Quality Assurance and Control質(zhì)量保證和質(zhì)量控制

7QualityAssuranceandControl質(zhì)量保證和質(zhì)量控制MICHAELC.VANDERZWANPharmaceuticalTechnical,RochePharmaceuticals,Basel,SwitzerlandI.Introduction介紹...........................235II.DefiningandAssuringtheQualityoftheActivePharmaceuticalIngredient原料藥質(zhì)量的定義和保證..................240III.TheRegulationsforQuality質(zhì)量監(jiān)管.................245IV.TheQualityControlandQualityAssuranceDepartment質(zhì)量控制和質(zhì)量保證.................273AppendixA附錄...........................280

目錄I.INTRODUCTION介紹 2A.TheProduct產(chǎn)品 3B.TheProcess工藝 4C.TheFacilities設(shè)備 5D.ThePeople人員 5E.TheQualityManagementDepartment質(zhì)量管理部門(mén) 6F.TheRegulatoryAuthorities監(jiān)管機(jī)構(gòu) 7G.TheRegulations法規(guī) 7II.DEFININGANDASSURINGTHEQUALITYOFTHEACTIVEPHARMACEUTICALINGREDIENT原料藥質(zhì)量的定義和質(zhì)量保證 9A.DefiningtheAPIQuality原料藥質(zhì)量的界定 10B.TestingtheAPIforItsDefinedAttributes原料藥定義的屬性測(cè)試 11C.DesigningQualityintotheProcess工藝中的質(zhì)量設(shè)計(jì) 12D.ValidationoftheProcess工藝驗(yàn)證 14E.Reality實(shí)際 16III.THEREGULATIONSFORQUALITY質(zhì)量法規(guī) 17Introduction:TheEmergenceofSpecificRegulationsforAPIs導(dǎo)言：API具體法規(guī)的出現(xiàn) 171.ICHQ7ASectionI:‘‘Introduction’’第一部分：簡(jiǎn)介 212.ICHQ7ASection2:‘‘QualityManagement’’第二部分質(zhì)量管理 223.ICHQ7ASection3:‘‘Personnel’’第三部分人員 244.ICHQ7ASection4:‘‘BuildingsandFacilities’’第四部分廠(chǎng)房和設(shè)施 265.ICHQ7ASection5:‘‘ProcessEquipment’’第五部分工藝設(shè)備 296.ICHQ7ASection6:‘‘DocumentsandRecords’’第六部分文件和記錄 317.ICHQ7ASection7:‘‘MaterialsManagement’’第7部分物料管理 368.ICHQ7ASection8:‘‘ProductionandIn-ProcessControls’’第8部分產(chǎn)品和過(guò)程控制 409.ICHQ7ASection9:‘‘PackagingandIdentificationLabelingofAPIsandIntermediates’’第9部分原料藥和中間體的包裝和標(biāo)識(shí)標(biāo)簽 4410.ICHQ7ASection10:‘‘StorageandDistribution’’儲(chǔ)存和發(fā)運(yùn) 4511.ICHQ7ASection11:‘‘LaboratoryControls’’第11部分實(shí)驗(yàn)室控制 4612.ICHQ7ASection12:‘‘Validation’’ 4613.ICHQ7ASection13:‘‘ChangeControl’’第13部分變更控制 5314.ICHQ7ASection14:‘‘RejectionandRe-UseofMaterials’’第14部分物料的拒收和再用 5515.ICHQ7ASection15:‘‘ComplaintsandRecalls’’第15部分投訴與召回 5916.ICHQ7ASection16:‘‘ContractManufacturers(IncludingLaboratories)’’第16部分協(xié)議制造商（包括實(shí)驗(yàn)室） 60IV.THEQUALITYCONTROLANDQUALITYASSURANCEDEPARTMENT質(zhì)量控制和質(zhì)量保證部 61

I.INTRODUCTION介紹Thequalityofactivepharmaceuticalingredients(APIs)isdefinedasmeetingtheappropriatespecificationsfortheAPIandbeingproducedinafacilitycompliantwithICHguidelines‘‘Q7A’’andFDA’scurrentgoodmanufacturingpractices(cGMPs)regulations.MostcountriesregulatethemanufactureofAPIs.TheseregulationsrequireatotalsystemsapproachtoassuringanAPIhastheappropriatelevelofquality.Allcomponentsinthissystemmustbeproperlydesigned,validated,maintained,andoperatedtoallowthemanufacturertoassuretheAPIconsistentlymeetsqualityrequirements.Thegeneralcomponentsofthesystemaretheprocess,facilities,andthepeople.Thischapterconcernsthesecomponents,aswellastheproductqualityitself,theregulations,andthequalitymanagement(QM)department.活性藥物成分（APIs）的質(zhì)量應(yīng)被定義為符合相應(yīng)的API規(guī)范，并且正在建設(shè)中的設(shè)施應(yīng)符合ICH指南'Q7A'和FDA現(xiàn)行的動(dòng)態(tài)藥品生產(chǎn)管理規(guī)范（cGMP）的規(guī)定。大多數(shù)國(guó)家對(duì)原料藥的生產(chǎn)制造都有規(guī)定。這些法規(guī)要求有一個(gè)總的系統(tǒng)方法來(lái)保證API的質(zhì)量在適當(dāng)水平。