A Manufacturer’s Perspective on Innovations in Biomanufacturing
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A presentation by Abhinav A. Shukla, Ph.D., KBI's Vice President of Process Development & Manufacturing delivered at the IBC’s Biopharmaceutical Development & Production Week, Huntington Beach, CA (2013)
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A Manufacturer’s Perspective on Innovations in Biomanufacturing
- 1. A Manufacturer’s Perspective on Innovations in Biomanufacturing Abhinav A. Shukla, Ph.D. Vice President Process Development & Manufacturing KBI Biopharma, Durham NC IBC’s Biopharmaceutical Development & Production Week, Huntington Beach, CA, 2013
- 2. Incremental vs. Disruptive Changes • Incremental changes improve upon existing technology • Disruptive changes offer a new way of doing things • Both are important drivers of innovation Gottschalk, Brorson & Shukla, Nature Biotechnology, 30(6), 489-491, 2012
- 3. Biopharmaceutical Innovation • ROI on biopharmaceutical products steadily decreasing in the last 30 years • Approaching 8-10% cost of capital levels • Paradigm shifts occur most commonly when there is a driver
- 4. What is driving change in the biopharmaceutical world? • Increased demand for biopharmaceuticals • Both number of products and quantity produced • Biosimilars • Reducing ROI on pharmaceutical investment • Increased competition • Multiple drugs for the same target/indication • Expanding geographies for production • Lower scales for commercial production • Personalized medicine • Higher cell culture titers • Novel proteins and other biologics • PAT & QbD initiatives – maintaining high quality is an ever present constraint
- 5. Increased demand for biopharmaceuticals Larger number of products • > 900 biopharmaceuticals in development for > 100 diseases • > $ 114 billion sales 0 50 100 150 200 250 300 350 PhRMA Biotechnology Report, 2011
- 6. Increased demand for biopharmaceuticals Follow-on biologics • All major markets have biosimilar legislation now • Comparability hurdles are being overcome • Large players are increasingly entering this segment
- 7. Decreasing ROI in pharmaceutical R&D investment • Average Internal Rate of Return on Investment (IRR) 7.5% vs. 12% in the late 1990’s • Heading towards cost of capital 0 2 4 6 8 10 12 14 16 18 20 A B C D E F G H I J K IRR Company Deloitte Thomson Reuters, Fundamental Productivity Challenge in Pharma, 2011
- 8. Increased competition Multiple drugs for the same target/indication Rheumatoid arthritis biologic drugs • Enbrel • Remicade • Humira • Orencia • Simponi • Cimzia • Actemra • Rituxan
- 10. Lower scales for commercial production Higher cell culture titers • Increase in cell culture titers will drive downstream process innovation • Continuous separations & Non-chromatographic separations are growing
- 11. Lower scales for commercial production Personalized medicine • Smaller product volumes • Omics, metabolic profiling and systems biology will all grow personalized therapeutics • Cost of sequencing 1 Mbp of DNA now <$1 instead of $10,000 in 2001
- 12. -Confidential- Novel proteins based on protein engineering Human antibody: Superposition
- 13. QbD/PAT initiatives • Increased emphasis on product safety • Increased emphasis on process understanding • Increased use of statistics in the bioprocess space • Innovations in biosensors & “measure to control” strategies
- 14. Innovations in the biopharmaceutical process & manufacturing space • > 100 fold titer improvement in cell culture since rDNA technology began to be used for biopharmaceutical production • Single-use manufacturing • Increasing dynamic binding capacity (DBC) of chromatographic media • Introduction of parvoviral grade filters & improvement of flux properties of viral filters • Membrane chromatography • Continuous processing in bioprocessing • Cell free protein synthesis • Pseudo affinity separations on non-affinity stationary phases • Non-chromatographic separations • Scale-down process characterization & validation studies as a key component of BLA/MAA filings
- 15. -Confidential- Innovations in the biopharmaceutical process & manufacturing space • > 100 fold titer improvement in cell culture since rDNA technology began to be used for biopharmaceutical production • Single-use manufacturing • Increasing dynamic binding capacity (DBC) of chromatographic media • Introduction of parvoviral grade filters & improvement of flux properties of viral filters • Membrane chromatography • Continuous processing in bioprocessing • Cell free protein synthesis • Pseudo affinity separations on non-affinity stationary phases • Non-chromatographic separations • Scale-down process characterization & validation studies as a key component of BLA/MAA filings
- 16. • 1996: Introduction of the Wave bioreactor • 1998: Introduction of first membrane adsorbers • 2004: First 250 L disposable stirred-tank bioreactor • 2006: First 1,000 L disposable stirred-tank bioreactor • 2009: First 2,000 L disposable stirred-tank bioreactor • Advantages: • Reduced risk of contamination • Reduced need for SIP (Steam in Place) • Reduced need for cleaning validation • Now: • Several manufacturing facilities and production trains with end-to-end disposable technologies • Stainless steel facilities also make significant use of disposables for capacity extension and flexibility • Multiple vendors for each single-use unit operation Disposable Manufacturing
- 17. Why are single-use systems growing? • Lower capital and utility costs (up to 40% reduction*) • Increasing titers driving bioreactor scales smaller • Single-use bioreactors now up to 2000L volume • Increased universalization of biomanufacturing • Co-location of manufacturing with markets • Biosimilars (estimated $ 17 billion market by 2020) • Smaller market sizes for novel drugs in niche/personalized applications • Market fragmentation making large single-product manufacturing facilities redundant • Single-use systems finding application in stainless steel facilities for enhanced operational flexibility Laukel et al, BioProcess International, May 2011 Supplement, pp. 14-21.
