CAR-T細(xì)胞療法發(fā)布最終行業(yè)指南

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TableofContents

I.INTRODUCTION 1

II.BACKGROUND 2

III.GENERALCONSIDERATIONSFORCARTCELLDESIGNAND

DEVELOPMENT 3

A.CARConstruct 3

B.Vector 3

C.CellularStartingMaterial 4

D.FreshorCryopreservedFinalProducts 5

IV.CMCRECOMMENDATIONS 5

A.VectorManufacturingandTesting 6

B.Collection,Handling,andTestingofCellularStartingMaterial 7

C.CARTCellManufacturingandTesting 8

1.CARTcellmanufacturingprocesscontrol 9

2.CARTcellanalyticaltesting 11

3.LabelingforCARTcells 15

D.ManagingManufacturingChangesandAssessingComparabilityDuringthe

CARTCellProductLifecycle 16

1.Changemanagement 17

2.Comparabilitystudydesign 18

E.Single-SiteorMultisiteCARTCellManufacturing 19

1.Single-sitemanufacturing 19

2.Multisitemanufacturing 19

3.Multisitetesting 20

V.NONCLINICALRECOMENDATIONS 20

A.NonclinicalConsiderationsfortheCARConstruct 20

B.NonclinicalConsiderationsfortheCellularComponentofCARTCells 22

C.InVivoTestingofCARTCells 22

D.CARTCellswithAdditionalModifications 23

VI.CLINICALRECOMMENDATIONS 24

A.StudyPopulation 24

1.Advancedvs.earlydiseasestage 24

2.Tissue-agnosticapproach 24

3.Targetidentification 25

4.Pediatricsubjects 25

B.TreatmentPlan 26

1.Doseselection,startingdose,anddoseescalation 26

2.Repeatdosing 27

3.Staggering 27

4.Considerationformanufacturingdelayorfailure 27

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5.Bridgingtherapy 28

C.ClinicalPharmacologyConsiderations 28

1.Pharmacokinetics 29

2.Pharmacodynamics 29

3.Immunogenicity 30

D.SafetyEvaluationandMonitoring 30

1.Clinicalmonitoring 30

2.Toxicitygrading 31

3.Dose-limitingtoxicities(DLTs),stoppingrulesandattribution 31

E.CARTCellPersistenceandLongTermFollow-up 32

F.AllogeneicCARTCells 33

VII.REFERENCES 34

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ConsiderationsfortheDevelopmentofChimericAntigenReceptor(CAR)TCellProducts

GuidanceforIndustry

ThisguidancerepresentsthecurrentthinkingoftheFoodandDrugAdministration(FDAor

Agency)onthistopic.ItdoesnotestablishanyrightsforanypersonandisnotbindingonFDAorthepublic.Youcanuseanalternativeapproachifitsatisfiestherequirementsofthe

applicablestatutesandregulations.Todiscussanalternativeapproach,contacttheFDAstaff

responsibleforthisguidanceaslistedonthetitlepage.

I.INTRODUCTION

Chimericantigenreceptor(CAR)Tcellproductsarehumangenetherapy

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productsinwhichtheTcellspecificityisgeneticallymodifiedtoenablerecognitionofadesiredtargetantigenfor

therapeuticpurposes.Thisguidanceisintendedtoassistsponsors,includingindustryand

academicsponsors,developingexvivo-manufacturedCARTcellproducts.Inthisguidance,

we,FDA,provideCARTcell-specificrecommendationsregardingchemistry,manufacturing,andcontrol(CMC),pharmacologyandtoxicology,anddesignofclinicalstudiesforoncologyindications(includinghematologicmalignanciesandsolidtumors).RecommendationsspecifictoautologousorallogeneicCARTcellproductsarenotedinthisguidance.ThisguidancealsoprovidesrecommendationsforanalyticalcomparabilitystudiesforCARTcellproducts.WhilethisguidancespecificallyfocusesonCARTcellproducts,someoftheinformationand

recommendationsprovidedmayalsobeapplicabletoothergeneticallymodifiedlymphocyte

products,suchasCARNaturalKiller(NK)cellsorTcellreceptor(TCR)-modifiedTcells.

