CAR-T细胞疗法发布最终行业指南

ContainsNonbindingRecommendations

i

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

ii

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

ContainsNonbindingRecommendations

ConsiderationsfortheDevelopmentofChimericAntigenReceptor(CAR)TCellProducts

GuidanceforIndustry

ThisguidancerepresentsthecurrentthinkingoftheFoodandDrugAdministration(FDAor

Agency)onthistopic.ItdoesnotestablishanyrightsforanypersonandisnotbindingonFDAorthepublic.Youcanuseanalternativeapproachifitsatisfiestherequirementsofthe

applicablestatutesandregulations.Todiscussanalternativeapproach,contacttheFDAstaff

responsibleforthisguidanceaslistedonthetitlepage.

I.INTRODUCTION

Chimericantigenreceptor(CAR)Tcellproductsarehumangenetherapy

1

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)

.

1

ContainsNonbindingRecommendations

2

Ingeneral,FDA’sguidancedocuments,includingthisguidance,donotestablishlegally

enforceableresponsibilities.Instead,guidancesdescribetheAgency’scurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutory

requirementsarecited.TheuseofthewordshouldinAgencyguidancemeansthatsomethingis

suggestedorrecommended,butnotrequired.

II.BACKGROUND

CARTcells

2

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

assessmentofCARTcellsischallenging.CarefuldesignandappropriatetestingoftheCARtransgene

3

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).

ContainsNonbindingRecommendations

3

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

ContainsNonbindingRecommendations

4

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.

4

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).

ContainsNonbindingRecommendations

5

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

ContainsNonbindingRecommendations

6

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.

ContainsNonbindingRecommendations

7

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“leukapheresisstartingmaterial”)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).

ContainsNonbindingRecommendations

8

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