Continued improvements in understanding RNA biology have led to significant success in the development of antisense oligonucleotide therapeutics, and several oligonucleotide drugs have now been approved. Manufacturing of oligonucleotides may be associated with the production of impurities. Current methods for quantification of impurities that co-elute with the main drug component rely on manual ion extraction and integration of the characteristic mass signal of each impurity. For certain applications however, especially those involving large sets of samples such as those generated in the optimization of oligonucleotide manufacturing processes, a rapid method that provides semi-quantitative determination of impurity levels would be sufficient. In this work, an automated approach has been developed to rapidly determine the relative amounts of co-eluting impurities in oligonucleotide samples. The most abundant mass in the isotopic distribution is automatically calculated from the impurity formula and used to detect the presence of the impurities. The principles of the approach are described, and representative examples are given. Impurities determined in different manufacturing lots are compared directly, and by principal component analysis. The ability of the method to determine impurity levels across large sample sets is illustrated for an oligonucleotide drug purification study.