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LaboratoryControlSystemOperationsinaGMPEnvironment
LaboratoryControlSystemOperations inaGMPEnvironment
DavidM.Bliesner,Ph.D.
DelphiAnalyticalServices,Inc.
IndianRocksBeach,Florida
Thiseditionfirstpublished2020
©2020JohnWiley&SonsInc.,
Allrightsreserved.Nopartofthispublicationmaybereproduced,storedinaretrievalsystem, ortransmitted,inanyformorbyanymeans,electronic,mechanical,photocopying,recordingor otherwise,exceptaspermittedbylaw.Adviceonhowtoobtainpermissiontoreusematerial fromthistitleisavailableathttp://www.wiley.com/go/permissions.
TherightofDavidM.Bliesnertobeidentifiedastheauthorofthisworkhasbeenassertedin accordancewithlaw.
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Inviewofongoingresearch,equipmentmodifications,changesingovernmentalregulations, andtheconstantflowofinformationrelatingtotheuseofexperimentalreagents,equipment, anddevices,thereaderisurgedtoreviewandevaluatetheinformationprovidedinthepackage insertorinstructionsforeachchemical,pieceofequipment,reagent,ordevicefor,amongother things,anychangesintheinstructionsorindicationofusageandforaddedwarningsand precautions.Whilethepublisherandauthorshaveusedtheirbesteffortsinpreparingthiswork, theymakenorepresentationsorwarrantieswithrespecttotheaccuracyorcompletenessofthe contentsofthisworkandspecificallydisclaimallwarranties,includingwithoutlimitationany impliedwarrantiesofmerchantabilityorfitnessforaparticularpurpose.Nowarrantymaybe createdorextendedbysalesrepresentatives,writtensalesmaterialsorpromotionalstatements forthiswork.Thefactthatanorganization,website,orproductisreferredtointhisworkasa citationand/orpotentialsourceoffurtherinformationdoesnotmeanthatthepublisherand authorsendorsetheinformationorservicestheorganization,website,orproductmayprovide orrecommendationsitmaymake.Thisworkissoldwiththeunderstandingthatthepublisheris notengagedinrenderingprofessionalservices.Theadviceandstrategiescontainedhereinmay notbesuitableforyoursituation.Youshouldconsultwithaspecialistwhereappropriate. Further,readersshouldbeawarethatwebsiteslistedinthisworkmayhavechangedor disappearedbetweenwhenthisworkwaswrittenandwhenitisread.Neitherthepublishernor authorsshallbeliableforanylossofprofitoranyothercommercialdamages,includingbutnot limitedtospecial,incidental,consequential,orotherdamages.
LibraryofCongressCataloging-in-PublicationData
Names:Bliesner,DavidM.,author.
Title:LaboratorycontrolsystemoperationsinaGMPenvironment/DavidM.Bliesner.
Description:Hoboken,NJ:Wiley,[2020]|Includesbibliographicalreferencesandindex.
Identifiers:LCCN2019052264(print)|LCCN2019052265(ebook)|ISBN 9781119529231(cloth)|ISBN9781119529279(adobepdf)|ISBN9781119529293(epub)
Subjects:LCSH:Medicallaboratories–Qualitycontrol.|Laboratories–Management. |Pharmacy–Research.|Manufacturingprocesses–Qualitycontrol.
Classification:LCCRB36.3.Q34B552020(print)|LCCRB36.3.Q34(ebook) |DDC610.28/4–dc23
LCrecordavailableathttps://lccn.loc.gov/2019052264
LCebookrecordavailableathttps://lccn.loc.gov/2019052265
CoverDesign:Wiley
CoverImage:©ImageJournal-Photography/GettyImages
Setin9.5/12.5ptSTIXTwoTextbySPiGlobal,Chennai,India
PrintedintheUnitedStatesofAmerica 10987654321
Tomywifeandbestfriend,Kathy
Contents
Preface xi
AbouttheCompanionWebsite xvii
1IntroductiontotheQualitySystemsBasedApproachtoCGMP Compliance 1
OverviewofQualitySystemsandtheLaboratoryControlSystem 1 RegulationsandRegulatoryBodies 4
RegulatoryGuidance 4
ApplicationofThisText 5
OverlapandRedundancy 6
ToolsandTemplates 6 References 7
2ComponentsoftheLaboratoryManagerialandAdministrative SystemsSubElement(MS) 9
DescriptionoftheLaboratoryManagerialandAdministrativeSystems SubElement 9
ContentsoftheSubElement 10 ToolsandTemplates 23 Reference 23
3ComponentsoftheLaboratoryDocumentationPracticesandStandard OperatingProceduresSubElement(OP) 25
DescriptionoftheLaboratoryDocumentationPracticesandStandard OperatingProceduresSubElement 25 ContentsoftheSubElement 26 ToolsandTemplates 44
4ComponentsoftheLaboratoryEquipmentSubElement(LE) 45
DescriptionoftheLaboratoryEquipmentSubElement 45 ContentsoftheSubElement 46
ToolsandTemplates 68 References 68
5ComponentsoftheLaboratoryFacilitiesSubElement(LF) 71
DescriptionoftheLaboratoryFacilitiesSubElement 71 ContentsoftheSubElement 71
ToolsandTemplates 81 References 81
