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1、QualityAssuranceandRegulatoryComplianceforPharmaceuticalProductProf.Dr.BasavarajK.NanjwadeM.Pharm.,Ph.DDepartmentofPharmaceuticsKLEUniversityCollegeofPharmacyBELGAUM-590010,Karnataka,IndiaE-mail:bknanjwadeyahoo.co.inCellNo:0091974243100004thOct.20111MaharashtraCollegeofPharmacy,NilangaQualityAssuran
2、ceQualityassuranceisawiderangingconceptcoveringallmattersthatindividuallyorcollectivelyinfluencethequalityofaproduct.Itisthetotalityofthearrangementsmadewiththeobjectofensuringthatpharmaceuticalproductsareofthequalityrequiredfortheirintendeduse.QAistheheartandsoulofqualitycontrolQA=QC+GMP04thOct.201
3、12MaharashtraCollegeofPharmacy,NilangaTheSystemofQualityAssurancelPharmaceuticalproductsaredesignedanddevelopedinawaythattakesaccountoftherequirementsofGMP and other associated codes such as those ofgood laboratory practice (GLP) and good clinicalpractice(GCP)lProductandcontroloperationsareclearlysp
4、ecifiedinawrittenformandGMPrequirementsareadopted04thOct.20113MaharashtraCollegeofPharmacy,NilangaTheSystemofQualityAssurancelManagerial responsibilities are clearly specified injobdescriptionlArrangementsaremadeforthemanufacture,supplyand use of the correct starting and packagingmaterials.lAllneces
5、sarycontrolsonstartingmaterials,intermediate products, and bulk products and otherin-processcontrols,calibrations,andvalidationsarecarriedout.04thOct.20114MaharashtraCollegeofPharmacy,NilangaTheSystemofQualityAssurancelThe finished products is correctly processed andcheckedaccordingtothedefinedproce
6、dures.lPharmaceutical products are not sold or suppliedbeforetheauthorizedpersonshavecertifiedthateachproductionbatchhasbeenproducedandcontrolledinaccordance with the requirements of the marketingauthorizationandanyotherregulationsrelevanttotheproduction, control and release of pharmaceuticalproduct
7、s04thOct.20115MaharashtraCollegeofPharmacy,NilangaTheSystemofQualityAssurancelSatisfactory arrangements exist to ensure, as far aspossible,thatthepharmaceuticalproductsarestoredby the manufacturer, distributed and subsequentlyhandledsothatqualityismaintainedthroughouttheirshelf-life.lThereisaprocedu
8、reforself-inspectionand/orqualityaudit that regularly appraises the effectiveness andapplicabilityofthequalityassurancesystem04thOct.20116MaharashtraCollegeofPharmacy,NilangaTheSystemofQualityAssurancelDeviationarereported,investigatedandrecordedlThere is a system for approving changes that mayhavea
9、nimpactonproductqualitylRegularevaluationsofthequalityofpharmaceuticalproductsshouldbeconductedwiththeobjectiveofverifyingtheconsistencyoftheprocessandensuringitscontinuousimprovement.04thOct.20117MaharashtraCollegeofPharmacy,NilangaQCGMPQAQuality relationships04thOct.20118MaharashtraCollegeofPharma
10、cy,NilangaQualityAssuranceItisthesumtotaloftheorganizedarrangementswiththeobjectiveofensuringthatproductswillbeofthequalityrequiredfortheirintendeduse04thOct.20119MaharashtraCollegeofPharmacy,NilangaGoodManufacturingPracticeIsthatpartofQualityAssuranceaimedatensuringthatproductsareconsistentlymanufa
11、cturedtoaqualityappropriatetotheirintendeduse04thOct.201110MaharashtraCollegeofPharmacy,NilangaGoodManufacturingPracticeRaworstartingmaterialsFinishedproductsPremisesandenvironmentEquipmentpersonnelTrainingHygiene04thOct.2011MaharashtraCollegeofPharmacy,Nilanga11GMP Covers all aspects of production
12、includingQuality System with Traceable DocumentationApproved MaterialsApprovedManufacturing InstructionsControlledEnvironmentControlled MaterialsHandling, Storage,Segregation, Packaging & LabellingMaterial,Intermediate & Finished Products Testing Internal Audits & ReviewsValidated Test MethodValidat
13、edManufacturing ProcessesValidatedEquipmentApproved ManufacturingFacilitiesTrained PersonnelGOOD MANUFACTURING PRACTICE04thOct.201112MaharashtraCollegeofPharmacy,NilangaQualityControlIsthatpartofGMPconcernedwithsampling,specification&testing,documentation&releaseprocedureswhichensurethatthenecessary
14、&relevanttestsareperformed&theproductisreleasedforuseonlyafterascertainingitsquality04thOct.201113MaharashtraCollegeofPharmacy,NilangaQA and QClQCisthatpartofGMPwhichisconcernedwithsampling,specifications,testingandwithintheorganization,documentation,andreleaseprocedureswhichensurethatthenecessaryan
