PDA TR63 PDA TR63 临床 Tri 即兴制备的质量要求（英文）

TechnicalReportNo.63

QualityRequirementsforthe

ExtemporaneousPreparationof

ClinicalTrialMaterials

parenteralDrugAssociation

PDAQualityRequirementsfortheExtemporaneousPreparationofClinicalTrialMaterials

TechnicalReportTeam

Authors

VinceL.Mathews,M.S.,MathewsQualityConsultingLLC(TeamLeader)

LoydV.Allen,Jr.,Ph.D,InternationalJournalofPhar-maceuticalCompounding

AmyAntipas,Ph.D,R.Ph,Pzer

LesleyR.Dandoy,M.S.,AstraZenecaPharmaceuticals

GeraldE.Finken,R.Ph.,CSM,Inc.

KathleenS.Greene,NovartisVaccinesandDiagnosticsRichardHoman,M.S.,RAC,EliLillyandCompanyMarkD.Leney,Ph.D.,MassBiologics,UniversityofMassachusettsMedicalSchool

WilliamMarinaro,Ph.D.,R.Ph.,Merck&Co.,Inc.

CathyMoll,R.Ph.,Covance

Disclaimer:ThecontentandviewsexpressedinthisTechnicalReportaretheresultofaconsensusachievedbytheauthorizingtechnicalreportteamandarenotnecessarilyviewsoftheorganizationstheyrepresent.

QualityRequirements

fortheExtemporaneous

PreparationofClinicalTrialMaterials

TechnicalReportNo.63

ISBN:978-0-939459-60-5

©2013ParenteralDrugAssociation,Inc.

Allrightsreserved.

parenteralDrugAssociation

TableofContents

1.0INTRODUCTION 1

1.1Purpose 1

1.2Scope 1

1.3BusinessConsiderations 1

1.4ScientificandClinicalRationale 2

2.0GLOSSARYOFTERMS 3

3.0EXTEMPORANEOUSPREPARATIONSTUDIES 5

3.1StudyTypesAppropriateforEP 5

3.2DosePreparationActivities 5

3.3DosePreparationConsiderations 5

4.0QUALITYSYSTEM 6

4.1RegulatoryOverview 6

4.1.1CurrentRegulatoryEnvironment 6

4.1.2RegulatorySubmissionRequirements 6

4.2QualitySystems 7

4.2.1QualitySystemsManagement 7

4.2.2FacilitiesandEquipment 9

4.2.3MaterialsManagement 9

Storage 10

MaterialReconciliation 10

4.2.4PreparationInstructionsandRecords 10

PharmacyManual 11

PreparationRecord 11

4.2.5CTMAssessment 11

4.2.6PackagingandLabeling 12

4.2.7SpecialCTMConsiderations 13

5.0PRE-PREPARATION,PREPARATIONAND

RELEASEOFCTM

14

5.1Pre-PreparationActivities 14

5.2PreparationActivities 14

5.3SterilePreparations 14

5.4ReleaseofCTM 14

6.0SITESELECTIONANDQUALIFICATION 16

6.1SiteSelectionConsiderations 16

6.2DueDiligenceAssessment 16

6.3Audits 16

7.0OVERSIGHTANDCONTROL 18

8.0REFERENCES 19

1.0Introduction

Thepharmaceuticalindustryisundercontinuouspressuretodiscovernewmedicineswithfewerresourcesinfastertimeframeswhilemaintainingthehighestquality.Withtheexceedinglyhighcostsofthedevelopmentandlaunchofeachnewmolecularentity(NME)andthelowchanceofsuccessduetohighattrition,theperformanceofclinicalstudiesliesonthecriticalpath(1).

Typically,thesupplyofclinicaltrialmaterials(CTMs)isprovidedthroughGMPmanufactureofxed-strengthformulations.RegulatoryguidelinesforGMPmanufactureanddocumentationofthesematerialsareavailableandenforcedbyregulatoryagenciesacrosstheworld.

