The melt-extrusion process is currently applied in the pharmaceutical field in the manufacturing of a variety of dosage forms and formulations, including solid dispersions. Though this technology is considered efficient and continuous, there are potential challenges of which, additional thermal degradation of drug substance because heat stress and shear forces are of a primary concern. This paper attempts to understand the impact of thermal and/or mechanical components of the melt-extrusion process on the stability of a thermosensitive drug substance during scale-up. The overall degradation profile of the drug substance was correlated with the various physical changes made to the extruder as well as the process temperature. The results suggested that the degradation profile of a thermosensitive drug substance could be controlled by proper design of screw assemblies and by optimization of screw rotations per minute, process temperature, and feed rate during development and scale-up.