這個(gè)系統(tǒng)中的所有組件必須經(jīng)過(guò)正確的設(shè)計(jì)，驗(yàn)證，維護(hù)和操作，以保證制造商的API始終符合質(zhì)量要求。該系統(tǒng)中普遍的組件包含工藝過(guò)程、設(shè)施和人員。本章內(nèi)容包括這些組件，以及產(chǎn)品質(zhì)量本身，法規(guī)條例和質(zhì)量管理部（QM）。A.TheProduct產(chǎn)品ThequalityofanAPIisdeterminedbytwofactors:itsconformancetopre-establishedspecificationsandwhetheritisproducedaccordingtoadocumentedvalidatedprocessinacGMPcompliantfacility.TheAPImustpossessappropriatechemicalandphysicalattributestoassurethatitdeliverstheintendedpharmacologicaleffect.Thechemicalattributesdescribetheappropriatepurityandimpuritylimits.Impurityspecificationsareestablishedfromclinicaltoxicologicalstudiesandarealsobasedonreasonableminimumsexpectedfromregulatoryauthoritiesandconsumers.Thephysicalattributesdescribethenecessarycharacteristicsforreliablepharmaceuticalprocessingintofinaldosageforms.Theseattributesaredeterminedbyempiricalevidencefromformulationtrialstoproduceuniformandstabledosageformsofadequatebioavailability.API的質(zhì)量是由兩個(gè)因素決定：是否與預(yù)先建立的標(biāo)準(zhǔn)相一致，是否在符合cGMP要求的設(shè)施內(nèi)并且根據(jù)成文的經(jīng)驗(yàn)證的工藝過(guò)程生產(chǎn)出來(lái)的。API必須具有適當(dāng)?shù)幕瘜W(xué)和物理屬性，以確保它提供預(yù)期的藥理學(xué)作用?；瘜W(xué)屬性描述了適當(dāng)?shù)募兌群碗s質(zhì)限度。雜質(zhì)規(guī)范根據(jù)臨床毒理學(xué)研究建立，同時(shí)基于從監(jiān)管部門(mén)和消費(fèi)者那里得到預(yù)期的合理最低值。物理屬性描述了可靠藥物加工成最終劑型的必要特征。這些屬性由配方試驗(yàn)的經(jīng)驗(yàn)證據(jù)確定，以生產(chǎn)具有足夠生物利用度、均勻且穩(wěn)定的劑型。B.TheProcess工藝ThequalityoftheAPIisdesignedintothemoleculethroughthedevelopmentofthefullmanufacturingprocess,fromthelaboratoryscalesyntheticprocessthroughtoendproduct.API的質(zhì)量通過(guò)全面的制造工藝的發(fā)展被設(shè)計(jì)成分子，從實(shí)驗(yàn)室規(guī)模的合成過(guò)程通向最終產(chǎn)品。Thesyntheticprocessmustbedesignedtominimizeimpurities,especiallythosethatprovedifficulttoremoveinthelaststep.Thus,througheffectiveprocessdevelopment,yieldsaremaximized,wasteisminimized,andimpuritiesarenotformed,eliminated,orcertainlyminimized.Thespecificcontrolsusedbythedevelopmentalchemisttoproducethehigh-yield,high-qualityproductmustbedocumented;thisdocumentationformsthebasisfortheproofofconceptandforthevalidationreport.Innearlyallcountriestoday,regulatoryauthoritiesrequiretheAPItobeproducedfromadocumentedprocessthatreliablymeetsallappropriatespecifications.ThiswasstrengthenedbytheissuanceandadoptionoftheInternationalConferenceonHarmonizationTripartiteGuidelineofQ7A‘‘GoodManufacturingPracticeGuideforAPIs.’’TheEuropeanUnion,theJapaneseMinistryofHealthandtheUnitedStatesFood&DrugAdministrationadoptedtheguide.合成方法必須被設(shè)計(jì)成最小化的雜質(zhì)，尤其是那些證明在最后一個(gè)步驟難以除去的。因此，通過(guò)有效的工藝開(kāi)發(fā)、產(chǎn)量最大化、廢棄物最小化、不形成、消除或最小化雜質(zhì)。所采用的發(fā)展化學(xué)家的具體控制來(lái)產(chǎn)生高收益、高品質(zhì)的產(chǎn)品必須被記錄;本文檔構(gòu)成了概念證明和驗(yàn)證報(bào)告的基礎(chǔ)。在今天幾乎所有的國(guó)家、監(jiān)管部門(mén)要求API應(yīng)在符合所有相應(yīng)規(guī)范、有記錄的工藝過(guò)程來(lái)生產(chǎn)。這方面因?yàn)閲?guó)際會(huì)議的三方協(xié)調(diào)指南Q7A“良好生產(chǎn)實(shí)踐指南的API”的發(fā)行和通過(guò)得到了加強(qiáng)。歐盟，日本監(jiān)管部門(mén)和美國(guó)食品藥品監(jiān)督管理局通過(guò)了這個(gè)指南。C.TheFacilities設(shè)施ThefacilitiesinwhichAPIsareproducedarealsoaddressedinthischapterbecauseacomponentofqualityofanAPIisthatitbeproducedincGMP-compliantfacilities.ThosecomponentsofthefacilitygovernedbycGMParethereforepartofthischapter.TheessenceofcGMPforfacilitiesor,forthatmatter,anyaspectofAPImanufactureisthatthefacilityperformsasdesignedtoassurethequalityoftheproduct.