6ComponentsoftheMethodValidationandMethodTransfer SubElement(MV) 83
DescriptionoftheMethodValidationandMethodTransferSub Element 83
ContentsoftheSubElement 84
ToolsandTemplates 93
Glossary 93 References 113
7ComponentsoftheLaboratoryComputerSystemsSub Element(LC) 115
DescriptionoftheLaboratoryComputerSystemsSubElement 115 ContentsoftheSubElement 116 ToolsandTemplates 129 Glossary 130 References 133
8ComponentsoftheLaboratoryInvestigationsSubElement(LI) 135
BackgroundandRegulatoryHistoryofOut-of-Specification Investigations 135
DescriptionoftheLaboratoryInvestigationsSubElement 135 ContentsoftheSubElement 139 CommonProblemsRelatedtoLaboratoryOOSInvestigations 148 ToolsandTemplates 149 Glossary 150 References 155
9ComponentsoftheLaboratoryDataGovernanceandDataIntegrity
SubElement(DI) 157
Background 157
PreceptsRegardingDataGovernanceandDataIntegrity 159
DescriptionoftheLaboratoryDataGovernanceandDataIntegritySub Element 162
ContentsoftheSubElement 164
PolicyforDataGovernance 164
ProceduralControls 165
TechnicalControls 166
DataMapsandDataWalks 166
RiskIdentification,Ranking,andFiltering 171
DataReviews 196
DataandOperationalAudits 196
EmployeeAwarenessandTraining 208
ManagementOversight 210
ToolsandTemplates 212
Glossary 212
References 214
FurtherReading 215
10ComponentsoftheStabilityProgramSubElement(SB) 217
DescriptionoftheStabilityProgramSubElement 217
ContentsoftheSubElement 218
ModelStandardOperatingProceduresforEstablishingand MaintainingaStabilityProgram 218
StabilityChambers 246
ToolsandTemplates 261
Glossary 262
References 268
11ComponentsoftheGeneralLaboratoryCompliancePracticesSub Element(CP) 269
DescriptionoftheGeneralLaboratoryCompliancePracticesSub Element 269
ContentsoftheSubElement 270
ToolsandTemplates 284
x Contents
12SummaryforEstablishingandMaintainingaLaboratoryControl System 285
ABriefReviewoftheLaboratoryControlSystemandItsSub Elements 285
HowThingsCanGoWrong:ExamplesofSomeRegulatoryCitations OrganizedbySubElement 285
SomeFinalThoughtsonEstablishingandMaintainingaCompliance LaboratoryControlSystem 296
Index 297
Preface
RegulatoryagenciessuchastheUSFoodandDrugAdministration(FDA)andthe EuropeanMedicinesAgency(EMA)mandatethatcompanieswhomanufacture drugsforhumanandanimalusebeoperatedinastateofcontrolbyemploying conditionsandcontrolscommonlyreferredtoasgoodmanufacturingpractices (GMPs).IntheUnitedStatestheGMPsorCGMPs(whereC = current)arecodifiedin21CodeofFederalRegulationsParts210and211.IntheEuropeanUnion theGMPsaredescribedinEudraLex–Volume4,theGoodManufacturingPractice (GMP)guidelines.OtherRegulatorybodies,suchastheWorldHealthOrganization(WHO)andtheInternationalCouncilforHarmonization(ICH)alsoprovide requirementsandguidelineswithrespecttoGMPs.
Attheturnofthetwenty-firstcenturytheFDAwasactivelyengagedinregulatoryactionsagainstpharmaceuticalcompanieswhomtheydeterminedtobein significantviolationoftheCGMPs.AspartofFDA’sactions,severallargecompaniesenteredintovoluntarylegalagreementsreferredtoasConsentDecrees. Theseagreementsexistedfortheexpressedpurposeofcorrectingthedeficiencies relatedtoCGMPs.ConsentDecreesroutinelyrequirethecontractingofindependentthird-partyexpertconsultants.Theseconsultants’dutiesincludeperforming abaselineauditoftheoffendingfacilities,documentingtheirfindingsandhelping thecompaniesdevelopandimplementcorrectiveactionplans.
Tohelpcollectevidencetosupportregulatoryactions,FDAbeganusingaQualitySystemsapproachtoevaluateafirm’slevelofGMPcompliance.
TheQualitySystemsapproachisaschemeofsystemsforthemanufactureof drugsand/ordrugproducts.ThegeneralschemeofsystemsFDAusedforauditing manufacturefacilitiesconsistsofthefollowing:
AccordingtoFDA“TheQualitySystemprovidesthefoundationforthemanufacturingsystemsthatarelinkedandfunctionwithinit.”1
Thisapproachiscommonlyreferredtoasthesix-systemmodelandisstillused todaybytheFDAtoconductinspectionsofGMPfacilities.
Duringthistime,DelphiAnalyticalServices,Inc.(Delphi)servedasoneofthe third-partyexpertconsultingfirmsonseveralConsentDecreesatmajorpharmaceuticalcompanies.Delphi’scorecompetencyisthepracticalunderstanding ofworkingsofthelaboratorycontrolsystem(LCS),thesixthqualitysystem mentionedintheFDAmodel.Delphiwasextensivelyinvolvedinperforming third-partyauditsofqualitycontrol(QC)andresearchanddevelopment(R&D) laboratoriesforcompaniesunderConsentDecree.
