FDA扩大准入研究新药方案 Pharmacy Compounding Advisory CommitteeInvestigational New Drug (IND) Development and Expanded Access (EA)

PharmacyCompoundingAdvisoryCommittee:

InvestigationalNewDrug(IND)Development

andExpandedAccess(EA)

December4,2024

LoriBickel,JD

RegulatoryCounsel

DivisionofRegulatoryPolicy,OfficeofNewDrugPolicyOfficeofNewDrugs,CDER

FDA

3

Objectives

•ExplainpathwaysunderwhichinvestigationaldrugscanbestudiedandusedfortreatmentbasedonquestionsraisedinpreviousPCACdiscussions

•ProvideabriefoverviewofanInvestigationalNewDrug(IND)submission

•ExplaintheprimarypurposeofExpandedAccess(EA)andhowitdiffersfromclinicaltrialstostudyinvestigationalproducts

•DiscussthethreecategoriesofExpandedAccessavailable

•IdentifyusefulresourcesfordeterminingifExpandedAccessisappropriateandpreparingrequests

4

AccesstoDrugProductsUnderanIND

•ClinicalTrialsUnderanIND

–Providenecessarydatatodeterminesafetyandeffectiveness

–Mostefficientpathtomarketandbroadavailability

–Goalisresearchaboutthedrugpotentiallyleadingtoapproval

•ExpandedAccess

–Presentsopportunitytoaccessaninvestigationalmedicalproductforpatientswithaseriousorimmediatelylife-threateningdiseaseorconditionwhohavenocomparableorsatisfactoryalternativetherapies

–Goalisaccessfortreatmentuse

•Pathwaysdistinctfrom503Aand503Bcompounding

–AvailabilityofanINDisnotaconsiderationindeterminingwhetheranominatedbulkdrugsubstanceisappropriateforinclusiononthe503Abulkslist

5

SomeKeyContentforINDSubmissions

•FDAFormsforIND

–FormFDA1571-InvestigationalNewDrugApplication/FormFDA1572-StatementofInvestigator

–FormFDA3926-IndividualPatientExpandedAccessInvestigationalNewDrugApplication

•InvestigatorQualifications(CV)

–Includessub-investigators

•Drugsubstanceanddrugproductinformation(allmanufacturingsites)orLetterofAuthorization(LOA)for

–Identity,Purity,strength,andquality

–Stability

–Distribution

6

SomeKeyContentforINDSubmissions(Continued)

•Safety

–Evidencethatthedrugisreasonablysafeatthedoseanddurationproposed

–Nonclinical/Clinical

•Efficacy

–Rationalefortheintendeduseofthedrug

•Protocol

–Descriptionofdiseaseorcondition

–Proposedmethodofadministration,dose,andduration

–Eligibilitycriteria

–Clinicalproceduresandmonitoringtoevaluateeffectsandminimizerisk

•InformedconsentformandInstitutionalReviewBoard(IRB)approval

WhatisExpandedAccess(EA)?

•ExpandedAccessistheuseofan

investigationaldrugorbiologicalproducttotreatapatientwithaseriousorimmediatelylife-threateningdiseaseorconditionwho

doesnothavecomparableorsatisfactory

alternativetherapiestotreatthediseaseorcondition

–Intentisclearlytreatment

•Contrastswithinvestigationaldruginaclinicaltrialwheretheprimaryintentisresearch

–Systematiccollectionofdatawiththe

intenttoanalyzeandlearnaboutthedrug

7

ThreeGeneralCategoriesofExpandedAccess

andTheirCommonRequirements

TreatmentInvestigationalNewDrug(IND)orTreatmentProtocol

Individualpatient

(includesnon-emergencyandemergencyuse)

