Continuous biomanufacturing : innovative technologies and methods

619 Pages·2018·74.642 MB·English

by  Subramanian, G

Editedby
GanapathySubramanian
Continuous
Biomanufacturing

Continuous Biomanufacturing
Innovative Technologies and Methods
Edited by Ganapathy Subramanian
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v
Contents
ListofContributors xix
PartOne: OverviewofState-of-the-ArtTechnologiesand
Challenges 1
1 ContinuousBioprocessDevelopment:MethodsforControland
CharacterizationoftheBiologicalSystem 3
PeterNeubauerandM.NicolasCruz-Bournazou
1.1 ProposedAdvantagesofContinuousBioprocessing 3
1.1.1 Introduction 3
1.2 SpecialChallengesforContinuousBioprocesses 5
1.2.1 TheBiologicalSysteminContinuousBiomanufacturing 5
1.2.2 InherentChangesintheMicrobialSystem–ProblemofEvolution 6
1.2.3 LackofProcessInformation 7
1.2.3.1 Models-BasedProcessDevelopmentandControlforContinuous
Processes 8
1.2.3.2 EngineeringApproachtoComplexSystems 8
1.2.4 LimitedControlStrategies 9
1.2.4.1 TraditionalControlStrategiesforContinuousCultures 9
1.3 ChangesRequiredtoIntegrateContinuousProcessesin
Biotech 11
1.3.1 ABetterPhysiologicalUnderstandingoftheOrganismsandTheir
ResponsesontheReactorEnvironment 11
1.3.1.1 ModelComplexity 11
1.3.1.2 Models 12
1.3.2 Model-BasedProcessMonitoring 13
1.3.3 ImplementationofModelPredictiveControl 14
1.3.3.1 Model-BasedControl 14
1.4 RoleofIterativeProcessDevelopmenttoPushContinuousProcesses
inBiotech 14
1.4.1 MethodsforDevelopmentofContinuousProcesses 14
1.4.1.1 Alternative:Fed-BatchasaSystemtoSimulateQuasiSteady-State
Conditions 16
vi Contents
1.4.2 MimickingIndustrialScaleConditionsintheLab:Continuous-Like
Experiments 17
1.4.2.1 ASimpleModelforContinuousProcesses 17
1.4.2.2 Continuous-LikeFed-BatchCultivations 18
1.4.3 FastandParallelExperimentalApproacheswithHighInformation
Content 20
1.4.3.1 Computer-AidedOperationofRoboticFacilities 20
1.4.3.2 ModelBuildingandExperimentalValidation 21
1.5 Conclusions 22
References 22
2 ToolsEnablingContinuousandIntegratedUpstreamandDownstream
ProcessesintheManufacturingofBiologicals 31
RimenysJ.CarvalhoandLedaR.Castilho
2.1 Introduction 31
2.2 ContinuousUpstreamProcesses 32
2.2.1 ContinuousBioprocesses:WithorWithoutCellRecycle? 33
2.2.2 Early/Scale-DownPerfusionDevelopment 34
2.2.3 FeedingandOperationalStrategiesinPerfusionProcesses 35
2.2.4 CellRetentionDevices 36
2.3 ContinuousDownstreamProcesses 41
2.3.1 ContinuousLiquidChromatography(CLC) 42
2.3.1.1 ContinuousAnnularChromatography(CAC) 42
2.3.1.2 TrueandSimulatedMovingBedChromatography(TMB/SMB) 43
2.3.1.3 MulticolumnCountercurrentSolventGradientPurification
(MCSGP) 45
2.3.1.4 PeriodicCountercurrentChromatography(PCC) 47
2.3.1.5 ContinuousCountercurrentTangentialChromatography
(CCTC) 50
2.3.2 NonchromatographicContinuousProcesses 51
2.3.2.1 ContinuousAqueousTwo-PhaseSystems 51
2.3.2.2 ContinuousProteinPrecipitation 52
2.3.3 Straight-ThroughProcesses 53
2.3.4 ContinuousVirusClearanceProcesses 54
2.4 IntegratedContinuousProcesses 55
2.5 ConcludingRemarks 59
References 60
3 EngineeringChallengesofContinuousBiomanufacturing
Processes(CBP) 69
HolgerThiess,SteffenZobel-Roos,PetraGronemeyer,ReinhardDitz,
andJochenStrube
3.1 Introduction 69
