1. FDA Workshop July 2003 Protein Delivery from Mechanical Devices Challenges and Opportunities Bill Van Antwerp and Poonam Gulati The Protein Formulation and Testing Group Medtronic Minimed

2. FDA Workshop July 2003 Why Protein Drugs in Devices Protein/peptide drugs are increasingly important Diabetes (Insulin, Symlin, Exendin, Somatokine) Cancer (Interferon, Monoclonal Antibodies, Vaccines) Cardiovascular Drugs (Natrecor, GPIIB receptor, Protein G receptor) Inflammation (TNF-a, IL1-RA) HIV/AIDS (Somatostatin, T20, T1249, IL-2, Interferon)

3. FDA Workshop July 2003 Why Use Pumps? Proteins and peptides need delivery Poor oral bioavailability Protein denaturation in the digestive system Acid hydrolysis in the stomach Enzymatic degradation Poor adsorption due to size Poor adsorption due to polar/charge distribution

4. FDA Workshop July 2003 0 1 2 3 4 5 6 04812162024 Advantages of Continuous Infusion for Protein Drugs Bolus Injection Continuous Infusion Time (hours) Therapeutic Range Side Effects Enzyme Activation P450 Activation Wasted Drug 14 x CSI Plasma Drug Concentration

5. FDA Workshop July 2003 Parenteral Delivery Today IV administration Subcutaneous injection Continuous Subcutaneous Infusion (Pumps) Continuous Intraperitoneal Infusion Subcutaneous Depot (leuprolide etc) PLGA microspheres PEG attached peptides Microemulsions Intrathecal, Intraparenchymal

6. FDA Workshop July 2003 Pump Challenges, Old and New Formulation Chemical Stability Clearance Physical Stability PK/PD Therapeutic Range and Toxicity (localized site reactions)

7. FDA Workshop July 2003 Regulatory Hurdles Let’s Not Re-invent the Wheel Device Physics Drug Chemistry Drug Packaging Pump/Drug Interactions ( in-vitro ) Drug Physical Stability ( in-vitro )

8. FDA Workshop July 2003 Stability in Pumps Chemical and physical stability can determine clinical efficacy Physical stability is difficult to measure Wide variety of measurements Turbidity Concentration Changes Fluorescence CD/Microcalorimetry/Denaturation Kinetics

9. FDA Workshop July 2003 Chemical Stability Chemical stability is determined by the molecule and by the formulation Relatively simple formulation changes can affect stability Pump chemical stability, in general, is the same as in primary packaging

10. FDA Workshop July 2003 Physical Interactions Protein physical stability in devices Materials of contact Teflon/Titanium/Polyolefin/Silicone Oil Pumping mechanism physics, shear and compliance can lead to denaturation Agitation in device Body temperature storage

11. FDA Workshop July 2003 Physical Interactions with Devices Protein adsorption to the device Protein denaturation after adsorption Partially unfolded intermediates dominate physical stability of protein formulations Protein aggregation on surface Protein aggregation in solution Uversky, V. N. Lee, H. J., Li, J., Fink, A. L. & Lee, S. J. (2001) Stabilization of Partially Folded Conformation During a-Synuclein Oligomerization in Both Purified and Cytosolic Preparations. J. Biol. Chem. 276, 43495-43498.

12. FDA Workshop July 2003 Proposed Aggregation Mechanism P2P2 2 P Surface P surf P surf den Partially Unfolded Intermediate P soln. den. P agg I + autocatalytic P = Protein P surf = surface bound protein P surf den = surface bound denatured protein P soln. den. = denatured protein in solution P agg = Protein aggregates P agg

13. FDA Workshop July 2003 Value 734.57m1 1.6383m2 0.00016847m3 4.5331e+05Chisq 0.99755R

14. FDA Workshop July 2003 Effect of Contact Material on Aggregation Rate (Insulin/Tris) 050100150200 0 50 100 150 Polyethylene Teflon Titanium Glass Time to Fixed Fluorescence % survival

15. FDA Workshop July 2003 Formulation and Drug Substance Effects GLP-1 0255075100125150 0 25 50 75 100 New Drug Substance Standard Drug Substance New Drug Low pH Standard Sub. Low pH Time to Reach Fixed Fluorescence % survival

16. FDA Workshop July 2003 Proteins in Pumps Formulation is the beginning of successful drug delivery Multiple potential interactions between the protein and the pump Control of the material interface is most important Device design and formulation need to work together and be regulated together

17. FDA Workshop July 2003

18. FDA Workshop July 2003 Conclusions Pump/Drug interactions need to be managed and understood Formulation and pump design need to work together Combination product components can be evaluated separately and historical data used for regulatory approval with proper attention to drug/device interactions

19. FDA Workshop July 2003