Intermediate-sizepopulation

CommonRequirements:*

1.Patientshaveseriousorimmediatelylife-threateningdiseaseorcondition

2.Nocomparableorsatisfactoryalternativetherapy

3.Patientisunabletoparticipateinaclinicaltrialfortheinvestigationalproduct

4.Potentialbenefitsmustjustifythepotentialrisksofthetreatment

5.ProvidingtheproductunderEAmustnotinterferewithorcompromisethepotential

developmentoftheexpandedaccessuse

*UnderEA,accesstoaninvestigationalproductadditionallydependsonasponsorormanufacturerchoosingto

maketheproductavailabletopatients.8

ExpandedAccessRegulationsandGuidance

•Describethegeneralcriteria

applicabletoallcategoriesof

expandedaccess,andadditionalcriteriathatmustbemetforeachexpandedaccesscategory

•Describetherequirementsforsubmission

•DescribethesafeguardsapplicabletoEAprograms,suchasinformedconsent,IRBreview,andreportingrequirements

9

Linktoguidance

21

CFR

312.300+

10

HumanSubjectProtectionsApplytoAllEACategories

•DrugsinEAareinvestigationaldrugs,andtheyaresubjecttothefollowingrequirementsfrom

21CFR

:

–Part50-ProtectionofHumanSubjects(includinginformedconsent)

–Part56-InstitutionalReviewBoard

–Part312-INDApplication(includingclinicalholdsbasedonsafety,andreportingrequirements(e.g.,adverseeventreports,annual

reports))

EAProgramInitiatives(DrugsandBiologicalProducts)

•CreationofFormFDA3926forIndividualPatientExpandedAccessInvestigationalNewDrugApplication(IND)(2016)

•Updatedguidancesandwebsite(2016,2017,updateddraftin2022)

•CollaborationwiththeReagan-UdallFoundation(RUF)

–ExpandedAccessNavigator(2017)

–ExpandedAccesseRequestmobileapp(2020)

•OncologyCenterofExcellence“ProjectFacilitate”(2019)

•Continualoutreacheffortsthroughpublications,meetings,andwebinars

11

•FDAEACoordinatingCommittee(EACC)

User-friendly

FDAWebpages

forEA

/news-events/public-health-focus/expanded-access

SeriesofInformationalVideos

12

Questions/ContactUs

•CDERDivisionofDrugInformation

druginfo@

•FDA’sEAcontactinfo

/news-

events/expanded-access/fdas-expanded-

access-contact-information

13

14

References

21CFRpart312:InvestigationalNewDrugApplication.Availableat

/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312

21CFR312.300onExpandedAccesstoInvestigationalDrugsforTreatmentUse.Availableat

/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.300

.

GuidanceforindustryExpandedAccesstoInvestigationalDrugsforTreatmentUse-QuestionsandAnswers(2017).Available

at

/media/85675/download

.

GuidanceforindustryIndividualPatientExpandedAccessApplications:FormFDA3926

(2017).Availableat

/media/91160/download

.

PharmacyCompoundingAdvisoryCommittee:

FDAImmunogenicityRiskofCompoundedPeptides

DanielaVerthelyi,MD,PhD

SupervisorySeniorBiomedicalResearchandBiomedicalProductAssessmentServiceExpertOfficeofPharmaceuticalQuality

CDER,FDA

17

Disclosure

•Thisspeakerhasnoconflictsofinteresttodisclose

18

TalkMap:

•Productimmunogenicity

•Describetheclinicalimmunogenicityconcernsforpeptides

•Briefintroductiontothemechanismsinvolvedingeneratinganimmuneresponsetoaproduct

•Discusstheimmunogenicity-relatedconcernsforcompoundedcomplexpeptideproducts

19

ImmunogenicityConcernsforPeptideProducts

•Immunogenicityistheunwanteddevelopmentofanimmune

response,usuallyantibodies,elicitedbyatherapeutic

product.

•Therapeuticpeptidescaninduceanunwantedantigen(Ag)-

specificimmuneresponsethatcanimpactonsafetyand/or

efficacy

20

ClinicalImmunogenicityConcernsforPeptideProducts

•None

Anti-DrugAntibodies

–Noapparenteffects

•Moderate

–Alterationsinpharmacokinetic/pharmacodynamic(PK/PD)leadingtolossofefficacyortoxicity

•Severe

•Hypersensitivity/Anaphylaxis(IgGorIgE)

•Immunecomplexdisease(IgG)

•Neutralizingantibody,precludesefficacyofeffectivetherapy

•Cross-reactiveneutralizationofuniqueendogenouscounterpart

ImmunogenicityRiskFactors:

Toleranceto

APIand

Product-related

impurities

•Homologytoself/sequence

•Concentrationof

endogenouspeptide

•Age

•Gender

•Race

•Genetics(MHC)

Patient

Product

API&

Impurities

Treatmentrelated

Immunestatus

IIRMI

•Immune

competency

•Underlyingdisease/s

•Concurrentmedication

Patient&

treatment

related

factors

•Aggregates

•Processrelatedimpurities

•Contaminants

•Excipients

•Leachables

Adjuvant

•Dose

•Route

•Regimen

Abbreviations:API=activepharmaceuticalingredient,IIRMI=innateimmuneresponsemodulatingimpurities,MHC=majorhistocompatibilitycomplex21

Impuritiescanincreasetheimmunogenicityriskofpeptides

EndogenousPeptide

TherapeuticPeptide

人

TherapeuticPeptide

BCR

Impurities

MemoryBcell

Aggregated

TherapeuticPeptide

Bcell

Short

lived

Plasma

cell

Antibodies

RLR

!

Inflammation(DC,Macrophage,

Monocytes,neutrophils,mastcellsetc.)

Long

lived

Plasma

cell

PKchangesReducedefficacy

Deficiencysyndrome

SR

Cytokinesandchemokines

Antibodies

Tolerance

T-cellspecificResponse

Lymphnode

Antigen

Cytokines

Peptide

CLR

HelperTcell

NLR

!

TLR

MHCIITCR

DC

22

Productandprocessrelatedimpuritiesimpactonthe

immunogenicityriskforpeptides

Formostpeptidescapableofinducinganimmune

response,impuritiescan

changethequantityandthequalityoftheimmuneresponse

Aggregationprofile

Visibleandsubvisibleparticles

Product-

Leachables,LAL,residualsolvents.InnateimmuneactivationbyIIRMIInvitro(IIRMI,Aguptake,DC

maturation)

Process-

related

impurities

related

impurities

LC-MS,MS-MS,Peptidemapping,etc.MethodsthatassessbindingtoMHC

Insilico

Invitro(MHCbinding,MAPPs)MethodsthatassessTcellactivation

Invitro(DC-Tcell)

23

24

Immunogenicityriskofpeptides

•Levelofconcernwithpeptidesisdifferentthanforsmallmolecule:Peptidesequencescanelicitanimmuneresponse,particularlyifaggregatedorpresentedonscaffolding.

•Peptidesadministeredviasubcutaneous,intravenous,intramuscular,intradermal,

inhalation,andintravitrealrouteshavegreaterimmunogenicriskthanoralortransrectalpeptides.

•Productformulationiscriticaltothequalityandstabilityofpeptidedrugproducts.Formulationdifferencescanmodifypeptidestabilityandimmunogenicity.

•Peptide-relatedimpuritiesmaymodifythetargetoftheantibodiesdeveloped.

•ImpuritiesorcontaminantsthatactivateimmunecellsmayincreasetheimmunogenicityoftheAPIorresultinimmuneresponsesthattargetnewsequencesthatmaycross-reactwithendogenouscounterparts.

25

Immunogenicityriskofimpuritiesinpeptides

•Peptide-relatedimpuritiescanbedifficulttodetect,analyze,andcontrolbecausetheimpuritiescanhavesimilaraminoacidsequencestothepeptideitself,necessitatingadvancedanalyticaltechniques,suchasliquidchromatography-highresolutionmassspectrometry,todetect,identify,andquantifyimpurities.

•Impuritiesandcontaminantscanactivatetheimmunecellswheretheproductisdepositedincreasingtheimmunogenicityriskattracelevels(pg-ng).

•Assessingtheimmunogenicityriskoftheimmunomodulatoryimpuritiesinpeptidesrequirescomplexinsilicoandinvitrostudies.

•Mitigatingtheimmunogenicityriskofpeptidesrequiressensitiveassaysandcontrolofproductandprocessimpurities.

26

Immunogenicityriskofpeptides

•TheriskofInnateImmuneResponseModulatingImpuritiesmayormaynotbemitigatedbythedrugproduct(DP)manufacturingprocess.

