Biotherapeutic drugs present new analytical challenges to the drug development and quality control process. Unlike traditional small molecule drugs where synthetic choices can be tightly controlled, biotherapeutic drugs rely on the integrity of host cell biosynthetic machinery to manufacture the drug. The host cells themselves also present an issue where the biotherapeutic product can be contaminated with trace amounts of host cell proteins (HCPs). The host cell proteins and errors in cellular biosynthetic machinery present a danger to patients, as if present in significant quantities could result in an immunogenic reaction to the treatment. Here, quantitation of host cell proteins with stable isotope labeling by amino acids in cell culture (SILAC) and a predictive method for identification of gene mistranslation products of a biosimilar have been tested in a bottom-up proteomic workflow. Quantitation with SILAC yields more precise measurement of HCPs than label-free methods, while predicting gene mistranslation products is shown to be possible but not yet comprehensive.