However,arecentbenchmarkingexerciseconductedbythePDAtechnicalreportteam(includinglargeandsmallpharmaceuticalcompanies,contractorganizationsandacademicinstitutions)indi-catesthatextemporaneouspreparation(EP)techniquesarewidelyusedtoprepareformulationsforavarietyofdosageformsforsmall-scaleclinicalstudieswheredosingisin-clinic(seeSection3.2fortypesofformulationsanddosageformnoted).

TheEPapproachmayoccuratpharmaciesassociatedwithahospital,aclinicalresearchunit(CRU),oracademicinstitution(i.e.,preparationsite)andthatspecializeindosepreparationactivities.ThesearenottraditionalGMPmanufacturingareasforclinicaltrialmaterial.

WhiletraditionalCGMPsystemsmaynotbeinplaceinsuchareas,therestillmustbeappropriatecontrolsinplacetoensurepatientsafety.SincethequalityrequirementsfordosepreparationactivitiesthatoccuratEPsitesisnotalwaysclear,thisgapbecomesveryimportantasinvestigatorsareincreas-inglyusingEPapproachestosupportsmall-scaleclinicalstudies.

1.1Purpose

ThisTechnicalReportdescribesaqualitysystemthatwillsupportthepreparationofCTMsinanonmanufacturingenvironment(preparationsite)inamannerthatwillensureproductqualityandpatientsafety.

Thisdocumentwillbeausefulresourcefordrugcompanies,clinicalsites,investigatorsandregulators.

1.2Scope

ThisTechnicalReportgivessuggestedqualityrequirementsforthepreparationofsmall-scaleCTMsutilizinganEPapproachforin-clinicdosing.Itisnotappropriatetosupportthepreparationofcom-mercialmaterialsforsale.

Althoughalternativeapproachesmaybeequallyvalid,pharmacists,healthcareprofessionals,andoth-ersengagedinthepreparationofclinicalsuppliesforsmall-scalestudiesareadvisedtoensurethatanyapproachtheychoosetoadoptisconsistentwithapplicableregionalornationallaws,regulations,andguidelines.

1.3BusinessConsiderations

Earlyphaseclinicalstudiesprovidecriticalunderstandingofacompound’ssafetyandpharmacoki-netics,andoccasionallyinsightintoearlyindicationsofe伍cacy.Practiceswhichreducethetimetosupplyingquality,t-for-purposeformulationsforearlyphasestudiesarecriticalinleadingtodatathatreduceslaterstageattritionandlowersthecostofdevelopingnewdrugs.Inthelexibleenviron-mentofassessingearlydrugsafetyorpharmacokinetics,wheretheclinicalinvestigatormaywanttoexplorealessdeneddosingrange,thepracticeofpreparingthedoseextemporaneouslymayo任erdistinctadvantages.ThebenetsofEPincludeasignicantcostsavingsfromreducingclinicalmanu-

TechnicalReportNo.63©2013ParenteralDrugAssociation,Inc.1

facture,testingandrelease,aswellasacceleratingthetimethecandidatedrugreachestheclinicandbecomesavailabletopatients.

1.4ScientificandClinicalRationale

Extemporaneouspreparationsareoftenusefulinlaterphaseclinicalstudiesassupplementstotradi-tionallymanufacturedprimaryformulations.Typically,theseareusedinsmallersupportivestudiesinsuchareasassafetyassessment,pharmacokinetics,andformulationenhancement.Insafetyassess-mentstudies,anextemporaneouslypreparedsolutionmaybeusedtoachieveexposurelevelsgreaterthanwouldbepossiblewithtraditionalsolidoraldosageforms.Inpharmacokineticstudies,analter-nateformulationorrouteofadministrationmaybeusedtoobtainpharmacokineticparametersorgaininsightintoanAdsorption,Distribution,MetabolismandExcretion(ADME)mechanism.Lastly,EPmaybeusedtoe伍cientlyscreeninnovativeformulationconceptsinordertoprovideaddedvaluetopatientsandextendthelifecycleofcurrentlymarketedmedications.

