Updated project metadata. In this study, we developed powerful and reproducible MS-based analytical workflows coupling optimized and efficient sample preparations, library-free DIA acquisition method and stringent validation criteria. The performances of several preparation protocols and DIA versus classical DDA were evaluated using a series of four commercially available Drug Products. Depending on the selected protocols, the user has access to different information: on the one hand, a deep profiling of tens of identified HCPs, and on the other hand an accurate and reproducible (CV<12%) quantification of major HCPs. Overall, a final global HCP amount of a few tens of ppm in these mAb samples was measured, while reaching a sensitivity down to the sub-ppm level. Thus, this straightforward and robust approach can be intended as a routine quality control for whichever Drug Products’ analysis.