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Shanghai 2010
Shanghai 2010
Shanghai 2010
Shanghai 2010
Shanghai 2010
Shanghai 2010
Shanghai 2010
Shanghai 2010
Shanghai 2010
Shanghai 2010
Shanghai 2010
Shanghai 2010
Shanghai 2010
Shanghai 2010
Shanghai 2010
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Shanghai 2010

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  1. “The new era of Downstream Processing:From a Bottleneck to a Pacemaker”Platzhalter BildBioManufacturing World Oct. 19 2010Uwe Gottschalk VP Purification Technologies, Sartorius Stedim Biotech
  2. Finally there seems to be a Bottleneck ... 6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan Associates Inc.
  3. Who is facing Limitations? “Obviously there is no downstream bottleneck  if you have unlimited cash” – K. John Morrow, Jr., PhD., 2009
  4. Agenda 1.Improving throughput – 1.Improving throughput – The Capacity Disconnect The Capacity Disconnect 2.Process Economy – Cost 2.Process Economy – Cost of Goods matter of Goods matter 3.Discovering new Shores - 3.Discovering new Shores - Fortune favors the Brave Fortune favors the Brave 4.Benchmarks of the Future 4.Benchmarks of the Future – No best, just better – No best, just better 5.The Future of DSP – 5.The Future of DSP – Revisiting the Past Revisiting the PastData adapted from: F. Wurm Production of recombinant Protein Therapeuticsin Cultivated Mammalian Cells. Nature Biotechnology 22, 1-6 (2004)
  5. Hot Topic: High Titer Processes Improving Titres – MAbs (Bulk API) Titre Improvements 4 Bioreactors 800 Important cost benefits as titres go beyond 1g/L 700 Estimate of CoG based on These diminish as we go 600 standard MAb process for beyond 5g/L bulk drug substance 500 COG ($/g) 400 Beyond 5g/L 300 Downstream cost dominates In this example the plateau 200 is just under $100/g 100 0 Challenge in DSP 0 2 4 6 8 10 12 Bioreactors decrease in size? Titre (g/L) Cope with increased titres 2000L 5000L Need to drive out costs Implications for facility design Results from Biopharm Services Generic MAb cost model Bulk API Direct manufacturing costs A universal cost model for single use systems in biomanufacturing. Andrew Sinclair, BioPharm Services; Berlin Oct. 2007
  6. Agenda 1.Improving throughput – 1.Improving throughput – The Capacity Disconnect The Capacity Disconnect 2.Process Economy – Cost of 2.Process Economy – Cost of Goods matter Goods matter 3.Discovering new Shores - 3.Discovering new Shores - Fortune favors the Brave Fortune favors the Brave 4. Benchmarks of the Future 4. Benchmarks of the Future – No best, just better – No best, just better 5.The Future of DSP – 5.The Future of DSP – Revisiting the Past Revisiting the Past
  7. Challenges of a Modern Downstream Process Technical challenge  Sensitive and technically demanding products require processes with inherent complexity and expensive infrastructure  Need for robust & scalable processes for the entire DSP  Increasing regulatory scrutiny (Comparability!) Financial challenge  Processes are fixed-cost driven (Investment vs Consumables)  Manufacturing costs 15 - 25% of sales price  Costs for DSP up to 75% of manufacturing costs  Cost Balance Benefit for innovative treatments  Biosimilars
  8. Typical COG breakdown by CategoryMAb manufacturing: 6 x 2,000L tanks, 2g/L, 90% utilisation; 211 #/a; 527 kg/yr; invest 172 Mio Euro;142 $/g; Sinclair 2006
  9. Hot Topic: Use of Disposables
  10. J. Zhou BPI Vienna 2008
  11. Agenda 1.Improving throughput – 1.Improving throughput – The Capacity Disconnect The Capacity Disconnect 2.Process Economy – Cost 2.Process Economy – Cost of Goods matter of Goods matter 3.Discovering new Shores - 3.Discovering new Shores - Fortune favors the Brave Fortune favors the Brave 4.Benchmarks of the Future 4.Benchmarks of the Future – No best, just better – No best, just better 5.The Future of DSP – 5.The Future of DSP – Revisiting the Past Revisiting the Past
  12. A Consensus – Value Chain in Bioseparation High Titer Implications: Increasing biomass and contaminant levels Protein A pool volumes and step cost DNA & HCP levels post Capturing Polishing load volumes and conductivity Pathogen clearance as a moving target
  13. Downstream Processing 1980 “If it ain’t broke, don’t fix it” – Bert Lance, 1977
  14. Downstream Processing 2010 “Le mieux est l’ennemi du bien” (better is the enemy of good) – Voltaire, 1772 “没有最好,只有更好” (No best – only better) – Chinese Movie Cliche
  15. Agenda 1.Improving throughput – 1.Improving throughput – The Capacity Disconnect The Capacity Disconnect 2.Process Economy – Cost 2.Process Economy – Cost of Goods matter of Goods matter 3.Discovering new Shores - 3.Discovering new Shores - Fortune favors the Brave Fortune favors the Brave 4.Benchmarks of the Future 4.Benchmarks of the Future – No best, just better – No best, just better 5.The Future of DSP – 5.The Future of DSP – Revisiting the Past Revisiting the Past
  16. Biomass Removal and Early Contaminant Clearance addresses: Increasing biomass and contaminant levels DNA & HCP levels post Capturing • New generation of lenticular filtration media • No Diatomeaceous Earth; Synthetic • Cell removal, clarification & early on contaminant removal
  17. The Vision of a Disposable Chromatography Process Robert van Reis: Future Trends in Bioseparations; Recovery XII, 2006
  18. Process Chromatography: What are the Options? John Curling and Uwe Gottschalk BioPharm Intl. October 2007 U. Gottschalk. Bioseparation in antibody manufacturing: The good, the bad and the ugly. Biotechnol Prog. 2008 May-Jun;24(3):496-503.
