case study: tech transfer of mammalian cell culture ...§ pid controlpossibilities ... process scale...
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Casestudy:Techtransferofmammaliancellcultureprocessfrom
labscaletoproductionscaleusingdisposabletechnology
DawidSuwałaaa.Mammalian Drug Substance Manufactruring Manager
PolpharmaBiologics
CellWorld 2017, April 26th Page 2Polpharma Biologics property
Techtransferofmammaliancellcultureprocessfromlabscaletoproductionscaleusingdisposabletechnology
AGENDA
Procesdevelopmentinlabscale
TechtransferGAPanalysis– riskevaluation
Processtransferandscale-upto50L
Processscale-upfrom50Lto250L
Final1000LscaleinSingleUseBioreactor
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Processdevelopmentchallengesinlabscale
§ Cellline development§ Production mediaselection§ Clonewiththehighest
productivity propertiesselection
§ Feeding andsuplementationstrategy optimization
§ Process parametersoptimization
§ Producttiter andqualityoptimization
§ Threeconsolidation runs inR&Dbefore transfer
§ Dataalignment betweenR&DandProduction Units
Earlystage Latestage Processtransfer
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TechTransferGAPanalysis– riskevaluation
Hardwarefeasibilitystudy
Rawmaterialsevaluation
Documentationanddataaligment
§ Proper quality materials usage during process development§ Risk assesment for materials - critical quality parameters analysis§ Raw materials list transfer from R&D to Production
§ Data transfer from R&D to Production – Product Trasfer planand protocols
§ R&D documentation data – clear description of process parametersand introduced changes
§ Criticalequipmentestablishment
§ R&DandProductionequipmentfunctionalitycomparison
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KEYELEMENTSOFPROCESSTRANSFER
Bioreactorscharacterization
§ Hardwarefeasibility study
§ Rawmaterialsevaluation
§ Documentation anddataalignmentRisk evaluation
§ Mixing studies
§ Masstransferdetermination (kLa)
§ Powerinputdetermination(empiricaldetermination)
§ CFDcharacterization
TechTransferGAPanalysis– riskevaluation
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VS
Laboratory andProduction scale – how toalign?
Two stepapproach
Processscaleupfrom10Lglassto50LSingleUseBioreactor
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Processscaleupfrom10Lglassto50LSingleUseBioreactor
Equipment functional performance
Newculture environment– glass toplasticexchangeandsingleuse bioreactor bag internal layer filminfluenceonculture performance
Process optimization – operational parameters adaptationtonew environment
GMPcell banks production andcharacterization;introductiontoroutine use
Whatisthecase?
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Firststep– process transfer
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What is thecase?
§ Vessel andstirrer geometry§ Material contact forcell culture
§ Gassing pathways
§ Spargers types§ PIDcontrol possibilities
Equipment functionalperformance1
Processscaleupfrom10Lglassto50LSingleUseBioreactor
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What is thecase?
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
0.0010.0020.0030.0040.0050.0060.0070.0080.0090.00100.00
0 24 48 72 96 120 144
VCC[0
6viablecells/ml]
ViabilityofCulture
[%]
ElapsedTime[h]
§ Vessel andstirrer geometry§ Material contact forcell culture
§ Gassing pathways
§ Spargers types§ PIDcontrol possibilities
Equipment functionalperformance1
§ Cellsviability andculture density§ Productivity
§ Productprofile(chargévariants,aggregation,etc.)
2Newculture environment–SUBinternal layer film
influenceonculture performance
Processscaleupfrom10Lglassto50LSingleUseBioreactor
CellWorld 2017, April 26th Page 10Polpharma Biologics property
What is thecase?
§ Vessel andstirrer geometry§ Material contact forcell culture
§ Gassing pathways
§ Spargers types§ PIDcontrol possibilities
Equipment functionalperformance1
§ Cellsviability andculture density§ Productivity
§ Productprofile(chargévariants,aggregation,etc.)
2
§ Gassingstrategy
§ Spargingstrategy§ PIDcontrolstartegy
§ SingleUseBioreactorprojectcustomization
Process optimization 3
Newculture environment–SUBinternal layer film
influenceonculture performance
Processscaleupfrom10Lglassto50LSingleUseBioreactor
CellWorld 2017, April 26th Page 11Polpharma Biologics property
What is thecase?
§ Cellsviability andculture density§ Productivity
§ Productprofile(chargévariants,aggregation,etc.)