Theserelatedproducttypescanbehighlyspecialized,andinmanycases,considerationsbeyondthoserecommendedinthisguidancewoulddependonthespecificproductandmanufacturing

process.Todiscussconsiderationsspecifictotheserelatedproductsornon-oncology

indications,werecommendsponsorscommunicatewiththeOfficeofTherapeuticProducts

(OTP)intheCenterforBiologicsEvaluationandResearch(CBER)beforesubmittingan

InvestigationalNewDrugApplication(IND)(e.g.,byrequestingapre-INDmeeting(Ref.1)).

1Humangenetherapyseekstomodifyormanipulatetheexpressionofageneortoalterthebiologicalpropertiesoflivingcellsfortherapeuticuse.FDAgenerallyconsidershumangenetherapyproductstoincludeallproductsthatmediatetheireffectsbytranscriptionortranslationoftransferredgeneticmaterial,orbyspecificallyalteringhost

(human)geneticsequences.Someexamplesofgenetherapyproductsincludenucleicacids,geneticallymodified

microorganisms(e.g.,viruses,bacteria,fungi),engineeredsite-specificnucleasesusedforhumangenomeediting,andexvivogeneticallymodifiedhumancells.Genetherapyproductsmeetthedefinitionof“biologicalproduct”insection351(i)ofthePublicHealthService(PHS)Act(42U.S.C.262(i))whensuchproductsareapplicabletotheprevention,treatment,orcureofadiseaseorconditionofhumanbeings(seeFederalRegisterNotice:ApplicationofCurrentStatutoryAuthoritiestoHumanSomaticCellTherapyProductsandGeneTherapyProducts(58FR

53248,October14,1993),

/media/76647/download)

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Ingeneral,FDA’sguidancedocuments,includingthisguidance,donotestablishlegally

enforceableresponsibilities.Instead,guidancesdescribetheAgency’scurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutory

requirementsarecited.TheuseofthewordshouldinAgencyguidancemeansthatsomethingis

suggestedorrecommended,butnotrequired.

II.BACKGROUND

CARTcells

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aregenetherapy(GT)productsthatareregulatedunderFDA’sexistingframeworkforbiologicalproducts.Werecognizethatthedevelopment,manufacture,testing,andclinical

assessmentofCARTcellsischallenging.CarefuldesignandappropriatetestingoftheCARtransgene

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anddeliveryvectorarecriticaltoproductsafety,specificity,andfunction.CARTcellmanufacturinginvolvesmultiplebiologicalmaterialsandcomplexmulti-stepprocedures,whicharepotentialsourcesofvariabilityamongproductlots.Thus,controlofthe

manufacturingprocessandappropriatein-processandlotreleasetestingarecrucialtoensure

CARTcellsafety,quality,andlot-to-lotconsistency.Inaddition,changestothemanufacturingprocessarecommonduringproductdevelopment.Itisessentialtounderstandtheeffectsofsuchchangesonproductquality.Comprehensiveproductcharacterizationstudiesarevaluablefor

identifyingrelevantcriticalqualityattributes(CQAs)thatcanbeassessedduringmanufacture,atlotrelease,andincomparabilityandstabilitystudiestoassuresafetyandefficacy(Ref.2).

Criticalprocessparameters(CPPs)canthenbeestablishedthroughprocessqualification,toensureconsistentCQAsforeverymanufacturedbatch.(Ref.2).FDA’sguidanceentitled“Chemistry,Manufacturing,andControl(CMC)InformationforHumanGeneTherapy

InvestigationalNewDrugApplications(INDs):GuidanceforIndustry,”January2020(Ref.3)(hereinafterreferredtoasthe“GTCMCGuidance”)describesthegeneralconsiderationsforGTproductmanufacturingandtesting.