QuantiblueOD

(subBackground)

2

1

工

CellbasedevaluationofIIRMI

0.200.150.100.05

0.00TTTTTTT—

工工T

FormulationBuffer

PC(LPS100pg)

DS1

DS2

DS3

DS4

DS5

DS6

DS7

DS8

CompoundedDSsamples

CommercialDSsamples

Filtered0.2uMPFTE

QuantiblueOD

(subBackground)

UnfilteredFiltered

2.5 2.0 1.5 1.0 0.50.20

FormulationBuffer

LPS100pg

DS1

DS2

DS3

DS4

DS5

DS6

DS7

DS8

0.150.100.050.00

CommercialDSsamples

CompoundedDSsamples

Abbreviations:DS=drugsubstance,LPS=lipopolysaccharide,PC=phosphorylcholine,PFTE=polytetrafluoroethylene

27

Summary

•Productimmunogenicityconstitutesariskforpeptides,includingcompounded

peptides,especiallywhendeliveredviacertainroutesofadministration,whichmayresultinsignificantrisksofharm,includinglife-threateningreactionssuchas

anaphylaxis.Controlofimpurities,includingaggregates,canmitigatethisriskbutrequiressophisticatedmanufacturingandtestingstrategies.

PharmacyCompoundingAdvisoryCommittee:

BulkDrugSubstance(BDS)DiscussionDecember4,2024

RussellWesdyk,BS,MBA

AssociateDirectorforRegulatoryAffairsOfficeofProductQualityAssessmentIIOfficeofPharmaceuticalQuality

CDER,FDA

30

Disclosure

•Thisspeakerhasnoconflictsofinteresttodisclose

31

RationaleandObjectives

•Inanevaluation(s)presentedtoday,FDAwilldiscussmultiple“related”butdistinctBDSsforinclusionon503ABulksList

•DespitethelackofclarityonwhichspecificBDSwasintendedinthenominations,duetoFDA’s

significantsafetyconcernsrelatedtotheuseofcertainBDSincompoundingdrugproducts,FDAhasdecidedtoevaluatethesemultiplerelatedBDSsonitsowninitiative

•Goalsofthispresentations

–ExplainregulatorydefinitionsforBDS,activepharmaceuticalingredient(API)andactivemoiety(AM)

–ExplainhowBDSdifferenceshaveimplicationsforthedrugproductsmadewiththem

–Provideotherrelevantbackground

32

AThoughtExperiment…

•HowmanyBDS,API,andAMintheexamplebelow?

-Diclofenac

-DiclofenacEpolamine

-DiclofenacSodium

-DiclofenacPotassium

-Naproxen

-NaproxenSodium

33

StatuteandRegulations

•Per21CFR207.3,aBDSisthesameanActivePharmaceuticalIngredient(API).

Section207.3reads“Bulkdrugsubstance,asreferencedinsections503A(b)(1)(A)and503B(a)(2)oftheFederalFood,Drug,andCosmeticAct,previouslydefinedin§

207.3(a)(4),meansthesameas"activepharmaceuticalingredient"asdefinedin§207.1.”

•APIisdefinedinFDAregulationsat21CFR207.1andthatsectionreads“Active

pharmaceuticalingredientmeansanysubstancethatisintendedforincorporation

intoafinisheddrugproductandisintendedtofurnishpharmacologicalactivityor

otherdirecteffectinthediagnosis,cure,mitigation,treatment,orpreventionof

disease,ortoaffectthestructureoranyfunctionofthebody.Activepharmaceuticalingredientdoesnotincludeintermediatesusedinthesynthesisofthesubstance.”

34

BDS/APIInPracticalTerms

•ThespecificformofAPIusedinaformulatedproduct,isoftenasaltoranesterofafreebaseoractivemoiety;eachadistinctAPI/BDS

•That“form”ischosenforitsphysical,chemical,orpharmacokinetic-pharmacodynamic(PKPD)characteristicswhichrendersthemmoresuitablefordrugproduct/compoundingprocessing

•TheselectioncanbedosageformspecificduetouniqueCriticalQualityAttributesassociatedwithadesireddosageform

35

WhatisanActiveMoietyandSaltForm?

