PDATR-29清潔驗(yàn)證中英對(duì)照（第一章-簡(jiǎn)介）

1.Introduction介紹1.1Background背景Inrecentyears,cleaninghasachievedapositionofincreasingimportanceinthepharmaceuticalindustry.Thecurrentgoodmanufacturingpractices(CGMP)regulationsrecognizethatcleaningisacriticalissuetoensureproductquality.Virtuallyeveryaspectofmanufacturinginvolvescleaning,fromtheinitialstagesofbulkproductiontothefinaldosageform.近年來(lái)清潔作業(yè)逐漸在制藥界占有重要的地位。現(xiàn)行的GMP法規(guī)也指出清潔作業(yè)是保證產(chǎn)品質(zhì)量的關(guān)鍵性工作。自大宗原料的生產(chǎn)以迄最終劑型的制造作業(yè)，幾乎每一個(gè)制造工序均含有清潔作業(yè)。TheCGMPsintheUnitedStates,Europeandotherpartsoftheworldhaveprovidedthepharmaceuticalindustrywithgeneralguidanceforcleaningrequirements.Forexample,intheU.S.,section211.67ofpart21oftheCodeofFederalRegulations(CFR)statesthat"Equipmentandutensilsshallbecleaned,maintained,andsanitizedatappropriateintervalstopreventmalfunctionsorcontaminationthatwouldalterthesafety,identity,strength,quality,orpurityofthedrugproductbeyondtheofficialorotherestablishedrequirements."Section211.182ofpart21oftheCFRidentifiesthatcleaningproceduresmustbedocumentedappropriately,andthatacleaninganduselogshouldbeestablished.InadditiontoCGMPs,variousinspectionalguidelinedocumentspublishedbytheFDAcontainexpectationsregardingcleaninginthepharmaceuticalindustry.CleaningisalsoaddressedinthePICrecommendationsoncleaningvalidationandintheSFSTPCommissionreport"Validationdesprocédésdenettoyage."美國(guó)、歐洲及全球其他地區(qū)均有制藥界清潔作業(yè)的通則性指南。例如，美國(guó)聯(lián)邦法規(guī)21章211.67小節(jié)描述設(shè)備和器具應(yīng)每隔適當(dāng)?shù)臅r(shí)間予以清潔、維護(hù)消毒處理，以防止其故障或污染而可能造成藥品安全性、效價(jià)、質(zhì)量或純度超購(gòu)法定或其他既定的標(biāo)準(zhǔn)。美國(guó)聯(lián)邦法規(guī)21章211.182小節(jié)明確指出清潔及使用日志。除了CGMP之外，F(xiàn)DA亦頒布各種包含F(xiàn)DA對(duì)于制藥業(yè)清潔作業(yè)之期許的檢查指南。另外，在PIC對(duì)于清潔驗(yàn)證的建議以及SFSTP委員會(huì)報(bào)告"Validationdesprocédésdenettoyage"中，低于清潔作業(yè)亦有所規(guī)定。程序應(yīng)適當(dāng)?shù)奈募?，并?yīng)建立清潔作業(yè)方法IthasalwaysbeentheresponsibilityoftheregulatedindustryandtheregulatoryagenciestointerprettheCGMPsandtocreateprogramsandpolicieswhichestablishthegeneralrequirementsasspecificpractices.Recognizingtheimportanceoftherelationshipbetweencleaningandproductquality,regulatoryagenciesaredemandinggreaterevidenceofcleaningeffectivenessthroughvalidationorverification.對(duì)CGMPs的解釋以及制理當(dāng)局的職責(zé)?；趯?duì)清潔作業(yè)查核證實(shí)以獲致大量有關(guān)清潔有定計(jì)劃與建立特定作業(yè)定的政策，一直是受法規(guī)約束之業(yè)者與管與產(chǎn)品質(zhì)量的重要關(guān)據(jù)。之通則性規(guī)系型的認(rèn)知，管理當(dāng)局乃要求必須經(jīng)由確效或效性的證