Preparingthedosesattheclinicalsiteallowsinvestigatorstoadjustthedose,asneeded,basedonreal-timecohortdata.Thisisadvantageouswhenthetherapeuticindexisstillbeingdeveloped,orthedosecanbeadjustedbasedonthepatient/subjectweightifrequired.FromanActivePharmaceuticalIngredient(API)perspective,lessAPIisrequiredforthestudysincedosesarepreparedbasedontheactualnumberofsubjectswhoparticipateinthestudy,theoverageislimited,andonlyasmallnum-berofdosingunitsareprepared.Fromaformulationperspective,thereisnoneedforalong-termstabilityprogramforthedrugproductandthereisnoneedtocommittoalarge-scalemanufacturingcampaign.However,datashouldbeavailabletosupporttheCTMstabilityfortheintendedlengthofstorageduringtheclinicaltrial.

AnaddedbenetofutilizingEPisthatseveralformulationscanbeclinicallyevaluatedbeforecom-mittingtoacommercialformulation.FormethodologystudieswherebiomarkersorotheragentsareusedtoensurethatthetestingmethodanddesignisappropriatetoanswerahypothesisforthenovelAPI,EPenablestheuseofthesebiomarkersorcomparativeagentswherethereisnocommerciallyavailableproduct.

GiventhecompellingcaseforusingEPpractices,guidanceisneededtoensurethatpatientsafetyandtheintegrityofthescienticprocessisnotcompromised.SinceEPfallsbetweenthetraditionalpracticesofGMPmanufactureandthepracticeofpharmacy,thisTechnicalReportdescribesaqualitysystemanddocumentationtoensurethatpatientsafetyandproductqualityaremaintained.

2©2013ParenteralDrugAssociation,Inc.TechnicalReportNo.63

2.0GlossaryofTerms

ActivePharmaceuticalIngredient(API)

Anysubstanceormixtureofsubstancesintendedtobeusedinthecompoundingofadrugprepa-ration,therebybecomingtheactiveingredientinthatpreparationandfurnishingpharmacologi-calactivityorotherdirecte任ectinthediagno-sis,cure,mitigation,treatment,orpreventionofdiseaseinhumansandanimalsora任ectingthestructureandfunctionofthebody(2).

ClinicalProtocol

Adocument,togetherwithanyamendmentstoit,thatdescribestheobjectives,design,method-ology,statisticalconsiderations,andorganiza-tionofaclinicaltrial.

ClinicalTrialMaterial(CTM)

Adrugorcombinationofdrugsand/orexcipi-entsthatareproducedwiththeintentthatitbeusedinaclinicaltrial,orthatisreleasedorother-wiseauthorizedforuseinsuch.Thiscould,sub-jecttoappropriateregulatoryapproval,beanexperimentalmedicine,aproductwithmarket-ingauthorizationusedinaclinicaltrialwithinorbeyondtheapprovedindicationand/oranypla-ceboarticlesproducedforuseinaclinicaltrial.

Compounding

Thepreparation,mixing,assembling,altering,pack-aging,andlabelingofadrug,drug-deliverydevice,ordeviceinaccordancewithalicensedpractitioner’sprescription,medicationorder,orinitiativebasedonthepractitioner/patient/pharmacist/compounderrelationshipinthecourseofprofessionalpractice.Compoundingincludesthefollowing:

•Preparationofdrugdosageformsforbothhumanandanimalpatients

•Preparationofdrugsordevicesinanticipationofprescriptiondrugordersbasedonroutine,regularlyobservedprescribingpatterns

•Reconstitutionormanipulationofcommercialproductsthatmayrequiretheadditionofoneormoreingredients

•Preparationofdrugsordevicesforthepurposesof,orasanincidentto,research(clinicalor

academic),teaching,orchemicalanalysis

•Preparationofdrugsanddevicesforprescriber’so伍ceusewherepermittedbyfederalandstatelaw(3).

