Biocatalytic cascade process of islatravir: Analytical and regulatory control strategy of minor enantiomer

Abstract

Commercial process of islatravir (MK-8591, EFdA) utilizes biocatalytic cascade reactions to construct the ribose moiety of the molecule which bears three chiral centers. However, this biocatalytic process also brought analytical challenges where all stereoisomers and process related compounds are controlled in one isolated intermediate, the final drug substance. A chiral LC method was developed to resolve all those compounds from islatravir and its minor enantiomer by thorough column screening and careful optimization. Detail of designing key method validation components such as method linearity, precision and robustness is discussed, and their results were presented. The method was successfully validated to fulfill various expectation from each individual health authority including FDA, EMA, PMDA, and ANVISA.