1. Linking Drug Stability to Manufacturing Risk Assessment Approaches L. E. Kirsch Stability team leader

2. Stability in Design Space Manufacturing stability measurements: criteria and uses 1.Rationality based on understanding of instability 2.Correlates to shelf-life 3.Correlates to risk: failure to reach desired shelf- life without exceeding critical instability target 2 Post- Manuf. Kinetic Model L t End of Expiry Manuf. Design Space Model L0D0L0D0

3. Correlation between Shelf-life and Manufacturing- stability Measurements (preliminary long term stability studies) Shelf-life estimated from linear extrapolation of room temperature stability data

4. Logistical Regression Model for Stability Risk Assessment Shelf-life = Time to 0.4 % lactam (linear extrapolation of long-term stability data) Stability failure: Shelf-life < Desired target dating (e.g. 2 years) Logistical Regression model: –probability of stability failure as a function of the manufacturing- stability measurements (L 0 and D 0, mole %) failure prob 0.00 0.25 0.50 0.75 1.00.175.200.225.250.275.300 D 0 + L 0 0 1

5. Estimated Stability Risk application of logistical regression model 5 Lab Bench Lots Lab Pilot Lots

6. Long-term stability Objectives 1.Demonstrate relationship between Manufacturing-related stability measurement (MSM: D 0 and L 0 ) and shelf-life 2.Demonstrate/validate solid state degradation model 3.Construct definitive “Risk-based” Design Space Models Current state –Studies underway