The Multi-attribute method (MAM) is an LC-MS assay developed for the direct measurement of product and critical quality attribute (pQA and CQA) levels in a biotherapeutic protein. Challenges to developing sensitive and reproducible MAM assays include class-specific analyte loss that biases measurements and limits assay sensitivity and robustness. Specifically, the chelating interaction between “acidic” peptides and metal surfaces inside chromatographic hardware can impact the overall MAM assay quality by causing peak tailing, low recovery, and irreproducible chromatography of metal sensitive peptides. In this study, we demonstrate optimization of a MAM analytical workflow for low level CQA peptides using instrumentation in which the LC fluidic pathway and chromatographic columns are engineered to be inert towards metal-sensitive peptides. This study compared two BioAccord LC-MS System configurations with differing ACQUITY^TM UPLC^TM system and column designs: one equipped with a stainless-steel flow path (conventional system) and one engineered with a hybrid organic/inorganic inert surface (inert system). Both LC systems were used for peptide MAM evaluation coupled to the RDa mass detector. A new study conducted by Birdsall et. al. (J. Chrom B 1179 (2021) 122700), first reported use of an LC system containing this inert flow path and column technology for improved peptide mapping performance, particularly for acidic peptides. Similarly, in this study, the inert LC system improved MAM assay results in terms of 1) increased MS sensitivity and 2) tighter %RSD for relative quantitation measurements of low abundance modified peptides . The data from the inert system also showed reduced peak tailing and baseline resolved deamidated peaks for several peptides, and increased MS sensitivity (2.5X) compared to the conventional LC system. In summary, the inert system and column design directly contributed to improvements for MAM assay robustness, tightened potential acceptance criteria, and achieved these improvements disproportionately for attributes represented by lower intensity peptides.