15、drelevanttestsarecarriedoutQA is the sum total of organized arrangements made with the object of ensuring that product will be of the Quality required by their intended use.04thOct.201114MaharashtraCollegeofPharmacy,NilangaQA and QClOperationallaboratorytechniquesandactivitiesusedtofulfilltherequire
16、mentofQualityAll those planned or systematic actions necessary to provide adequate confidence that a product will satisfy the requirements for quality04thOct.201115MaharashtraCollegeofPharmacy,NilangaQA and QClQCislabbasedQA is company based04thOct.201116MaharashtraCollegeofPharmacy,Nilanga04thOct.2
17、01117MaharashtraCollegeofPharmacy,Nilanga04thOct.201118MaharashtraCollegeofPharmacy,NilangaQuality Assurance-HighlightslInprocessqualitycheckinginmanufacturinglValidationoffacilities,equipments,process,productsandcleaninglComplainthandlinglStorageofqualityrecordsandcontrolsampleslStabilitystudies04t
18、hOct.201119MaharashtraCollegeofPharmacy,NilangaQuality Assurance Activities 1.Technology Transfer2.Validation3.Documentation Control4.Assuring Quality of Products5.Quality Improvement Plans04thOct.201120MaharashtraCollegeofPharmacy,Nilanga1.TechnologyTransferlReceiptofproductdesigndocumentsfromR&DDe
19、partmentlDistributionofdocumentstodifferentdepartmentslCheckingandapprovalofdocumentsgeneratedbasedonR&Ddocumentsi.e.batchmanufacturingrecordlScaleupandvalidationofproduct04thOct.201121MaharashtraCollegeofPharmacy,Nilanga2.ValidationPreparationofvalidationplansforfacility,equipments/processincluding
20、cleaningApproval of protocol for validation of facility/equipment/product/processTeam member for execution of validation offacility/equipment/product/process04thOct.201122MaharashtraCollegeofPharmacy,Nilanga3.DocumentationControllControlleddistributionandarchivingofdocumentslControlofchangesmadebypr
21、operchangecontrolprocedurelApprovalofalldocuments04thOct.201123MaharashtraCollegeofPharmacy,Nilanga4.AssuringQualityofProductslcGMPtraininglSOPcompliancelAuditoffacilityforcompliancelLineclearancelInprocesscountercheckslCriticalsamplinglRecordverificationlReleaseofbatchformarketinglInvestigationofma
22、rketcomplaints04thOct.201124MaharashtraCollegeofPharmacy,Nilanga5.QualityImprovementPlanslTotakeFeedbackfromdifferentdepartmentslProposalsforcorrectiveandpreventiveactionslAnnualProductsreviewlTrendanalysisofvariousqualityparametersforproducts,environmentandwater04thOct.201125MaharashtraCollegeofPha
23、rmacy,NilangaFACTORSINDRUGQUALITYASSURANCEDRUGPRODUCTQUALITYLabeling&ProductInformationImport&ExportControlRawMaterials-Active&InactiveManufacturingProcesses&ProceduresStorageTransportDistributionDispensing&UseQC&AnalysisHumanResources-ProfessionalsLegislativeFramework-RegulationsPackaging04thOct.20
24、1126MaharashtraCollegeofPharmacy,Nilanga04thOct.201127MaharashtraCollegeofPharmacy,Nilanga In process quality checking in manufacturing Validation of facilities, equipments, process, products and cleaning Complaint handling Storage of quality records and control samples Stability studiesQuality Assu
25、rance Highlights04thOct.201128MaharashtraCollegeofPharmacy,Nilanga04thOct.201129MaharashtraCollegeofPharmacy,NilangaEquipment/InstrumentQualificationlBefore a process can be validated the equipment,facilities & services used in that process mustthemselvesbevalidatedsuchanoperationisreferredtoasquali
26、ficationlQualification therefore, an integral part of processvalidationwhichinturnispartofGMP04thOct.201130MaharashtraCollegeofPharmacy,NilangaEquipment/InstrumentQualification04thOct.201131MaharashtraCollegeofPharmacy,NilangaEquipment/InstrumentQualification04thOct.201132MaharashtraCollegeofPharmac
27、y,NilangaWhytoqualifyAccording to GLP, cGMP, GAMP, ISO 9000 etc.Produced in validated environmentDesign/Development stage of equipment/instrumentStructural ValidationBegins at Vendors siteQualification is the part of validationIftheinstrumentisnotqualifiedpriortouse&ifaproblemoccurs,thesourceofprobl
28、emwillbedifficulttoidentify.04thOct.201133MaharashtraCollegeofPharmacy,NilangaQualificationInvolvesPerformance Qualification (PQ)Operational Qualification (OQ)Site Acceptance Test (SAT)Installation Qualification (IQ)Factory Acceptance Tests (FAT)Design Qualification (DQ)Functional Design Specificati