生產(chǎn)API的設(shè)施在本章節(jié)也進(jìn)行討論，因?yàn)锳PI的質(zhì)量的組成部分是通過(guò)cGMP的標(biāo)準(zhǔn)設(shè)施來(lái)生產(chǎn)的。因此，由cGMP管轄的設(shè)施的組成部分是本章節(jié)的一部分。對(duì)于這個(gè)問(wèn)題，cGMP的設(shè)施或API制造的任何方面的的本質(zhì)是設(shè)施執(zhí)行的設(shè)計(jì)，以保證產(chǎn)品的質(zhì)量。Further,theperformancecharacteristicmustbedocumented,andmanagementmustdemonstratethefacilitycontinuallyperformsasdesigned.Performancecontrolmonitoring,preventativemaintenance,andcarefullycontrolledandapprovedrepairsorchangestofacilitycomponentsareallconsideredpartofassuringqualityofAPIs.此外，性能特點(diǎn)必須記錄，管理必須證明該設(shè)施持續(xù)按設(shè)計(jì)執(zhí)行。性能控制監(jiān)控、預(yù)防性維護(hù)、精密控制和批準(zhǔn)的設(shè)備部件的維修或變更都被認(rèn)為是保證API質(zhì)量的一部分。D.ThePeople人員ThepeoplewhoproducetheAPIareconsideredacriticalpartofthesystemand,assuch,becomepartoftherequirementsforqualityofAPIs.TodotheirjobseffectivelyandtoassurequalityoftheAPI,theymustbeproperlytrainedandequipped.Qualifiedpersonnelmustconductthetraining;theequipmentmustbeofproperdesignandfunction.ThesupervisorsofpeoplemanufacturingAPIsmustalsobeproperlytrainedtodotheirjobs.Finally,theremustbeanadequatenumberofpeopletoallowsufficienttimetoperformtheseresponsibilitiesinasatisfactorymanner.生產(chǎn)API的人員是該系統(tǒng)的一個(gè)重要組成部分，因此，成為API的質(zhì)量要求的一部分。為了有效地做好本職工作，以確保API的質(zhì)量，就必須進(jìn)行適當(dāng)?shù)呐嘤?xùn)和裝備。合格人員必須進(jìn)行培訓(xùn);設(shè)備必須有適當(dāng)?shù)脑O(shè)計(jì)和功能。人造API的監(jiān)管人員也必須進(jìn)行適當(dāng)?shù)呐嘤?xùn)來(lái)做好本職工作。最后，必須有適當(dāng)?shù)娜藬?shù)，以便有充足的時(shí)間、以令人滿(mǎn)意的方式執(zhí)行這些職責(zé)。E.TheQualityManagementDepartment質(zhì)量管理部門(mén)Asinmostanyothermanufacturingenterprise,thereisaqualitycontrolandoraqualityassurancedepartment.Today,thesedepartmentsareusuallycombinedintoaQMdepartment.因?yàn)樵诖蠖鄶?shù)的任何其他制造企業(yè)，有一個(gè)質(zhì)量控制部和/或質(zhì)量保證部。如今，這些部門(mén)通常被合并成一個(gè)質(zhì)量管理部門(mén)。TheroleoftheQMdepartmenthasalsoadvancedfrom‘‘check-test-decide’’responsibilitytobeinganequalpartnerwithmanufacturingandengineeringtomanageandimprovethequalityoftheentireprocessandsystem.質(zhì)量管理部門(mén)的角色也從''檢查、測(cè)試、決定'的職責(zé)變?yōu)榕c制造和工程平等的參與者來(lái)提高全過(guò)程和系統(tǒng)的質(zhì)量。ForAPIsanddrugproducts,theQMdepartment,throughitsqualityassurancearm,stillhastheresponsibilityvestedinitbyregulationstoreleaseallproductsforuseandeventuallytothemarket.AsacomponentofthesystemtoproduceAPIs,theactivitiesandresponsibilitiesoftheQMdepartmentarealsoacomponentofproductquality.MostcGMPsrequirethattheQMdepartmentisresponsibletoreviewandapproveproductionprocedures,andanychangestothem,mostreports,procedures,andcontrols,deemednecessarytoassurethequalityoftheprocessandproduct.對(duì)于原料藥和藥物產(chǎn)品，質(zhì)量管理部門(mén)，通過(guò)其質(zhì)量保證的手臂，還有賦予的責(zé)任，通過(guò)法規(guī)來(lái)釋放所有產(chǎn)品中使用，并最終推向市場(chǎng)。作為該系統(tǒng)的一個(gè)組成部分來(lái)生產(chǎn)原料藥，活動(dòng)和QM部門(mén)的職責(zé)是也產(chǎn)品質(zhì)量的一個(gè)組成部分。大多數(shù)的cGMP要求質(zhì)量管理部門(mén)負(fù)責(zé)審查和批準(zhǔn)生產(chǎn)的程序，并且對(duì)它們的更改，大多數(shù)報(bào)告，程序和控制，認(rèn)為有必要確保過(guò)程和產(chǎn)品的質(zhì)量。Finally,theQMdepartmentmusthaveadequatelaboratoryfacilitiesandproperlytrainedandexperiencedpeopletoeffectivelycarryouttheirresponsibilities.最后，質(zhì)量管理部門(mén)必須有足夠的實(shí)驗(yàn)室設(shè)施和適當(dāng)?shù)呐嘤?xùn)，經(jīng)驗(yàn)豐富的人來(lái)有效地履行其職責(zé)。