Open-tubular CEC and non-aqueous CE (NACE) methods were developed for the analysis of six pharmaceutical compounds and their respective process-related impurities, comprising 22 analytes in total with a range of functional groups and lipophilicities. These methods were assessed for orthogonality of analyte separation with respect to existing CZE-ESI-MS and HPLC-ESI-MS methods, in order to complement a generic analytical strategy for impurity profiling of pharmaceutical compounds. Open-tubular CEC, using etched and chemically modified capillaries, induced weak reversed-phase-type interactions between some of the analytes and the bonded phases (0.811 < k(app) < 0.996). However, the separations were primarily influenced by electrophoretic mobility rather than chromatographic retention, and hence no significant change in selectivity compared with CZE was observed. NACE optimum separating conditions were 10 mM ammonium acetate 100 mM acetic acid in methanol far UV acetonitrile (1/1 v/v ratio). The ion-pair reagents triethylamine or dimethylhexylamine did not induce further changes in selectivity, but tridecafluoroheptanoic acid significantly modified the electrophoretic mobility of bases. The results indicate that one of three generic CZE methods previously reported should be replaced by NACE, due to its improved separation capabilities. The NACE-ESI-MS method complements the two CZE-ESI-MS and the four HPLC-ESI-MS methods recommended in a previous publication; these together form the basis of a generic approach to impurity profiling of pharmaceutical compounds.