3.1.1 ContinuousManufacturing 69
3.1.2 ContinuousManufacturingofSyntheticMolecules 69
3.1.3 ContinuousManufacturingofBiologics 69
3.2 AnalysisofCBPStatus 71
Contents vii
3.3 CaseStudies 74
3.4 StatusandNeedsforResearchandDevelopment 77
3.5 EngineeringChallenges 79
3.5.1 PlatformMethodofQbD-DrivenProcessModelingInsteadofUnit
OperationOrientedPlatformApproaches 80
3.5.2 DataDrivenDecisions 81
3.5.3 Analytics 82
3.5.4 QbDMethods 82
3.5.5 UpstreamandDownstreamIntegration 82
3.5.6 BufferHandling/Recycling 83
3.5.7 ProcessIntegrationofInnovativeUnitOperations 84
3.5.8 ABC(AnythingButorBeyondChromatography)andAAC(Anything
andChromatography) 84
3.5.8.1 Liquid–LiquidExtractionBasedonATPE 84
3.5.8.2 Precipitation 86
3.5.8.3 MembraneAdsorbers 87
3.5.8.4 InnovativeMaterialsLikeFibersorMatrices 88
3.5.9 ProcessConceptsformAbsandFragments 88
3.5.10 Single-UseTechnology 91
3.5.11 GuidedDecisionforCBP 91
3.6 ConclusionandOutlook 96
Acknowledgments 97
References 97
PartTwo: AutomationandMonitoring(PAT) 107
4 ProgressTowardAutomatedSingle-UseContinuousMonoclonal
AntibodyManufacturingviatheProteinRefinery
OperationsLab 109
DavidPollard,MarkBrower,andDouglasRichardson
4.1 Introduction 109
4.2 ProteinRefineryOperationsLab 111
4.2.1 Introduction 111
4.2.2 ProteinRefineryOperationsLab:DesignandImplementation 112
4.2.3 ProteinRefineryOperationsLab:ProcessAnalyticalTechnology
(PAT)andProductAttributeControl(PAC)fortheTransitionto
Real-TimeRelease(RTR) 117
4.2.3.1 ProteinRefineryOperationsLab:CurrentStateofPAT
Technologies 118
4.3 ProteinRefineryOperationsLab:CaseStudies 122
4.3.1 CaseStudy:Perfusion 122
4.3.2 CaseStudy:ContinuousPurification 124
4.3.3 CaseStudy:ProofofConceptAutomatedHandlingofDeliberate
ProcessDeviations 127
4.3.3.1 PerfusionProcessDeviationAnalysis(Bioreactor
TemperatureShift) 127
viii Contents
4.3.3.2 DownstreamProcessDeviationAnalysis
(ViralInactivationpH) 128
4.4 Summary 129
Acknowledgments 129
References 129
PartThree: SingleUseTechnologiesandPerfusion
Technologies 131
5 Single-UseBioreactorsforContinuousBioprocessing:Challengesand
Outlook 133
NicoM.G.Oosterhuis
5.1 Introduction 133
5.2 Single-UseReactorTypes 135
5.3 MaterialAspects 136
5.4 Sensors 139
5.5 ReactorDesign 141
5.5.1 MassTransferandMixingRequirementsforContinuous
Processing 141
5.6 Scale-UpAspects 142
5.7 ContinuousSeedTrain 145
5.8 NewMixerDesigns 145
5.9 FutureOutlook 146
References 147
6 TwoMutuallyEnablingTrends:ContinuousBioprocessing
andSingle-UseTechnologies 149
MarcBisschops,MarkSchofield,andJulieGrace
6.1 Introduction 149
6.2 Single-UseTechnologies 150
6.2.1 HistoryofSingle-UseTechnologies 150
6.2.2 Single-UseUpstreamProcessing 151
6.2.3 Single-UseDownstreamProcessing 151
6.2.3.1 TangentialFlowFiltration 151
6.2.3.2 ChromatographySteps 152
6.2.4 EarlySkepticism 152
6.2.5 CurrentTrendsandFuturePredictions 153
6.3 ContinuousBioprocessing 154
6.3.1 ContinuousUpstreamProcessing 154
6.3.2 ContinuousDownstreamProcessing 155
6.3.2.1 TangentialFlowFiltration 156
6.3.2.2 ContinuousChromatography 157
6.3.3 ConcernsforContinuousBioprocessing 158
6.4 IntegratedSingle-UseContinuousBioprocessing:CaseStudies 159
6.4.1 Case1:Genzyme 159
6.4.2 Case2:Merck 160
Contents ix
6.4.3 Case3:BayerTechnologyServices 161
