Accelerating Your API Into the Clinic – Getting GMP Ready

Developing small molecule drugs can be exceptionally challenging. Pharmaceutical companies face high costs, huge attrition rates and considerable risk. Therefore, understanding the pitfalls that can impede early development, and how the associated risks can be effectively managed, will ultimately drive a program to the clinic and commercial success.

Our presentation highlights our work, from early discovery through to candidate1 nomination and early development. We have successfully utilised high quality data to drive our decision-making process, enabling candidate selection with good pharmaceutical properties including potency, solubility and toxicity. Furthermore, we will describe the steps taken during development that enabled a crucial First-In-Human (FIH) clinical studies that focussed on quality and speed. The process development towards a topical pan-Trk inhibitor was carried out on an eight-step synthetic sequence which included the development of a decarboxylative sp2-sp3 cross coupling which had not previously been demonstrated on scale.2 Parameters were explored, balancing the safety aspects with conversion and selectivity. This cross-coupling showed high diastereoselectivity, with the opposite diastereomer not observed. Through this work, identification of all impurities and strategies for their control was also achieved. The route has been reproducibly demonstrated in several GMP campaigns3 on kilogram scale delivering API in >98% purity; as well as a 6-fold increase in overall yield from the initial medicinal chemistry route. Getting a small molecule to phase I clinical trials is a monumental task — and the stakes are high. But success is by no means out of reach. Companies that phase appropriately optimize their synthetic route, prioritize a stable API solid form, and deploy a suite of verified analytical tools will be well on their way to phase I clinical manufacturing success. Most importantly is to start answering those ‘questions’ early to achieve success in the required timeframe.