ExtemporaneousPreparation(EP)

Atypeofcompoundingwherebyadrugorcom-

binationofdrugsand/orexcipientsisprepared

underthesupervisionofapharmacisttocreate

acustomizedmedicationdosageforminaccor-

dancewithaclinicalprotocol.

Investigator

Aclinicianscientisttakingpartinaclinicaltrial

havingdirectandimmediateclinicalresponsibil-

ityforthesubjectorpatientandtheirtreatment

withtheclinicaltrialmaterial.

KeyAttributes

Asubsetofthecharacteristicsofthedrugwhich

aredeterminedtobemostimportanttoquality.

Manufacturing

Theproduction,packing,testing,storage,re-

leaseanddistributionofdrugsormedicalde-

vicesforuseinhumansoranimalswherethe

manufacturingisindentedtoproducedoses,

typicallyinsignicantnumbers,foranunde-

nedpopulationoffuturepatientsorclinical

trialsubjects(4).

PharmacistinCharge

Alicensedpharmacistwhoisassignedthere-

sponsibilityandauthorityforestablishingand

implementingpoliciesandproceduresforall

operationsofthepharmacyandtoensurethe

pharmacyoperationsandpracticescomplywith

allrequirementsofnationalandlocalpharmacy

anddruglaws,rules,andregulations.

PharmacyManual

Amanualtypicallycreatedandprovidedbythe

studysponsorthatcontainsspecicinformation

anddocumentationtoallowtheclinicalsitesto

properlyreceive,store,prepare,label,dispense

andreturnclinicaltrialmaterialanddocument

therelatedactivitiesattheclinicalsite.

Note:Forthisreport,thepharmacymanualwill

alsocontainspecicinstructionsfortheextem-

poraneouspreparation,labelinganddispensing

ofclinicaltrialmaterials.

TechnicalReportNo.63©2013ParenteralDrugAssociation,Inc.3

PracticeofPharmacy

Theinterpretation,evaluationandimplementa-tionofmedicalorderswhichmayincludethead-ministering,preparing,compounding,preserv-ing,and/orthedispensingofdrugs,medicinesandtherapeuticdevicesonthebasisofprescrip-tions,clinicalprotocolorotherlegalauthority.

Note:Manylocalitieshavebroaderdenitionsdescribingveryspecicactivitiesandresponsibili-tiesthatfurtherdenesthepracticeofpharmacy.

PreparationRecord

AnapproveddocumentthatgivesthedetailedinstructionsforpreparationoftheClinicalTrialMaterials(CTM).

preparationsite

Thelocationwhereextemporaneousprepara-tionsofClinicalTrialMaterials(CTM)aremade.

ReferenceStandard

Areferencestandard,orreferencematerial,isasubstancepreparedforuseasthestandardinanassay,identication,orpuritytest.Itshouldhaveaqualityappropriatetoitsuse.Itisoftencharac-terizedandevaluatedforitsintendedpurposebyadditionalproceduresotherthanthoseusedinroutinetesting.Fornewdrugsubstancereferencestandardsintendedforuseinassays,theimpuritiesshouldbeadequatelyidentiedand/orcontrolled,andpurityshouldbemeasuredbyaquantitativeprocedure(5).

ShelfLife(alsoreferredtoasexpirationdatingperiod)

Thetimeperiodduringwhichadrugproductisexpectedtoremainwithintheapprovedshelflifespecication,providedthatitisstoredundertheconditionsdenedonthecontainerlabel(6).

4©2013ParenteralDrugAssociation,Inc.TechnicalReportNo.63

3.0ExtemporaneousPreparationStudies

WhilethisTechnicalReportframesarecommendedapproachtomanagingthequalityofdosespro-ducedbyextemporaneouspreparation,individualsshouldconrm,andcomplywithlocal,nationaland/orregionalregulationswhereverapplicable.