•

••••

••

Anactivemoietyisdefinedat21CFR314.3as“Activemoietymeansthemoleculeorion,excluding

thoseappendedportionsofthemoleculethatcausethedrugtobeanester,salt(includingasaltwithhydrogenorcoordinationbonds),orothernoncovalentderivative(suchasacomplex,chelate,or

clathrate)ofthemolecule,responsibleforthephysiologicalorpharmacologicalactionofthedrugsubstance.”

Diclofenac–FreebaseandactivemoietyNSAID

DiclofenacEpolamine–EpolaminesaltofdiclofenacfreebaseDiclofenacSodium–Sodiumsaltofdiclofenacfreebase

6DistinctBDSs

DiclofenacPotassium–Potassiumsaltofdiclofenacfreebase

Naproxen–FreebaseandactivemoietyNSAID

NaproxenSodium–Sodiumsaltofnaproxenfreebase

36

WhyDoesThisMatter?

•FDAhaspreviouslystated"whenasaltoresterofanactivemoietyislisted,onlythat

particularsaltorestermaybeused.Thebasecompoundandothersaltsorestersofthesameactivemoietymustbeevaluatedseparatelyforeligibility[…].”

–See2016proposedrule:

/d/2016-30109/p-108

–Thisrulewasfinalizedin2019.

37

WhyDoesThisMatter?

•Differentsalts,estersandthefreebasecanhaveverydifferentproperties

–Physicochemicalproperties

•Chemicalformula/Molecularweight

•Solidstatestability

•Solutionstability

•Solubility

•Polymorphism

–Pharm/Toxprofile

–PK/PDprofile

•Thesedefinitionsanddistinctionsareasimportantincompoundingastheyareindrugproduct

manufacturing.Thisisnotjustamatterofregulationsordefinitions;thisisacriticalmatterofchemistryasthesedifferentformshavedifferentchemicalstructuresaswellasdifferentphysical,chemical,PK/PDcharacteristics.Thiscanimpactpatientsafetyandproductefficacy.

38

PhysicalandChemicalCharacterization

•[For]physicalandchemicalcharacterizationofthesubstance,FDAwouldconsidereachsubstance'spurity,identity,andquality.Basedonattributessuchasthesubstance's

molecularstructure,stability,meltingpoint,appearance,likelyimpurities,and

solubilities,FDAwoulddeterminewhetherthesubstancecanbeidentifiedconsistentlybasedonitsphysicalandchemicalcharacteristics.Ifasubstancecannotbewell

characterizedchemicallyandphysically,theAgencyproposesthatthiscriterionweigh

againstitsinclusion[…]becausetherecanbenoassurancethatitspropertiesand

toxicities,whenusedincompounding,wouldbethesameasthepropertiesandtoxicitiesreportedintheliteratureandconsideredbytheAgency."

–2016ProposedRule,DocketNo.FDA-2016-N-3464.

–See81FR91071

39

UniqueIdentifiersandRelatedDatabases

•GlobalSubstanceRegistrationSystem(GSRS)

–Usedbymultipleworldwideregulatoryagencies

–HomeofaUniqueIngredientIdentifier(UNII)

•ChemicalAbstractsServices

–HomeofuniqueidentifierknownasCASRegistryNumber(CASRN)

•Manufacturers/supplierspopulatethesedatabases

–Theyprovidestructureandrelatedinformationandrequestuniqueidentifier

–Regulatorsdonotownorpolicethedatacontainedtherein

Conclusion

•BDSisdefinedasthesameasanAPIintheregulations.AfreebaseformaswellaseachofthesaltformsareeachdistinctBDS,eachwithuniquephysical,chemicalandPK/PDcharacteristicswhichcanimpactpatientsafetyandproductefficacy

•Nominators,BDSManufacturers,andCompoundersneedtobeawareofwhatsingleBDSisnominated,manufactured,andusedtoformulateacompoundedproduct

•UNIIandCAS#areuniqueidentifiersforAPI/BDSsbutnotcontrolledbyFDA

40

•OurphysicalchemicalcharacterizationassessmentandconclusionisspecifictoeachuniqueBDS

