Identification, Synthesis, and Control Strategy of Process-Related Impurities in the Development and Manufacturing of Bis-Boc-Lisdexamfetamine

The identification, synthesis, and control of process-related impurities in active pharmaceutical ingredient (API) development are critical for regulatory compliance and process optimization. During the manufacturing of Bis-Boc-lisdexamfetamine, five impurities Boc-Lys(H)-D-amphetamine, Boc-lisdexamfetamine, and three diastereomeric Bis-Boc-lisdexamfetamine isomers were detected at an advanced stage. A refined process was developed to effectively minimize these impurities within ICH-specified limits. This study details the analytical strategies used to trace impurity origins, establish process controls, and optimize synthesis. The impurities were synthesized, characterized using spectroscopic techniques (1H, 13C NMR, mass-spectrometry, and IR spectroscopy), and successfully controlled in the final process, ensuring robust impurity management for commercial manufacturing.