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The Application of QbD Concepts toAnalytical Methods- EnablingEfficient, Rapid and EffectiveBioprocess Development.CMC Strategy Forum Europe 2015Copenhagen, DenmarkMay 5, 2015Brian Fahie, Ph.D.Director, Technical DevelopmentBiogen Confidential and Proprietary1
QbD Quality by Design QbD A systematic approach to development that begins withpredefined objectives and emphasizes product and processunderstanding and process control, based on soundscience and quality risk management - ICH Q8(R2) QbD A systematic approach to development that begins withpredefined objectives and emphasizes product and processunderstanding and process control, based on soundscience is good business.Biogen Confidential and Proprietary2
Control Strategy Historically a linear approachWhat goes inWhat goes onWhat comes outBernie OlsenBiogen Confidential and Proprietary3
QbD for Analytical Methods QbD Concepts Applied to Qualification andTransfer of Analytical Methods CMC Strategy Forum, Latin America 2014, Patrick Swann Biogen Targeting Quick but Decisive (QbD) Analytics toSupport Advanced Process Controls CMC Workshop 2015, DIA Kazumi Kobayashi - BiogenBiogen Confidential and Proprietary4
Control Strategy Historically a linear approachWhat goes inWhat goes onWhat comes outBernie OlsenAnalytical MethodsBiogen Confidential and Proprietary5
Control Strategy Historically a linear approachWhat goes inWhat goes onWhat comes outBernie OlsenAnalytical MethodsBiogen Confidential and Proprietary6
Control Strategy Historically a linear approachWhat goes inWhat goes onWhat comes outBernie OlsenAnalytical MethodsBiogen Confidential and Proprietary7
Control Strategy Historically a linear approachWhat goes inWhat goes onWhat comes outBernie OlsenAnalytical MethodsBiogen Confidential and Proprietary8
Control Strategy A QbD approachWhatGoesInWhatComesOutWhatGoesOnThroughout Development, Throughout CommercializationBiogen Confidential and Proprietary9
Process Validation Guidance FDA, 2011Lifecycle Approach Stage 1 – Process Design Process defined during developmentand scale upStage 2 – Process Qualification Process evaluated to determine ifcapable of reproducible commercialmanufacturingStage 3 – Continued Process Verification Ongoing assurance is gained duringroutine productionAnalytical Methods Validated analytical methods are notnecessarily required during product- andprocess-development activities or whenused in characterization studies.New analytical technology andmodifications to existing technology arecontinually being developed and can beused to characterize the process or theproduct.Use of these methods is particularlyappropriate when they reduce risk byproviding greater understanding or controlof product quality.Biogen Confidential and Proprietary10
Process Validation Guidance FDA, 2011Lifecycle Approach Stage 1 – Process Design Process defined during developmentand scale upStage 2 – Process Qualification Process evaluated to determine ifcapable of reproducible commercialmanufacturingStage 3 – Continued Process Verification Ongoing assurance is gained duringroutine productionAnalytical Methods Validated analytical methods are notnecessarily required during product- andprocess-development activities or whenused in characterization studies.New analytical technology andmodifications to existing technology arecontinually being developed and can beused to characterize the process or theproduct.Use of these methods is particularlyappropriate when they reduce risk byproviding greater understanding or controlof product quality.Reducing Risk is Good BusinessBiogen Confidential and Proprietary11
QbD for Analytic Method Development:Enabling and Confirming Good Process andProduct Development and ManufacturingQbDAnalytical atoryEfficiencyEffectivenessAdvanced ProcessControlBiogen Confidential and Proprietary12