NonclinicalevaluationofCARTcellsisnecessarytosupportaconclusionthatitisreasonablysafetoadministertheproductinaclinicalinvestigation(Title21oftheCodeofFederal

Regulations312.23(a)(8)(21CFR312.23(a)(8)).NonclinicaltestingofCARTcellscanbe

challengingduetotheinherentbiologicalcomplexityandvariabilityofthisproducttypeandthelimitedavailabilityofsuitableanimalmodelstotestsafetyandactivity.Acase-by-case

nonclinicaltestingstrategyshouldbeappliedusinginvitro,insilico,andinvivotesting

strategies,asappropriate,inconjunctionwithavailablenonclinicalandclinicaldatafromrelatedproductstosupportuseofCARTcellsinaproposedclinicaltrial.

Well-designedearly-phaseclinicalstudiesarecriticaltoestablishsafetyoftheproduct,adequacyofriskmitigationmeasures,dose-responserelationship,differencesinoptimaldosebasedon

differencesinindication,preliminaryevidenceofefficacy,andfeasibilityofmanufacturing.ForautologousCARTcells,early-phasestudiesalsoprovideinformationonhowlongitwilltaketomanufacturetheproductandwhetherbridgingtherapywillorwillnotbeusedasanattemptto

2CARTcellproductswillbereferredtoasCARTcellsthroughoutthisguidance.

3Forthepurposesofthisguidance,transgenemeansanexogenousgenethatisintroducedintoahostcell.Seealso(Ref.10).

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controltheactivediseasewhilesubjectswaitfortheCARTcelltreatment.ForallogeneicCARTcells,early-phasestudiescanbeinformativewithregardstotherisksofgraftversushost

disease(GVHD).Informationgainedfromtheseearly-phasestudiessupportthedevelopmentofCARTcellsinlater-phaseclinicalstudiesandmayexpeditetheclinicaldevelopmentofCARTcells.

III.GENERALCONSIDERATIONSFORCARTCELLDESIGNAND

DEVELOPMENT

CARTcellsarecomplexproductsthatmayincorporatemultiplefunctionalelements.The

natureofthesefunctionalelements,howthefunctionalelementsareintroducedintothecells

(i.e.,vectortype),thecellularstartingmaterial,andthefinaldrugproductformulationareallcriticaltoproductsafety,specificity,andfunction.Here,webrieflyoutlinekeyconsiderationsforCARTcelldesignanddevelopment.

A.CARConstruct

CARsgenerallycontaintwotypesofdomains:antigenrecognitionandsignaling.

AntigenrecognitiondomainsallowCARTcellstobindtooneormoretargetantigen(s).Werecommendsponsorsassesstheabilityofeachantigenrecognitiondomainto

specificallybindtoitstargetantigen,asdescribedinsectionV.Bofthisguidance.

Manyantigenrecognitiondomainsarederivedfrommurinemonoclonalantibodiesthatmaybeimmunogenicinhumans,leadingtorejectionoftheCARTcellsorothersafetyrisks(e.g.,anaphylaxis).Ifapproachestoreduceimmunogenicity(e.g.,“humanization”byComplementarity-DeterminingRegiongrafting)areused,werecommendtheIND

describethesechangesandtheirimpactontargetbindingandbiologicalactivity(Refs.4,5,6).WhenmultipleCARsareexpressedinasingledrugproduct,theCARconstructdesignshouldreducetheriskofrecombinationevents,iffeasible.

SignalingdomainsinitiateTcellactivation.Werecommendthatthefunctionalityofsignalingdomainsbewellsupportedbyinformationfrompreviousnonclinicaland

clinicalexperienceorthoroughlydemonstrated,asdescribedinsectionV.Bofthis

guidance.Forexample,thecontributionoftransmembranedomain,hinge,andlinkerregionsusedtoseparatedifferentfunctionalregionsoftheconstructshouldbe

evaluated,asthesemayaffectCARTcellspecificity,persistence,andactivity(Refs.7,8,9).