Whileexecutingtheseconsultingassignmentsitbecameapparentthatthe CGMPsregulations,FDAGuidanceDocumentsandFDAInternalCompliance ProgramGuidesofferedlittledirectionorspecificsofwhatwasexpectedofa CGMPcompliantLCS.Becauseofthis,Delphidevelopedanddocumenteda systematicmeansforperformingthebaselineaudits,capturingdeficiencies, reportingtheresults,anddevelopingsubsequentcorrectiveactionplans,forQC laboratories.Inaddition,Delphialsocreatedinstructionalmaterialsandbegan teachingcoursesonauditingQClaboratoriesatvariousclientsitesandscientific conferences.
DuetotheinherentcomplexityoftheLCS,Delphidivideditintosevensubsystemsorsubelements.Theseincludedthefollowing:
1.LaboratoryManagerialandAdministrativeSystems
2.LaboratoryDocumentationPracticesandStandardOperatingProcedures
3.LaboratoryEquipmentQualificationandCalibration
4.LaboratoryFacilities
5.MethodsValidationandTechnologyTransfer
6.LaboratoryComputerSystems
7.LaboratoryInvestigations
Basedonreal-worldexperiences,Delphithen,inturn,developeddetailedaudit checklistsforeachLCSsubelement.ThesebecamethebasisformostofDelphi’s consultingcontractsandinstructionmaterial.
InMarch2004atthePittsburghConferenceonAnalyticalChemistryand AppliedSpectroscopy(PittCon© ),DelphiAnalyticalServices,Inc.’spresident, Dr.DavidM.Bliesner,Ph.D.,taughtaone-daycoursetitled“HowtoEstablish aGMPLaboratoryAuditSystem.”Thecoursewaswellattendedwhichledto ameetingwitharepresentativeofWiley-Interscience,JohnWiley&Sons,Inc. Attheconclusionofthatmeeting,itwasagreedthathewouldwriteaproposal
1FDAGuidanceforIndustryQualitySystemsApproachtoPharmaceuticalCGMPRegulations, September,2006.
forpublicationofabook.Theproposalwasacceptedandbecamethebooktitled EstablishingaCGMPLaboratoryAuditSystem:APracticalGuide in2006.
Overthecourseofthenext12years(2006–2018),thepharmaceuticalindustry experiencedamassiveparadigmshiftinitsbusinessandoperationalmodels.This inturnresultedinchangestothemannerinwhichregulatoryagenciesenforced theGMPs.Somekeyelementsofthesechangesincluded:
• Substantialoutsourcingofdrugdevelopment,manufacturing,testing,andother functions
• Offshoringofmanufacturingandtestingofactivepharmaceuticalingredients (APIs)anddrugproducts
• Profitversusqualitydrivendecisionmaking
• Reductionsinexperienced,permanentworkforces
• IncreasedregulatoryactivitybyUSFDAatoverseasplants
• IncreasedGlobalRegulatoryAgencyoversight,guidance,andcooperation
Becauseofthesechanges,andotherfactors,itbecameobviousthat Establishing aCGMPLaboratoryAuditSystem:APracticalGuide hadmuchbroaderutilitythan justservingasanauditguide.Inparticular,therealvalueofthebookovertheyears hasnotbeenasanauditingguidebut:
• Ameanstointroduceaualityassurance(QA)andQCpersonneltotheconcept ofqualitysystemsandtheLCSinparticular
• AsabasisforinstructingQAandQCpersonnelonLaboratoryGMPs
• ToassistininterpretingandclarifyingregulatoryexpectationsfortheLCS
• AsthebasisforassistinglaboratorymanagementinimplementingandmaintainingCGMPcompliantpracticesintheirownQClaboratories
Therefore,thepurposeofthisnewbooktitled LaboratoryControlSystemOperationsinaGMPEnvironment istofocusonLCS operations versus auditing Thegoalinwritingthisbookistopublishatext,whichwhenimplementedin QCandR&Dlaboratories,providesthebasisforoperatingaCGMPcompliantLCS. Thiswillimproveanorganization’schancesforwithstandingregulatoryscrutiny andenhanceoperationalefficiency.Thisnewbookisdesignedtobeusedinseveral ways,including:
• Designingandimplementinganew,fromscratch,CGMPcompliantLCS
• UpgradingortweakinganexistingLCS
• LayingabasisforinitialandperiodicLCSGMPtraining
• Layingabasisforimprovingoperationalefficiency
• Servingasanoperationalreferenceguide:Thirdparty“sanity”checktohelp solvecompliancechallengesastheyarise
LaboratoryControlSystemOperationsinaGMPEnvironment buildsontheoriginalauditingtextdescribedearlier.However,insteadofemphasizingauditing,this
newtextnotonlyfocusesandupgradestheoperationalaspectsoftheoriginal sevenLCSsubelementsbutalsoexpandstheLCStoencompassthreeadditional subelements,whicharemarkedwithanasterisk(*)inthefollowinglist.This resultsinthefollowing10chaptersinthebook:
1.LaboratoryManagerialandAdministrativeSystems
2.LaboratoryDocumentationPracticesandStandardOperatingProcedures
3.LaboratoryEquipment
4.LaboratoryFacilities
5.MethodValidationandMethodTransfer
6.LaboratoryComputerSystems
7.LaboratoryInvestigations
8. DataGovernanceandDataIntegrity*
9. StabilityProgram*
10. GeneralLaboratoryCompliancePractices*
EachchapterinthistextdescribesthecriticalfunctionsoftheLCSsubelement sothereaderunderstandswhatisexpectedfromtheFDAandotherGlobalRegulatoryAgencies.Inaddition,eachchapterlinkstotools,templates,checklists, andGlobalRegulatoryAgencies’guidances.Allofthesetoolsandtemplatesare accessiblefordownloadonlinethroughaWileyIntersciencewebportalforeasy modificationandapplicationbytheend-userintheirownlaboratories.