29、on (FDS)User Requirement Specification (USR)04thOct.201134MaharashtraCollegeofPharmacy,NilangaDetailsRecordinChangeControllRequestforchangelChangecontrolNo.lDatelChangerelatedtoproduct/document/system/facilitylConcerneddocumentswithnumberlDescriptionofchangelReasonforchangelImpactofchange04thOct.201
30、135MaharashtraCollegeofPharmacy,NilangaDetailsRecordinChangeControllProposedmethodologyforimplementationlCategoryofchangelTypeofchangelComparisoncriteriaforevaluationofthechangelAssessmentofimpactofchangelApprovalofchangelImplementationofchangelClosureofchange04thOct.201136MaharashtraCollegeofPharma
31、cy,NilangaDetailsRecordedinDeviationApprovallDeviationno.lDeviationrelatedtolConcernedidentitynumber(BatchNo.,CodeNo.etc)lTypeofdeviation(Planed/Unplaned)lDescriptionofdeviationlReason/InvestigationwithdocumentlCategoryofdeviationlRootcauseanalysis04thOct.201137MaharashtraCollegeofPharmacy,NilangaDe
32、tailsRecordedinDeviationApprovallImpactofdeviation(onbatches,Products,Items,etc)lImmediateactionlCAPA(CorrectiveandPreventiveAction)lImpactofCAPAlIntimationtoconcernedlCommentsfromconcernedlPeriodicreviewlFinalreviewlDeviationclose-outlEvaluationofimplementedCAPA04thOct.201138MaharashtraCollegeofPha
33、rmacy,NilangaDetailsRecordedInOutofSpecificationReportlOOSNo.(OutofSpecification)lReportingofOOSlInformationofOOStoimmediateseniorlAssessmentofanalyticaldatabyimmediateseniorlDiscussionbetweenanalystandimmediateseniorlSamplingandanalysislDatacompilationlAssignablecauseidentificationlFullscaleOOSinve
34、stigation(Causenotidentified)lEvaluationlConclusionlCAPAlOOSresultssummary04thOct.201139MaharashtraCollegeofPharmacy,NilangaAreaofSelfInspectionlPersonal&PersonaldetailslPremisesincludingpersonnelfacilitieslMaintenanceofbuilding&equipmentlStorageofstartingmaterial&finishedproducts(Stores)lEquipmentl
35、Production&In-processcontrolslCephalosporinMfg&PackinglManufacturinglPackinglQualitycontrollDocumentationlSanitation&HygienelValidationandrevalidationprogram04thOct.201140MaharashtraCollegeofPharmacy,NilangaAreasofSelfInspectionlCalibrationofinstrumentsormeasurementsystemlRecallprocedurelComplaintsm
36、anagementlLabelscontrollComputerizedsystemlEngineeringlDocumentsrelatedtoregulatoryaffairslDiscardingofresidueslQualityassurancelControloncontractanalysislResultsofpreviousselfinspection,qualityauditandanycorrectivestepstaken04thOct.201141MaharashtraCollegeofPharmacy,NilangaDetailsRecordedinComplain
37、tInvestigationReportlComplaintNo.lProductNamelManufacturingandExpiryofproductlSourceofcomplaintlDateofreceiptofcomplaintlNatureofcomplaintlCategoryofcomplaint04thOct.201142MaharashtraCollegeofPharmacy,NilangaDetailsRecordedinComplaintInvestigationReportlInvestigationlImpactofcomplaintonotherbatches/
38、productslBatches/ProductslReviewlCAPAlImpactofCAPAlImplementationofPreventiveactionlCloseoutofcomplaint04thOct.201143MaharashtraCollegeofPharmacy,NilangaAcceptanceCriteriaSr. No.RPN RatingRPN Category1.Upto25Minor2.26to50Moderate3.51to75Major4.76to125Critical04thOct.201144MaharashtraCollegeofPharmac
39、y,NilangaRPN:RiskPriorityNumber04thOct.201145MaharashtraCollegeofPharmacy,NilangaROOTCAUSEANALYSIS04thOct.201146MaharashtraCollegeofPharmacy,NilangaRegulatoryComplianceForPharmaceuticalProduct04thOct.201147MaharashtraCollegeofPharmacy,NilangaRegulatoryRequirementslRegulatory requirements are part of
40、 the process of drugdiscoveryanddrugdevelopment.lRegulatoryrequirementsdescribewhatisnecessaryforanewdrugtobeapprovedformarketinginanyparticularcountry.lIn the US, it is the function of the Food and Drug Administration(FDA)toestablishtheseregulatoryrequirements.lTheEuropean Medicines Agency (EMA)and
41、lJapanese Pharmaceuticals and Medical Devices Agency (PMDA) are also important regulatory authorities in drugdevelopment.Thesethreeagenciesoverseethethreelargestmarketsfordrugsales04thOct.201148MaharashtraCollegeofPharmacy,NilangaRegulatoryCompliancelIngeneral,compliancemeansconformingtoarule,suchas
42、aspecification,policy,standardorlaw.lRegulatory compliance describes the goalthatcorporationsorpublicagenciesaspiretoin their efforts to ensure that personnel areaware of and take steps to comply withrelevantlawsandregulations.04thOct.201149MaharashtraCollegeofPharmacy,NilangaPharmaceuticalProductQu