QbD for Analytical Methods - Avoiding theStreetlight EffectSome scientific research is shaped by the need to performreplicable measurements. But these measurements do notalways accurately reflect the phenomenon that is beinginvestigated. The term “streetlight effect” is sometimes usedto name this form of observational bias.Biogen Confidential and Proprietary13
QbD for Analytical Methods - Avoiding theStreetlight inutes45.0050.0055.0060.0065.0070.0075.00Biogen Confidential and Proprietary14
QbD for Analytical Methods – We Seldom Knowexactly where to nutes45.0050.0055.0060.0065.0070.0075.00Biogen Confidential and Proprietary15
Protein Glycoform Distribution during ProteinManufacturingQbDAnalytical atoryEfficiencyEffectivenessAdvanced ProcessControlBiogen Confidential and Proprietary16
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Protein Glycoform Distribution during ProteinManufacturing2-AA with Ion-exchange chromatography160.00Increase in degree of glycan 60.00Sialylated 075.00Biogen Confidential and Proprietary18
Protein Glycoform Distribution during ProteinManufacturing2-AA with Ion-exchange chromatography160.00Increase in degree of glycan 60.00Sialylated 075.00Peaks need to be identified and generated.Biogen Confidential and Proprietary19
Protein Glycoform Distribution during ProteinManufacturingQbDAnalytical MethodDevelopmentMass reconstruction of TOF MS: 19.533 to 19.700 min from Sample 10 (std 30d) of Avonex 0Glycoform 4400Mono -Sialylated-Glycoform 1Non-SialylatedQbD Mass Spec:QSTAR (ESI-q-TOF)ProcessDevelopment500(BiNA0)600The interplay betweenAnalytical andProcess QbD.TriNA2Deconvoluted ialylated-1000Di-Sialylated-LC-MS, deconvolutedmassspectrumIntactprotein of proteinanalysis:glycoforms1100(BiNA2) 3Glycoform1200Signal Intensity, cpsMax. 1210.7 cps.22379230562.25e4Mass, amu2342223767234742.30e42.35e42.40e4Mass, amuAdvanced ycan 6Glycan 2Glycan 1500.00BiNA3600.00TriNA3700.00TriLacNA3 5Glycan800.002AAchromatogram,Carbohydrateprofile byenzymaticallyreleasedandAEC with fluorescencedetection (2AA)fluorescencelabeled glycansGlycanBiNA2 3900.00EUFluorescence Intensity1000.00Glycan esBiogen Confidential and Proprietary20
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Glycoform Distribution as a Function of Time.2-AA with Ion-exchange chromatographyGlycan analysis ofharvest samples?Biogen Confidential and Proprietary22
Glycoform Distribution as a Function of Time.LC-MS method vs release 2-AA IEC assayrpLC-MS riNA320022088(BiNA0)300TetraNA2Mass Spec:QSTAR (ESI-q-TOF)400(BiNA3)500Mono -Sialylated-Glycoform 1Non -Sialylated600Glycoform 4TriNA2Deconvoluted 900(BiNA2) 3Glycoform1000Di-Sialylated-LC-MS, deconvolutedmassspectrumIntactprotein of proteinanalysis:glycoforms1100230562.25e4Mass, amu2342223767234742.30e42.35e42.40e4Mass, amuGlycan 2500.00300.00BiNA1400.00200.00100.00TriLacNA3 5Glycan600.00Glycan ile byenzymaticallyreleased andAEC with fluorescencedetection (2AA)fluorescencelabeled glycansTriNA3900.00GlycanBiNA2 31000.00Glycan 41100.00Glycan 1– Measures released and labeled glycans– Need protein purification (multi step process)– Analysis time: 2-3 daysMax. 1210.7 cps.22379BiNA02AA IEC analysis:Mass reconstruction of TOF MS: 19.533 to 19.700 min from Sample 10 (std 30d) of Avonex 2D.1200Signal Intensity, cps Tests whole moleculeApplicable to unpurified sampleAnalysis time: couple of hoursAmenable to full automationEU––––Fluorescence Intensity 0050.0055.0060.0065.0070.0075.0080.00MinutesBiogen Confidential and Proprietary23