Priortoadministeringanyinvestigationaldrugtohumansubjects,theinvestigationalplans(protocol)mustbeapprovedbyanInstitutionalReviewBoard(IRB)aswellasthegoverningregulatorybodyinthecountryinwhichthestudywilloccur(i.e.,approvedClinicalTrialApplication(CTA)oropenInvestigationalNewDrug(IND)),RadioactiveDrugResearchCommittee(RDRC)approvalforra-dioactivedrugstudies).PatientsmustalsosigntheInformedConsentForm(ICF).

3.1StudyTypesAppropriateforEP

TheEPapproachisappropriateforconductingsmall-scalein-clinicstudieswhichincludeFirstinHu-manSingle/MultipleAscendingDose,Pharmacokinetic,PharmacodynamicAssessment,ProofofConcept,Radiolabeled(PETorADME),andnewformulationstudies.

Note:Thisdocumentisnotappropriateforusetosupportthepreparationofcommercialmaterialsforsale.

3.2DosePreparationActivities

Extemporaneouspreparationactivitiesmayincludethefollowing:

•weighingofAPIforpreparationofcapsules,tablets,solutionsandsuspensions

•reconstitution,mixing,and/ordilutingsolidsterileornonsterileAPI

•steriledosepreparation

•overencapsulation

•preparationofradiolabeledmaterials

TheseactivitiesproduceCTMsthatinclude,butarenotlimitedto,thefollowing:

•powderordrugincapsule

•formulatedcapsulesortablets

•oralsolutionincludingsuspensions

•sterilepreparationsformulatedfromsterileornonsterileAPI

•topicalformulations

•inhalationdoses

•nasalsprays

•ophthalmics

•radiolabeleddosageformsfromradiolabeledAPI

•comparatorsorplacebos

3.3DosePreparationConsiderations

EPisintendedforthepreparationofalimitednumberofdoses.Forexample,asingleascendingdosestudyinvolvingasmallnumberofsubjectsisconducivetoextemporaneouspreparationofCTM,whereaslargerstudiesinvolvingmultipledosesforalargenumberofsubjectsarenotincludedinthescopeofthisreport.

TechnicalReportNo.63©2013ParenteralDrugAssociation,Inc.5

4.0QualitySystem

Asstatedin1.0Introduction,thepreparationofCTMsmaytakeplaceatalocationotherthanonewhichischaracterizedbytraditionalCGMPregulations,requirementsandactivities.Whiletradition-alCGMPsystemsmaynotbeinplaceinsuchareas,therestillmustbeappropriatecontrolsinplacetoensurepatientsafetyandappropriaterecordkeepinganddocumentation.

TheauthorsbelievetheapproachesdescribedinthisTechnicalReportprovidethefoundationthatsupportsthepreparationofCTMsinanonmanufacturingenvironment(e.g.,preparationsite).Al-thoughalternativeapproachesmaybeequallyvalid,pharmacists,healthcareprofessionals,andothersengagedinthepreparationofclinicalsuppliesforsmall-scalestudiesareadvisedtoensurethatanyapproachtheychoosetoadoptisconsistentwithapplicableregionalornationallaws,regulations,andguidelines.

4.1RegulatoryOverview

4.1.1CurrentRegulatoryEnvironment

AnumberofpublisheddocumentsgloballyaddresstherequirementsforpreparationofCTMs.Insomeregions,theresponsibleregulatoryauthoritieshavelaiddownspecicGMPregulatoryrequire-mentsorguidanceapplicabletotheirpreparation(7–11).

TheextemporaneouspreparationofCTMsatapreparationsitemayrequirecompliancewiththeprinciplesassociatedwiththepracticeofpharmacy.Suchrequirementsmayappearinlocallaw,suchasstateboardsofpharmacyintheU.S.,federallaw,pharmacopeiaapplicabletothelocalregion,orotherrecognizedbodies(12).

HealthCanadahasdevelopedaguidancedocumentwhichisusefulfordi任erentiatingbetweentheapplicationofcGMPsandtheuseofEP(13).

