Linking Drug Stability to ManufacturingRisk Assessment Approaches

L. E. KirschStability team leader

2

Stability in Design Space

• Manufacturing stability measurements: criteria and uses1. Rationality based on understanding of instability2. Correlates to shelf-life3. Correlates to risk: failure to reach desired shelf-

life without exceeding critical instability target

Post-Manuf.Kinetic Model

Lt

End of

Expiry

Manuf. Design Space Model

L0

D0

Correlation between Shelf-life and Manufacturing-stability Measurements

(preliminary long term stability studies)

Shelf-life estimated fromlinear extrapolation of roomtemperature stability data

1

2

3

4

5

6

0 0.05 0.1 0.15 0.2 0.25 0.3

Ext

rap

ola

ted

Sh

elf-

life

(yea

rs)

D0 + L

0 (mole %)

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 (L0 and D0, mole %)

fail

ure

pro

b

0.00

0.25

0.50

0.75

1.00

.175 .200 .225 .250 .275 .300

D0 + L0

0

1

5

Estimated Stability Risk application of logistical regression model

0.001 0.01 0.1 1 10 100

APIAPIAPI

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MILLINGMILLINGMILLINGMILLINGMILLINGMILLINGMILLINGMILLINGMILLINGMILLINGMILLING

Risk of Shelf-life Failure (%)

Lab Bench Lots Lab Pilot Lots

0.01 0.1 1 10 100

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Risk of Shelf-life Failure (%)

Long-term stability• Objectives

1. Demonstrate relationship between Manufacturing-related stability measurement (MSM: D0 and L0) and shelf-life

2. Demonstrate/validate solid state degradation model

3. Construct definitive “Risk-based” Design Space Models

• Current state– Studies underway