F.TheRegulatoryAuthorities監(jiān)管機(jī)構(gòu)Healthauthoritiesineverycountryregulatedrugproducts.Inmostcountries,theseregulationsalsoincludeAPIs.ThesecGMPregulationsrequirethatadrugmustmeetallpredefinedqualityspecificationsandbeproducedfromadocumentedvalidatedprocess.Further,ifthedrug,orAPI,isnotproducedandcontrolledaccordingtotheestablishedprocess,thenthedrugisconsideredadulterated,andthereforenotfitforuseorsale.Theregulationsaddresseveryaspectofdrugproductmanufacture,andessentiallyrequirethattheproducerhasdocumentedevidenceofproofofcontroloveranyaspectthatmightaffectproductquality.Theregulatorsweredeliberateintheiruseoftheword‘‘current’’whenthecGMPswerepromulgated.Thisqualifierenablestheagenciestocontinuouslyrequirethatmanufacturersmaintaintheirfacilitiesandprocessesatthestateoftheart,therebyalwaysassuringthepublicthatdrugproductsareassafeandeffectiveaspossible.每一個(gè)國(guó)家由衛(wèi)生主管部門(mén)管制藥品。在大多數(shù)國(guó)家，這些法規(guī)還包括原料藥。這些的cGMP法規(guī)要求藥品必須符合所有預(yù)定的質(zhì)量標(biāo)準(zhǔn)，并從記錄驗(yàn)證過(guò)程中產(chǎn)生的。此外，沒(méi)有按已建立的方法制備并控制的藥物或API，則該藥物被認(rèn)為是摻假，因此不適合使用或出售。該法規(guī)涉及藥品生產(chǎn)每一個(gè)環(huán)節(jié)，而且基本上要求生產(chǎn)者記錄控制證明可能影響產(chǎn)品質(zhì)量的任何方面。監(jiān)管機(jī)構(gòu)頒布的法規(guī)即cGMP，不斷要求制造商維持其設(shè)備和工藝的狀態(tài)，從而保證始終如一的生產(chǎn)安全有效的藥品。G.TheRegulations法規(guī)TheproductionofAPIsisregulatedinmostcountries.TheICH-harmonizedtripartiteguidelineQ7AentitledasGoodManufacturingPracticeGuideforAPIswasrecommendedforadoptionatStep4oftheICHprocessonthe10thofNovember2021.Thisdocumentwasadoptedbythefollowingagenciesdenotingitswidespreadacceptance:原料藥的生產(chǎn)在大多數(shù)國(guó)家是受監(jiān)管的。良好生產(chǎn)實(shí)踐指南APIICH-三方協(xié)調(diào)指導(dǎo)Q7A（2021年11月10日）被建議使用。下列機(jī)構(gòu)表示普遍接受：_EuropeanUnion(EU)adoptedbyCPMP,November2021,issuedasCPMP/ICH/1935/00歐盟采用CPMP，2021年11月，以CPMP/ICH/1935/00發(fā)行_JapaneseMHLWadoptedNovember2nd,2021MSBnotificationNO.1200日本MHLW采用2021年11月2日的MSB通知，第1200期_UnitedStatesFDApublishedintheFederalRegister,Vol.66,No186,September25th,2021,pages49028–49029.美國(guó)FDA發(fā)表在聯(lián)邦注冊(cè)，第66卷第186期，2021年9月25日，2021年，第49028-49029頁(yè)TheproductionprocessandalltestsandcontrolsmustbeapprovedbytheregulatinggovernmentinwhichAPIswillbeused,andthefacilitiesandsystemsinwhichtheyareproducedmustmeetthemanufacturingstandardssetdownbythegoverningbody.Thus,thequalityofAPIsisbasedontwocomponents:meetingfinalqualityspecificationsandbeingproducedaccordingtotheregulated,approvedprocessinafacilitycompliantwiththeappropriatemanufacturingstandards.Itisimportanttonotethatbothcriteriamustbemet:finalspecificationsandcompliancetomanufacturingstandards.Thesetwocomponentswillbedealtwithseparatelyinthischapter.ItisalsoimportanttonotethattheapproachtowardqualitydescribedinthischaptershouldapplytoanyAPIregardlessofthecountryinwhichitwillbeusedorsold,orwhetherornotitwillbearegulateditem.生產(chǎn)過(guò)程中，所有的測(cè)試和控制必須由政府監(jiān)管包括API，設(shè)施和系統(tǒng)，生產(chǎn)必須滿(mǎn)足的制造標(biāo)準(zhǔn)。因此，原料藥的質(zhì)量是基于兩部分組成：符合最終質(zhì)量規(guī)范，按規(guī)定的已批準(zhǔn)的工藝在適合的設(shè)施中生產(chǎn)。注意，兩個(gè)標(biāo)準(zhǔn)都必須滿(mǎn)足。這兩部分將在本章中另行闡述。同樣重要的是要注意，在本章中描述的API質(zhì)量適用于原料藥將在其中使用或出售，不管這個(gè)國(guó)家是否受法規(guī)管制。Theapproachtoquality,describedinthischapter,isbasedonsoundscientificprinciples,goodQMprinciples,andappliestoanyAPI.Infact,theseprinciplesapplytothemanufactureofanychemicalthatrequiresahighassuranceofquality.ThischapterwilldealwiththechemicalsynthesisofAPIs.However,alltheprinciplesandregulationsalsoapplytoothermeansofpreparation,suchasfermentationroutesorextractionfromnaturalsources.