The Pharmaceutical Technology...
Transcript of The Pharmaceutical Technology...
ThePharmaceuticalTechnologySpecialists
www.drugdeliveryexperts.com
ChristopherA.Rhodes,PhD,President,CEO,Founder
FormulationChallengesandOpportunitiesforPeptideDrugProductCPCSymposium,11OCT2017
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PeptideProductDevelopmentConsiderations
• WhatMakesaProductDevelopmentScientist?• IntroductionandDeliverySystemPreferences• TheImportanceofTargetProductProfile• Exenatide LifeCycleProgram• Questions
HowDidIGetHere?LotsofHelp!
YERhodes- DISchuster- CSFoote- JIBerson --- SSSteiner- WCVincek - ABaron-- DBradbury-- FriendsandColleagues
MentorsandInfluencesandExperiencesPhysicalOrganicChemistryPhotochemicalandThermalRearragementsSingletOxygenandElectronTransferRxns
Small,Mid-sizeBiotech,DrugDeliveryLabandteamstartupsFunctionalleaderandteamleader
StartupsandConsultingCTO,HeadR&DDrugDeliveryExperts
1981 1992 2011 2014
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CenterofExcellenceforPeptideDrugProduct
MissionBringingOurGlobalPartners
theBestDrugProductSolutions
VisionChangingLivesThrough
LeadershipinDrugDeliverySystems
SpecialistsincombinationdrugproductdevelopmentComplexformulationdesignanddeviceintegrationDeepexperienceinpeptidedrugdevelopment30highlyexperiencedPhDandBSscientists
AchievingTargetProductProfileRequiresADeepUnderstandingofActive,Formulation,Device
DiscoverySupport• Leadmoleculeprofiling• Clinicalcandidateevaluation• Biologichalf-lifeextension
DrugProductDevelopment• Formulationdesign• Drugproductdevelopment• Analyticalmethods
DeviceDevelopment• Deviceidentification• Integrationwithformulation• Developmentandselection
Leveragingadeepunderstandingofmolecularproperties,formulation,anddeviceIntegratingdeliverysystemR&Dprojectintoyourdevelopmentprogram
Optimizingtargetproductprofiletoenhancevalueproposition
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MarketPreferenceforNon-invasiveDelivery
Injection Oral
device---Transdermal--- patchNasalBuccalSublingual
Onceperday>>>BIDorTID
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DailyInjection
WeeklyInjection
MonthlyInjection
QuarterlyInjection
6to12MonthInj
MultipleDailyInj
PatientSelf-InjectionCommon:ProductProfileMoreCritical
PotentialforOfficeAdministeredProduct:GoodProductProfileNotCritical
ProductProfileParameters• Complexityofproducthandling• Ready-to-useproduct• Needlesizeforinjection(viscosity)• Injectionforce(viscosity)• Painoninjection(volume)• Durationofinjection(volume)• In-Usestabilityconstraints
DecreasingInjection/AdministrationFrequency
InjectionFrequencyPreferences
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LimitedExamplesofCommerciallyTestedSystemicDeliverySystemsforPeptides
NewPolymer
Scaffolds
PEGylation
MicrosphereswithReconstitution
PenInjectors
VialandSyringe
InjectionSystems
Lipidsystems
Risk
Reward
Non-Invasive
Pulmonary Oral
Transdermal
Risk
Reward
=CommercializedProducts
=ProductsinDevelopment
Nasal
DDAVP,sCT,Buserelin,Nafarelin,Oxytocin
Pulmozyme,Insulin
Characteristics:• LowDose• LowBA• Variability• PulsatileExposure
Characteristics:• ModeratetoHighBA• AcceptableVariability• ContinuousExposure