QbD for Analytical Methods – Using DifferentMethods, Looking Different PlacesMass reconstruction of TOF MS: 19.533 to 19.700 min from Sample 10 (std 30d) of Avonex 26226702.25e4Mass, 52311022670230562.25e4Mass, amu230562.30e4Mass, e4100.00Glycan 6300.00200.00BiNA3400.00Glycan 4Glycan 2BiNA1500.00TriLacNA3 e Intensity800.002AACarbohydratechromatogram,profile byenzymaticallyreleased andAEC with fluorescencedetection (2AA)fluorescencelabeled glycansGlycan oform5TriNA320022088TetraNA2300(BiNA0)400Glycoform 4Mass Spec:QSTAR (ESI-q-TOF)TriNA2500Mono -Sialylated-Glycoform 16002254322232Mass, amu1000.00Tri-Sialylated-Deconvoluted massspectrum700225241100.00(BiNA2) 3Glycoform800Glycoform(BiNA1)2900Non -SialylatedSignal Intensity, cps1000Di-Sialylated-LC-MS, deconvolutedmassspectrumIntactprotein of proteinanalysis:glycoforms11002.15e42274422399Max. 1210.7 100Glycoform5TriNA320022088TetraNA2300(BiNA3)Mass Spec:QSTAR (ESI-q-TOF)400Glycoform 4TriNA2500Mono -Sialylated-Glycoform 1Non -Sialylated600Tri-Sialylated-Deconvoluted massspectrum700(BiNA2) 3Glycoform800Glycoform(BiNA1)2900(BiNA0)Signal Intensity, cps1000Di-Sialylated-LC-MS, deconvolutedmassspectrumIntactprotein of proteinanalysis:glycoforms1100Mass reconstruction of TOF MS: 19.533 to 19.700 min from Sample 10 (std 30d) of Avonex 2D.Max. 1210.7 atogram,profile byenzymaticallyreleased andAEC with fluorescenceiNA2ensity1000.00can 31100.00Biogen Confidential and Proprietary24
Correlation of rpLC-MS method vs 2AA IEC release assay% Glycoform 3% Glycoform 485343280Y 0.6633X 28.408R2 0.857930Y 0.6962X 2.2635R2 ogen Confidential and Proprietary25
QbD for Analytic Method Development:Enabling and Confirming Good Process andProduct DevelopmentDevelopmentQbDAnalytical MethodDevelopment2AA encyEffectivenessLC/MS MethodBiogen Confidential and Proprietary26
QbD for Analytic Method Development:Enabling and Confirming Good Process andProduct Development and ManufacturingDevelopmentQbDAnalytical acturingAdvanced gen Confidential and Proprietary27
Enables APC during ManufacturingGlycan analysis ofharvest samples byLC/MS2-AA IEC assayWe now know that the process willmeet release specifications!Biogen Confidential and Proprietary28
QbD Enabled APC during ManufacturingDevelopmentQbDAnalytical acturingAdvanced gen Confidential and Proprietary29
APC Enabling QbD during Developmentand Lifecycle ManagementProductQuality &YieldProcessInput Process ControlRobust process designAdvanced process fficiencyEffectivenessAdvancedProcessControlBiogen Confidential and Proprietary30
APC Enabling QbD during Developmentand Lifecycle ManaagementImpact of raw material quality on the glycoform distributionRawMaterialProductQuality &YieldProcessInput Process ControlRobust process designAdvanced process controlGlycan analysis ofharvest samples byLC/MSBiogen Confidential and Proprietary31
APC Enabling QbD during Developmentand Lifecycle ManagementImpact of raw material quality on the glycoform distributionProductQuality &YieldProcessInputRawMaterial DevelopmentQbDAnalytical acturingAdvanced ProcessControlProcess ControlRobust process designAdvanced process controlLaboratoryEfficiencyEffectivenessBiogen Confidential and Proprietary32
Control Strategy A QbD approachWhatGoesInWhatComesOutWhatGoesOnThroughout Development, Throughout CommercializationBiogen Confidential and Proprietary33
The application of QbD concepts toanalytical methods- Enabling efficient,rapid and effective bioprocessdevelopment.DevelopmentQbDAnalytical MethodDevelopmentOr yEfficiencyEffectivenessAdvancedProcess ControlGood Process and Product Development It Starts and Ends with the RightAnalytics!!Biogen Confidential and Proprietary34
Acknowledgements Patrick Swann Ruth Frenkel Kazumi Kobayashi Iva Turyan Li Zhang Zoran Sosic Shiranthi Jayawickreme Evan Guggenheim Tyler Carlage Bassam Nakhle Yelena LyubarskayaBiogen Confidential and Proprietary35
The Application of QbD Concepts to . Rapid and Effective Bioprocess Development. Brian Fahie, Ph.D. Director, Technical Development. CMC Strategy Forum Europe 2015. Copenhagen, Denmark. May 5, 2015 . A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process .