質(zhì)量方針，以本章所述，基于合理的科學(xué)原則，良好的質(zhì)量管理原則，適用于任何API。事實(shí)上，這些原則適用于任何需要高質(zhì)量的化學(xué)品的生產(chǎn)。本章將涉及原料藥的化學(xué)合成。然而，所有的原則規(guī)定也適用于其它的制備工藝，如發(fā)酵路線(xiàn)或者從天然提取。Finally,sinceitisassumedthroughoutthischapterthattheAPIwillbesubjecttoregulatoryrequirements,referencewillbemadetotheregulations.Ifthereaderisdealingwithanunregulateditem,suchreferencemaybeignored,butthescientificprinciplesonwhichtheregulationisbasedshouldbeseriouslyconsidered.II.DEFININGANDASSURINGTHEQUALITYOFTHEACTIVEPHARMACEUTICALINGREDIENT原料藥質(zhì)量的定義和質(zhì)量保證Thissectionofthechapteraddresseshowto:_definethenecessaryqualityattributes_testforthem,_designthemintotheprocess,and_validatetheprocesstoassureconsistentproduction.AsAPIsareregulatedarticles,theirqualityisdeterminednotonlybysatisfactorytestresults,butalsotheassurancethattheprocesswasconductedaccordingtoavalidatedprocess.本節(jié)解決了如何：_定義必要的質(zhì)量屬性_檢驗(yàn)_將設(shè)計(jì)融入工藝_驗(yàn)證工藝，以確保生產(chǎn)的一致性。由于A(yíng)PI是受管制物品，其質(zhì)量不僅取決于令人滿(mǎn)意的測(cè)試結(jié)果，也認(rèn)為工藝是由驗(yàn)證過(guò)程來(lái)保證的。A.DefiningtheAPIQuality原料藥質(zhì)量的定義TheAPImusthaveitsfinalchemicalpurityandimpurityanditsfinalphysicalattributesspecified;somearticlesalsorequiremicrobiologicalanalysestobedetermined,dependingonthefinaldosageformandthemanufacturingprocessinvolved.TheseattributesareestablishedtoassureanAPIwillperformsatisfactorilyinthepharmaceuticalmanufacturingprocessandwillresultinafinaldosageform;i.e.,thedrugproductthatwillmeetitsinitialreleasespecificationsandfinalstabilityrequirements.Thechemicalpurityminimumisusuallysetat98%toassureproperdosinginthedrugproductandtoassureaminimalamountofimpurities.Thephysicalparametersshouldbeestablishedwithknowledgeofthepharmaceuticalprocessandtheultimatefinaldosageform.Otherattributesusuallyincludecolorofthesolidformandorasolution,meltingpoint,specificrotationifopticallyactive,crystalmorphology,andsoforth.AlistoftypicalAPIspecificationsisprovidedinAppendixAalongwiththerationaleforeachone.API必須具有其最終的化學(xué)純度和雜質(zhì)，并規(guī)定其最終的物理屬性;一些還需要微生物分析，這取決于最終的劑型和所涉及的制造工藝上。這些屬性被建立以保證一個(gè)API將在藥物制造過(guò)程中令人滿(mǎn)意地執(zhí)行，并導(dǎo)致最終劑型即藥品將滿(mǎn)足其最初版本的規(guī)格和最終穩(wěn)定性的要求?；瘜W(xué)純度最低通常設(shè)定在98％，以保證藥品的適當(dāng)劑量，并且確保最小量的雜質(zhì)。物理參數(shù)應(yīng)建立與制藥過(guò)程和最終劑型的知識(shí)基礎(chǔ)上。其他屬性通常包括固體形式的顏色和或溶液，熔點(diǎn)，比旋度（如果有光學(xué)活性），晶體形態(tài)，等等。附錄A提供了典型API的規(guī)范列表。WhensettingAPIphysicalattributespecifications,themostimportantaspecttoconsiderisitsuseinthepharmaceuticalprocess;namely,whetheritwillbewettedforgranulation,dissolvedforsolution,dryblended,andsoon,andthetypeofdrugproducttobemade:tablets,capsules,solutions,sterileornonsterile,orother.Itisalsoimportanttoknowhowthedrugproductwillbeusedbythepatient;forexample,ifitwillbeusedasapowderblendedwithotherexcipients,carefulconsiderationshouldbegiventorateofdissolutionandtheeventualcolorofsolution(foraestheticreasons)whendissolvedbythepatient(orhealthcaregiver)priortouse.Forthisreason,finalAPIspecificationsarealwaysdefinedwiththecooperationofthepharmaceuticaldevelopmentarea.ThequalityassurancefunctionapprovesfinalAPIqualitystandards,takingintoconsiderationallrequirements:processrelated,governmental,andcustomer.