Developments in facility design

1. Large scale Mammalian plant design from 1980’s to present day Dave Wolton VP manufacturing 1

3. Development of Large scale Mammalian Monoclonal factories

4. 1985-1990

5. 1990-1995

6. 1995-2006

7. Present day

8. Next Generation Factories

9. Impact of the new design on the rest of the organisation

10. CMC prototyping of disposable harvest systems

11. Summary2

13. Upstream/Downstream – process development and manufacture

14. Analysis, Characterization, Formulation, Quality and Regulatory3

15. Development of Large scale Mammalian Monoclonal factories Late 80’s 4

16. Late 80’s The dawn of automation Simple semi manual fermentors Validation becoming more involved Containment being actively pursued CIP/SIP systems becoming more complicated Automation seen as reducing Headcount, Turn-round time Operator errors 5

17. Early 90’s 6

18. Early 90’s Some companies begin to realise complex automation systems have drawbacks. They see increasing Headcount Complexity of plant Turn-round times Complexity of investigations (variables) Facility build costs Facility construction times 7

19. Early 90’s Example of early 90’s Bioreactor Additive manifold Air Out Air to headspace Air to sparger Jacket heat exchanger Sample device 8

20. Late 90’s to 2006 9

21. Late 90’s to 2006 Some companies start to reduce cost by simplifying. Stainless steel reactors are simplified by reducing numbers of valves/items. Disposables reduce the need for CIP/SIP. Innovations Tubing welders Lynx valves Pod filters Wave reactors SUM’s 10

22. The fastest CIP? Reduce the number of inlets that need cleaning. How to simplify stainless vessels 11

23. How to simplify stainless vessels Additive manifolds 12

24. How to simplify stainless vessels Air Out 13

25. How to simplify stainless vessels Air To Head Space 14

26. How to simplify stainless vessels Air To Sparger 15

27. How to simplify stainless vessels 16 Number of sterile boundary elastomers Pre Lynx Modifications Approximately 70 Post Lynx modifications Approximately 30

28. Present Day 17

29. Single use bioreactors 18

30. Present day Elan’s plant design breaks new ground (2008). Large scale disposables are widely accepted 2000L reactors are launched onto the market (2010) 19

31. Next generation factories 20

32. The Facility – the next generation of plant after élan 2g/l monoclonal antibody- fed batch 10 x 4,000L batches per month 80 cm column, 3 cycles = 2 x 12,000L stainless plant 21

33. The Facility – The next generation after Élan Foot print Comparison Purification Bioreactors. X X Buffer prep. Media prep. 22

34. The Facility – the next generation of plant after élan How do you make media next to the bioreactor without contaminating the room with powder? 23

35. Contained media mixing – GEA 24

36. Contained media mixing – Hyclone HyclonePowdertainer 25

37. Contained media mixing - Lormac 26

38. Use of Buffer towers in Downstream worked example 27

39. The Facility – the next generation of plant after élan How do you make and store up to 6,000L of buffer and not use large numbers of buffer bags? 28

40. Buffer towers - Prototype Answer By positioning 2,000L buffer towers close to the column and ‘topping up’ from 1,000L single use mixers. Prototype 29

41. Buffer towers - worked example Buffer Modeling Buffer storage in 1000L Buffer hold bags VS Five 2,000L buffer towers; replaced monthly Buffer b Adsorption chromatography buffer - Max 4,000L Buffer a UltrafiltrationDiafiltration buffer – Max 6,000L 30

42. The Facility – the next generation of plant after élan Buffer b Buffer a 31

43. Waste comparison example 32

44. Impact of the new design on the organisation 33

45. The Facility – the next generation of plant after élan Cell Culture 12 technicians – 9:00 to 5:30 – 7 days a week Purification 24-36 technicians – 24hr – 7 days a week Buffer - Media 0 technicians HR 1 manager – 1 admin. QC No change from current factories Maintenance 1 HVAC, 1 Utilities, 2 Equipment/Cal Plant Automation 0 IT 3-4, Electronic batch records preferable Stores Same as current factories 34

46. CMC prototyping of disposable harvest systems 35

47. Integrated 500L depth filter system 500L 36

48. Integrated 500L depth filter system 37

49. 38 Integrated 2000L depth filter system 2000L

50. Integration harvest hollow fibber into concentrated fed batch system Connections for the harvest hollow fiber 39

51. Summary 40

52. Industry trends and expectations Reduced facility footprint Reduced production costs Decreasedcapitalinvestments More flexibleplantswith faster turnaround time Risk management and mitigation Increasedcontrol over products, processes, timelines Close cooperation, partnership, strategic alliances Culturewith a continuousimprovementsmindset Source: www.contractpharma.com, articleOctober 2010: Biotechnology Trends & Outsourcing, Lou Schmukler and John Korte, Pfizer Global Manufacturing Single use 41

53. What next at CMC…….. Installation of 2000L disposable Bioreactor/Harvest capacity in 2011 42