The extension of mass spectrometry to late development and QC environments has promised significant advantages for multiplex monitoring critical quality attributes (CQAs) at the molecular level, providing an in-depth understanding of the biotherapeutic production process and facilitating implementation of Quality by Design (QbD) initiatives for upstream and downstream processing, stability, and formulation activities. Here, we demonstrate the applicability of HRMS for multi-attribute monitoring (MAM) at both the peptide and subunit levels, using an HRMS platform capable of operating under the compliance requirements typical to regulated development and QC organizations. Subunit MAM exhibited minimimal sample preparation artifacts, and enabled higher assay throughput, both key advantages in for routine monitoring of domain-specific CQAs. Peptide-map based MAM enables site-specific information and the ability to monitor deamidation and isomerization attributes , but resulted in greater sample preparation complexity, greater data analysis complexity, and longer analysis run times. In this work, we have evaluated and compared these two analytical workflows (Subunit MAM and Peptide Map MAM) to determine the capacity of MS-based methods for monitoring several common classes of biotherapeutic attributes.