FDA 制剂生产厂检查指南

DosageFormDrugManufacturerscGMPs(10/93)FDA制剂生产厂检查指南GUIDETOINSPECTIONSOFDOSAGEFORMDRUGMANUFACTURER'S-CGMPR'SNote:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s).注：此指南是FDA检查官和其工作人员的参考资料。此文件不约束FDA，也不赋予任何人任何权利，特权，利益或豁免权。I.简介ThisdocumentisintendedtobeageneralguidetoinspectionsofdrugmanufacturerstodeterminetheircompliancewiththedrugCGMPR's.ThisguideshouldbeusedwithinstructionsintheIOM,otherdruginspectionguides,andcomplianceprograms.AlistoftheinspectionguidesisreferencedinChapter10oftheIOM.Someoftheseguidesare:该文件旨在为检查药品生产厂家提供一个总体性的指导，以决定他们是否符合药物生产的cGMP法规。该指南应该与IOM(InvestigationsOperationsManual，即检查操作手册)，其他的药品检查指南，及法规符合性程序中的指导一起使用。在IOM的第十章中提供了一个检查指南清单，其中有：oGuidetoInspectionsofBulkPharmaceuticalChemicals.o原料药检查指南oGuidetoInspectionsofHighPurityWaterSystems.o高纯水系统检查指南oGuidetoInspectionsofPharmaceuticalQualityControlLaboratories.o药品QC实验室检查指南oGuidetoInspectionsofMicrobiologicalPharmaceuticalQualityControlLaboratories.o微生物药品QC实验室检查指南oGuidetoInspectionsofLyophilizationofParenterals.o冻干注射剂检查指南oGuidetoInspectionsofValidationofCleaningProcesses.o清洁验证检查指南oGuidetoInspectionsofComputerizedSystemsinDrugProcessing.o制药过程中的计算机化系统检查指南oGuidelineonGeneralPrinciplesofProcessValidation.o工艺验证总体原则指南II.CURRENTGOODMANUFACTURINGPRACTICEREGULATIONSII.CGMPPrescriptionvs.Non-prescription处方药和非处方药AlldrugsmustbemanufacturedinaccordancewiththecurrentgoodmanufacturingpracticeregulationsotherwisetheyareconsideredtobeadulteratedwithinthemeaningoftheFD&Cact,Section501(a)(2)(B).RecordsrelatingtoprescriptiondrugsmustbereadilyavailableforreviewinaccordancewithSec.704(a)(1)(B)oftheFD&CAct.IftheproductisanOTCdrugwhichiscoveredbyanNDAorANDA,FDAmayreview,copyandverifytherecordsunderSec.505(k)(2)oftheFD&CAct.However,iftheproductisanOTCdrugforwhichthereisnoapplicationfiledwithFDA,thefirmisnotlegallyrequiredtoshowtheserecordstotheinvestigatorduringaninspectionbeingconductedunderSection704oftheFD&CAct.Nonetheless,allmanufacturersofprescriptionandOTCdrugsmustcomplywiththedrugCGMPRrequirements,includingthoseinvolvingrecords.Theinvestigatorshouldreviewtheserecordsaspartoftheinspectionindeterminingthefirm'scompliancewiththeCGMPregulations.Onrareoccasions,afirmmayrefusetoallowreviewofOTCrecordsstatingtheyarenotlegallyrequiredto.Whilethefirmmaybeundernolegalobligationtopermitreviewofsuchrecords,thisdoesnotrelievethefirmofitsstatutoryrequirementtocomplywiththegoodmanufacturingpracticesundersection501(a)(2)(B)oftheFoodDrugandCosmeticAct,includingtherequirementsformaintainingrecords.所有药物的生产过程都必须遵循cGMP原则，否则依据FD&C法令,501(a)(2)(B)将认定其为掺假行为。必须提供处方药的记录以便按照FD&C法令第704（a）(1)(B)进行审核。如果药物是NDA或ANDA范围内的OTC药物，FDA可以根据505（k）(2)进行记录的审核，复制和确认。然而，如果该OTC药物并没有在FDA注册申请，在依据Section704oftheFD&C法规进行检查时将不会从法律上要求工厂必须提供给检查官这些记录。尽管如此，所有的处方药和OTC生产商必须符合cGMP的要求，包括涉及的记录。检察官应当把对记录的审核作为决定生产商是否符合cGMP要求的一部分。偶尔会有公司可能拒绝提供OTC的记录，因为并没有法定要求他们这样做。工厂虽没有法律义务去提供这些记录以供审核，但是这并不减轻工厂仍需符合501（a）(2)(B)cGMP的法定要求，其中包括对记录保持的要求。IfafirmrefusesreviewofOTCrecords,theinvestigatorshoulddeterminebyotherinspectionalmeanstheextentofthefirm'scompliancewithCGMPR's.InspectionalobservationsandfindingsthatCGMPR'sarenotbeingfollowedaretobecitedonaListofInspectionalObservations,FDA-483,forbothprescriptionandnon-prescriptiondrugs.如果一个工厂拒绝审核OTC的记录，检查官应当根据其他检查手段决定该公司对cGMP的符合程度。要把在检查处方药和非处方药时观察到的、发现的不遵循cGMP的地方援引到检查发现列表（即FDA-483）中。OrganizationandPersonnel[21CFR211SubpartB]组织和人员ThefirmmusthaveaqualitycontroldepartmentthathastheresponsibilityandauthorityasdescribedinthereferencedCFR.Thequalitycontroldepartmentmustmaintainitsindependencefromtheproductiondepartment,anditsresponsibilitiesmustbeinwriting.Obtainthename,titleandindividualresponsibilitiesofcorporateofficersandotherkeyemployeesasindicatedintheIOM.工厂必须有质量控制部门，其职责和权限应与CFR描述的一致。QC部门必须与生产部门保持独立，其职责必须有书面规定。要获取IOM中公司官员和其他关键人员的姓名，头衔和个人职责。Inthedrugindustry,anemployee'seducationandtrainingfortheirpositionhasasignificantimpactontheproductionofaqualityproduct.Reportwhetherthefirmhasaformalizedtrainingprogram,anddescribethetypeoftrainingreceived.Thetrainingreceivedbyanemployeeshouldbedocumented.在制药工业，员工的教育背景和岗位培训对于产品的质量有着非常重要的影响。报告工厂是否有正式的培训计划，并描述接受的培训类型。培训应当有文件记录Qualitycontrolmustdoproductannualreviewoneachdrugmanufactured,andhavewrittenannualreviewprocedures.Reviewthesereportsindetail.Thisreportwillquicklyletyouknowifthemanufacturingprocessisundercontrol.Thereportshouldprovideasummaryalllotsthatfailedin-processorfinishedproducttesting,andothercriticalfactors.Investigateanyfailures.对每种生产的药品，QC都必须进行产品年度回顾，并有书面的年度回顾规程。详细审核这些报告。通过报告你将很快了解生产过程是否受控。报告必须要提供所有的中控或成品检测中失败的批次，和其他关键因素。调查所有的失败。Qualitycontrolmustvalidatethemanufacturingprocessforeachdrugmanufactured.Reviewandevaluatethisdata.质量控制一定要对药品生产过程进行验证。审核并评估这些数据。BuildingsandFacilities[21CFR211SubpartC]建筑和厂房Reviewtheconstruction,size,andlocationofplantinrelationtosurroundings.Theremustbeadequatelighting,ventilation,screening,andproperphysicalbarriersforalloperationsincludingdust,temperature,humidity,andbacteriologicalcontrols.Theremust