Updated project metadata. In this study, we investigated the benefits of adding high-field asymmetric ion mobility spectrometry (FAIMS) separation prior to data dependent acquisition (DDA) and gas phase fractionation (GPF) prior to data independent acquisition (DIA) LC-MS/MS analysis. Native digestion followed by LC-MS/MS with FAIMS allowed the identification of 221 HCPs among which 158 were reliably quantified for a global amount of 880 ng/mg of NIST mAb Reference Material. Our methods have also been applied to commercial DPs and demonstrate their ability to dig deeper into the HCP landscape with the identification of 60 and 67 HCPs, and accurate quantification of 29 and 31 of these impurities in nivolumab and trastuzumab respectively, with sensitivity down to the sub-ng/mg of mAb level.