- 18. Ever-present need for accelerated early-stage process development & manufacturing
- 19. -Confidential- Media and Feed preparation utilizing disposable mixing, filtration and storage systems Disposable shake flasks or disposable spinner flasks MCB or WCB vial Disposable expansion reactor Disposable seed bioreactor Disposable production bioreactor Disposable fluid path centrifuge Disposable depth filtration system 0,2 µm filter Hold vessels (Bags) Hold vessel (bag) Disposable fluid path purification system Disposable mixing tank 0,2 µm filter Retentate Permeate PD Disposable fluid path purification system Disposable mixing tank 0,2 µm filter BPC Virus filter BPC 0,2 µm filter BPC BPC Sterile bulk fill and sampling bags Buffer preparation utilizing disposable mixing, filtration and storage systems 0,2 µm filter Disposable fluid path UF/DF system Aseptic connection Hold vessel (bag) Hold vessel (bag) Hold vessel (bag) Hold vessel (bag) Hold vessel (bag)
- 20. Process Reproducibility 4 manufacturing runs in Single Use Bioreactors Highly consistent process
- 21. -Confidential- Scalability • 4 different scales • 3L and 15L scales in non-disposable bioreactors • Process performance with different working volumes is also reproducible
- 22. Single-use technologies in downstream processing • Centrifugation (kSep® Systems) • Closed, continuous centrifuge with class VI product contact surfaces • Counteraction of Centrifugal force and fluid flow force • Very low shear • Continuous operation • Reversal of flow direction empties the chamber • Up to 7.2 L/min
- 23. Single-use technologies in downstream processing • Depth filtration: • Harvest depth filters have traditionally been single-use except for their holders • Based on particle entrapment in a fibrous bed • Can be used as the primary cell separation step for smaller cell culture harvest volumes • Millipore – POD® system • Pall - Stax® system • Sartorius – Sartoclear P ® • Cuno – Zeta Plus ® Pall – Stax System Millipore - POD
- 24. Single-use technologies in downstream processing • Chromatography • Membrane adsorbers • Mustang® (Pall), Sartobind® (Sartorius), Chromasorb® (Millipore), Adsept® (Natrix), • Q, S, HIC and salt-tolerant ion-exchange functionalities • Most widely used for trace impurity removal in a flow-through mode (DNA, endotoxin, viral clearance) • Pre-packed chromatography columns • ReadyToProcess (GE Healthcare), Opus (Repligen), GoPure (Life Technologies) • Monoliths • CIM monoliths (BIA Separations), Uno monoliths (Biorad) Up to 20 cm D available
- 25. What is next for single-use systems? • Further expansion of scale (up to 5000L?) • Better systems for integrating unit operations seamlessly • More vendors for downstream single-use technologies (columns, UF/DF) • Improved biosensors for single-use systems • Improved standardization of systems • Extractables studies from vendors • IQ/OQ documentation and system controls from vendors
- 26. -Confidential- Shukla, A., Mostafa, S., Wilson, M., Lange, D. Vertical Integration of Disposables in Biopharmaceutical Drug Substance Manufacturing, Bioprocess International, 10(6), 34-47, 2012. Gottschalk, U., Shukla, A. Single-use disposable technologies for biopharmaceutical manufacturing, Trends in Biotechnology, 31(3), 147-154, 2013.