Readers,inusingthisbook,mayaccomplishthefollowing:
• FullyimplementafunctionalLCSwhichcanwithstandGlobalRegulatory scrutiny
• Increaseoperationalefficiency
• StaycurrentwithGMPsandindustrytrends
• Savetimebyusingthereal-worldtoolsandtemplatesfoundinthebook,which canbemodifiedandusedbythereader
• Usethetextasabenchmarkreferencetowhichtheycanassessthestatusof complianceoftheirownlaboratories
LaboratoryControlSystemOperationsinaGMPEnvironment iswrittenfor abroadaudience.ItisapplicabletobothQCandQAprofessionalsinsmall, medium,andlargecompanieswithinthepharmaceuticalandbiopharmaceutical industries.R&Dpersonnelworkinginnon-GMPenvironmentswillalsobenefit byapplyingtheorganizationalschemesandprincipalspresentedinthistext.
Thisbookisparticularlyhelpfulforpersonnelwhoworkinsmallercompanies becausetheyoftendonothavethefinancial,personnelresources,andexisting “corporateknowledge”thatlargeUS-andEuropean-basedcompaniesmaypossess.Thismeansthatsmallerorganizationsareoftenleftto“figureitout”on theirown.Forthesesmalleroperations,thistextisparticularlyvaluablebecause oftheexample-templatesandchecklistsitincludes.
Preface xv
Toourknowledgenosuchdetailedoperationaltextorguideexistsinthe marketplace.Wehopeyoufind LaboratoryControlSystemOperationsinaGMP Environment usefulandwishyouthebestinyourcontinuingquesttoestablisha quality-mindedculture,improveoperationalefficiency,andthriveunderGlobal Regulatoryscrutiny.
January2020
DavidM.Bliesner,Ph.D. IndianRocksBeach,Florida
AbouttheCompanionWebsite
Thisbookisaccompaniedbyacompanionwebsite: www.wiley.com/go/Bliesner/LabControl_GMPEnvironment
ScanthisQRcodetovisitthecompanionwebsite
ThewebsiteincludesAppendicesandWeblinks.
IntroductiontotheQualitySystemsBasedApproachto CGMPCompliance
OverviewofQualitySystemsandtheLaboratoryControl System
TheUSFoodandDrugAdministration(USFDA)mandatesthatadrugfirm,and thereforethelaboratory,beoperatedinastateofcontrolbyemployingconditionsandpracticesthatassurecompliancewiththeintentoftheFederalFood, Drug,andCosmeticActandportionsoftheCurrentGoodManufacturingPractice (CGMP)regulations(e.g.21CFRParts210and211)thatpertaintoit.Activities foundindrugfirms,includingoperationofthelaboratory,canbeorganizedinto systemsthataresetsofoperationsandrelatedactivities.Controlofallsystems helpstoensurethefirmwillproducedrugsthataresafe,havetheproperidentity andstrength,andmeetthequalityandpuritycharacteristicsasintended[1,2].
Fordrugfirms,FDAhasoutlinedthefollowinggeneralschemeofsystemsthat impactthemanufactureofdrugsanddrugproducts:
(1) QualitySystem.ThissystemassuresoverallcompliancewithCGMPsand internalproceduresandspecifications.Thesystemincludesthequality control(QC)unitandallofitsreviewandapprovalduties(e.g.changecontrol,reprocessing,batchrelease,annualrecordreview,validationprotocols, reports,etc.).Italsoincludesallproductdefectevaluationsandevaluationof returnedandsalvageddrugproducts.(SeetheCGMPregulation,21CFR211 subpartsB,E,F,G,I,J,andK.)
(2) FacilitiesandEquipmentSystem.Thissystemincludesthemeasuresandactivitiesthatprovideanappropriatephysicalenvironmentandresourcesusedin theproductionofthedrugsordrugproducts.Itincludes:
(a)Buildingsandfacilitiesalongwithmaintenance.
(b)Equipmentqualifications(installationandoperation);equipmentcalibrationandpreventativemaintenance;andcleaningandvalidationof cleaningprocessesasappropriate.Processperformancequalificationsare
LaboratoryControlSystemOperationsinaGMPEnvironment, FirstEdition.DavidM.Bliesner. ©2020JohnWiley&Sons,Inc.Published2020byJohnWiley&Sons,Inc. Companionwebsite:www.wiley.com/go/Bliesner/LabControl_GMPEnvironment
1IntroductiontotheQualitySystemsBasedApproachtoCGMPCompliance includedaspartofprocessvalidation,whichisdonewithinthesystem wheretheprocessisemployed.
(c)Utilitiesthatarenotintendedtobeincorporatedintotheproductsuch asheating,ventilation,andair-conditioning(HVAC),compressedgases, steam,andwatersystems.(SeetheCGMPregulation,21CFR211subparts B,C,D,andJ.)