B.Vector

A“vector”isavehicleconsistingof,orderivedfrom,biologicalmaterialthatisdesignedtodelivergeneticmaterial.Examplesofvectorsincludeplasmids,viruses,andbacteriathathavebeenmodifiedtotransfergeneticmaterial(Ref.10).ForCARTcells,the

vectorisacriticalcomponentthatfurnishesapharmacologicalactivityforthetreatmentofdisease(sectionIV.BoftheGTCMCGuidance(Ref.3)).VectorsthatintegrateintocellularDNA(e.g.,retroviral-basedvectorsortransposons)canprovidelongterm

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transgeneexpressioncomparedtonon-integratingvectors.Longtermfollowupis

recommendedforproductsthatincludeintegratingvectors,becauseintegratingvectorsmayincreasetheriskofdelayedadverseevents(Ref.10).Thepredictedriskofdelayedadverseeventsisthoughttobelowfornon-integratingvectors,andgenerallylongtermfollowupwouldnotbeneeded.

InadditiontotheCAR,vectorsmayexpressadditionalfunctionalelements.For

example,vectorsmayexpressadditionalfunctionalelementsthatallowfortheselectionorenrichmentofcellularsubsetsduringmanufacturing(Ref.11);thatmodifyTcell

persistenceand/oractivity(Ref.11);orthatallowselectiveinvivoablation(“suicidegenes”)ofCARTcells(Refs.12,13,14).

ItshouldbenotedthateachadditionalfunctionalelementmayaffectCARTcellsafetyandeffectiveness.Werecommendsponsorsprovidejustificationandrelevantdatatosupportincorporationofadditionalelements.Thejustificationshouldincludean

assessmentofanyimpactthattheseadditionalelementswillhaveonCARTcell

specificity,functionality,immunogenicity,orsafety(seesectionV.Eofthisguidance).

Transgenesequencesthatareunnecessaryforthebiologicalfunctionofaproductmay

beimmunogenicinvivoorhaveotherunanticipatedeffectsonproductpersistenceor

activity.Asageneralguidingprinciple,werecommendthatunnecessarytransgenes

(e.g.,antibioticresistancegenesusedforplasmidselection)shouldnotbeincludedinthevector.

C.CellularStartingMaterial

ThestartingmaterialforCARTcellmanufactureisgenerallyobtainedbyleukapheresisofpatients(forautologousproducts)orhealthydonors(forallogeneicproducts).Safetyandregulatoryconsiderationsdifferforautologousandallogeneicproducts,asoutlinedinsectionIV.Bofthisguidance.

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ParticularconsiderationshouldbegiventopatientswhohavereceivedCARTcells

previously.SuchpatientsmaybeconsideredfordifferentCARTcellclinicalstudiesduetolackofresponsetothepreviouslyadministeredCARTcells,relapseofthesame

condition,ortreatmentforadifferentmalignancy.CARTcellsmanufacturedusingcellularstartingmaterial(e.g.,leukapheresis)frompatientswhohavereceivedCART

cellspreviouslymaydifferfromthesametypeofCARTcellsmanufacturedusing

cellularstartingmaterialfrompatientswhohavenot.PreviouslyadministeredCART

cellsinthestartingmaterialmayhaveunexpectedeffectsonCARTcellmanufacturing(e.g.,expansionortransductionrates),potency,invivoexpansion,safety,andefficacy.

Therefore,evaluationofthepreviouslyadministeredCARTcelllevelsinthecellular

startingmaterialmaybeappropriate.ThismaybeaccomplishedbydetectionofcommonvectororCARfeaturestoevaluatethepresenceofpreviouslyadministeredCARTcells.Inaddition,werecommendyoucollectretentionsamplesofleukapheresismaterialinthe

4SeealsoFDA’sguidanceentitled“HumanGeneTherapyProductsIncorporatingHumanGenomeEditing:GuidanceforIndustry,”January2024(GEGuidance)(Ref.15).

