Presented by Ken Kleinhenz, VP of Regulatory Affairs on Monday, January 24 2011 at the Phaciliate Cell & Gene Therapy Forum

1. Unique Challenges with Autologous Cell Therapies Kenneth K. Kleinhenz Vice President Regulatory Affairs and Quality Assurance Phacilitate Cell & Gene Therapy Forum The Grand Hyatt, Washington, D.C. January 24-26, 2011 1

2. Applicable Regulations (Europe)

4. Individual Member States may have regulations and rules that exceed the EU Directives and Regulations

5. Examples:

6. German Law treats all cells as drugs

7. UK has an HTA authority to regulate cell banks

13. A somatic Cell Therapy 2001/83/EEC

19. The cells or tissues are not intended to be used for the same essential function in the recipient as in the donor.

20. Minimally manipulated allogeneic tissues used homogonously? Regulated?

21. No. Why? Bone Marrow Transplantation

26. Annex I Exemptions

27. US Food and Drug Administration Considerations

28. Key US FDA Regulations 21 CFR 1271.15(b) – you are not required to comply with the requirements of this part if you are an establishment that removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same surgical procedure.

29. Minimally Manipulated Autologous Peripheral Blood Stem Cell Draft Guidance Document -2007 For autologous PBSCs processed at the clinical site, the presence of all the following 5 factors supports the conclusion that the cells are removed and subsequently implanted in the “same surgical procedure” and, therefore, compliance is not required. The cells are autologous and are intended for use for a specific clinical indication The cells are minimally manipulated The device is solely responsible for the production of the autologous cells (i.e., no other manufacturing steps take place outside of the device other than the recovery of the source cells) The cells are used within a short period of time (i.e., they are not stored or shipped) The device and selected cells are only used at the point of care (i.e., cell processing is performed at and by the clinical site where cells are directly administered).

31. The HCT/P in intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent

32. The manufacture of the HCT/P does not involve the combination of the cell or tissue component with a drug or a device, except for a sterilizing, preserving, or storage agent, if the addition of the agent does not raise new clinical safety concerns with respect to the HCT/P, and

34. Is for allogeneic use in a 1st degree or 2nd degree blood relative, or

37. Minimum Manipulation

40. Regulations are Proportional to the Risks

41. Procedure Risks

42. Autologous cells – low risk

43. Non-manipulated cells – low risk

44. Allogeneic cells – higher risk

46. Rinsing Rinsing Matrix Digestion ADRCs Fat mixing with ADRCs Centrifugation Automating and Standardizing An Existing Laboratory / Manual Process 29

47. Not Available in the United States of America

48. Celution Disposables – Closed System 31

49. Disposables mounted onto Device 32

51. Endothelial progenitor cells

52. Other key cell typesAutologous in Same Surgical Procedure 33

53. Defined Population of Regenerative Cells Adipose Tissue Aspiration Liquid fat Fat cells/collagen Washing media Cellpellet Pre / Endothelial 7% Hematopoietic stem cells 2% Adipose Stem Cells 2-5% Fibroblasts 47% Pericyte/ Smooth muscle 2% Other 33% Adipose Derived Regenerative Cells (ADRC)

55. Cell Viability

56. Cell Count

57. Validation

58. CFU-F

59. CD Markers- Flow Cytometry

60. Residual Reagents

61. Cells/g of tissue