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Developments in facility design

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  1. 1. Large scale Mammalian plant design from 1980’s to present day <br />Dave Wolton<br />VP manufacturing<br />1<br />
  2. 2. Overview<br /><ul><li>CMC
  3. 3. Development of Large scale Mammalian Monoclonal factories
  4. 4. 1985-1990
  5. 5. 1990-1995
  6. 6. 1995-2006
  7. 7. Present day
  8. 8. Next Generation Factories
  9. 9. Impact of the new design on the rest of the organisation
  10. 10. CMC prototyping of disposable harvest systems
  11. 11. Summary</li></ul>2<br />
  12. 12. CMC Biologics – Overview<br /> Target & Lead ID<br /> Pre-tox<br />Tox<br />Phase I<br /> Phase II <br />Phase III<br />Commercial Production<br />CMC Biologics<br />Contract Manufacturer of Biological Therapeutics utilizing <br />MAMMALIAN & MICROBIAL CELL CULTURE TECHNOLOGIES<br /><ul><li>Cell-line Development – CHEF1™ technology
  13. 13. Upstream/Downstream – process development and manufacture
  14. 14. Analysis, Characterization, Formulation, Quality and Regulatory</li></ul>3<br />
  15. 15. Development of Large scale Mammalian Monoclonal factories <br />Late 80’s<br />4<br />
  16. 16. Late 80’s<br />The dawn of automation<br />Simple semi manual fermentors<br />Validation becoming more involved<br />Containment being actively pursued<br />CIP/SIP systems becoming more complicated<br />Automation seen as reducing <br />Headcount, <br />Turn-round time<br />Operator errors<br />5<br />
  17. 17. Early 90’s<br />6<br />
  18. 18. Early 90’s<br />Some companies begin to realise complex automation systems have drawbacks. <br />They see increasing <br />Headcount<br />Complexity of plant<br />Turn-round times<br />Complexity of investigations (variables)<br />Facility build costs<br />Facility construction times<br />7<br />
  19. 19. Early 90’s<br />Example of early 90’s Bioreactor<br />Additive manifold<br />Air Out<br />Air to headspace<br />Air to sparger<br />Jacket heat exchanger<br />Sample device<br />8<br />
  20. 20. Late 90’s to 2006<br />9<br />
  21. 21. Late 90’s to 2006<br />Some companies start to reduce cost by simplifying.<br />Stainless steel reactors are simplified by reducing numbers of valves/items.<br />Disposables reduce the need for CIP/SIP.<br /> Innovations<br />Tubing welders<br />Lynx valves<br />Pod filters<br />Wave reactors<br />SUM’s<br />10<br />
  22. 22. The fastest CIP? <br />Reduce the number of inlets that need cleaning.<br />How to simplify stainless vessels<br />11<br />
  23. 23. How to simplify stainless vessels<br />Additive manifolds<br />12<br />
  24. 24. How to simplify stainless vessels<br />Air Out<br />13<br />
  25. 25. How to simplify stainless vessels<br />Air To Head Space<br />14<br />
  26. 26. How to simplify stainless vessels<br />Air To Sparger<br />15<br />
  27. 27. How to simplify stainless vessels<br />16<br />Number of sterile boundary elastomers<br />Pre Lynx Modifications<br />Approximately 70<br />Post Lynx modifications<br />Approximately <br />30<br />
  28. 28. Present Day<br />17<br />
  29. 29. Single use bioreactors<br />18<br />
  30. 30. Present day<br />Elan’s plant design breaks new ground (2008).<br />Large scale disposables are widely accepted<br />2000L reactors are launched onto the market (2010)<br />19<br />
  31. 31. Next generation factories<br />20<br />
  32. 32. The Facility – the next generation of plant after élan<br />2g/l monoclonal antibody- fed batch<br />10 x 4,000L batches per month<br />80 cm column, 3 cycles<br /> = 2 x 12,000L stainless plant<br />21<br />
  33. 33. The Facility – The next generation after Élan<br />Foot print Comparison<br />Purification<br />Bioreactors.<br />X<br />X<br />Buffer prep.<br />Media prep.<br />22<br />
  34. 34. The Facility – the next generation of plant after élan<br />How do you make media next to the bioreactor without contaminating the room with powder?<br />23<br />
  35. 35. Contained media mixing – GEA<br />24<br />
  36. 36. Contained media mixing – Hyclone<br />HyclonePowdertainer<br />25<br />
  37. 37. Contained media mixing - Lormac<br />26<br />
  38. 38. Use of Buffer towers in Downstream worked example<br />27<br />
  39. 39. The Facility – the next generation of plant after élan<br />How do you make and store up to 6,000L of buffer and not use large numbers of buffer bags?<br />28<br />
  40. 40. Buffer towers - Prototype<br />Answer<br />By positioning 2,000L buffer towers close to the column and ‘topping up’ from 1,000L single use mixers.<br />Prototype<br />29<br />
  41. 41. Buffer towers - worked example<br />Buffer Modeling<br />Buffer storage in 1000L Buffer hold bags <br />VS<br /> Five 2,000L buffer towers; replaced monthly<br />Buffer b <br />Adsorption chromatography buffer - Max 4,000L<br />Buffer a <br />UltrafiltrationDiafiltration buffer – Max 6,000L<br />30<br />
  42. 42. The Facility – the next generation of plant after élan<br />Buffer b<br />Buffer a<br />31<br />
  43. 43. Waste comparison example<br />32<br />
  44. 44. Impact of the new design on the organisation<br />33<br />
  45. 45. The Facility – the next generation of plant after élan<br />Cell Culture<br />12 technicians – 9:00 to 5:30 – 7 days a week<br />Purification<br />24-36 technicians – 24hr – 7 days a week<br />Buffer - Media<br />0 technicians<br />HR<br />1 manager – 1 admin.<br />QC<br />No change from current factories<br />Maintenance<br />1 HVAC, 1 Utilities, 2 Equipment/Cal<br />Plant Automation<br />0<br />IT<br />3-4, Electronic batch records preferable<br />Stores<br />Same as current factories<br />34<br />
  46. 46. CMC prototyping of disposable harvest systems<br />35<br />
  47. 47. Integrated 500L depth filter system<br />500L<br />36<br />
  48. 48. Integrated 500L depth filter system<br />37<br />
  49. 49. 38<br />Integrated 2000L depth filter system<br />2000L<br />
  50. 50. Integration harvest hollow fibber into concentrated fed batch system<br />Connections for<br /> the harvest <br />hollow fiber<br />39<br />
  51. 51. Summary<br />40<br />
  52. 52. Industry trends and expectations<br />Reduced facility footprint<br />Reduced production costs<br />Decreasedcapitalinvestments<br />More flexibleplantswith faster turnaround time<br />Risk management and mitigation<br />Increasedcontrol over products, processes, timelines<br />Close cooperation, partnership, strategic alliances<br />Culturewith a continuousimprovementsmindset<br />Source: www.contractpharma.com, articleOctober 2010: Biotechnology Trends & Outsourcing, Lou Schmukler and John Korte, Pfizer Global Manufacturing<br />Single use<br />41<br />
  53. 53. What next at CMC……..<br />Installation of <br />2000L disposable <br />Bioreactor/Harvest<br /> capacity <br />in 2011<br />42<br />

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