43、alityCannotBeTestedin-ItIsBuiltinlPharmaceuticalproductqualityisassuredbyComprehensivedevelopmentprogramExtensivemanufacturingandenvironmentalcontrolsRigorousvalidationproceduresandrequirementsCompliancetoregulatoryrequirementslThehighqualitythusbuiltintothefinalproductisensuredthroughin-process con
44、trols and verified in a series of confirmatory testsbeforeeachmanufacturedbatchisreleasedtothemarket04thOct.201150MaharashtraCollegeofPharmacy,NilangaQuality = Quality of Manpower (Qualification, Training) + Quality of Materials (Specifications, Approved Suppliers.) + Quality of Means (Qualified equ
45、ipments, maintenance) + Quality of Media (GMP premises, Controlled environment) + Quality of Methods (Calibration, Validation)Product / ServiceMaterialsMethodsMeansManpowerMediaCompositionofQuality04thOct.201151MaharashtraCollegeofPharmacy,NilangaFunctionsofaQualityUnitFunctionsofaQualityUnitQuality
46、 ControlSampling and testing of components (raw materials, Packing materials), intermediates and finished products Compliance to Good Laboratory Practices (GLPs)04thOct.201152MaharashtraCollegeofPharmacy,NilangaFunctionsofaQualityUnitFunctionsofaQualityUnitQuality AssuranceDesigning robust quality s
47、ystemsEnsure compliance to relevant regulatory requirementsEnsure compliance to requirements of Good Manufacturing Practices (GMP) 04thOct.201153MaharashtraCollegeofPharmacy,NilangaValueadditioninQAfunctionQuality Assurance:Perform structured self-inspection audits at regular intervals to prevent an
48、y failure or non-conformance Critically analyze the quality non-conformance issues and suggest corrective and preventive actions04thOct.201154MaharashtraCollegeofPharmacy,NilangaValueadditioninQAfunctionQuality Assurance:Perform documentation audit to ensure realistic recording of all the relevant p
49、rocess parametersReview the adequacy of in-process control checks to prevent any potential failures 04thOct.201155MaharashtraCollegeofPharmacy,NilangaValueadditioninQAfunctionQuality Assurance:Training & Knowledge ManagementPerform literature survey of FDA / ICH / ISO guidelines, revisions in the Ph
50、armacopoeial specifications and the current regulatory requirements and provide training to the production personnel.04thOct.201156MaharashtraCollegeofPharmacy,NilangaValueadditionofRegulatoryfunctiontoenhanceQualityAssuranceRegulatory Compliance:Knowledge of the current international regulatory req
51、uirementsComprehensive compilation of the Product Registration Dossiers for the specific customer countries04thOct.201157MaharashtraCollegeofPharmacy,NilangaRegulatoryApprovalAPIDrug ProductManufacturing PlantCROBioequivalenceClinical TrialsAPIDrug ProductRegulatory dossiersNationalRegionalGlobalRe-
52、registration/RenewalPost Approval ChangesRegulatoryCompliance04thOct.201158MaharashtraCollegeofPharmacy,NilangaRegulatory ComplianceNationalRegionalGlobalRegulatoryCompliance04thOct.201159MaharashtraCollegeofPharmacy,NilangaNational(India)LicenseApplicationReceiptManufacturing licenseForm No. 24Form
53、 No. 25Test licenseForm No. 30Form No. 29Import licenseForm No. 12Form No.11Compliance to (Drugs & Cosmetics Act 1940 & Rules under)04thOct.201160MaharashtraCollegeofPharmacy,NilangaNational(India)Drug Regulatory approvalSchedule Y ComplianceForm 44ManufacturingSchedule M ComplianceDocumentationSche
54、dule U CompliancePackagingSchedule P ComplianceAPI/Excipients/FP/PM IP Inputs if not BP/USP/ or IH04thOct.201161MaharashtraCollegeofPharmacy,NilangaRegional(US)ParametersUSAPIUSP(USDMFTypeII)ExcipientsUSPPackagingmaterialsComplyingtoUSP(TypeIIIDMF)FinishedProductUSPSubmissionbatch1Submissionbatchsiz
55、e100,000unitsor1/10thofcommercialbatchStabilityZoneIIrequirement25+2C/60+5%RH&40+2C/75+5%RHReferenceproductUSRLD(Orangebooklisted)BioequivalencestudyGenerallybothfast&fedconditionComplianceto21CFRanditssubpartssuchaspart210211,part11,part314,part350,ICHetc.,GenericapplicationFDAform356h04thOct.20116
56、2Regional(Europe)ParametersEuropeAPIPh.Eur.COS(CEP)/EDMFExcipientsPh.Eur.PackagingmaterialsPh.Eur.FinishedProductAsperPh.Eur.GeneralrequirementSubmissionbatch2Submissionbatchsize100,000unitsor1/10thofcommercialbatchStabilityZoneIIrequirement25+2C/60+5%RH&40+2C/75+5%RHReferenceProductEuropeBioequival