(3) MaterialsSystem.Thissystemincludesmeasuresandactivitiestocontrolfinishedproductsandcomponentsincludingwaterorgasesthatareincorporated intotheproduct,containers,andclosures.Itincludesvalidationofcomputerizedinventorycontrolprocesses,drugstorage,distributioncontrols,and records.(SeetheCGMPregulation,21CFR211subpartsB,E,H,andJ.)
(4) ProductionSystem.Thissystemincludesmeasuresandactivitiestocontrol themanufactureofdrugsanddrugproductsincludingbatchcompounding, dosageformproduction,in-processsamplingandtesting,andprocessvalidation.Italsoincludesestablishing,following,anddocumentingperformanceof approvedmanufacturingprocedures.(SeetheCGMPregulation,21CFR211 subpartsB,F,andJ.)
(5) PackagingandLabelingSystem.Thissystemincludesmeasuresandactivities thatcontrolthepackagingandlabelingofdrugsanddrugproducts.Itincludes writtenprocedures,labelexaminationandusage,labelstorageandissuance, packagingandlabelingoperationscontrols,andvalidationoftheseoperations. (SeetheCGMPregulation,21CFR211subpartsB,G,andJ.)
(6) LaboratoryControlSystem.Thissystemincludesmeasuresandactivities relatedtolaboratoryprocedures,testing,analyticalmethoddevelopment, validationand/orqualification/verification,andthestabilityprogram.(See theCGMPregulation,21CFR211subpartsB,I,J,andK.)
AccordingtoFDA,“TheQualitySystemprovidesthefoundationforthemanufacturingsystemsthatarelinkedandfunctionwithinit.”Graphically,thescheme ofsystemslookslike[1](Figure1.1):
Thisapproachiscommonlyreferredtoasthesix-systemmodelandisstillused todaybyFDAtoconductinspectionsofgoodmanufacturingpractice(GMP) facilities.
Asstatedin(6)earlier,FDAconsidersafirm’sLaboratoryControlSystem(LCS) tobeakeyelementinCGMPcompliance.WithintheLCSareatleast10additional subsystemsorsubelements,whichmayinclude:
• LaboratoryManagerialandAdministrativeSystems(MS)
• LaboratoryDocumentationPracticesandStandardOperatingProcedures(OP)
• LaboratoryEquipment(LE)
• LaboratoryFacilities(LF)
• MethodValidationandMethodTransfer(MV)
Quality system
Figure1.1 FDAguidanceforIndustryQualitySystemsapproachtopharmaceutical CGMPregulations,September2006[1].
• LaboratoryComputerSystems(LC)
• LaboratoryInvestigations(LI)
• DataGovernanceandDataIntegrity(DI)
• StabilityProgram(SB)
• GeneralLaboratoryCompliancePractices(CP)
These10subelementsoftheLCSarenotpartofanyguidelinedocument,internationalcouncil,orinspectionconvention.Insteadtheyhavebeencreatedbythe author,topromotetheestablishmentandmaintenanceofQualitySystemsandsub systems,whichdemonstrateyouareincontrolofyourlaboratoryoperationsand thusincompliancewiththeCGMPregulations.
These10subelementtopicsconstitute10chapterswithinthisbook.Each chapterwilldescribethecriticalfunctionsoftheLCSsubelementsothereader understandswhatisexpectedfromtheUSFDAandotherGlobalRegulatory Agencies.
AlistingoftheprimaryGlobalRegulations,theAgenciesthatenforcethem,and theinternationalcouncilsorinspectionconventionsthathelptoharmonizetheir effortsarelistedinthesucceedingtext.
1IntroductiontotheQualitySystemsBasedApproachtoCGMPCompliance
RegulationsandRegulatoryBodies
Theprimary,globallysignificant,regulationsrelatedtothemanufacturing, processing,packing,orholdingofdrugsinclude:
• 21CodeofUSFederalRegulationsPart210and211CurrentGoodManufacturingPracticeRegulations
• EudraLex–Volume4–GoodManufacturingPractice(GMP)guidelines
Themajorregulatorybodiesororganizationsthatenforcetheregulationsor assistinharmonizinginternationalregulatoryeffortsinclude:
• USFoodandDrugAdministration(USFDA,UnitedStates)
• EuropeanMedicinesAgency(EMA,EuropeanUnion)
• MedicinesandHealthcareproductsRegulatoryAgency(MHRA, UnitedKingdom)
• HealthCanada(Canada)
• BrazilianHealthRegulatoryAgency(ANVISA,Brazil)
• PharmaceuticalsandMedicalDevicesAgency(PMDA,Japan)
• TherapeuticGoodsAdministration(TGA,Australia)
• WorldHealthOrganization(WHO-International)
• CentralDrugsStandardControlOrganization(CDSCO,India)
• TheInternationalCouncilforHarmonisationofTechnicalRequirementsfor PharmaceuticalsforHumanUse(ICH-International)
• PharmaceuticalInspectionConvention(PIC)andthePharmaceuticalInspectionCo-operationScheme(PICScheme)(PIC/S-International)
Therearenumerousothercountry-specificbodies,whichenforcetheirownlaws relatedtothemanufacturing,processing,packing,orholdingofdrugs.Thereader isencouragedtoconsulttherequirementsoftheirowncountry’slawsandregulationsregardingthemanufactureofpharmaceuticals.