41

FinalThoughts

•BotanicalBDSarecomplexmixtures,andcaremustbetakentoidentifyasingleBDS

•Useof“commonnames”fornominatedsubstancecanbeproblematicandcauseconfusion

•SyntheticpathwayconsiderationsformorecomplexBDSs

CJC-1295-relatedBulkDrugSubstances

PharmacyCompoundingAdvisoryCommitteeMeetingDecember4,2024

MarianneSanAntonio,DO

Physician

PharmacyCompoundingReviewTeam(PCRT),OfficeofSpecialtyMedicine(OSM),OfficeofNewDrugs(OND)

and

MaiTu,PhD

SeniorPharmaceuticalScientist

OfficeofProductQualityAssessmentII(OPQAII),OfficeofPharmaceuticalQuality(OPQ)CenterforDrugEvaluationandResearch(CDER),U.S.Food&DrugAdministration(FDA)

CJC-1295-relatedBDSEvaluationTeam

MaiTu,Ph.D.,OPQAII,OPQ

RussellWesdyk,B.S.,MBA,OPQAII,OPQ

AshleeMattingly,PharmD,MPH,BCPS,OfficeofCompoundingQualityandCompliance(OCQC),OfficeofCompliance(OC)TracyRupp,PharmD,MPH,BCPS,RD,OCQC,OC

EdnaAlbuquerque,PhD,DivisionofPharmacology/Toxicology,OfficeofRareDiseases,Pediatrics,Urologic,andReproductiveMedicine(DPT-RDPURM),OND

AndreaBenedict,PhD,DPT-RDURM,OND

MarianneSanAntonio,DO,PCRT,OSM,ONDSuhailKasim,MD,PCRT,OSM,OND

SpecialThanksto:

OfficeofNewDrugs-DivisionofGeneralEndocrinology

44

Nomination

•VariousCJC-1295-relatedbulkdrugsubstances(BDSs)werenominatedforinclusiononthelistofbulkdrugsubstancesthatcanbeusedto

compounddrugproductsinaccordancewithsection503AoftheFederalFood,Drug,andCosmeticAct(FD&CAct)(503ABulksList)

•CJC-1295-relatedBDSswereevaluatedfortreatmentof:

–GrowthHormoneDeficiency(GHD)

•Proposedproduct:

–subcutaneous(SC)injectionadministrationina2,000mcg/mLconcentration

•Thenominationswerewithdrawn,andFDAisevaluatingthesubstancesatitsdiscretion

45

EvaluationCriteria

•Physicalandchemicalcharacterization

•Historicaluseincompounding

•Safety

•Availableevidenceofeffectivenessorlackofeffectiveness

46

InconsistentNamingConventionsoftheBDSs

•CJC-1295-relatedBDSsareanaloguesofgrowthhormonereleasinghormone(GHRH)

•TherehavebeenmanymodificationstoGHRHovertime

•ConjuChemBiotechnologiesmayhavedevelopedCJC-1295withDrugAffinityComplex(DAC)originally,DACisamaleimidopropionamide-lysine(MPA-Lys)unitaddedattheCterminuswhichwerefertoas“CJC-1295DAC(freebase)”

•However,thereareothermodificationsofCJC-1295thatmayhavebeenstudiedincludingversionswithouttheDACcomplex

•Itisnotpossibletoknowwhichcompound/structureisintendedwhenreferencedascommonnames

•CommonnamesbeingusedforCJC-1295relatedBDSsintroducesrisks:Safetyriskforpatients,errorinchemicalanalysis

47

SummaryofBasicInformationonCJC-1295-relatedBDSs

CJC-1295(freebase)

CJC-1295Acetate

CJC-1295DAC(free

base)

CJC-1295DACAcetate

CJC-1295DAC

Trifluoroacetate(TFA)

UNIICode

Notavailable

Notavailable

62RC32V9N7

Notavailable

Notavailable

CASNo.

