(367c) Moving to a Chromatography-Free Synthesis: Establishing Product-Related and Polymeric Impurity Control Strategy during Process Development

The process to make an active pharmaceutical ingredient (API) evolves as a project advances through clinical stages, requiring project teams to implement innovative control strategies throughout drug development to maintain API quality. An enabling process is typically used to generate small quantities of API quickly for early clinical trials, yet these enabling processes typically are not optimized and in some cases rely on costly chromatographic purifications to ensure the API meets quality requirements. As processes evolve and maturate, a common goal among project teams is to improve the overall process efficiency and scalability (e.g. obviate the need for chromatography) while producing high-quality API.

In this presentation, we highlight the evolution of the control strategy employed for a complex small molecule API as it transitioned from an early-stage enabling process to a more commercially viable process. As part of this process development, a new synthetic route was implemented; we chose to use the penultimate step as the synthetic quality gatekeeper to mitigate any risk to the final API quality. There were substantial challenges to achieve comparable purity of the penultimate between the enabling and desired process. While the penultimate step of the enabling process consisted of simple nucleophilic deprotections using chromatographed input, the penultimate step of the intended long-term process consisted of a complex telescoped reaction (intramolecular phosphoramidate cyclization + 2 nucleophilic deprotections) with substantially less pure inputs. In an attempt to move away from chromatographic purifications, we designed and implemented a two-drop crystallization procedure to remove product-related impurities, obtaining solids with > 99 LCAP. Despite high purity, the potency was low due to impurities generated from the polymerization of a by-product of the cyclization reaction. Controlling these oligomers and polymers required two mitigations: extractive work-up to remove the precursor monomer and recrystallization to remove the polymer. Through this process development, we have realized the targets of a commercially viable process by increasing the overall yield 10-fold, reducing our process mass intensity (PMI) by 98%, removing all chromatographic purifications, and, critically, maintaining API quality requirements.