6.4.4 Comparison 162
6.4.5 ChallengesandSolutions 163
6.4.6 AlternativeScenarios 164
6.5 RegulatoryAspects 164
6.6 AdoptionRateofSingle-UseandContinuousBioprocessing 165
6.7 Conclusions 166
References 167
7 PerfusionFormatsandTheirSpecificMediumRequirements 171
JochenB.Sieck,ChristianSchild,andJörgvonHagen
7.1 Introduction 171
7.1.1 HistoryofPerfusion 172
7.1.2 ComebackofPerfusion 172
7.2 CharacterizationofPerfusionProcesses 173
7.2.1 ProductivityofPerfusionProcesses 175
7.2.2 CellRetentionDevices 176
7.2.3 Steady-StateDefinition 176
7.3 PerfusionFormats 177
7.3.1 InnovativePerfusionFormats 178
7.4 DevelopmentStrategiesforPerfusionMedia 179
7.4.1 CellLine-SpecificRequirements 181
7.4.2 Scale-DownModelsforPerfusionProcesses 181
7.4.3 Scale-DownCultivationMethods 182
7.4.4 ExamplesforPerfusionScale-DownApplications 184
7.5 ProcessDevelopmentforPerfusionProcesses 185
7.6 CaseStudy 185
7.6.1 Material&Methods 186
7.6.1.1 SemicontinuousChemostat(SCC) 187
7.6.1.2 RepeatedBatch(RB) 187
7.6.1.3 SemicontinuousPerfusion(SCP) 187
7.6.2 Results 187
7.6.2.1 DeterminationoftheStartingCellDensity 187
7.6.3 Scale-DownModelComparison 188
7.6.4 MediaScreening 189
7.6.5 BioreactorConfirmation 191
7.7 Conclusion 192
Abbreviations 193
References 194
PartFour: ContinuousUpstreamBioprocessing 201
8 UpstreamContinuousProcessDevelopment 203
SanjeevK.Gupta
8.1 Introduction 203
8.2 UpstreamProcessesinBiomanufacturing 205
x Contents
8.2.1 UpstreamOperatingModes 206
8.2.1.1 Fed-BatchProcess 206
8.2.1.2 Continuous/PerfusionProcess 207
8.3 TheUpstreamContinuous/PerfusionProcess 207
8.3.1 UpstreamProcess-TypeSelection 209
8.3.2 ComponentofContinuousUpstreamandDownstream
Processes 209
8.3.2.1 UpstreamComponents:StainlessSteelandSingle-Use(Su) 209
8.3.2.2 DownstreamComponents:StainlessSteelandSingle-Use(Su) 209
8.3.3 CellRetentionDevicesUsedinPerfusionProcess 210
8.3.3.1 SpinFilters 210
8.3.3.2 TheATFSystem 210
8.3.3.3 BiosepAcousticPerfusionSystem 212
8.3.3.4 TFFCellRetentionDevice 213
8.4 ManufacturingScale-UpChallenges 214
8.4.1 ProcessComplexityandControl 214
8.4.2 CellLineStability 215
8.4.3 Validation 215
8.5 Single-UseTechnologies:AParadigmChange 215
8.5.1 ApplicationofSUBsinContinuousProcessing 218
8.5.2 Single-UseContinuousBioproduction 218
8.5.3 Single-UsePerfusionBioreactors 219
8.5.3.1 TypeofSingle-UseBioreactorsforPerfusionCulture 219
8.5.4 Single-UseAccessoriesSupportingPerfusionCulture 220
8.5.4.1 HollowFiberMediaExchange 220
8.5.4.2 ContinuousFlowCentrifugation 220
8.5.4.3 AcousticWaveSeparation 220
8.5.4.4 Spinfilters 220
8.6 FDASupportsContinuousProcessing 221
8.7 MakingtheSwitchfromBatch/Fed-BatchtoContinuous
Processing 222
8.8 CostsandBenefitsofContinuousManufacturing 222
8.9 CostsofAdoption 223
8.10 ContinuousDownstreamProcessing 223
8.11 IntegratedContinuousManufacturing 224
8.12 ConcludingRemark 227
Acknowledgment 228
References 228
9 StudyofCellsintheSteady-StateGrowthSpace 233
StenErm,KristoAbner,AndrusSeiman,KaarelAdamberg,andRaivoVilu
9.1 Introduction 233
9.1.1 OnPhysiologicalStateofCells:Steady-StateGrowthSpace
Analysis 234
9.1.2 ChallengeofComprehensiveQuantitativeSteady-StateGrowthSpace
Analysis(SSGSA) 236
9.1.3 ChemostatCulture–AClassicalToolforSSGSA 236