Inanycase,theexpectationisthatthequalitysysteminplaceisappropriatefortheactivitiesbeingconductedandthatitwillensurepatientsafetyistheprimaryconsiderationgoverningthedecisionmakingprocess.Inadditionthequalitysystemshouldhelpensurethescienticvalidityofdatagener-atedduringthepreparationanduseoftheseCTMs.

4.1.2RegulatorySubmissionRequirements

Inmanycountries,itisnecessarytoprovidechemistry,manufacturingandcontrol(CMC)informa-tionfortheinvestigationalmedicalproductaspartoftheclinicaltrialapplication;however,theserequirementsvaryaccordingtotheirrespectiveregionalornationallaws,regulationsandguidelines.AnumberofcurrentguidancedocumentsexistwhichcanassistasponsorwhencompilingCMCinformationfortheCTA(14–16).WhendescribingthequalityinformationforanextemporaneouslypreparedCTM,themethodologyisnotsignicantlydi任erentascomparedtoatraditionalCTM(i.e.,GMPmanufactured).However,thefollowingspecicrecommendationsshouldbeconsidered:

•ThedescriptionoftheextemporaneouspreparationshouldcontainallofthekeystepsutilizedforthepreparationoftheCTM.

•ShelflifeoftheextemporaneouslypreparedCTMshouldbesupportedbydata.

•ThepreparationrecordshouldbeavailableatthetimeoftheCTAsubmissiondependingonspeciccountryrequirements.

Ultimately,itisthesponsor’sresponsibilitytoprovideenoughinformationtotheregulatorsthatsat-isesregulatoryagency’sparticularguidance,regulation,orlaw.Adheringtotherecommendationswithinthissectionandthefollowingsectionswillimprovethechancesofasuccessfulclinicaltrialapplication.

6©2013ParenteralDrugAssociation,Inc.TechnicalReportNo.63

4.2QualitySystems

Aqualitysystemmaybethoughtofastheorganizationalstructure,responsibilities,procedures,pro-cesses,andresourcesforimplementingquality.Inthecontextofthisreport,theoperativequalitysysteminplacemustalsoensurepatientsafetyinthepreparationandadministrationofCTMs.

Thefollowingsubsectionsdescribethequalitysystemelementsthatsupportthepreparationofsmall-scaleCTMsatapreparationsite.Morerigorousqualitycontrols(e.g.,training,testing,sterilitycon-trols)mayberequiredinsomecasesbaseduponthetypeofformulation,thelevelofcomplexity,thepotencyofthedrugsubstanceandotherfactorsthatinluencetheamountofrisk(17,18).

4.2.1QualitySystemsManagement

AqualityassuranceprogramisnecessarytoensurethequalityofCTMpreparations.Asoundqualityas-suranceprogramincludesdetailedSOPs,responsiblequalitypersonnel,properdocumentation,utilizationofriskmanagementapproaches,investigationofdeviations,appropriateanalyticaltesting,andnalrelease.Qualityriskmanagement(QRM)isanintegralpartofthequalitysystemtoreducerisktothequalityoftheproduct,andtothepatient.ForadditionaldetailonQRMpleaserefertoTechnicalReportNo.54(19).

ResponsibleQualityPersonnel

Qualiedpersonnelshouldbeassignedoverallresponsibilityfortheestablishmentandexecutionofthequalityprogram.Responsiblequalitypersonnelareessentialinassuringthesafety,identity,strength,quality,andpurityofCTMs.Inapreparationsitesettingthisisthepharmacistinchargeorotherappropriatelytrainedpharmacist,whileinaGMPsettingthisisqualityassurancepersonnel.

Responsiblequalitypersonnelshouldensurethatwrittenprocedureshavebeenfollowed.Ifdeviationsfromapprovedproceduresorspecications(orkeyattributes)occur,itisthedutyoftheresponsiblequalitypersonneltoinvestigatethesituation,notifythesponsorasnecessary,andimplementappropri-atecorrectiveactions.Asanalcheck,responsiblequalitypersonnelshouldrevieweachexecutedprep-arationrecordandexaminethenishedpreparationtoensurethatitappearsasexpected;additionally,theyshouldensureanyrequiredtestingisperformedandreleaseofthebatchorprepareddose.

