Module 3 - Strategic case studies in practice

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

10.4

Example 4: Selecting an Appropriate Starting Material

R 1

Step 1

Step 2

Step 3

A

C

D

R 2

R 3

( B )

Step 4

R 1

“ Crude” Drug Substance R 3 R 4 R 1

Step 6

Step 5

Purification

F

E

R 4

R 3

Final Drug Substance

This example illustrates the importance of considering all general principles described in Section 5.1.1 when selecting an appropriate starting material, rather than applying each general principle in isolation. The example is fictional, based on a linear synthesis for a relatively simple molecule, and is not intended to convey any particular meaning in relation to the number of steps. The desired stereochemical configuration in the drug substance results from the synthesis of compound B in Step 1 from a commercially available achiral precursor A and a stereo-selective reagent. A small amount of the opposite enantiomer of compound B is also formed in Step 1. Once formed, both stereochemical configurations persist through the synthetic steps that follow, so the drug substance also contains a small amount of its undesired enantiomer as a specified impurity. In accordance with the principle that manufacturing steps that impact the drug substance impurity profile should normally be included in the manufacturing process described in Section 3.2.S.2.2

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