjection(WFI)注射水•Non-compendialwater(RO,DI,etc.)饮用水©AlfaLavalSlide5SterilebulkAPIorBPCWFI&PW,inpracticeWFI和PW的使用InjectabledosageformWFINon-injectabledosageformPWBulkAPIorBPCSuitablenon-compendialAPI=ActivePharmaceuticalIngredient活性药用成分（原料药）BPC=BulkPharmaceuticalChemical（医药中间体）MinimumwatertypeEquipmentcleaningandrinsingISPErecommendationISPE推荐©AlfaLavalSlide6USPSpecifications定义:PWvs.WFI*In-linemeasurement,fromequivalentvaluesfromUSPtableCFU=ColonyFormingUnitsAllPharmaceuticalwatermustalsomeettheEPAstandardformicrobiologicalqualityofpotablewaterPW(PurifiedWater)WFI(WaterforInjection)WaterconductivityandpH1,3μS/cmat25°C*pH5-71,3μS/cmat25°C*pH5-7TotalOrganicCarbon(TOC)0.5ppm0.5ppmAerobicMicrobialContamination100CFU/ml10CFU/100ml(0.1CFU/ml)EndotoxincontentNotSpecified0.25EU/mlProductionMethodsObtainedbysuitableprocessObtainedbysuitableprocessandpurifiedbydistillation.©AlfaLavalSlide7Bacteriabasicsforwatersystems水系统中的微生物基本知识•AerobicBacteria好氧菌–GramNegative葛兰氏阴性菌–GramPositive葛兰氏阳性菌•Endotoxin内毒素•Biofilm生物膜©AlfaLavalSlide8Bacteriabasicsforwatersystems水系统中的微生物基本知识MostcommonbacteriainpharmaceuticalwatersystemsareGramnegativebacteria.Gramnegativebacteriadonotgrowabove60ºC,however,cautionsforGrampositivebacteria,whicharemoreheatresistant,shouldbetakenandperiodicsanitizationandtestproceduresarerecommended.通常在水系统中的微生物多为葛兰氏阴性菌，在高于60ºC情况下不生长，然而，对于耐热菌，建议要定期清洁处理Bacteriainpharmaceuticalwatersystemsgenerallyrangefrom0,3m–5m.水系统中的微生物大小通常在0,3m–5m©AlfaLavalSlide9Bacteriabasicsforwatersystems水系统中的微生物基本知识KilledGramnegativebacteriareleasesendotoxins,whichisalipopolysaccharidemoleculethatcausefeverwheninjectedintothebloodstream.(Thesesubstancesaretermed”pyrogens”meaninggeneratingheat,fever).Pyrogenshavealsobeenlinkedtomoreseriousreactionswheninjectedintotheblood(e.g.lethalsepticshock)andareamajorconcernforeverydosageformincontactwiththebloodstream.杀死葛兰氏阴性菌会释放内毒素，内毒素是一种多糖分子，当内毒素被注射入血液时，就会导致热病。（这些物质的学术术语为“热源”，即产生热量，发热的意思）Endotoxinsareheatstable(boilingfor30minutesdoesnotdestabilizeendotoxin沸腾30分钟不能降解内毒素),butcertainpowerfuloxidizingagentssuchassuperoxide,peroxideandhypochlorite,degradethem.内毒素是热稳定性物质，但过氧化物、次氯酸盐能够降解EndotoxinsarecommonlyremovedbyRO,UF,(UV*)andflushing通常RO、UF(UV)和冲洗能够去除内毒素*ArguedbysomeUVmanufacturer©AlfaLavalSlide10Bacteriastructure细菌结构ProfilesofthecellenvelopetheGram-positiveandGram-negativebacteria.TheGram-positivewallisauniformlythicklayerexternaltotheplasmamembrane.Itiscomposedmainlyofpeptidoglycan(murein).TheGram-negativewallappearsthinandmultilayered.Itconsistsofarelativelythinpeptidoglycansheetbetweentheplasmamembraneandaphospholipid-lipopolysaccharideoutermembrane.Thespacebetweentheinner(plasma)andoutermembranes(whereinthepeptidoglycanresides)iscalledtheperiplasm.Gram-positivecellwall葛兰氏阳性菌细胞壁Gram-negativecellwall葛兰氏阴性菌©AlfaLavalSlide11Bacteriabasicsforwatersystems水系统中的微生物Inordertogrowinnatureorinthelaboratory,abacteriummusthave:微生物为了生长，必须具备：•anenergysource能量来源–asourceofcarbon碳源–otherrequirednutrients其他要求的营养源•apermissiverangeofphysicalconditionssuchas理化条件–O2concentration氧浓度–Temperature温度–pH©AlfaLavalSlide12BacteriaandpH微生物和pHGrowthratevs.pHforthreeenvironmentalclassesofprocaryotes.原核生物在不同pH条件下的生长速率©AlfaLavalSlide13BacteriaandTemperature微生物和温度Growthratevstemperatureforfiveenvironmentalclassesofprocaryotes.Mostprocaryoteswillgrowoveratemperaturerangeofabout30degrees.原核生物在不同温度下的生长速率比较，适宜温度大多数在30度左右©AlfaLavalSlide14BacteriaandTemperature微生物和温度Pharmaceuticalwatersystemsareverylowinorganicmaterials,mineralsandsalts.TheseconditionsarenotsuitableforThermophilicbacteria,whichrequireveryuniquephysicalconditions.制药用水中有机物、矿物质和盐含量非常低，不适宜嗜热菌的生长AlsothePsychrophilicbacteria,whicharemainlyfoundiniceandmeltwater,areseldomfoundinpharmaceuticalwatersystems.很少在制药用水系统中发现主要生长在冰水中的喜寒性菌ThisonlyleavestheMesophilicbacteriaasthemaincandidateforbacteriathatarefoundinpharmaceuticalwatersystems.这样在制药用水系统中主要考虑的就是嗜温菌©AlfaLavalSlide15BacteriaandTemperature微生物和温度Optimunanduppertemperaturelimitsforgrowthofsometypicalpurewaterorganimsandpathogens:不同微生物的生长适宜温度：BacteriumOptimum(°C)/Upper(°C)Escherichiacoli37/45(埃希氏菌)Staphylococcusaureus30-37/45(葡萄状球菌)Pseudomonasmaltophilia35/41(嗜麦芽假单胞菌)Pseudomonasaeruginosa37/42(绿浓杆菌)Pseudomonasfluorescens25-30/39(荧光假单胞菌)Vibriocholerae18-37/43(霍乱孤菌）Listeriamonocytogenes30-37/45（单核增生性李斯特菌）Campylobacterjejuni37-42/45（空肠弯曲菌）Bacilluscereus28-42/55（蜡状芽孢杆菌）Clostridiumperfringens37/50（产气英膜梭菌）Shigellaspp.35-37/47（志贺菌）©AlfaLavalSli