QbD is considered an important, fundamental, and integral part of dosage form development. Despite its significance in drug formulations, the knowledge, reference, and guidance for using QbD in analytical science have not been thoroughly documented in the literature. The present study is aimed at bridging the gap between its generated data and the unexplored terrain in formulation science. This study is novel because, for the first time, an exclusive shorter run time UHPLC method for estimating degradation products was developed through the QbD approach, validated, and proved stability indicative. Five degradation impurities were separated and well characterized. Further, the degradation pathway of the anticancer drug nintedanib (NIN) was explored for the first time in the soft gel formulation using tandem quadrupole MS abetted mass identification, and ESI/MS/MS aided structure elucidation was performed. By carefully demonstrating the step-by-step procedure for QbD-based optimization, parameters such as the analytical target profile (ATP) and critical quality attributes (CQAs) were assessed. The risk assessment was performed using failure mode effect analysis (FMEA). Critical method attributes and critical method parameters were identified based on the magnitude of the calculated risk priority number (RPN) value. Designed experiments using 4-factor two-level factorial design monitored three critical quality attributes to arrive at a method operable design space (MODS). The effect of individual method attributes was also analyzed using half-normal and Pareto charts. Control strategies design and RPN values were recalculated based on the DOE output. This RPN value is eventually identified to be significantly smaller and satisfactory within the allowable limit. © 2020 The Authors