RESUMO
Control of process impurities during manufacturing of drug substance is critical to ensure quality and process robustness. During commercial process development for the gefapixant citrate drug substance, several process impurities were found to derive from sulfuryl chloride, an impurity in the raw material, chlorosulfonic acid (CSA). This made controlling the CSA quality essential for commercial production of this drug substance. Various direct analysis methods were evaluated and found unsuitable because of the highly reactive nature and structural similarity of sulfuryl chloride and CSA. Therefore, a robust derivatization reversed-phase high performance liquid chromatography (RP-HPLC) method was developed and validated to accurately quantify sulfuryl chloride in CSA. The derivatization method was utilized to evaluate many CSA batches from different commercial suppliers and to establish a correlation between sulfuryl chloride levels in CSA and the levels of process impurities in downstream materials. The methodology described herein informed the development of setting the specification on sulfuryl chloride for CSA to ensure a robust process for manufacturing high-quality gefapixant citrate drug substance. The derivatization method was successfully validated and transferred to the commercial commodity supplier for release testing of CSA as a raw material for gefapixant citrate commercial campaigns.