RegulatoryGuidance
Traditionally,RegulatoryAgenciesthemselveshaveprovidedlimitedinsightand assistanceintohoworganizationsoperatingwithinthepharmaceuticalindustry cancomplywiththeregulations.However,overtime,regulatoryguidancesand otherinstrumentshavearisenandevolvedandtodayconsistofafairlylargebody ofknowledge,whichcanbeusedbyorganizationstoaidincompliancewiththe CGMPs.
WhenitcomestoregulatoryguidanceforQualityControl(QC)Laboratories, thefollowingdocumentsmaybehelpful:
• USFDAComplianceProgramstoFDAstaff,Chapter56:DrugQualityAssurance7366.002DrugManufacturingInspections
• USFDAGuidanceforIndustry,QualitySystemsApproachtoPharmaceutical CGMPRegulations
• ICHHarmonisedTripartiteGuideline,Q1AtoQ1FStability
• ICHHarmonisedTripartiteGuideline,Q2AnalyticalValidation
• ICHHarmonisedTripartiteGuideline,Q3AtoQ3DImpurities
• ICHHarmonisedTripartiteGuideline,Q4toQ4BPharmacopoeias
• ICHHarmonisedTripartiteGuideline,Q6AtoQ6BSpecifications
• ICHHarmonisedTripartiteGuideline,Q7GoodManufacturingPracticeGuide forActivePharmaceuticalIngredients
• ICHHarmonisedTripartiteGuideline,Q8PharmaceuticalDevelopment
• ICHHarmonisedTripartiteGuideline,Q9QualityRiskManagement
• ICHHarmonisedTripartiteGuideline,Q10PharmaceuticalQualitySystem
• ICHHarmonisedTripartiteGuideline,Q12LifecycleManagement
• ICHHarmonisedTripartiteGuideline,Q14AnalyticalProcedureDevelopment
• WHOAnnex2:GoodManufacturingPracticesforPharmaceuticalProducts: MainPrinciples
• FDAGuidanceforIndustryQualitySystemsApproachtoPharmaceutical CGMPRegulations,September2006
Itshouldbenotedthatalthoughnotlegallybinding,violationoftheprincipals ofICHHarmonisedTripartiteGuideline,GoodManufacturingPracticeGuidefor ActivePharmaceuticalIngredients,Q7,aresometimesdocumentedasfindings byFDA.
AdditionalFDAandICHguidelinesexistandcanbelocatedat:https://www.fda .gov/drugs/guidances-drugs/all-guidances-drugs,https://www.ich.org/products/ guidelines/quality/article/quality-guidelines.html,andhttps://www.fda.gov/ drugs/guidance-compliance-regulatory-information/drug-compliance-programs
ApplicationofThisText
Theremainderof“LaboratoryControlSystemOperationsinaGMPEnvironment” isdedicatedtodescribingthecriticalfunctionsoftheLCSsubelementssothe readerunderstandswhatisexpectedfromtheFDAandtheGlobalRegulatory Agencieslistedearlier.Inaddition,eachchapterwillpresentorlinktotools,templates,checklists,andsomeoftheGlobalRegulatoryAgencies’guidancelisted previously.
Itshouldbenotedthattextiswrittenforabroadaudience.Itisapplicableto bothQualityControlandQualityAssuranceprofessionalsinsmall,medium,and
1IntroductiontotheQualitySystemsBasedApproachtoCGMPCompliance
largecompanieswithinthepharmaceuticalandbiopharmaceuticalindustries. R&Dpersonnelworkinginnon-GMPenvironmentswillalsobenefitapplyingthe organizationalschemesandprincipalspresentedinthistext.1 Also,foreignfirms inChinaandIndiawillfindthisbookespeciallyuseful.
Thisbookisparticularlyhelpfulforpersonnelwhoworkinsmallercompanies becausetheyoftendonothavethefinancial,personnelresources,andexisting “corporateknowledge”thatalargeUS-andEuropean-basedcompanymayhave andarethereforeoftenleftto“figureitout”ontheirown.Inthisrespecttheguide isparticularlyvaluableintheexample-templatesandchecklistsitincludes.
OverlapandRedundancy
Asthereaderprogressesthroughthistext,theywillnoticethatsometopics,notes, andclarificationsareaddressedmorethanonceandindifferentlocationswithin thebook.Thiswasdonebytheauthoronpurposetoensurethatimportanttopics areaddressedappropriatelyandreinforced.
Additionally,theQClaboratoryisaverycomplexanddynamicentity,which continuallygrowsandevolvesovertime.Thismeansthatthe10subelements intowiththeLCSisdivided(whichispurelyamatterofchoiceonthepartof theauthor)canbereduced,modified,orexpandedtoaddresschangeswithinthe organizationandtheevolutionofRegulatoryAgencyexpectationsandstandard industrypractices.Thisiswhythereisa“C”inCGMP:Cmeanscurrent,whichis today,notyesterday.
ToolsandTemplates
ThefollowingareprovidedinelectronicformatintheChapter1Appendix (www.wiley.com/go/Bliesner/LabControl_GMPEnvironment):
• 21CodeofFederalRegulationsParts210and211–CurrentGoodManufacturingPracticeRegulations,RevisedasofApril1,2005
• USFDAComplianceProgramstoFDAstaff,Chapter56:DrugQualityAssurance7366.002DrugManufacturingInspections,October31,2017.
