1 / 32

Simplicity is the key Continuous purification of monoclonal antibodies L. Landric-Burtin

Simplicity is the key Continuous purification of monoclonal antibodies L. Landric-Burtin Head of Downstream Processing Development, France Integrated Continuous Biomanufacturing Conference, Barcelona, 2013. mAbs manufacturing processes have reached a good level of maturity.

conlan
Download Presentation

Simplicity is the key Continuous purification of monoclonal antibodies L. Landric-Burtin

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Simplicity is the key Continuous purification of monoclonal antibodies L. Landric-Burtin Head of Downstream Processing Development, France Integrated Continuous BiomanufacturingConference, Barcelona, 2013

  2. mAbsmanufacturingprocesses have reached a good level of maturity Experience Cell line platforms High titers in cell culture Purification platforms Single use QbD Capacity ≥ Demand

  3. But ourmanufacturingprocesses are still.. LONG ! EXPENSIVE ! COMPLEX !

  4. COMPLEX. OPERATOR INTERVENTION Equilibration buffer #1 Equilibration buffer #2 Wash buffer #1 Wash buffer #2 OPERATOR INTERVENTION Elution buffer #1 Elution buffer #2 HOLD TIME HOLD TIME pH, concentration adjustment, sampling OPEN PHASE OPEN PHASE Sampling & Storage Sampling & Storage OPEN PHASE BulkHarvest 0.2 µm filtration 0.2 µm filtration Protein A Chrom2 LowpH & Neutralization OPERATOR INTERVENTION Equilibration buffer #3 OPERATOR INTERVENTION OPERATOR INTERVENTION HOLD TIME Wash buffer #3 HOLD TIME OPEN PHASE Sampling & Storage Sampling & Storage OPEN PHASE OPEN PHASE pH, conductivityadjustment Nanofiltration TFF & storage Chrom3 ≥ 7 different buffers 7 consecutives, discontinuedsteps (12 incl. storage) Contaminations, Humanerrors

  5. LONG, DISCONTINUED. Around 50 hr to completethe purification process Processing time (hr) « n » stepcannotstartbeforecompletion of « n-1 » Interruption betweensteps for concentration, pH or conductivityadjustement and storage.

  6. EXPENSIVE. • ≥ 100 €/gr • Chromatographyresin = 30 to 75 % of DSP costs.

  7. COMPLEX, LONG, EXPENSIVE... Any solution ?

  8. SIMPLIFY, SIMPLIFY, SIMPLIFY. → SIMPLICITY is key to get a quick, reliable and cheap process.

  9. Simplicity • & • Purification of Mabs?

  10. Let’s go back to the essentials Equilibration buffer #1 Equilibration buffer #2 Wash buffer #1 Wash buffer #2 Elution buffer #2 Elution buffer #1 pH, concentration adjustment, sampling Sampling & Storage Sampling & Storage BulkHarvest 0.2 µm filtration 0.2 µm filtration Protein A Chrom2 LowpH & Neutralization Equilibration buffer #3 Wash buffer #3 Sampling & Storage Sampling & Storage pH, conductivityadjustment TFF & storage Nanofiltration Chrom3

  11. Simplicitymeans NO inter-step ADJUSTMENT. →Wehave selectedresinsthatafford no inter-stepadjustment.

  12. Simplicitymeans FEW BUFFERS. →We have imagined a buffer strategycomposed of only 3 components for the entireprocess.

  13. Simplicitymeans FEW BUFFERS. →4 buffers in total, ensuring pH and conductivity compatibility between all steps.

  14. How simplicity looks like.

  15. SIMPLE. BulkHarvest Equilibration buffer #1 Wash buffer #1 Elution buffer #1 Equilibration buffer #1 Elution buffer #2 Wash buffer #1 Sampling & Storage Low pH TFF & storage Nanofiltration Protein A AEX Mixed mode • 4 different buffers • 6 steps (7 incl. storage), 4 beingcontinuous.

  16. Can a simplifiedprocessmakethe job ? Endotoxins < 0.05 EU/mLalong the process Overallyield ≥ 90 %

  17. Can a simplifiedprocessbe a platform ? Project 2 Yield : 89% Isoelectric point Project 4 Yield : 94% Project 3 Yield : 92% Project 1 Yield : 93% Project 5 Yield : 86% → Successfullyevaluated on 5 differentprojectswithoutoptimization.

  18. Simplicity advantages

  19. SIMPLIFIED PROCESS GAINS → reducedourprocess time: 2X higherper-hourproductivity. • → reducednumberof buffers: • 30 % costsaving on buffers.

  20. SIMPLIFIED PROCESS GAINS • →Continuous manufacturing with no human handling. • Reducedrisk of contamination • Reducedsampling plan • Reducedstorageneeds • Possibility to run the process in a multicycle mode.

  21. SIMPLE. BulkHarvest Equilibration buffer #1 Wash buffer #1 Elution buffer #1 Equilibration buffer #1 Elution buffer #2 Wash buffer #1 Sampling & Storage Low pH TFF & storage Nanofiltration Protein A AEX Mixed mode • 4 different buffers • 6 steps (7 incl. storage), 4 beingcontinuous.

  22. SIMPLE, SMALL and AUTOMATED. BulkHarvest Equilibration buffer #1 Wash buffer #1 Elution buffer #1 Equilibration buffer #2 Elution buffer #2 Sampling & Storage Wash buffer #1 Run X Run 3 Run 2 Run 1 Low pH Mixed mode Protein A AEX TFF & storage Nanofiltration →We have automated the process to runit in multi cycles withsmallcolumns.

  23. ASAP process gains. • 66% of resin volume saved for an equivalent batch duration. • Up to 97% for > duration. • Perfectapplication for disposablecolumns. • No packing • Full use of resinlifetime • No storage Continuous Multi-cycling Batch Mode

  24. SIMPLE, SMALL and CHEAP. • Smallersystems and facilities. • Limited staff requested. Batch Mode Continuous Multi-cycling

  25. SIMPLE, SMALL and PRODUCTIVE 14.1 L resin, 4 cycles prot A, (24 hr* to 72h duration) Productivity : 2.7 g/L/hr* 1 m3 BulkHarvest (*):with shift work 1.2 L resin - 47 cycles - 71 hrsduration Productivity : 10.5 g/L/hr

  26. SIMPLE and ADAPTATIVE → Adaptyourcolumn size to yourrequirements Processing time 50 hr X hr High productneeds, facilityconstraints: → Bigcolumns to processrapidely one batch Batch cost 0 << 100€/g ~100€/g Costconstraint: → Small columns to decreaseresincosts and optimizeresinlifetime

  27. CASE STUDY:Continuous purification atlabscale 70 L of buffers 50 or 100 mLresin volume 43 L of supernatant

  28. CASE STUDY:Continuous purification atlabscale • 43 L of supernatantfullypurifiedcontinuously in 69h : • 45 runsperformedautomatically. • 67g of purifiedmAbcollected • 93% yield

  29. SCALE UP and GMP complianceevaluation (On-going) • 500 L batch • Final target : > 1Kg of purifiedmAb • Column < 10L • < 10 runswith a final duration of 16h

  30. CONCLUSION • →If youseekfor quick, reliable and cheap process, get the superfluous off yourprocess. • → Startingfromthis perspective, we have designed • a simplified purification platform, • able to runcontinuously, • with 4 foldincrease in productivity • significant gain on resincost.

  31. and excellent staff • Simplicity is the key • Continuous purification of monoclonal antibodies Specialthanks to: Benoit MOTHES Didier DUTHE Céline HEMET

More Related