Module 3 - Strategic case studies in practice

Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)

determined to be insignificant based on prior knowledge and risk assessment.

The reaction was expected to follow second-order kinetics according to the equation below:      FOHk dt impurity hydrolysis d 2 _  Where   F refers to the concentration of intermediate F . Through simple experimentation the following graph linking the extent of hydrolysis to time and the water content of intermediate E can be generated:

Hydrolysis Degradation at Reflux

0.60

0.50

2.0% 1.5% 1.0% 0.5% 4.0% 2.0% 1.0% 0.5%

0.40

0.30

0.20

0.10

Hydrolysis Impurity (%) in Intermediate F

0.00

0.0

1.0

2.0

3.0

4.0

5.0

Reflux Time (hours)

Traditional Approach:

In a traditional approach this information would be used to set a proven acceptable range for % water and time that achieves the acceptance criteria for the hydrolysis impurity of 0.30% in intermediate F. This is typically done by setting a target value and maximum such as:

 Dry Intermediate E to a maximum water content of 1.0%;

 Target reflux time of 1 hour and a maximum reflux time of 3 hours.

Enhanced Approach:

The 2 nd order rate equation can be integrated and solved explicitly (Chemical Reaction Engineering, Levenspiel 2 nd Edition, 1972).

  

 X M XM F   



 kt F OH



   

ln

o

2



o

1





F

Where:

  o F

refers to the initial concentration of intermediate F ,

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