1.2Purpose目的Thepurposeofthispublicationistoidentifyanddiscussthemanyfactorsinvolvedinthedesign,validation,implementationandcontrolofcleaningprogramsforthepharmaceuticalindustry.本刊物的目的在于討論制藥工業(yè)清潔程序的設(shè)計(jì)、驗(yàn)證、執(zhí)行與控制的許多重要事項(xiàng)。ThedocumentdoesnotattempttointerpretCGMPsbutprovidesguidanceforestablishingacleaningvalidationprogram.Itidentifiesthemanyfactorstobeconsideredforallsegmentsofthepharmaceuticalindustry.Italsoidentifiesspecificpointstobeconsideredbydosageformmanufacturers,manufacturersofclinicaltrialmaterials(CTMs)andmanufacturersofbulkpharmaceuticalchemicalsandbiochemicals.Thereportcoversthedifferentapproacheswhichmaybeappropriateforthedifferentstagesofproductdevelopmentfromtheearlyresearchstagestothecommerciallymarketedproduct.本文件并不是要解釋CGMPs，而是在于作為建立清潔驗(yàn)證程序的指南。它確定制藥行業(yè)的所有環(huán)節(jié)考慮的很多因素，也指出藥品制劑制造企業(yè)、臨床試驗(yàn)用原料制造企業(yè)及原料藥與生物制品制造企業(yè)個(gè)別所應(yīng)考慮的特定問(wèn)題點(diǎn)。本報(bào)告覆蓋了各種不同的方案，能適用于自早期研究階段至商業(yè)化上市的產(chǎn)品研發(fā)過(guò)程的不同階段。1.3Scope適用范圍Thispaperappliestobiopharmaceutical,bulkpharmaceuticalandfinisheddosageformoperations;liquid,dry,solidandsemi-soliddosageformsarecoveredinbothsterileandnon-sterilepresentations.Bothclinicalandmarketedproductcleaningvalidationprogramsareidentified.本文件適用于生物制藥、原料藥及最終劑型：液體、干品、固體及半固體劑型，包括其無(wú)菌與非無(wú)菌兩種形態(tài)，及臨床試驗(yàn)與上已市兩類(lèi)產(chǎn)品的清潔驗(yàn)證程序Themanufactureofmodernpharmaceuticalsisacomplexprocessinvolvinghighlytechnicalpersonnel,complexequipment,sophisticatedfacilitiesandcomplicatedprocesses.Individualsresponsibleforallaspectsoftheproduction,approvalandvalidationofproducts,suchasqualitycontrol,qualityassurance,engineering,validation,production,researchanddevelopment,contractorsandvendorsandregulatoryaffairspersonnelmayusethisdocumentasaresourceforestablishingorreviewingthecleaningprogramswithintheirfacilities.現(xiàn)代藥品的制造是一種需要高技術(shù)人員、復(fù)雜設(shè)備、精密且復(fù)雜的設(shè)施及復(fù)雜的工藝的復(fù)合式程序。負(fù)責(zé)質(zhì)量、質(zhì)量保證、工程、驗(yàn)證、生產(chǎn)、研發(fā)、接受委托加工、供應(yīng)商及法規(guī)事務(wù)等所有有關(guān)藥品生產(chǎn)、審核及驗(yàn)證方面的人員均可參照使用本文件以建立或復(fù)核其工廠內(nèi)的清潔計(jì)劃。

Thevalidationprogramsdescribedhereinassumethatanoverallvalidationprogramwithappropriatecontrolsisalreadyinplaceforthefacility,utilities,equipmentandprocesses.Thecleaningoftheenvironmentisnotspecificallycovered,howevermanyofthesameconcernsthatareconsideredforthecleaningofprocessequipmentalsoimpactthecleaningoftheenvironment.Themonitoringofmicrobiologicalandendotoxincontaminationandstepsfortheireliminationarementionedinseveralsectionsandshouldbepartofthecleaningvalidationprogram.Howeverthisdocumentisnotintendedtobeacomprehensivetreatiseonmicrobiologicalcontrol,orendotoxinlimitation.Otherdocumentshaveaddressedmicrobiologicalprogramsandmethodsfortheenvironmentalmonitoringwhichcanbeappliedtocleaning.