57、encestudyGenerallyfastingconditionCompliancetoOrangeguide,EDQM,CHMP,CPMPguidelines,ICHGenericapplicationASperArticle10anditssubsections04thOct.201163Regional(Others)ParametersOther marketsAPIUSP/Ph.Eur.(DMFrequirementdependsonthetargetmarket)ExcipientsUSP/Ph.Eur.PackagingmaterialsUSP/Ph.Eur.Finished
58、ProductUSP/Ph.Eur.Submissionbatch2or3SubmissionbatchsizeDependsonthetargetmarketStabilityDependsontheTargetmarket(E.g.:ASEAN:ZoneIVb)ReferenceProductDependsontheTargetmarketBioequivalencestudyGenerallyfastingconditionCompliancetoRespectivecountryguidelinesGenericapplicationASperrespectivecountryguid
59、elines04thOct.201164GlobalParametersGlobalAPIHarmonizationofspecificationExcipientsHarmonizationofspecificationPackagingmaterialsHarmonizationofspecificationFinishedProductHarmonizationofspecificationSubmissionbatch3Submissionbatchsize100,000unitsor1/10thofcommercialbatchStabilityZoneIII&IVReference
60、ProductMultipleregionBioequivalencestudyFasting&FedconditionCompliancetoGlobalStandardsGenericapplicationASperrespectivecountryguidelines04thOct.201165RegulatoryDossierCTD dossier componentModule 1- Administrative & prescribing information (Region specific)Module 2: CTD summaries (Quality overall su
61、mmary, the non-clinical overview/summaries, clinical overviews/Summaries)Module 3: Quality (CMC)Module 4: Non clinical study reports (Documentation on Toxicological and pharmacological tests)Module 5: Clinical study reports (For Generics: Bioequivalence study)CTD ORGANIZATION IS BASED ONM4: Organiza
62、tion of the CTDM4E: The CTD EfficacyM4Q: The CTD QualityM4S: The CTD Safety04thOct.201166MaharashtraCollegeofPharmacy,Nilanga04thOct.201167MaharashtraCollegeofPharmacy,NilangaRegulatoryDossiervRegulatory approach:ParametersUSEuropeOther marketsIndiaAPIUSPPh.Eur.USP/Ph.Eur.IPUSDMFCOS(CEP)/EDMFDMFrequ
63、irementdependsonthetargetmarketExcipientsUSPPh.Eur.USP/Ph.Eur.IPReferenceproductUSEuropeDependsonthetargetmarketIndian(ifnotavailable,thenUSorEurope)PackagingmaterialsComplyingtoUSPPh.Eur.USP/Ph.Eur.IPFinishedproductUSPAsperPh.Eur.GeneralrequirementUSP/Ph.Eur.IPSubmissionbatch122or3-Submissionbatchs
64、ize100,000unitsor1/10thofcommercialbatch100,000unitsor1/10thofcommercialbatchDependsonthetargetmarketNosuchrequirement04thOct.201168RegulatoryDossiervRegulatory approach:ParametersUSEuropeOther marketsIndiaStabilitydata1batch2batches2or3batches3batchesStabilityconditionZoneI&IIconditionZoneI&IIcondi
65、tionDependsonthetargetmarketZoneIVconditionComparativedissolutionstudy3media3mediaDependsonthetargetmarket1to3mediaInputmaterialsTSE/BSE,OVIstatementsTSE/BSEDependsonthetargetmarketNosuchrequirementPackagingmaterialsFoodgradecertificateFoodgradecertificateDependsonthetargetmarketNosuchrequirementMet
66、hodvalidationdataAsperICHICHICHNosuchguidelineProcessvalidationdataNotrequiredNotrequiredDependsonthetargetmarketNotrequiredforsubmissionBioequivalencestudyUSreferenceproductunderfastandfedconditionEuropeanreferenceproduct(generallyunderfastingcondition)GenerallyfastingbiostudyFastingbiostudyBioequi
67、valencestudyInUSFDAapprovedCROanywhereintheworldMHRA/EUapprovedCROanywhereDependsonthetargetmarketIndianstudyrequired04thOct.201169SpecificrequirementsofanUSANDAvQOS:inQbRformat(Qualityoverallsummary:Question-basedreview)vExhibitbatches(1batch)vStabilitydataatthetimeofsubmission(3Months)vTSE/BSEcert
68、ificate(Transmissiblespongiformencephalopatics/Bovinespongiformencephalopathy)vStructuredProductLabeling(SPL)&sidebysidelabelingcomparisonvOVIstatement(Organicvolatileimpurities)vFinancialcertification/disclosurestatement(Bioequivalencestudy)vEnvironmentalassessmentorclaimforcategoricalexclusionvDec
69、larationunderGenericDrugEnforcementAct(Debarmentcertification&convictionstatement)vPatentcertification&exclusivitystatementvAppointmentofUSagent&letterofUSagentauthorizationvCopyofexecutedbatchrecords04thOct.201170MaharashtraCollegeofPharmacy,NilangaSpecificrequirementsofanEUdossiervReleasetestingin
70、EU(QP)vExhibitbatches(2batches)vStabilitydata(6Months)vProcessvalidationstudyvReleaseandshelflifespecificationvMicrobiologicalconsiderationsvTSE/BSEcertificatevSPC(Summaryofproductcharacteristics)vBraillelabeling(JustanotherwaytoreadandwriteEnglish)vReadabilitytesting04thOct.201171MaharashtraCollege
