Small-molecule API synthesis

The active pharmaceutical ingredient (API) of a small-molecule cancer drug is made by multi-step organic synthesis in glass-lined or stainless steel reactors, starting from key starting materials that are themselves bought from a small number of chemical suppliers. Kinase inhibitors such as imatinib need ten or more steps with chromatography-free purification and tight control of impurities and crystal form; platinum drugs such as cisplatin start from potassium tetrachloroplatinate and are simple but hazardous; some payloads and natural products are semi-synthetic, paclitaxel from 10-deacetylbaccatin III harvested from yew needles and vincristine from Madagascar periwinkle. API makers file a drug master file with the regulator and work under ICH Q7, the GMP guide for active substances.

API manufacture for off-patent oncology drugs is concentrated in India and China, and for many old cytotoxics only two or three plants supply the world. The FDA's 2019 root-cause report on drug shortages found that the market does not reward manufacturing quality or redundancy, so low-margin sterile injectables and their APIs are the drugs that vanish first. When Teva stopped making vincristine in 2019 a single supplier was left for the United States, and childhood leukaemia protocols were rationed until it caught up. Branded companies mostly keep API synthesis for new molecules in-house or with contract makers such as Lonza, WuXi STA (part of WuXi AppTec), Sterling and Thermo Fisher's Patheon, and file the route as part of the CMC section of the marketing application.