當(dāng)建立API的物理屬性時(shí)，要考慮的最重要的方面是其在制藥過(guò)程中的使用;如被潤(rùn)濕造粒，溶解于溶液中，干燥混合等，且可以制成的藥品類(lèi)型有：片劑，膠囊劑，溶液劑，無(wú)菌或非無(wú)菌的，或其他。同樣重要的是要明白藥品將用于患者;例如，賦形劑的粉末應(yīng)考慮到由患者（或保健給予者）溶解的速率和溶液在使用前的最終的顏色（用于美觀(guān)的原因）。出于這個(gè)原因，最終的API規(guī)范始終說(shuō)明需與藥物開(kāi)發(fā)領(lǐng)域的合作。質(zhì)量保證職能應(yīng)在最終批準(zhǔn)的API質(zhì)量標(biāo)準(zhǔn)中同時(shí)考慮到所有要求：工藝相關(guān)的要求，政府和客戶(hù)的要求。B.TestingtheAPIforItsDefinedAttributes原料藥質(zhì)量屬性的測(cè)試EachqualityattributerequiredoftheAPImusthaveasoundandproventestprocedure.Inregulatorycomplianceterms,thismeansthetestmustbevalidated;thatis,tohavedocumentedproofthatitperformsreliably,isindicativeoftheattributeunderquestion,andisnotbiasedbyinterferingcomponents.Thereareeightspecificcomponentsofavalidatedtest,andforanexcellenttreatiseonthis,thereaderisreferredtothecurrentUSPortheICHguidanceonanalyticaltestvalidation.MostregulatoryauthoritiesrequireatestforallsignificantAPIqualityattributesoneachlotproduced.API的每個(gè)質(zhì)量屬性都必須有一個(gè)健全的和可靠的測(cè)試程序。在合規(guī)性方面，這意味著必須在試驗(yàn)中驗(yàn)證；也就是說(shuō)，已經(jīng)證明程序的執(zhí)行可靠，而不是由干擾組分造成。一個(gè)驗(yàn)證過(guò)程包括8個(gè)特定的部分，讀者可參考現(xiàn)行USP或ICH分析方法驗(yàn)證的指導(dǎo)。大多數(shù)監(jiān)管部門(mén)都要求每批進(jìn)行API關(guān)鍵質(zhì)量屬性的測(cè)試。Innearlyallcases,thepharmaceuticalmanufacturerrequiresacertificateofanalysis(CofA)documentingtheresultsobtainedoneachlot,aswellasastatementfromthequalityofficethatthebatchmetitsestablishedqualitycriteria.在幾乎所有情況下，藥品生產(chǎn)商需要COA（分析證書(shū)）來(lái)記錄每批的結(jié)果，證明符合質(zhì)量部分規(guī)定的質(zhì)量標(biāo)準(zhǔn)。C.DesigningQualityintotheProcess工藝中的質(zhì)量設(shè)計(jì)Asdescribedabove,thepharmaceuticalmanufacturingprocessandenduseofthedrugproductdosageformarethebasisforestablishingthelimitsofchemicalpurityandphysicalattributes.Havingpredefinedtheseattributes,thesyntheticchemistandchemicalengineerhavethetaskofdesigningqualityintotheprocess;therebyassuringeverylotwillmeetitscriteria.Thisisperhapsthemostsignificantaspectofchemicalprocessvalidationandacornerstoneofmostregulatoryrequirementsforqualityassurance.Afterthechemicalprocessisdeveloped,atechnicaldocument,whichexplainshowandwhycertainreagents,steps,controls,etc.werechoseninordertobuildqualityintotheproduct,shouldbeprepared.如上所述，藥物的制造過(guò)程和最終用途的藥品劑型受到化學(xué)純度和物理屬性的限制。為達(dá)到預(yù)定義的屬性，合成化學(xué)家和化學(xué)工程師有將質(zhì)量設(shè)計(jì)于工藝的任務(wù)，從而確保每一批將符合其標(biāo)準(zhǔn)。這也許是化學(xué)工藝驗(yàn)證最顯著的方面和大多數(shù)法規(guī)要求的質(zhì)量保證基石?；瘜W(xué)過(guò)程開(kāi)發(fā)后，技術(shù)文件將解釋試劑，步驟，控制等的方式為什么和怎樣被選擇的將質(zhì)量設(shè)計(jì)于產(chǎn)品中。Whenthemanufacturingteamtakesonthecommercialimplementationoftheprocess,andgoesthroughtheformalmanufacturingvalidationprocess,theyshouldrelyheavilyonthistechnicaldocumenttoprovethequalityofthefinalAPI.Asstatedintheintroduction,qualityisdesignedintotheprocessnotforregulatorypurposes,butbecauseitmakesgoodmanufacturingandbusinesssensetodoso.Manufacturerswantaprocessthatsafelyandreliablydelivershighyieldandqualityforeconomicandenvironmentalreasons.當(dāng)制造團(tuán)隊(duì)需要對(duì)工藝進(jìn)行商業(yè)化生產(chǎn)，并進(jìn)行正規(guī)的生產(chǎn)驗(yàn)證過(guò)程，在很大程度上依賴(lài)于該技術(shù)文件以證明最終API的質(zhì)量。正如在簡(jiǎn)介中說(shuō)名，質(zhì)量是設(shè)計(jì)于過(guò)程中，不是出于監(jiān)管目的，而是因?yàn)橛辛己玫纳a(chǎn)和經(jīng)營(yíng)意識(shí)才這樣做。處于經(jīng)濟(jì)和環(huán)境的原因制造商希望有一個(gè)安全，可靠地工藝來(lái)達(dá)到產(chǎn)品的高產(chǎn)量和高質(zhì)量。