71、ofPharmacy,NilangaRegulatoryApprovalvProduct Approval / AuthorizationSuccessfulregistrationoftheproductinthetargetmarketinvolves:SuccessfulreviewofAPIDMF/COSSuccessfulauditofAPIplant(whereverapplicable)SuccessfulreviewofDrugProductDossier(ANDA,MAAetc.)CMCdatareviewBioequivalencestudydatareviewAdmini
72、strativedatareviewSuccessfulauditofthedrugproductmanufacturingplantSuccessfulauditofthebioequivalencestudyCRO04thOct.201172MaharashtraCollegeofPharmacy,NilangaQualityAssurance:CommonRegulatoryComplianceIssuesvAPIInfringingrouteofsynthesisNotconsistentwithrespectivePharmacopoeialrequirementImpuritypr
73、ofileoutoflimitResidualsolventsnotmeetingtherequirementsUnapprovedsiteofmanufacture(byconcernedregulatorybody)Unacceptablephysico-chemicalproperties(particlesize,polymorphism,bulkdensity,etc.)FrommanufacturerwhodoesnotassureuninterruptedsupplyofAPIUnapprovedvendor(bydrugproductmanufacturer)UseofnonD
74、MF/COSmaterial(e.g.:US,Europeetc.)Highcost(commercialviability)04thOct.201173vExcipientUseofrarelyavailable/orcommonlynotusedexcipientsUseofNonGRASmaterials(Generallyrecognizedassafe)IncompatibleNotconsistentwithrespectivePharmacopoeialrequirementResidualsolventsnotmeetingtherequirementsTSE/BSE/GMO(
75、Geneticallymodifiedorganisms)UnapprovedvendorUnacceptablephysico-chemicalandfunctionalproperties(particlesize,bulkdensity,viscositygrade,surfacearea,degreeofpolymerizationetc.)FrommanufacturerswhodonotassureuninterruptedsupplyHighcost(commercialviability)QualityAssurance:CommonRegulatoryComplianceIs
76、sues04thOct.201174MaharashtraCollegeofPharmacy,NilangavFormulationdevelopmentvPre-formulation ImproperAPIcharacterizationIntrinsic solubilitypH dependent solubilitySaturation solubilityParticle sizePolymorphBulk densityHygroscopicity studyImpurity profile etc.,Wrongchoiceofreferenceproduct(e.g.Notse
77、lectinginnovatorproduct)Referenceproductnotmatchingwiththeproposedmarket(e.g.:EuropeanproductselectedforUSmarket)InadequatedrugexcipientcompatibilitystudiesQualityAssurance:CommonRegulatoryComplianceIssues04thOct.201175MaharashtraCollegeofPharmacy,NilangavFormulation developmentUseofoverageswithoutp
78、roperjustificationUseofbanned/unapprovedcolours(intargetmarket)Useofexcipientswithoutproperjustification(e.g.:surfactantsetc.)UseofexcipientsnotconsistentwiththeproposedrouteofadministrationUseofPharmacopoeialgradenotconsistentwiththetargetmarketInfringingprocessLackofproperdevelopmentreportInadequa
79、teoptimizationstudydataonprocesscontrolsComplex/costlyprocess/lengthyoperatingcycleUseofnon-aqueoussolvents(tobeavoided)QualityAssurance:CommonRegulatoryComplianceIssues04thOct.201176MaharashtraCollegeofPharmacy,NilangaQualityAssurance:CommonRegulatoryComplianceIssuesvFormulation(Finishedproduct)Dis
80、solutionprofilenotmatchingwiththereferenceproductDissolutionprofilenotmatchingwiththebiostrengthincaseofmultistrengthproducts(forbiowaiverpurpose)NotmeetingPharmacopoeialrequirementDissolutionLackofjustificationforselectionof:MediaApparatusRPMVolumeofmediaSamplingpointDissolutionlimitJustificationfo
81、radditionofsurfactant(e.g.:SLS),enzymes(e.g.:Pepsin,Pancreatinetc.)inthedissolutionmedium04thOct.201177MaharashtraCollegeofPharmacy,NilangaQualityAssurance:CommonRegulatoryComplianceIssuesvFormulation(Finishedproductspecification)NotmeetingPharmacopoeialrequirement/ICHQ6ALackofsecondidentificationte
82、st(fornonspecifictest)Inadequateimpurities&residualsolventspecification(ICHQ3A,B,Q3C)Lackoftestingforpreservatives,anti-oxidantswhereverusedLackoftestforbreakability/contentuniformityforhalftablets(whenfunctionalscorelineexists)LackoftestforestablishingpolymorphicconversionsColoridentificationtest(e
83、.g.:Europe)Testforwatercontentinsoliddosageform(e.g.:US)MissingofmicrobiologicaltestsLackofspecificationfortestingafterreconstitution04thOct.201178MaharashtraCollegeofPharmacy,NilangaQualityAssurance:CommonRegulatoryComplianceIssuesvPackagingMaterialsImproperjustificationfortheselectionofpackagingma
84、terialsLackofdataonrelease/sorption/leachingstudy(speciallyforthoseusedinliquid/parenteralpreparations)Lackofstudytodemonstrateintegrityofcontainerclosuresystem(whereapplicable)Primarypackagingmaterialnotsuitableforitsintendedperformance(e.g.:childresistant)Lackofidentificationtestinthespecification
