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

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

FDA WorkshopJuly 2003