Tech Transfer And Scale-Up For Custom APIs

The complexity of small molecule APIs is growing rapidly. Many drug substances contain multiple heterocyclic rings and functional groups; they are designed with ever-increasing specificity in mind. While these novel compounds targeting cancer and other diseases enable more and more personalized treatments, they also pose immense challenges from a manufacturing perspective.

Producing most of these molecules requires multiple process steps that involve sophisticated chemistries. A thorough understanding of the pitfalls of these chemistries is necessary for effective implementation at a large scale. Tight control of process conditions ensures acceptable yields and minimizes impurities. These  compounds often have poor solubility in typical reaction solvents and require unique synthetic strategies.

For example, most modern processes employ powerful cross-coupling reactions mediated by precious metal catalysts, for which the controlling factors are often quite subtle. These reactions frequently require development of unique purification protocols for removal of the catalytic metal, as required by the new ICH Q3D Guidelines on elemental impurities. In another common example, amide coupling reactions often must be performed in the presence of highly sensitive substituents while avoiding unwanted side reactions, which again requires development of a specifically tailored process.