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eventthatadditionalanalysisisnecessary.IfanautologousCARTcellclinicalstudy

willenrollpatientswhohavereceivedCARTcellspreviouslyandpatientswhohavenot,thepotentialdifferencesintheCARTcellsshouldbeevaluatedandconsideredinthe

clinicalstudydesignandanalysis.Werecommendsponsorsdiscusstheseconsiderationsforproductcharacterization,testing,dosing,andclinicalstudydesignwithOTPpriortotheINDsubmissionaspartofapre-INDmeeting(Ref.1).

D.FreshorCryopreservedFinalProducts

CARTcellsmaybeformulatedforfreshinfusionorcryopreservedforlater

administration.Thechoiceofformulationdependsontheproductdevelopmentstrategyandpracticalconstraints.

FreshCARTcellshavealimitedshelflifebeforeproductqualitydegrades.We

recommendthatthemaximumtimebetweenformulationandinfusionbedefinedandsupportedbystabilitystudiesandincludeconsiderationsforpreparationpriorto

administration.Additionally,thetimeframeinwhichreleasetestscanbeperformedis

limited.Therefore,itiscrucialtodevelopandimplementwell-designedlogistics,whichmayinclude:timingforsamplingandtestingforlotrelease;reportingQualityControl(QC)testingresultsandQualityAssurance(QA)reviewforlotrelease;scheduling

productshipping;andreceivingandhandlingofthefreshproductattheclinicalsite.

Ontheotherhand,cryopreservationallowssufficienttimeforfullreleasetestingand

flexibilityinschedulingpatientsforinfusion.WegenerallyrecommendcryopreservationwhenCARTcellsaremanufacturedatacentrallocationandshippedtoclinicalsitesforadministration.ForcryopreservedCARTcells,therisksassociatedwithinfusionofthecryoprotectantshouldbeassessed,andcontrolledthawingoftheproductattheclinical

sitemaybecriticaltomaintainproductquality.

Regardlessoftheformulation,thereshouldbeappropriateprocedurestoensureadequatecontroloftheCARTcellsduringshippingtotheclinicalsite.TheseproceduresshouldbedescribedintheINDandinplacebeforeinitiatingclinicalstudies.TheprocedurestoensureCARTcellproductqualityduringshipping,receipt,storage,andpreparationforinfusionshouldbevalidatedpriortolicensure.

IV.CMCRECOMMENDATIONS

ThissectionoftheguidanceaddressesconsiderationsspecifictoCARTcellproductsandisnot

designedtobeastand-aloneCMCguidance.PleaserefertothegeneralCMCguidancedocumentsoncellandgenetherapiesavailablefromFDA’swebsite:

/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-

guidances.

WerecommendsponsorsorganizeinformationintheCommonTechnicalDocument(CTD)

formatwiththevectorCMCinformationdescribedinacompleteDrugSubstance(DS)section

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andtheCARTcellinformationorganizedintoaseparateDSsectionandaseparateDrug

Product(DP)section,asdiscussedinsectionIV.BoftheGTCMCGuidance(Ref.3).When

CARTcellsaremanufacturedusingacontinuousprocesswherethereisnocleardivision

betweentheDSandDP,werecommendthatyouprovideanexplanationtosupportyourDS/DPdistinctioninthesummaryinformationinModule2oftheCTDsubmission.TheCTDDS

sectionsshouldfollowtheformatandnumberingschemerecommendedinModule3ofFDA’sGuidanceforIndustry:“M4Q:TheCTD–Quality,”August2001(Ref.16),andthesectionsshouldbedistinguishedfromoneanotherbyincludingtheDSnameandmanufacturerinthe

heading(e.g.,section3.2.S.1GeneralInformation[name,manufacturer]).