本文件內(nèi)所描述的驗(yàn)證程序是以其場(chǎng)所、公用設(shè)施、設(shè)備及工藝均已經(jīng)過(guò)確認(rèn)與適當(dāng)?shù)目刂茷闇?zhǔn)。雖然本文件并未特別包含環(huán)境清潔，但環(huán)境清潔可參考引用許多已應(yīng)用于制藥設(shè)備的清潔方法。在部分章節(jié)提及的微生物及內(nèi)毒素污染的監(jiān)控與清潔步驟，也必須成為完整的清潔驗(yàn)證程序的一部分。然而，本文件并能擬成為微生物控制和內(nèi)毒素限度的綜合論著，清潔程序也可參照其他專著及微生物與環(huán)境監(jiān)測(cè)方法的文件。1.4ReportOrganization本報(bào)告的組織架構(gòu)Eachofthemajortopicsofthisdocumentstartswithageneralsectionwhichappliestoallsegmentsofthepharmaceuticalindustry.Pointstobeconsideredforspecificindustrysegmentssuchasbiopharmaceuticals,bulkpharmaceuticalchemicals,clinicalproductsmayvary,dependingonthespecificproducttype.Aglossaryisprovidedattheendofthereport.本文件的每一個(gè)主題的開(kāi)始都有一個(gè)適用于各種類(lèi)型制藥企業(yè)的通則性章節(jié)。對(duì)于諸如生物藥品、原料藥、臨床試驗(yàn)用藥等特點(diǎn)藥物類(lèi)型所需的個(gè)別考量點(diǎn)，擇依其產(chǎn)品形態(tài)而有所不同。于本文件末列有詞匯表供參考。FinishedPharmaceuticals藥物成品Finishedpharmaceuticalsrepresentsolidformulations,semi-solidformulations,liquidandaerosolformulationswithvariousroutesofadministration.Over-the-counterandprescriptionpharmaceuticalsforbothhumanandveterinaryuseareincludedinthiscategory.藥物成品系指具有多種給藥途徑的固體制劑、半固體制劑、液體及噴霧劑。本類(lèi)別制劑包括人用及動(dòng)物用處方藥與非處方藥。Thecommoncharacteristicssharedbyfinishedpharmaceuticalsaretheirmanufacturebycombiningrawmaterialsandactiveingredientstocreatethefinaldosageform.藥物成品所具有的共同特征是其制造方法是將原料與火星成分組合以制造出最終劑型。Pharmaceuticalmanufacturersoftenmakealargenumberofproducttypesinonefacility;oftenthereareseveraldifferentstrengthspreparedofthesameproduct.Thecleaningproblemsincludethelargenumberofprocessesandproducttypesmanufacturedwithinonefacility.Thenumberofcleaningmethods,assaysandtypesofequipmenttobetestedare

oftenstaggering.Thisiscomplicatedbytheissuessurroundingtheuseofnon-dedicatedequipment.Thus,theestablishmentofacleaningvalidationpolicywhichisapplicabletoallproductsisoftenverydifficult.制藥企業(yè)通常在一個(gè)工廠內(nèi)生產(chǎn)大量不同劑型產(chǎn)品，而且一種產(chǎn)品常常有多種不同效價(jià)。其清潔作業(yè)的困難包括在一個(gè)場(chǎng)所內(nèi)有大量不同形態(tài)的工藝和產(chǎn)品。其清潔方法與含量測(cè)定方法得種類(lèi)，及需要加以檢測(cè)的是被的類(lèi)別時(shí)常重疊。在使用非專用性設(shè)備時(shí)，情況會(huì)更加復(fù)雜。因此，要建立一個(gè)適用于所有產(chǎn)品的清潔驗(yàn)證方法，通常十分困難。Biopharmaceuticals生物制劑Bioprocessmanufacturing,startingwithmicrobial,animalorinsectcells,orDNAderivedhostcellsorothercellsmodifiedtomakeaspecializedproduct,canbeperformedinseveralways.Indeed,newmethodsforbioprocessingareconstantlybeingdeveloped.Themostcommonmethodisthroughlargescalefermentation(suchasbacterialcellcultureormammaliancellculture)followedbyhighlyspecificpurificationsteps.Othermethodsincludethedevelopmentofanantibodyinhostanimals(suchasascites),cloningofcellsortissues,ortransgenicgenerationofcellularcomponents,namely,proteins.Manyinthebiopharmaceuticalindustryconsiderthestagesoffermentationtobesimilartootherpharmaceuticalindustryprocesses.Forexample,theinitialstagesofthelargescalefermentationhaveastrikingsimilaritytobulkpharmaceuticalchemicalproduction.Later,harvestandpurificationstepsfindmoreincommonwithpharmaceuticalprocesses.Itisimportanttorememberhowever,thatotherbioprocessingmethodsusedinthebiopharmaceuticalindustrydiffergreatlyfromtraditionalpharmaceuticalprocesses.所謂生物科技方法得制造方法是將微生物、動(dòng)物或昆蟲(chóng)細(xì)胞，或DNA衍生宿主細(xì)胞（DNAderivedhostcells）、或其種途徑進(jìn)行。經(jīng)過(guò)大量的發(fā)酵（例如細(xì)菌細(xì)胞培養(yǎng)或哺乳動(dòng)物細(xì)胞培養(yǎng)），驟。氣氛方面包括在宿主細(xì)胞（如ascites）產(chǎn)生抗體、細(xì)胞或組織的無(wú)性或細(xì)胞成分（即所謂的蛋白質(zhì)）的基因轉(zhuǎn)移（transgenicgeneration）。許多生物制劑工廠認(rèn)為發(fā)酵的步驟與其他只要工廠的工藝相似。例如，大量發(fā)酵的初始步驟就明顯的與原料藥的生產(chǎn)似。其后的收集和純化步驟則更與制劑的工藝具有相同性。然而很重要的是，要記得其他生物制品所使用的方法與傳統(tǒng)的制劑工藝有很大的差異。他細(xì)胞，改造成特殊化的產(chǎn)品，此等方法可以利用多事實(shí)上，事務(wù)科技的新方法一直持續(xù)不斷地被開(kāi)發(fā)出來(lái)。最常見(jiàn)的方法是再經(jīng)過(guò)高度專一的純化步相Cleaningforbiopharmaceuticalspresentsspecialconcernsduetothelargenumberofimpuritiessuchascellulardebris,wasteproductsofcellularmetabolism,mediaconstituentsandbuffersaltsgeneratedoraddedduringmanufacturewhichmustbeeliminatedfromtheequipment.Inthecaseofmammaliancellcultures,duetothenatureofthesourcematerial,microbialcontaminationisofgreatconcern.Identificationoftheresiduesisoftenquitedifficultbecausetheymayvaryfrombatchtobatch.Thelargevarietyofproteinaceousmaterialspresentintheresiduemakedifferentiationofthecontaminantsfromoneanotherachallenge.由于生物藥品的清潔作業(yè)必須將大量不純物（諸如細(xì)胞殘骸、細(xì)胞代謝廢棄物、培養(yǎng)基除，所以須特別關(guān)注清潔程序。在成分及制造過(guò)程中添加或產(chǎn)生的緩沖劑類(lèi)）從設(shè)備清

哺乳動(dòng)物細(xì)胞培養(yǎng)的場(chǎng)合，由于基源物質(zhì)的本質(zhì)應(yīng)特別關(guān)心微生物的污染。其殘留物會(huì)逐批不同，所以殘留物的鑒別通常相當(dāng)困難。殘留物中的蛋白質(zhì)物質(zhì)會(huì)有很大的變異，，所以污染物的區(qū)別是一項(xiàng)挑戰(zhàn)。Duetothenatureofthebiopharmaceuticalproduction,multi-productfacilitiesrepresentanareaofregulatoryconcern.Inordertocontroltheproductionwithinamulti-productfacility,itisnecessarytoensurethatspecialprecautionsaretakenwhichprecludeproducttoproductcarryover.Cleaningisanintegralpartofthestrategiesdesignedtoensurethatthereisnocross-contaminationinthesefacilities.Thetermscleaningandcleaningvalidationinmulti-productfacilitiesoftenincludethefacilityitself,andthereforeemphasisisplacedonchangeovervalidation.由于生物制品生產(chǎn)作業(yè)的本質(zhì)，使多種產(chǎn)品制造場(chǎng)所在管理上個(gè)具有相當(dāng)?shù)闹匾浴榱丝刂贫喾N產(chǎn)品在制造場(chǎng)所內(nèi)的生產(chǎn)操作，需保證有特別的預(yù)防措施以防止產(chǎn)品與產(chǎn)品之間的殘留物轉(zhuǎn)移。