OneshouldbegintheapproachtodesigningqualityintotheAPI,withtheconceptofdesigningaperfectsystem.Keepinmindthatallthesafety,environmental,andeconomicreasonsfordevelopingaperfectchemicalsynthesisarepreciselyconsistentwiththegoalofdesigningqualityintotheprocess,andverywellserveallregulatoryprocessvalidationandcontrolrequirements.Ifoneimaginesaperfectprocess,therewillbenotoxicemissionsaboutwhichtobeconcerned,nosafetyconcernsorneedforspecialsafetycontrols,andtheyieldofeachstepwillbe100%ofthedesiredintermediate,stereoisomer,andendproduct.Suchaprocesswouldbefreeofanyimpuritiesandwouldassayfor100%purity.Thenextchallengeistodesignthesynthesissothateachstepcanbepreciselycontrolledtoalwaysprovidethesameendresult.用API質(zhì)量設(shè)計(jì)的方法來(lái)設(shè)計(jì)一個(gè)完美的系統(tǒng)。為開(kāi)發(fā)一個(gè)完美的化學(xué)合成過(guò)程，精確符合將質(zhì)量設(shè)計(jì)于工藝的目標(biāo)，需考慮所有的安全、環(huán)境和經(jīng)濟(jì)原因，還需符合工藝驗(yàn)證的法規(guī)和控制要求。如果想象一個(gè)完美的工藝，沒(méi)有有毒物排放，沒(méi)有安全問(wèn)題或需要特殊的安全控制，每一步獲得的中間體，立體異構(gòu)體和最終產(chǎn)品的收率都是100%。這種工藝將是沒(méi)有任何雜質(zhì)，100%純度，下一個(gè)挑戰(zhàn)就是設(shè)計(jì)合成路線(xiàn)精確控制每一步以得到相同結(jié)果。Thedesignworkrequiresacompleteunderstandingofthechemicalreactionsinthesyntheticprocessunderdevelopment.Thenacleverdesigncanbedevelopedtoeliminateanyundesirablesidereactions.Insomeinstances,thiscanbeachievedbysophisticateduseoffunctionalgroupprotectingagents,andinotherinstancesbychangingthesequenceoffunctionalgroupintroductionontotheendproductbuildingblockandsometimesbysimplecarefulcontroloverreactionparameters.Oncetheprocesshasbeenperfectlydesigned,developed,andcontrolled,thelastconcernisoverthecontrolofqualityandreliabilityoftherawmaterials,properfunctioningofequipment,anderror-freeoperationsbypersonnel.Withthevisionofaperfectsysteminmind,onecanimaginehowtheAPIqualitywouldbeperfectandconsistent.設(shè)計(jì)工作需要對(duì)開(kāi)發(fā)中的合成方法的化學(xué)反應(yīng)有一個(gè)完整的理解。然后，一個(gè)巧妙的設(shè)計(jì)可以開(kāi)發(fā)用以消除任何不良副反應(yīng)。在一些情況下，這可以通過(guò)使用官能團(tuán)的保護(hù)劑來(lái)實(shí)現(xiàn)，并且在通過(guò)改變官能團(tuán)引入的順序到最終產(chǎn)品來(lái)構(gòu)建，有時(shí)需簡(jiǎn)單小心地控制反應(yīng)參數(shù)。一旦過(guò)程已經(jīng)完全設(shè)計(jì)，開(kāi)發(fā)和控制，最后值得關(guān)注的是在質(zhì)量和原材料，設(shè)備的正常運(yùn)作的可靠性，并通過(guò)人員無(wú)誤差操作的控制。隨著設(shè)想的完善制度的實(shí)行，可以想見(jiàn)的API質(zhì)量將是完美的，一貫的。D.ValidationoftheProcess工藝驗(yàn)證Thisaspectoftheregulationsisperfectlyalignedwithbusinessinterests.Theregulationsrequirethatachemicalmanufacturingprocessbevalidated,whichtheauthorpersonallydefinesasproofofknowledgeofcontrol.法規(guī)這方面是與商業(yè)利益完全一致的。法規(guī)要求化學(xué)品制造過(guò)程必須進(jìn)行驗(yàn)證，作者個(gè)人定義為控制知識(shí)的證明。Whiletheterm‘‘validation’’hasvariousdefinitionsinseveraldifferentregulations(cGMPs),allessentiallymeanorimply‘‘proofofknowledgeofcontrol.’’Inessence,thevalidationoftheprocessisthedescriptionoftheprocessafteralldevelopmentworkiscompleted,withtheelaborationoftheproofofsyntheticpathway,controlsoverprocessconditions,andfinally,soundanalyticalproofofqualityfromsamplesobtainedduringactualmanufacturingcampaignsintheplant.Criticalprocessparameterssuchastime,temperature,andmixingconditionsshouldbedefined,controlled,andmonitored.Thekineticsofthesyntheticpathwayisdocumentedinaprocessmanual.TheestablishmentofaprocessmanualforeachAPIisthefoundationofprocessvalidation.Inthismanual,onedescribesproofoftheknowledgeoftheprocessandthecontrolsnecessaryforconsistentresults.Hence,thescientificdesignprocesstobuildtheperfectprocessrequiresfullknowledgeofthechemistryoftheprocess.ThatknowledgeisdescribedinthechemicalpathwayfromrawmaterialstothefinalAPI.