• USFDAGuidanceforIndustry,QualitySystemsApproachtoPharmaceutical CGMPRegulations,September2006.
1InJune2018theICHAssemblyendorsedICHQ14“AnalyticalProcedureDevelopment Guideline”andthus,bydefault,requiringalevelofcompliancewiththeGMPsbyR&D laboratories.
References
1 21CFRParts210and211CurrentGoodManufacturingPracticeforFinished Pharmaceuticals.
2 USFDA(2017).ComplianceProgramstoFDAstaff,Chapter56:DrugQuality Assurance7356.002DrugManufacturingInspections.
ComponentsoftheLaboratoryManagerialand
AdministrativeSystemsSubElement(MS)
DescriptionoftheLaboratoryManagerial andAdministrativeSystemsSubElement
TheLaboratoryManagerialandAdministrativeSystemsarethosesubelements thatprovidetheinfrastructureforefficientandcompliantoperationsofan analyticallaboratory.Itissometimesdifficulttodirectlyrelateitemswithinthis subelementtotheCurrentGoodManufacturingPractices(CGMPs).However, deficiencieswithinthissubelement,whichcannotbedirectlyattributedtothe CGMPs,canleadtocompliancefailures.Forexample,21CFRSections210and 211donotspecificallyrequirethatsomeonebeassignedthedutiesoftraining manager.However,failingtohaveanindividualresponsiblefortrainingand consequentlynothavinganeffectivetrainingprogramcandegradetheoverall qualityofdatathatisgeneratedbylaboratorypersonnel,andUSFoodandDrug Administration(USFDA)hascitedcompaniesfornothavingatrainingprogram forlaboratorypersonnel[1].
TheLaboratoryManagerialandAdministrativeSystemssubelementincludesat leastsixindividualtopics.AlaboratorythatisincompliancewithCGMPsshould atleastaddresseachofthesetopics(asapplicable).Thesetopicsinclude(i)OrganizationalStructureandRolesandResponsibilities,(ii)TrainingandQualification, (iii)LaboratoryBudgeting,Purchasing,andRequisition,(iv)LaboratoryAdministrationandOperations,(v)LaboratoryChemicals,Solutions,ReagentsandSupplies,and(vi)LaboratoryReferenceStandardsandSolutions.
Thesesixtopicsarelistedwithinthetextofthechapteralongwithsomesuggestionsonwhatitemsshouldbeaddressedineachtopic.Thelistofitemsunder eachtopicisfairlycomprehensivebutmaynotbetotallyinclusiveofallthose components,whichmayconstitutethesubelement.
LaboratoryControlSystemOperationsinaGMPEnvironment, FirstEdition.DavidM.Bliesner. ©2020JohnWiley&Sons,Inc.Published2020byJohnWiley&Sons,Inc. Companionwebsite:www.wiley.com/go/Bliesner/LabControl_GMPEnvironment
2ComponentsoftheLaboratoryManagerialandAdministrativeSystemsSubElement(MS)
ContentsoftheSubElement
ThesixtopicsmentionedearlierarepresentedinTable2.1intheformofquestions relatedtoeachtopic.Foreachtopic,additionaldetails,or“pointstoconsider,”are offeredalongwithnotesandclarificationsasappropriate.Thequestions,notes, andclarificationsareallbasedonactualinspectionalfindingsfromRegulatory Inspectorsorpointsthathavebeenfoundtodirectlyorindirectlyimpactcompliantandefficientreal-worldLaboratoryControlSystemoperations. Itisenvisionedthatthebelowtablemaybeusedasabasisfor:
• Evaluatingyourownlaboratory’smanagerialandadministrativesystems
• Upgradingyourownlaboratory’smanagerialandadministrativesystems
• Establishingyourownlaboratory’smanagerialandadministrativesystemsif itisanewlaboratoryorifyouaremakingsubstantialchangestoanexisting LaboratoryControlSystem
Table2.1 Componentsofthelaboratorymanagerialandadministrativesystemssub element.
#
Laboratorymanagerialand administrativesystems subelementtopicNotesandclarifications
2.1 OrganizationalStructureand RolesandResponsibilities
2.1.1Arecurrentorganizationcharts availableforreviewandarethey accurate?
2.1.2Isthereapolicy/procedurethat definestheresponsibilityand authorityoftheQualityControl(QC) unit?
2.1.3Havetheresponsibilitiesofeach functionalgroupandsupervisorbeen clearlydefined,includingtestingand operationalrequirements,Standard OperatingProcedures(SOPs),andall othercriticalfunctions?
Organizationalchartswillbeoneof thefirstthingsanauditorwillrequest whenyourlaboratoryisbeing inspected.Makesurethedocumentis currentandcorrectinordertomakea goodfirstimpression.
(Continued)
# Laboratorymanagerialand administrativesystems subelementtopicNotesandclarifications
2.1.4Isanorganizationalstructurein placewhichisproperlystaffedto assurethatallrequired testing/monitoringandsupport activitiesareperformed?
Section211.25Personnel qualificationsoftheGood ManufacturingPracticesregulations states“(c)Thereshallbeanadequate numberofqualifiedpersonnelto performandsupervisethe manufacture,processing,packing,or holdingofeachdrugproduct.”This appliestothelaboratoryandfailingto meetthisrequirementisoftentheroot causeofmanyissueswhichoccurin poorlyoperatedQClaboratories.
