Strong Technical Foundation is a Start
The complexity of small molecule APIs is growing rapidly. Many drug substances contain multiple heterocyclic rings and functional groups and are designed with ever-increasing specificity in mind. While these novel compounds targeting cancer and other diseases are enabling increasingly personalized treatments, they pose immense challenges from a manufacturing perspective.
Production of most of these molecules requires multiple process steps involving sophisticated chemistries. A thorough understanding of the pitfalls of these chemistries is needed to enable effective implementation at a large scale. Tight control of process conditions is essential to ensure acceptable yields and to minimize impurities. Often, these large compounds have poor solubility in typical reaction solvents and require unique synthetic strategies. For example, most modern processes employ powerful cross-coupling reactions that are 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.