StandardOperatingProcedures

TheoverallqualitymanagementprogramisguidedbywrittenproceduresthatdeneresponsibilitiesandpracticesthatensureCTMsareproducedwithqualityattributesappropriatetomeettheneedsofregulatoryagencies,patients,andhealthcareprofessionalsinthestudy.Proceduresshouldbewrittenthatdescribeallmajorqualityrelatedtasksincludingbutnotlimitedtothefollowing:

•SOPspreparationandmanagement

•documentationpractices

•personnelresponsibilities

•personnelcleanlinessandattire

•training

•complaintsandadverseeventreporting

•continuousqualitymonitoring

•materialsprocurement

•materialmanagement(receipt,dispensing,storageanddistribution)

•measuringandweighing

•equipmentmaintenance,calibration,andoperation

•facilityrequirements

•cleaninganddisinfecting

•environmentalqualitycontrolsandmonitoring

•preparationrecords

•packagingandrepackaging

•labeling

•testing

•stabilityanddating

•shipping(e.g.,transfertotheclinicalsite).

AllSOPsshouldbereviewedregularlyandupdatedasnecessary.

TechnicalReportNo.63©2013ParenteralDrugAssociation,Inc.7

Training

Responsiblequalitypersonnelshouldensurethatthereisatrainingprograminplacetoenableper-sonnelpreparingCTMstohavetheappropriatedocumentededucation,training,andexperiencetoperformsuchtasks.PreparationsitepersonnelinvolvedinnonsterileorsterilepreparationofCTMs,requireadditionaltrainingbeyondthatprovidedforroutinedispensingoperations.Allemployeesinvolvedwiththeseoperationsshouldbefamiliarwithlocalregulations,regulatoryguidances,andpharmacopeiasasrequired.

Alltrainingactivitiesshouldbedocumented.

ProciencyofpersonnelinvolvedinCTMpreparationshouldbeevaluatedannually.

Trainingontheparticulardosepreparationofinterestshouldbeperformedbythesponsortoen-surecompetencyofthepreparationsitepersonnel.TheextentoftrainingisdependentuponthecomplexityoftheCTMmanipulationandtheexperienceofthesitepersonnel.Practicerunsmaybenecessary,especiallyformorecomplexornon-routineoperations.Whenthepharmacistinchargeissatisedwithanemployee’sprociency,theywilldocumentthattheemployeeissu伍cientlytrained.

InsomeinstancespersonnelpreparingCTMsrequireknowledgeandapplicationofGMPsdependingonthespecicregionoftheworldwheretheactivitiesareperformed(e.g.,EU).

Additionaltrainingisalsorequiredforthepreparationofradiolabeledmaterialsandsterileprepara-tions,asapplicable(e.g.,traininginaseptictechniques,personnelqualicationstudies).

Documentation

Documentationshouldprovidearecordofallaspectsofpreparationactivitiesandexecutionofpro-cedures.Informationonthepreparationrecordshouldbeenteredasthetasksareperformed.Prepa-rationrecordsshouldbereviewedforaccuracy,completenessandapprovedbyresponsiblequalitypersonnel,priortodispensingoftheCTM.

QualityAgreements

Considerationshouldbegiventoclarifyingrolesandresponsibilitieswithineitheraqualityagree-mentorbusinessagreement.Whilethereisnothingintrinsicallywrongwithstand-alonequalityagreements,embeddingthequalityrequirementsandresponsibilitieswithinthecontract/scope-of-workdocumentisapossibleapproachtoclarifyingrolesandresponsibilities.QualityagreementsmayberequiredbyGMPregulationsforoperationsgovernedbytheGMPs.

SelfInspections

Selfinspectionsshouldbeperformedonaperiodicbasistoensurecompliancewithinternalaswellasexternalqualityrequirements.Inapreparationsitesetting,thepharma