TheemphasisforCMCinallphasesofdevelopmentisproductsafetyandmanufacturing

control.WerecommendthatCARTcellsbedevelopedfollowingalifecycleapproachwhereinformationisgatheredoverthecourseofproductdevelopmentandsubmittedinastage-

appropriatemanner.TheamountofCMCinformationtobesubmittedinyourINDdependsonthephaseandthescopeoftheclinicalinvestigationproposed(21CFR312.23(a)(7)).Therefore,youmaynotneedtocompleteallCTDsectionsinyouroriginalINDsubmission.Similarly,

manufacturingmustcomplywithCurrentGoodManufacturingPractice(CGMP),asappropriate

forthestageofdevelopment(section501(a)(2)(B)oftheFederalFood,Drug,andCosmeticAct(FD&CAct)(21U.S.C.351(a)(2)(B))(seealsoRef.17,and21CFR210.2).AdditionalCMC

informationmaybeneededtoalignproductdevelopmentwiththeclinicaldevelopment,

especiallywhenthelatterisrapidlyprogressingunderanexpediteddevelopmentprogram.Forexample,analyticalassaysshouldbefitforpurposetosupportearlyphasestudiesandqualified

beforeinitiatingclinicalstudiesthatareintendedtoprovidetheprimaryevidenceofeffectivenesstosupportamarketingapplication.

ForCARTcellsintheearlystagesofclinicaldevelopment,veryfewspecificationsare

finalized,andsometestsmaystillbeunderdevelopment(sectionV.A.4.aoftheGTCMCGuidance(Ref.3)).Characterizationdatacollectedduringearlystudiescaninformreleasecriteriausedinlaterdevelopmenttoensureproductandprocessconsistency.Thus,

characterizationstudiesarecrucialtosupportproductdevelopmentandcomparability

assessments.Forstudiesinwhichaprimaryobjectiveistogathermeaningfuldataaboutproduct

efficacy,werecommendthatacceptancecriteriaberefinedtoensurebatchesarewell-definedandconsistentlymanufactured.IntheBiologicsLicenseApplication(BLA),theproposed

commerciallotreleasecriteriashouldbebasedondatafromproductlotsshowntobesafeandeffectiveinclinicalstudies.

A.VectorManufacturingandTesting

TheGTCMCGuidance(Ref.3)providesrecommendationsformanufacturingand

testingofthevector.Thevectorsafetyandqualityshouldbesufficientlycharacterizedpriortoinitiationofclinicalstudies.Forlaterphasestudiesandforlicensure,thevector

mustbemanufacturedaccordingtoCGMPundersection501(a)(2)(B)oftheFD&CAct,andanalyticalassaysshouldbevalidated.(Ref.18).DuringCARTcellBLAreview,

vectormanufacturingfacilitiesaresubjecttoinspection.

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VectorqualitydirectlycontributestothequalityandconsistencyoftheCARTcells.Werecommendthatsponsorsdescribethevectorstructure,characterizationandtestingoftheMasterandWorkingCellBanks,characterizationofreferencematerials,andvector

manufactureandtesting.WealsorecommendstabilitystudiesforvectorsbeconductedtosupportholdandstoragetimesasdescribedinsectionV.A.7oftheGTCMCguidance(Ref.3).Vectorlotreleasetestingshouldincludemeasuresofsafety,identity,purity,

andbiologicalactivity.Anassaythatassessesthebiologicalactivityofthetransgene

maybedevelopedincoordinationwiththeCARTcellpotencyassay(seesectionIV.C.2ofthisguidance).Transgeneexpressionaloneasameasureofbiologicalactivitymaybesufficienttosupportearly-phaseINDstudies;however,additionalmeasuresofbiologicalactivitywilllikelyberequestedforclinicalstudy(s)intendedtoprovideprimaryevidenceofeffectivenesstosupportamarketingapplication.Additionally,werecommendthat

vectorstrengthbedeterminedduringlotreleasetestingtonormalizetheamountofvectorusedfortransductionduringCARTcellmanufacturing.Forexample,werecommend

testingviralvectorsfortransducingunitspermilliliter(mL)inasuitablecelllineor

healthydonorcells.ThisallowsdeterminationoftheamountofvectorthatisaddedpercelltoachievethetargetpercentageofCAR-positivecellsintheCARTcellDPwhileensuringthatthevectorcopynumberremainswithintargetspecifications.

