Impurity Control Strategy of TMS-Triol in the Manufacture Development of Islatravir

The identification, quantification, understanding, and control of impurities in starting materials, intermediates, and substances are crucial during the evaluation of new molecular entities in the clinical development of the pharmaceutical industry. Through process characterization development in islatravir (MK-8591), two impurities from the regulatory starting material, TMS-Triol, were discovered in a late stage that persisted in the product. However, they were not detectable by the gas chromatography (GC) method that the process used. This paper describes the use of orthogonal analytical approaches for impurity investigations, which aim to provide a comprehensive understanding of the impurity profile of a drug substance with a particular emphasis on comprehending the origin and fate of impurities from upstream steps. The understanding serves as a guide for making decisions on process controls and optimizations of the islatravir drug substance. This paper also outlines quality control strategies for the starting material of the islatravir drug substance commercial process. The knowledge gained from these investigations forms a solid foundation for establishing specifications for impurities in regulatory starting materials.