446036-97-1

Notavailable

446262-90-4

Notavailable

Notavailable

MF/MW(g/mol)

C152H252N44O42/3367.95

C152H252N44O42xCH3COOH/NA

C165H269N47O46/3647.95

C165H269N47O46xCH3COOH/NA

C165H269N47O46xCF3COOH/NA

ChemicalStructure

.xCH3COOH

.xCH3COOH

.xCF3COOH

Supplier

Yes

Yes

Yes

No

No

ActiveMoiety

CJC-1295(freebase)

CJC-1295(freebase)

CJC-1295DAC(free

base)

CJC-1295DAC(free

base)

CJC-1295DAC(free

base)

CAS=ChemicalAbstractsService;MF=molecularformula;MW=molecularweight48

SummaryofInformationSubmittedin

TwoWithdrawnNominations

Nominator

1

2

NominatedBDS

CJC-1295(freebase)

CJC-1295Acetate

BDSperUNIIcode

62RC32V9N7(matchesCJC-1295

DAC(freebase))

62RC32V9N7(matchesCJC-1295DAC(freebase))

CertificateofAnalysis(CoA)

Notprovided

CoAprovidedforCJC-1295Acetate

CASNo.

Notprovided

863288-34-0(deletedCAS)

MF

Notprovided

C152H252N44O42(providedintheCoA)(matchesCJC-

1295(freebase))

MW(g/mol)

Notprovided

3367.97(providedintheCoA)(matchesCJC-1295

(freebase))

ChemicalName

InformationProvidedDoesNot

CorrespondtoAnyCJC-1295-

relatedBDSs

Tyr-D-Ala-Asp-Ala-lle-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-

Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-

Asp-lle-Leu-Ser-Arg-NH2(matchesCJC-1295(free

base))

ActiveMoietyinClinicalReferences

CJC-1295DAC(freebase)

CJC-1295DAC(freebase)

ItalicsinthetableaboverepresentstheinformationidentifiedbytheFDA.

49

PhysicalandChemicalCharacterization(1)

CJC-1295Acetate

•AcetatesaltofCJC-1295(freebase),thatissynthetic29aminoacidanalogue(Tyr-DAla-Asp-Ala-Ile-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Leu-Ser-Arg-NH2)ofGHRH.

•Whitelyophilizedpowder;solubleinwaterat5mg/mL

•NoUSPdrugsubstancemonograph

•BDSstorageandstability

–Manufacturerrecommendslong-termstorageat2。C-8。Cinarefrigeratororfreezer

–Remainstableupto3yearswhenstoredat-20°C

–Sensitivetoproductformulation,processandenvironmentconditionswhichmayleadtoaggregationanddegradation

•PotentialforImpurities

–Peptide-relatedimpuritiesandpeptidesynthesisprocess-relatedimpurities(e.g.,startingmaterials,residualsolvents,couplingreagents,activators,catalysts)

50

PhysicalandChemicalCharacterization(2)

•Potentialforimmunogenicity

–CoAincludespeptidepurity,largestsingleimpuritylimitlessthan2.0%,butnoinformationregardingthenatureofindividualimpuritiesoraggregates

–Lackofinformationonthepotentialofpeptideaggregation,especiallywhenformulatedinaninjectabledosageformforSCadministration

Conclusion:CJC-1295Acetateisnotwell-characterized

•ConcernsarisingfrominconsistentnamingconventionsexistfortheBDS

•Lackofcertaincriticalcharacterizationdata(impurities,aggregates,andbioburden/endotoxinlevels)

•PotentialforimmunogenicitywhenformulatedinaninjectabledosageformforSC

administrationduetopotentialforaggregationaswellaspeptide-relatedimpurities.

51

PhysicalandChemicalCharacterization(3)

CJC-1295(FreeBase)

•Synthetic29aminoacidanalogue(Tyr-DAla-Asp-Ala-Ile-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Leu-Ser-Arg-NH2)ofGHRH

•Whitelyophilizedpowder;limitedsolubilityinwater(solublein1%aceticacid)

•NoUSPdrugsubstancemonograph

•BDSstorageandstability

–Manufacturerrecommendsstorageat-20°C

–Sensitivetoproductformulation,processandenvironmentconditionswhichmayleadtoaggregationanddegradation

•PotentialforImpurities

–Peptide-relatedimpuritiesandpeptidesynthesisprocess-re