清潔規(guī)程是一個(gè)保證場(chǎng)所內(nèi)無(wú)交叉污染而設(shè)計(jì)的完整策略的一部分。在多種產(chǎn)品的制造場(chǎng)所，清潔程序與清潔驗(yàn)證兩個(gè)名詞通常也包括場(chǎng)所本身，因此應(yīng)強(qiáng)調(diào)產(chǎn)品更替方面的驗(yàn)證。Cleaningforbiotechnologyproductshasbeendescribedin"CleaningandCleaningValidation:ABiotechnologyPerspective,"PDA,Bethesda,MD,1996.生物制品的清潔規(guī)程在"CleaningandCleaningValidation:ABiotechnologyPerspective,"PDA,Bethesda,MD，1996文件中有所描述。BulkPharmaceuticalChemicals原料藥Bulkpharmaceuticalchemicalprocessesaretypicallybiochemicalorchemicalsynthesescarriedoutonarelativelylargescale.Thebulkpharmaceuticalchemicalsmaybeprovidedtopharmaceuticalmanufacturersasactiveorinactiveingredientsforeventualinclusioninafinisheddosageformpharmaceutical.Thebulkpharmaceuticalchemicalmanufacturingprocessforactiveingredientsistypicallyenclosedinlargetankswithdirecttransferofmaterialsfromtanktotankafteraparticularchemicalreactionhasoccurred.Theinitialstagesofthebulkpharmaceuticalchemicaldrugdevelopmentarereminiscentofthechemicalindustry.Atsomepointduringtheprocess,themanufacturermust,inaccordancewithCGMPshaveidentifiedaprocessstepafterwhichtheprocesswillstrictlycomplywiththeCGMPs.原料藥的工藝通常為相當(dāng)大量的生化或化學(xué)合成。原來(lái)藥可為活性或非活性成分，而供應(yīng)給制劑生產(chǎn)商使用，經(jīng)制作程序而被包含于最終劑型的制劑中，活性成分的原料藥工藝通常將原料置于大型罐中，直接于罐與罐之間轉(zhuǎn)移知道產(chǎn)生特定的化學(xué)反應(yīng)。原料藥藥物研發(fā)階段的初始步驟會(huì)令人懷念往昔的化學(xué)工業(yè)。制藥企業(yè)必須依照CGMPs的規(guī)定，在其所指定的工藝中某一階段以后的操作均需完全的符合CGMPs規(guī)范。Bulkpharmaceuticalchemicalproduction,dueinlargeparttothescaleofmanufactureanditsuseofstrongreagentsandchemicals,isoftenperformedinclosedsystemswhichmayuseautomatedorsemi-automatedClean-In-Placetechnologies.Thedifficultiesinthevalidation

ofcleaningprocessesoftenstemfromtheinaccessibilityofmanyareastodirectsampling.Thecontaminantstoberemovedincludeprecursormolecules,intermediates,byproducts,impuritiesorotherphysicalformssuchasisomersorpolymorphs,whichexistfromearlystagesintheprocess.由于是以較大規(guī)模制造以及使用強(qiáng)烈的化學(xué)試劑，使得合成原料藥的工藝通常于密閉系統(tǒng)執(zhí)行（該系統(tǒng)可以使用自動(dòng)化或半自動(dòng)的CIP技術(shù)）。其清潔驗(yàn)證程序的困難是因?yàn)樵S多不易接近而無(wú)法直接取樣的部位。其應(yīng)該清除的污染物包括前藥、中間產(chǎn)物、副產(chǎn)物、雜質(zhì)、或諸如異構(gòu)體或多晶型體等物理結(jié)構(gòu)物（自工藝初期即以存在）。ClinicalProducts臨床試驗(yàn)用藥Inthisdocument,clinicalproductsidentifythoseproductswhicharecurrentlyregisteredasaninvestigationalstatusduetotheirinvolvementinclinicaltrials.TheClinicalProductscategoryidentifiesthespecialcarethatmustbetakenwiththeseproductswhichmaynotbeasfullycharacterizedasmarketedmaterials.Bothpharmaceuticalandbiopharmaceuticaldrugpr