術(shù)語(yǔ)''驗(yàn)證''有幾種不同的規(guī)定定義（cGMP），基本意味著或暗示'控制知識(shí)的證明''。在本質(zhì)上，該方法的驗(yàn)證是開(kāi)發(fā)工作完成后的過(guò)程的證明，用擬定合成途徑，在控制的工藝條件，實(shí)際生產(chǎn)出可獲得的樣品。關(guān)鍵的工藝參數(shù)，如時(shí)間，溫度，和混合條件應(yīng)該被定義，控制和監(jiān)測(cè)。合成途徑的動(dòng)力學(xué)記錄在一個(gè)工藝手冊(cè)中。對(duì)于每個(gè)API的工藝建立是工藝驗(yàn)證的基礎(chǔ)。在這個(gè)手冊(cè)中，描述了工藝知識(shí)和一致的結(jié)果對(duì)照的證明。因此，科學(xué)的工藝設(shè)計(jì)的完美過(guò)程需要充分了解化學(xué)知識(shí)。該知識(shí)闡述了從原料到最終API的化學(xué)途徑。Thescientificevidence,suchasintermediatestructureelucidation,spectrographicanalysis(IR,NearIR,massspec,UV,NMR,C13NMR,etc.),andtheproposedchemicalmechanismforeachtransformation,servesastheproofofthatknowledge.Finally,duringthecourseoftheprocessdevelopment,fullknowledgeisgainedconcerningthoseparametersandconditionsthataffectthekinetics,yield,andpurityofeachstep.Experimentstooptimizeeachstepforpurityandyieldleadtheprocessengineertodescribethenecessarycontrolsandconditions.Thesecontrolsaredescribedinaprocessmanualandareusedinthescale-upworkandultimatefull-scaleoperationinthechemicalplant.科學(xué)證據(jù)，如中間結(jié)構(gòu)解析，光譜分析（紅外光譜，近紅外光譜，質(zhì)譜，紫外光譜，核磁共振，C13NMR，等等），以及所提出的每個(gè)轉(zhuǎn)化的化學(xué)機(jī)理，都作為這種知識(shí)的證明。最后，工藝開(kāi)發(fā)過(guò)程中應(yīng)充分了解，獲得關(guān)于那些影響動(dòng)力學(xué)，產(chǎn)率和純度的每個(gè)步驟的參數(shù)和條件的知識(shí)。為優(yōu)化每一步的純度和收率所進(jìn)行的實(shí)驗(yàn)，都作為工藝工程師用來(lái)描述必要的控制手段和反應(yīng)條件。這些控制在流程手冊(cè)中有描述，并在化工廠(chǎng)進(jìn)行規(guī)模化生產(chǎn)，并最終得到全面運(yùn)轉(zhuǎn)使用。E.Reality實(shí)際Werealizethattheperfectsyntheticprocesswill,inalllikelihood,betooelusive.Eventually,wemustmakethedecisiontofocusourresourcesonthebestprocessavailableafterthoroughdevelopmentworkyieldsasoundandreliableprocess.EachsyntheticchallengerepresentsrealityofthebusinessofAPImanufacturing,andsoatsomepoint,mercializingwhathasbeenachievedtodatemustbeevaluatedonarisk(loosingprecioustimeinthemarket)toreward(achievingasuperiorprocess)basis.ItissufficienttosayherethattoensurequalityofthefinalAPI,thedevelopmentoftheprocessprovidesthenecessaryinformationtodesignin-processcontrolsneededtomonitortheprogressofeachstep.Thesecontrolsarethechemicalandphysicalmonitorsthatinformtheoperatorthatthesynthesisisproceedingaccordingtotheoriginaldesign.Theyareusedalsotoinformtheoperatorwhenthereactioniscompleteandwhenthenextstepmayoccur.Inmanycases,especiallywhentheprocessiswelldefinedanddesigned,includingthequalityofstartingmaterialsandreagents,agoodcontrolissimplytheuseoftime,basedonaknowledgeofthekineticsofthereaction.我們意識(shí)到在所有的可能性中完美的合成過(guò)程是很難的。最后，我們必須集中資源提供最佳的工藝。每次合成的挑戰(zhàn)都代表原料藥制造業(yè)的現(xiàn)實(shí)，因此在某些時(shí)候，進(jìn)一步的研究與商業(yè)化風(fēng)險(xiǎn)必須進(jìn)行評(píng)估其可行性（失去寶貴的時(shí)間在市場(chǎng)上）去獲得（實(shí)現(xiàn)一個(gè)卓越的技術(shù)）。它足以確保最終的API的質(zhì)量，該方法的發(fā)展提供了必要的信息，設(shè)計(jì)過(guò)程中的控制，以監(jiān)測(cè)每個(gè)步驟的進(jìn)展是需要的。這些控制是化學(xué)和物理監(jiān)測(cè)，即告知操作者該合成是按照原設(shè)計(jì)跟進(jìn)。它們還用來(lái)告知操作時(shí)反應(yīng)完??全和可能發(fā)生的下一個(gè)步驟。在許多情況下，特別是在工藝已被很好定義和設(shè)計(jì)時(shí)，基于化學(xué)反應(yīng)的動(dòng)力學(xué)知識(shí)，包括起始物料和試劑的質(zhì)量，良好的控制能很大的節(jié)省時(shí)間。In-processcontrolsshou