85、LackoffoodgradecertificationforthematerialsNonuseofvirgingradepolymers04thOct.201179MaharashtraCollegeofPharmacy,NilangaQualityAssurance:CommonRegulatoryComplianceIssuesvManufacturingofsubmissionbatchesInadequatebatchsize(e.g.:lessthan100,000unitsor1/10thofthecommercialbatchsizewhicheverishigher)Ina
86、dequatenumberofbatches(e.g.:minimum1batchforUS,2batchesforEuropeetc.)Inadequatepackagingquantity(e.g.:minimum100,000unitspackedquantityforUS)Lackofprocessvalidation(applicabletomanyAsiaPacificcountries)Lackofstratifiedsamplingduringin-processtest(e.g.:US)Holdtimestudy04thOct.201180MaharashtraCollege
87、ofPharmacy,NilangaQualityAssurance:CommonRegulatoryComplianceIssuesvAnalyticalmethodsAnalyticalmethodsnotvalidatedAnalyticalmethodsnotstabilityindicating(forstabilitystudies)ForceddegradationstudiesnotperformedInadequatejustificationforchoice/selectionofmethod(UVvsHPLC)Inadequatejustificationforsele
88、ctionofconditions(column,wavelength,runtime,mobilephase,flowrate,temperatureetc.)NonavailabilityofmethoddevelopmentreportInadequatemethodvalidationparameters(e.g.:LOD,LOQinRSmethod)04thOct.201181MaharashtraCollegeofPharmacy,NilangaQualityAssurance:CommonRegulatoryComplianceIssuesvStabilityStudyInade
89、quatebatchsize(e.g.:lessthan100,000unitsor1/10thofthecommercialbatchsizewhicheverishigher)Inadequatenumberofbatches(e.g.:minimum1batchforUS,2batchesforEuropeetc.)Chambertemperatureandhumidityconditionnotappropriatetothetargetmarket(e.g.:ZoneI&IIandZoneIIIandZoneIVconditionsaredifferent)Inadequatedat
90、aatthetimeofsubmission(e.g.:3monthsdataforUS,6monthsdataforEurope)04thOct.201182MaharashtraCollegeofPharmacy,NilangaQualityAssurance:CommonRegulatoryComplianceIssuesvStabilityStudyPhotostabilitystudynotconsideredImpropercontainerorientation(speciallyforliquidproducts)Inadequatestabilitystudyonbulksh
91、ipmentpack(ifintendedtoshipitforrepackaging)Inadequateparameterscoveredunderstabilityprotocol(e.g.:microbialtesting)Notchargingsamplesunderfallbackcondition04thOct.201183MaharashtraCollegeofPharmacy,NilangaStabilityvGlobalclimaticzonesZoneMean Kinetic Temperature (C)Yearly average RH (%)ZoneI(Modera
92、te)2145ZoneII(Mediterranean)2560ZoneIII(Hot&Dry)3035ZoneIV(Hot&humid)307004thOct.201184StabilityDistributionofnationsintodifferentclimaticzones:RegionZones I & IIZone III & IVEuropeanAllcountries-AmericanChile,Canada,UnitedStatesBrazil,Jamaica,VenezuelaAsianChina,Japan,TurkeyIndia,Philippines,SriLan
93、kaAfricanSouthAfrica,Zambia,ZimbabweBotswana,Ghana,UgandaAustralian/OceanicAustralia,NewZealandFiji,Papua-NewGuinea04thOct.201185QualityAssurance:CommonRegulatoryComplianceIssuesvBioequivalencestudyUseofwrongstrength(incaseofmultiplestrengthproducts)Useofinappropriatereferenceproduct(e.g.:USreferenc
94、eproductforEuropestudy)InadequatenumberofvolunteersInadequatesamplingintervalstocapturetmax/cmax(maximumtimepointsshouldbetherearoundtheexpectedtmax/cmax)InadequatewashoutperiodDesignfaultindecidingwhattotest(e.g.testingofparentcompoundoractivemetaboliteorboth)Choiceofstudy(Fast/Fedstudyorboth)04thO
95、ct.201186MaharashtraCollegeofPharmacy,NilangaQualityAssurance:CommonRegulatoryComplianceIssuesvBioequivalencestudyUseofnonvalidatedmethodfortestingStabilityofplasmasamplesnotestablishedInadequatenumberofreservesamples(e.g.:5timesofthesamplerequiredforcompleteanalysis)UseofunapprovedCROInappropriated
96、ocumentationIEC/IRBapprovalofprotocol,informedconsent,CRF,pharmacokineticdata,statisticaldata(SAS),etcBioequivalencestudysampleformuladifferentfromcommercialbatchformulaBioequivalencestudysamplesarenotfromGMPpivotalbatch04thOct.201187MaharashtraCollegeofPharmacy,NilangaQualityAssurance:CommonRegulat
97、oryComplianceIssuesvRegulatoryauditsTrainingofpersonnelFacilityupkeepEquipmentupkeepandpreventivemaintenanceprogramAreaandenvironmentalmonitoringQAsystems,documentationcontrolandtraceabilityVendorapprovalprocedureInventorycontrolandstorageChangecontrols,deviationsOOS04thOct.201188MaharashtraCollegeo
98、fPharmacy,NilangaQualityAssurance:CommonRegulatoryComplianceIssuesvRegulatoryauditsQualification/validationofsystem,facility,equipmentetc.WatersystemHVACsystem(Heating,ventilationandairconditioning)StabilityprogramProcessvalidationLaboratorycontrol,testingandreleaseofmaterialsDocumentationreview(Bat