Vectorsafetytestingshouldincludemicrobiologicaltestingsuchassterility,

mycoplasma,endotoxin,andadventitiousagenttestingtoensurethattheCARTcellDPisnotcontaminated.Additionaltestingmayberecommendeddependingonthetypeof

transgenevectorbeingused.Forexample,thereareadditionalsafetyconcernsand

testingexpectationsrelatedtotheuseofretroviral-basedvectors(sectionV.A.4.b.iioftheGTCMCGuidance(Refs.3and19)).Therecommendationsforlongtermfollow-upofpatientsgenerallydependsonthesafetyconcernsassociatedwiththevectorandthe

propensityforthevectortointegrate(Ref.10).

B.Collection,Handling,andTestingofCellularStartingMaterial

Here,wedescribeconsiderationsforcellularstartingmaterial,usingstartingmaterialobtainedfromleukapheresis(referredtoas“l(fā)eukapheresisstartingmaterial”)asan

example.Therecommendationsinthissectionmaybeapplicabletoothertypesof

cellularstartingmaterialaswell.TestingrecommendationsforcellbanksoriginatingfromallogeneiccellsortissuesarediscussedinsectionV.A.2.c.ii.boftheGTCMCGuidance(Ref.3).

Collectionoftheleukapheresisstartingmaterialshouldbeconductedinaccordancewiththeregulationsin21CFRpart1271.Autologousleukapheresisstartingmaterialdoesnotrequireadonoreligibilitydetermination(21CFR1271.90(a)(1)andRef.20),butyou

mayconsiderarisk-basedapproachforscreeningortesting(Ref.3).Allogeneic

leukapheresisstartingmaterial,ontheotherhand,doesrequireadonoreligibility

determination,includingscreeningandtestingforrelevantcommunicablediseaseagentsanddiseases(21CFRpart1271,SubpartC).

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Werecommendthatproceduresusedforhandlingtheleukapheresisstartingmaterial

fromcollectiontothestartofthemanufacturingprocessaredescribedintheINDas

discussedinsectionV.A.2.c.iioftheGTCMCGuidance(Ref.3).Thisdescription

shouldincludeanywashstepsorcryopreservationprocedures.Werecommendthese

procedures,includinghandlingofthecellsandshipmenttothemanufacturingsite,beinplaceatallleukapheresiscollectionsitestoensurequalityofthematerial.Youshould

haveappropriateproceduresinplacetoensureadequatecontroloftheleukapheresis

startingmaterialduringshippingtothemanufacturingfacility(e.g.,temperaturecontrol),andinformationregardingshippingcontainersandtemperaturemonitoringshouldbe

provided.Validationoftheshippingprocessandanyholdorcryopreservationsteps,

includingassessmentofleukapheresisstartingmaterialstabilityundertheintended

conditions,shouldbeincludedforlicensure.Oncetheleukapheresisstartingmaterialhasbeenreceivedbythemanufacturingfacility,subsequentmanufacturingmustcomplywithCGMPasappropriateforthestageofdevelopment(seeRef.17,and21CFR210.2).

Duetopatientordonorvariability,thecellularstartingmaterialcanrepresentamajor

sourceoflot-to-lotvariabilityinCARTcellqualityandfunction.Theprobabilityof

manufacturingsuccessmaybeincreasedbyestablishingacceptancecriteriaforthe

leukapheresisstartingmaterialusedinCARTcellmanufacturing,asexperienceis

gainedthroughoutproductdevelopment.Forexampl