Newculture environment–SUBinternal layer film
influenceonculture performance2
§ Cellbanks characterization
§ Cellbanks quality§ Newcell banks influenceon
process performance
MCB&WCBproductionandintroductiontoroutine use
4
§ Gassingstrategy
§ Spargingstrategy§ PIDcontrolstartegy
§ SingleUseBioreactorprojectcustomization
Process optimization 3
§ Vessel andstirrer geometry§ Material contact forcell culture
§ Gassing pathways
§ Spargers types§ PIDcontrol possibilities
Equipment functionalperformance1
Processscaleupfrom10Lglassto50LSingleUseBioreactor
CellWorld 2017, April 26th Page 12Polpharma Biologics property
Processscaleupfrom50Lto250LSingleUseBioreactor
50LSUBTechnicalTrial Dataanalysis 250LSUBTechnicalTrial
§ Riskevaluation§ R&DDataevaluation§ Techtransferprotocols
establishment§ Technicaltrialsperformance
andexecution§ Technicaltrialdatacollection
§ Technicaltrialdataevaluation
§ Analyticaldataevaluation§ Processmismatches/
unexpectedeventsrootcauseinvestigations
§ Transferreportpreparationincludingconclusionstoachieveddataandrecommendationsfornexttrials
§ TechnicaltrialrepetitionifneededorprocessoptimizationinR&Dformoredatacollection
§ Preliminaryprocessparametersestablishment
§ Techtransferprotocolsestablishment
§ Technicaltrialsexecution§ Technicaltrialdatacollection
CASE:WCBqualityinfluenceonprocessperformance
Bioreactors characterization is akey element
Secondstep– process scale-up
CellWorld 2017, April 26th Page 13Polpharma Biologics property
250LSUBTechnicalTrial 1000LSUBTechnicalTrial
§ Preliminaryprocessparametersestablishment
§ Techtransferprotocolsestablishment
§ Technicaltrialsexecution§ Technicaltrialdatacollection
§ Technicaltrialdataevaluation
§ Analyticaldataevaluation§ Processmismatches/
unexpectedeventsrootcauseinvestigations
§ Transferreportpreparationincludingconclusionstoachieveddataandrecommendationsfornexttrials
§ ProcessPrametersestablishment
§ Engeeneringbatchesperformanceandexecution
§ Processoptimization§ IPCstrategyestablishment
Processscaleupfrom250Lto1000LSingleUseBioreactor
Bioreactors characterization is akey element
Secondstep– process scale-upDataanalysis
CellWorld 2017, April 26th Page 14Polpharma Biologics property
Parameter Specification 1000LBatch Consolidation runs*
mAb content 18-22mg/ml 21,3mg/ml 19,8÷20,3mg/ml
Purity (SEC)
HMWI≤0,2% N/A N/A
dimers ≤1,0% 0,3% 0,2÷ 0,4%
Purity ≥97,0% 99,0% 98,4÷ 98,9%
Purity (CE) ≥92,0% 97,7% 98,0÷ 98,3%
CEX
Sumofacidic peaks ≤18,0% 13,4% 14,8÷ 15,8%
Main Peak ≥70% 72,6% 70,8÷71,6%NA 14,0% 13,213,613,4
HCP ≤100ppm 20ppm 9÷ 20ppm
DNA ≤33ppb Below LOD<0.075 0,1÷ 0,3ppb
ProteinA ≤10ppm 0,1ppm 0,2ppm
Glycan mappingG0F:38,8-71,1% 48,2% 54,1÷ 53,9%
SumofG1F,G1F',G2F:32-58% 45,9% 38,3÷ 38,7%
Polisorbate 80content 0,1- 0,3mg/ml 0,2mg/ml N/A
Potency 80-125% 103% 100÷ 102%
Endotoxin ≤7,3IU/ml <0,125IU/ml N/A
Bioburden ≤1CFU/10mL <1CFU/10mL N/A
pH 5,5÷ 5,9 5,7 5,7÷ 6,1
Osmolarity ≥240mosmol/kg 296mosmol/kg 281÷ 291mosmol/kg
*Minandmaxresults fromtheconsolidation round 3(Run1,2and3)
Processscaleupfrom250Lto1000LSingleUseBioreactor
CellWorld 2017, April 26th Page 15Polpharma Biologics property
Riskevaluationandbioreactorscharacterizationarekeyforprocesstransferandscale-up
Twostepapproachgavepositiveresultofprocessoptimizationindisposablesystems
Finalscale-updonewithproductqialityspecificparametrspreservationafterallproblemweresolvedinpreviousactivities
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Techtransferofmammaliancellcultureprocessfromlabscaletoproductionscaleusingdisposabletechnology
SUMMARY
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TakeHomeMessage
To avoid mismatches between lab scale and production platform during technology transfer it is needed to predict production performance at early stage of lab scale process description and hardware setup. Wellknown bioreactors characteristic and risk evaluation are key elements
during process transfer and scale-up.
Techtransferofmammaliancellcultureprocessfromlabscaletoproductionscaleusingdisposabletechnology
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