- 27. How can existing downstream process steps be made more efficient? • Most current chromatographic steps are designed to remove impurities based on differential binding to the stationary phase surface • Conventional wisdom: wash conditions are between binding and elution conditions • Orthogonal approach à disrupt impurity-product interactions Washes that disrupt protein-protein interactions Conventional washes
- 28. Enhancing HCP clearance across Protein A • HCPs form a diverse set of impurities • HCP clearance is a key concern in biopharmaceutical separation processes • Conventional wisdom: use washes with a pH intermediate between load and elution solutions to wash the Protein A column post-loading
- 29. -Confidential- Enhancing HCP clearance across Protein A Washes can be developed to disengage HCPs from the product rather than disrupt product-Protein A ligand interactions 96 11635 9243 34655 935491 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 Null supernatant MAbSelect eluate (load = null supernatant) MAbSelect eluate (load = null supernatant + product) Prosep A eluate (load = null supernatant) Prosep A eluate (load = null supernatant + product) HostCellProteins(ng/mL) Normalized Yield vs. normalized CHOP for a variety of washes on MAbSelect Protein A 0% 20% 40% 60% 80% 100% 120% 140% 0% 20% 40% 60% 80% 100% 120% Yield normalized to control experiment CHOP(ppm)normalizedto controlexperiment Direction of desired trend
- 30. Enhancing HCP clearance across Protein A • Use washes at high pH (pH > 7) to preserve Protein A – mAb interactions • Include chaotropes in washes to disrupt HCP-mAb interactions E v a lu a tio n o f in te rm e d ia te w a s h e s a t p H > 7 .0 0 % 2 0 % 4 0 % 6 0 % 8 0 % 1 0 0 % 1 2 0 % 1 4 0 % 0 % 2 0 % 4 0 % 6 0 % 8 0 % 1 0 0 % 1 2 0 % N o rm a liz e d yie ld % o f c o n tro l NormalizedCHOP (%ofcontrol) Shukla, A. Hinckley, P. Host cell protein clearance during Protein A chromatography - development of an improved column wash step, Biotechnology Progress, 24, 1115-1121, 2008.
- 31. Mixed Mode Chromatography • Takes advantage of more than one type of interaction • Can reduce process steps • Provides enhanced selectivity, “pseudo-affinity” • Several mixed mode resins have recently been developed with: » Increased loading capacities » Higher ionic strength tolerance Mixed Mode GE Healthcare, Capto MMC ligand Ionic interactions Hydrophobic interactions Hydrophobic interactions Ionic interactions GE Healthcare, Capto Adhere ligand
- 32. Log k’ vs Log [NaCl] 0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 2.60 2.80 3.00 3.20 3.40 3.60 Log k' Log [NaCl] Lysozyme pH 7.0 1M urea 5% ethylene glycol 50mM arginine -‐0.40 -‐0.20 0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.50 2.00 2.50 Log k' Log [NaCl] RNase pH 7.0 1M urea 5% ethylene glycol 50mM arginine -‐0.20 0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 2.10 2.30 2.50 2.70 Log k' Log [NaCl] Monoclonal an6body pH 7.0 1M urea 5% ethylene glycol 50mM arginine
- 33. Wash development on mixed mode 0 50 100 150 200 250 300 350 400 450 500 0.0% 20.0% 40.0% 60.0% 80.0% 100.0% HCP (ppm) Recovery Capto MMC HCP Clearance 25mM Tris pH 7.0 (baseline) 25mM Tris pH 7.0, 5% ethylene glycol 25mM Tris pH 7.0, 50mM arginine 25mM Tris pH 7.0, 50mM NaSCN 25mM Tris pH 7.0, 1M urea 25mM Tris pH 7.0, 1M ammonium sulfate 25mM Tris pH 7.0, 0.1M NaCl 25mM Tris pH 7.0, 0.5M ammonium sulfate 25mM Tris pH 7.0, 0.1M NaCl, 1M urea 25mM Tris pH 7.0, 0.1M NaCl, 1M urea, 5% ethylene glycol 25mM Tris pH 7.0, 0.1M NaCl, 1M urea, 5% glycerol • Selective wash strategies can eliminate one chromatographic step in non-mAb processes • Pseudo-affinity separations by combining mixed mode interactions with highly selective mobile phase modulators
- 34. Process Analytical Technology • PAT: “a system for designing, analyzing and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in- process materials and processes, with the goal of ensuring final product quality” FDA Guidance Hou, Y., Jiang, C., Shukla, A., Cramer, S. Improved Process Analytical Technology (PAT) for Protein A chromatography using predictive PCA tools, Biotechnology and Bioengineering, 108(1), 59-68, 2011.
- 35. -Confidential- Innovations in Biopharmaceutical Process Development & Manufacturing “E pluribus unum” Biochemical/Chemical Engineering/Biochemistry/Molecular Biology Pharmaceutical Manufacturing (continuous processing) Statistics (QbD) Materials Science (resins, membranes)
- 36. What does the plant of the future look like? or