2.1.5Isthespanofcontrolandauthority assignedtotheQClaboratory adequatetoallowproperexecutionof theseactivities?
2.1.6Istheratioofsupervisorstoanalyst appropriate?(Aratioofnomorethan 1:8isrecommended)
2.1.7Aretherolesandresponsibilitiesfor eachpositionwithinthelaboratory clearlydefined?
2.1.8Aretherolesandresponsibilitiesfor eachpositionintheorganizational chartdefinedinformal,controlled, accurate,andcurrentjob descriptions?
Ifasupervisorhastosupervisemore thaneightemployeesdirectly,the effectivenessoftheirabilitytodoso decreasesdramatically.
2.1.9Aresignatureauthority, responsibility,andaccountabilities appropriateandclearlydefined?
2.1.10Dosystemsexisttoenhance communications,understanding, andworkingrelationshipsbetween laboratoryandQualityAssurance (QA)personnel?
Upuntilrecently,jobdescriptions wereconsideredthepurviewofthe humanresourcesdepartmentand thereforedidnotfallunderthe umbrellaofGMPs.Thishasnow changed,andthegeneralexpectation ofregulatoryagenciesisthatjob descriptionsshouldbemaintained andcontrolledlikeanyotherGMP document.
Ahealthy,respectfulrelationship betweenQCandQAwilldowonders foreveryone’sabilitytomanufacture, test,and,shipproduct.QCmanagers shouldencourageQApersonnelto spendtimeinthelaboratoryandteach QApersonnelasmuchaboutproduct testingandanalyticaltechniquesas theycan.
(Continued)
2ComponentsoftheLaboratoryManagerialandAdministrativeSystemsSubElement(MS)
Table2.1 (Continued)
# Laboratorymanagerialand administrativesystems subelementtopicNotesandclarifications
2.1.11Doesapersonnelperformance evaluationsystemexist,whichtracks laboratorypersonnelstrengthsand weaknessesandestablishesameans toimprovetechnical,administrative, andmanagerialskills?
2.1.12Doesamastertestingscheduleor similardocument(s)existtoensure smoothandefficientworkflow,and minimizelaboratorypersonnel over-commitment?
2.1.13ArecurrentcopiesofCV’sand resumesforallpersonnel,including consultants,availableforreview?
2.2 TrainingandQualification
2.2.1Havetheeducational,training,and workexperiencerequirementsfor eachlaboratorypositionbeenclearly definedanddotheyreflectcurrent standardsintheindustry?
2.2.2Istherequirementfortrainingand qualificationclearlydescribedinan SOPorsimilardocumentforall laboratorymanagers,supervisors, analysts,support,temporarystaff, andconsultants?
Performanceevaluationshouldnotbe aone-time-a-yearevent.Agoodleader willcontinuallyevaluateandassist theiremployeestobecomethebest thattheycanbe.
2.2.3Hasatrainingandqualification curriculumbeendevelopedforeach positionthatclearlyidentifies trainingrequirementsforallrequired SOPsandPolicies,TestMethods, SafetyProcedures,andtheGMPsas wellasallotherinternalandexternal coursesorprograms?
Trainingisdefinedasanactivity designedtoprovidetheskillsand/or knowledgethatindividualsneedto performassignedjob-relatedduties andresponsibilities. Qualificationisdefinedastheprocess, includingdocumentationand approval,wherebyapersonistrained anddemonstratesproof-of-proficiency inspecifiedtests,tasks,procedures,or techniques.
(Continued)
#
Laboratorymanagerialand administrativesystems subelementtopicNotesandclarifications
2.2.4Isthereasysteminplace(e.g. electronic,paper-based,orhybrid)to capture,track,andmanagetraining andqualificationoflaboratory personnel?
Electronictrainingsystemsshould haveasetofstandard file + curriculumforeachunique positionontheorganizationalchart. Forexample,thepositionfora laboratorytechnicianresponsiblefor glasswarewashingshouldbeloaded intothetrainingsystemasifitwasa realperson.Itwillincludeallthe necessarySOPsrequiredforthe position,qualificationtasks,safety training,etc.
This“standardposition”willserveas atemplate.Itthenlaysthebasisforan individual’strainingrecord,which willgrowandchangeastheemployee istrainedandqualifiedinthat position.
2.2.5Doeseachemployeehaveatraining fileorsimilarrecordwithinthe trainingsystem?
2.2.6Arethetraininghistoriesforeach individualemployeekeptcurrent?
2.2.7Havealllaboratorypersonnelbeen properlytrainedandqualified?
Thispointseemsobvious;however duringauditingitisnotunusualtosee someonewhowas“thrownintoa position”becauseoflaborshortages, whohasneverbeentrainedonthe taskstheyarepreforminginthe laboratory.
2.2.8Arethetraininghistoriesforeach individualemployeereadilyavailable forreview?
2.2.9IsSOPtrainingconductedina fashionotherthan“readand understand”asappropriate?
Unfortunately,organizationshavea tendencytoperformallSOPtraining inthisfashion.Itisnoteffectivein manycircumstancesandthepractice shouldberestrictedtoreviewofminor changesonpreviouslytrained-on procedures.
(Continued)