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ImportanceofTargetProductProfileMostParametersAffecttheUserExperience
Criteria SuggestedforConsiderationRouteofAdministration Subcutaneous, Intravenous,Intramuscular
Non-invasive(Nasal,microneedle)
Dose FrequencyandPharmacokinetics
Daily ormultipledailyinjection(withnativePKprofile)Weekly,Monthly,Quarterly(withcontinuousexposure)
Projected Dose Projectedhuman,animal,toxicitydoses(drivesconcentrationindosageform)
DoseVolume < 1mL forsubcutaneousinjection(alsodrivesconcentrationindosageform)
EaseofUseandHandling Easilyinjectedthrougha26GorsmallerneedleMinimalhandling bycaregiver(simplereconstitution)
DeviceandContainerClosureSystem
Vialandsyringe, pre-filledsyringe,dual-chambersyringe,cartridgeMulti-usepen,orauto-injector
StabilityIn-use 25oC,1week to1monthStabilityfor LongTermStorage
2-8oC,minimum24months
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InSitu Gel-FormingSystem
Suspension
Liposome
Microsphere
Implant
DailyInjection
WeeklyInjection
MonthlyInjection
IncreasingDrugPotency
Non-AqueousSolution/Suspension
QuarterlyInjection
Atrigel
Sustained ReleaseFormulationApproaches
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Exenatide Properties– ADeliveryScientistsDream
Highlypotentdrug– 10to20microgramsperdayHighlywatersolublepeptides– 100smg/mlGoodstabilityinaqueoussolutionGoodmetabolicstabilityHalf-lifeof1to2hoursinhumansChoicesfordeliverysystemarevirtuallyunlimitedYet,mistakescanbe(andwere)made
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DrugProductProfileExample:Exenatide
Exenatide Drug Substance• 39 amino acid peptide
Disposable Pen-injector• 5 mcg or 10 mcg per injection• Storage : 2 year shelf-life• In-use: 30 day period at RT
Container Closure System• 1.2 & 2.4 mL cartridge for pen• 0.25 mg/mL strength
Byetta (exenatide injection)• LaunchedbyAmylinandEliLillyPartnership(nowownedbyAstraZeneca)• DiscoveredbyJohnEng (VAHospital)1996
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GLP-1sMovetoMaximizeContinuousExposure
Liraglutide (Victoza)Half-life 13 hrs
Kothare P A et al. J Clin Pharmacol2008;48:1389-1399
Byetta (exenatide)Half-life 1-2 hrs
KimDetal.Dia Care2007;30:1487-1493
0 4 8 12 16 20 24 280
50100150200250300350400450500550
Last Injection
Active Treatment Period Follow-Up Period
Time (wk)
Pla
sma
Exe
natid
e (p
g/m
L)
Bydureon (exenatide MS)
-0.9%
-1.5%
HbA1CReduction
-1.2%
US2005EU2006
EU2009US2010 EU2011
US2012
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MicrospherestoAchieveContinuousExenatide
Exenatide WeeklyPLGAMicrospheres(SEM)
LicensePLGATechnologyfromAlkermes (2000)(Neutropin Depot)wasprecedentforwork
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Exenatide MicrosphereManufactureandQC
Exenatide MSReleaseandPolymerDegradation Exenatide MSParticleSizeDistribution
PolymerType,FormulationandProcess
ControlsReleaseProfileAndPharmacokinetics
ParticleSizeisControlledbyProcessand
DictatesDeviceandNeedleGuage
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Exenatide Microsphere(Bydureon)LifeCycle
• Bydureon isanexenatide microsphereformulation• Vialandsyringe,pen,suspensioninauto-injector• MSinjectablesuspensiontobesubmittedbyAZ20172018?