99、chrecords,analyticalrecords,etc.)BatchreleasebyQA04thOct.201189MaharashtraCollegeofPharmacy,NilangaQualityAssuranceinLifeCycleManagementTasks to be performed v Pharmacovigilance Safety reportsv Post Approval Changes / Variations To implement necessary up-dates and changes of the dossier v Line exten
100、sions (major changes, requiring new MAA) To implement necessary up-dates and changes of the dossierv Renewal / Re-registration04thOct.201190MaharashtraCollegeofPharmacy,NilangaQualityAssuranceinLifeCycleManagementPostApprovalChangesFormulaBatchsizeProcessSiteChangeEquipmentChangeSource/Spec&testproc
101、edureMultipleChangesAPI/Excipients/PkgMaterials04thOct.201191QualityAssuranceinLifeCycleManagementPost approval changesReportingLevel1AnnualReportLevel2ChangesBeingEffected(CBE)ChangesBeingEffectedin30days(CBE-30)Level3Scale-UpandPost-ApprovalChangesChangesBeingEffected(CBE)ChangesBeingEffectedin30d
102、ays(CBE-30)PriorApprovalSupplement(PAS)Post Approval Changes (US SUPAC)04thOct.201192MaharashtraCollegeofPharmacy,NilangaQualityAssuranceinLifeCycleManagementCategoryReportingMinorType1AModerateType1BMajorTypeIIstandardCriticalTypeIIcomplexPost Approval Changes (Europe)04thOct.201193MaharashtraColle
103、geofPharmacy,NilangaQualityAssuranceinLifeCycleManagementOther marketsIndiaNotificationse.g.AustraliaPartA:Non-assessablechangesPartB:Self-assessablechangesPartC:ChangesrequiringapprovalNosuchrequirementPost Approval Changes (Other markets)04thOct.201194MaharashtraCollegeofPharmacy,NilangaQualityAss
104、uranceinLifeCycleManagementvRegistrationvalidityUS:AnnualreporteveryyearEurope:Re-registrationoncein5yearsIndia:Licenserenewalevery5yearsOthercountries:Generally5years04thOct.201195QualityAssurance:ThemostimportantelementofregulatorycompliancelThemostimportantelementforcomplianceis.Manpower Manpower
105、 ManpowerlItisthepeoplewhoensureRegulatorycomplianceatevery stage of product life cycle i.e. starting fromproductdevelopmenttolifecyclemanagementlThebestwaytoenhancetheircapabilityisthrough.Training.Training . Training04thOct.201196QualityAssurance:ThestateofcompliancelEverythingislikelytoundergocha
106、ngeduringthelifecycleofaproduct.Formula,Process,Equipment,Batchsize,Suppliers,Manufacturingsite,Tradedress,Indications,Regulatoryrequirements,Specifications&testprocedures,PeopleandsoonlTheonlythingthatcannotbechangedisthe.“StateofCompliance”04thOct.201197RegulatoryAuthoritiesv India: DCGI & State D
107、rug Administrationv European Union: EMEA and nationalv USA : Food and Drug Administration (FDA)v Australia : Therapeutic Goods Administrationv Newzeland : Medsafev South Africa: Medicines council controlv Japan : Ministry of Health & Labour Welfarev Switzerland : Swissmedicv Brazil : ANVISA (TheNati
108、onalHealthSurveillanceAgency)v Mexico: COFEPRIS (TheFederalCommissionfortheProtectionagainstSanitaryRisk)v Chile : ISP - Instituto de Salud Pblica de Chilev Columbia: INVIMA Instituto Nacional de Vigilancia de Medicamentos Alimentos Carrera 68 D No. 17 - 11 / 21v Argentina: ANMAT - set in 1992 Argen
109、tine National Administration of Drugs, Food & Medical TechnologyvFrance: Agence Franaise de Scurit Sanitaire des Produits de SantvGermany: Federal Institute for Drugs and Medical Devices04thOct.201198MaharashtraCollegeofPharmacy,NilangaImportantsitesRegulatory sites: vwww.fda.govvwww.tga.gov.au vhtt
110、p:/www.emea.europa.eu/v www.ministeriodesalud.go.crv www.mspas.gob.gtvhttp:/www.minsa.gob.pa/minsa2006/inicio.phpvhttp:/www.minsa.gob.nivhttp:/www.salud.gob.hn/vwww.cssp.gob.svvhttp:/www.sns.gov.bo/vhttp:/www.inh.gov.ec/vhttp:/www.mspbs.gov.py/vhttp:/www.msp.gub.uy/index_1.htmlvhttp:/digemid.minsa.g
111、ob.pevhttp:/www.inhrr.gov.vevhttp:/pharmacos.eudra.org04thOct.201199MaharashtraCollegeofPharmacy,NilangaImportantsitesv(http:/pharmacos.eudra.org/F2/eudralex/index.htm)vwww.bfarm.de/de/index.php vagmed.sante.gouv.fr/htm/5/repec/repec0.htmvwww.nam.fivhttp:/heads.medagencies.org/mrfg/sops04thOct.20111
112、00MaharashtraCollegeofPharmacy,NilangaImportantsitesUseful links: lwww.usp.org lwww.pheur.org lwww.jpdb.nihs.go.jp lwww.picscheme.org lwww.pda.org lwww.phrma.org lwww.pharmacy.org 04thOct.2011101MaharashtraCollegeofPharmacy,NilangaThank YouE-mail:bknanjwadeyahoo.co.inCellNo:0091974243100004thOct.2011102MaharashtraCollegeofPharmacy,Nilanga
