In the current study, we are presenting a fast separation method for mAb fragments rituximab, trastuzumab, infliximab, and bevacizumab using a novel supermacroporous reversed phase (SMP RP) column. The mAb fragments were then generated by subsequent DTT reduction, papain digestion, or IdeS protease digestion. Baseline separation of light chain and heavy chain, Fc and Fab fragments, scFc and F(ab’)2 was achieved in all cases using a 10-min gradient with water/acetonitrile/FA/TFA mobile phases. Using an orbitrap mass spectrometer accurate masses of mAb fragments were measured and the presence of oxidation variants was detected. The fast LC/MS approach described here can be generally applicable to mAb variant characterization.