Bydureon (EU2011US2012)OnceweeklySCinjection2mgperweekdose
Bydureon Pen(US2014)OnceweeklySCinjection2mgperweekdose
Bydureon Suspension(US2018?)OnceweeklySCMSsuspension2mgperweekdose
VialandsyringepresentationdiscontinuedJan2016withpenlaunch
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Bydureon:SingleDosePKProfile(10to12weeks)
SDPKDoseSelectionStudy2.5mg,6mg,7mg,10mg DoseSelectionStudy0.8mgand2mgexenatide
• Initialreleaseinfirstdaysubjectofsignificantformulationandclinicalwork• Targetproductprofilewasoncepermonthinjection– couldnotbeachievedduetoinitialrelease• 300pg/mlwasachievablewithlowinitialreleasebyweeklyinjectionofthesameformulation
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Exenatide DeliveryOpportunitiesEvaluated
• Nasalformulationtakenintoclinic• Transdermalmicroporation takenintoclinic• Pulmonarydrypowderevaluatedinpreclinicalwork• Oraldeliveryevaluatedinpreclinicalwork• AlloftheseformulationssufferedfromPKissues
• Lowbioavailability,variability,shorterexposuretimesthanSCinjection
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NasalExenatide HumanData(Nastech Formulation)
NasalTargetProductProfile:• Aqueoussolutionformulation• Simplemanufacturingprocess• Commerciallyavailabledevices• Nasalpeptideproductsinmarket• BIDorTIDadministration
0 60 120 180 240 300 360 420 4800
100
200
300
400 5 ug SC600 ug IN
10 ug SC(previous study)
Time (min)Pl
asm
a Ex
enat
ide
(pg/
mL)
OpportunityAbandoned- un-attractivefrommarketingperspective• 3or4XNasalSprayrequiredtoachieveAUCequivalenttoSCInjection(andclinicaleffect)
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TransdermalMicroporation HumanData(Altea)
TransdermalTargetProductProfile:• Simplebandaid-likeproductadministeredwdevice• Nopainonadministration• Continuous24hourexposure(Bydureon-like)• Onceperdayadministration(twiceasfallback)
OpportunityAbandoned- duetosignificantinvestmentrequied (device,patch,manufacturing)• Onceperday24hourcontinuousexposurenearlyachieved
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Exenatide Lessons
• Byetta waslaunchedinagoodpen,but,witharefrigerationpack• CMCpost-approvalsupplementrequiredtogetRTfor30days
• Challengesofmicrospheresustainedreleaseformulationnotwellunderstood• Initialinterestinaoncemonthlyproduct• Weeklyproductwasacompromiseduetoinitialreleasefromparticles
• Bydureon waslaunchedinavialandsyringe• Importanceofdevicewasrecognizedtoolate
• Bydureon dualchamberpenwasdifficultandtooktoolong• Atlaunch,inferiortootherweeklyGLP-1productsonthemarket
• Bydureon MSsuspensioncouldhavebeencompletedearlier($!)• DecisiontobuildMSplantinsteadofworkingwithCMOs($$$)• SingularfocusonMSinvestmentpreventedothermeaningfulapproaches
MoleculeDesign• Peptide,proteinvariants• Conjugatesforhalf-life
DeliverySystemDesign• Aqueousornon-aqueousvehicle• Sustainedreleaseformulation• Triggeredortargetedsystems
DrugProductDesign• Pen,auto-injector• Pre-filledsyringe• Nasal,oculardropsorspray
TechnologyTransferGMPMfg
ProcessDevelopmentScaleUp
FormulationDevelopment
AnalyticalResearch
DevelopmentAssessment
LeadMoleculeDesign
AnalyticalMethods
Qualification
DevelopmentStability
AnalyticalDevelopment
Preformulation
DeliverySystemFeasibility
FormulationPKScreening
LeadMoleculeSelection
DeliverySystemSelection DrugProductDevelopment
DeviceSelectionandDevelopment
TestArticleSupplyforPreclinicalandToxicityStudies
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ActivitiesRequiredtoAchieveTargetProductProfile
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TakeHomeMessageforDrugProductDevelopment
Integrationofmolecularproperties,formulation,anddeviceiskeytoachievingthedesiredproductprofile
Productuseandself-administrationcontraints drivedeviceconfiguration,formulationdesign,molecularproperties
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GLP-1AGONIST MOLECULAR ENGINEERING
GLP-1dimer
97%homologytoGLP-1Ex-4pluspolyLys
LiraplusoptimizedAlbuminbinder
TwoGLP-1sonFcfragment
CARhodesGSK-CRS18APR2017
TwiceDailyInjection OnceDailyInjection
OnceWeeklyInjection
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LIRAGLUTIDE AND SEMAGLUTIDE
• Lipidated GLP-1analoguesbasedonNovolipidation system• Liraglutide is97%homologoustoGLP-1• Albuminbindingbylipidforhalf-lifeextension• Semaglutide hasanoptimizedalbuminbindingsidechain
LiraglutideApprovedEU2009/US2010DailySCinjection1.2to1.8mgperdose
CARhodesGSK-CRS18APR2017
1mgatsteadystate
SemaglutideNDA2016WeeklySCInjection1-2mgperdose