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FDA WorkshopJuly 2003
Protein Delivery from Mechanical Devices
Challenges and Opportunities
Bill Van Antwerp and Poonam Gulati
The Protein Formulation and Testing Group
Medtronic Minimed
FDA WorkshopJuly 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)
FDA WorkshopJuly 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
FDA WorkshopJuly 2003
0
1
2
3
4
5
6
0 4 8 12 16 20 24
Advantages of Continuous Infusion for Protein Drugs
Bolus InjectionContinuous Infusion
Time (hours)
TherapeuticRange
Side EffectsEnzyme ActivationP450 Activation Wasted Drug
14 x CSI
Pla
sma
Dru
g C
on
cen
trat
ion
FDA WorkshopJuly 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
FDA WorkshopJuly 2003
Pump Challenges, Old and New
• Formulation• Chemical Stability• Clearance • Physical Stability• PK/PD Therapeutic Range and
Toxicity (localized site reactions)
FDA WorkshopJuly 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)
FDA WorkshopJuly 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
FDA WorkshopJuly 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
FDA WorkshopJuly 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
FDA WorkshopJuly 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.
FDA WorkshopJuly 2003
Proposed Aggregation Mechanism
P2 2 PSurface P surf Psurf den Partially
Unfolded Intermediate
Psoln. den.PaggI +
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
Pagg
FDA WorkshopJuly 2003
0
100
200
300
400
500
600
700
800
-20 0 20 40 60 80 100
Curve Fit Results to Autocatalytic Model
Time (hr)
Value
734.57m1
1.6383m2
0.00016847m3
4.5331e+05Chisq
0.99755R
FDA WorkshopJuly 2003
Effect of Contact Material onAggregation Rate (Insulin/Tris)
0 50 100 150 2000
50
100
150
Polyethylene
Teflon
Titanium
Glass
Time to Fixed Fluorescence
% s
urv
iva
l
FDA WorkshopJuly 2003
Formulation and DrugSubstance Effects
GLP-1
0 25 50 75 100 125 1500
25
50
75
100
New Drug Substance
Standard Drug Substance
New Drug Low pH
Standard Sub. Low pH
Time to Reach FixedFluorescence
% s
urv
ival
FDA WorkshopJuly 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
FDA WorkshopJuly 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
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