  19. Medarex: Non-Protein A based Purification Processes: Scheme Evolution 2 columns + 1 column + 3 columns 1 membrane 2 columns 1 membrane Unprocessed Bulk Unprocessed Bulk Unprocessed Bulk Unprocessed Bulk CEX CEX CEX CEX Chromatography Chromatography Chromatography Chromatography Viral Inactivation Viral Inactivation Viral Inactivation Viral Inactivation AEX AEX Membrane HCIC AEX Membrane Chromatography chromatography Chromatography Chromatography Mixed Mode Mixed Mode Viral Filtration Viral Filtration chromatography chromatography Viral Filtration Viral Filtration Page 26 Alahari 2009
  20. Two Birds – one Stone: Contaminant Precipitation at Pfizer and Medarex addresses: Fig 7a. precipitation based process Fig 7b. TFF based process Contaminant precipitation Protein A pool volumes TFF and step cost DNA & HCP levels post HCP < 1000 ng/mg CEX HCP < 10ng/mg CEX Dilution Capturing Dilution Q Membrane Q Membrane HCP < 1000 ng/mg HCP BDL 2 g/ml 20 g/ml Dilution VF Mix Mode VF Process Scale Precipitation of Precipitation of Process-Derived Impurities in Mammalian Cell Culture Impurities in Non-Protein A Broth; J. Glynn et al. In: Gottschalk U Purification Schemes for MAb; J. Wang (ed) Process-scale Purification of et al. BioPharm Intl. 10/2009, 2-9 Antibodies. Wiley, NY.
  21. Source: 2nd Annual Survey of the Bioprocessing Marketfor Single-Use SolutionsAspen Brook Consulting, 2010
  22. Chromatography Technologies for DSP Polishing (Membranes) • Highly porous structure • Pore size: 3 – 5μm • Convective Flow Capturing/IP (Resins) • Minimal buffer use • Bead size distribution: 15 -160 μm • Average pore size: 15 - 40 nm • Diffusion limited flow • High capacity
  23. Capture Costs: Why bother? Jim Davis, Lonza Economics of Monoclonal Antibody Production: The relationship between upstream titer and downstream costs; IBC San Diego March 2008
  24. Protein A costs are not an issue at large scale with full total capacity utilization 6th Annual Survey of Biopharmaceutical Manufacturing. Eric S. Langer, BioPlan Associates Inc.
  25. Alternatives to Protein A Capture• Product precipitation batch/continuous• Impurity precipitation (followed by non-Protein A process)• Alternative Capturing (Protein A Mimetics, Mixed Mode, CEX)Issues: Selectivity, Scale up, Reproducibility, Comparability
  26. addresses: Protein A pool volumes and step costD. Low BioManufacturing Paris 2007
  27. Alternative Protein A Chromatography Formats:Goal: Intensified Use/Volume Reduction• Simulated Moving Bed (SMB) and related: » Tarpon („single use flow path“) » Novasep » Chromacon » Chromatan » ... ______________________________________________________________________• Expanded Bed Chromatography » DSM/Upfront („single use flow path“)Issues: Complexity, Scale up, Reproducibility, Comparability
  28. Alternative Protein A Formats:Goal: Low Cost – Real Single Use 2000: Oleosin Platform 2005: TMV Nanoparticles 2010: Bio Polyester Platform Polyester Synthase Polyester Granule Immunoabsorbent nanoparticles based on a 100-300 nm tobacco mosaic virus displaying protein ALimitation: Oleosin yields < 1kg/ha S. Werner et al. PNAS 103, 17678 - 17683 Grage, K. and Rehm, B.H.A. (2008) Bioconj. Chemistry, 19(1):254-62.
  29. Convective Media are Part of the Design Space in Polishing ...
  30. Agenda 1.Improving throughput – 1.Improving throughput – The Capacity Disconnect The Capacity Disconnect 2.Process Economy – Cost 2.Process Economy – Cost of Goods matter of Goods matter 3.Discovering new Shores - 3.Discovering new Shores - Fortune favors the Brave Fortune favors the Brave 4.Benchmarks of the Future 4.Benchmarks of the Future – No best, just better – No best, just better 5.The Future of DSP – 5.The Future of DSP – Revisiting the Past Revisiting the Past
  31. The Renaissance of Protein Purification Michelangelo de Lodovico Buonarotti
  32. Old Enabling Technology: Boring but Reliable • Centrifugation • Extraction • Precipitation • Filtration • Crystallization • UV-Inactivation
  33. Thank you!Uwe.Gottschalk@sartorius-stedim.com

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