Setting expectations for current and future directions of native mass spectrometry in the biopharmaceutical industry.

Abstract

While native mass spectrometry (native-MS) has been widely explored in academic laboratories, its practical role within biopharmaceutical research remains less clearly defined. In this perspective, we present an industry-driven view of how native-MS is currently applied, where it offers unique advantages over established analytical technologies, and where alternative methods remain more practical for routine characterization. Within biopharma workflows, characterization strategies traditionally rely on orthogonal techniques such as size-exclusion chromatography (SEC), ion-exchange chromatography (IEX), electrophoresis, light scattering, calorimetry, and denaturing liquid chromatography (LC) MS. Native-MS complements these methods by enabling direct assessment of intact molecular assemblies, including monoclonal antibodies (mAbs), multispecific antibodies, antibody-drug conjugates (ADCs), glycoproteins, and protein complexes. Applications include evaluation of higher-order assembly, ligand or cofactor binding, stoichiometry of target complexes, and heterogeneity that may be obscured under denaturing conditions. However, challenges related to throughput, sensitivity, automation, and accessibility have limited widespread adoption in industrial laboratories. Emerging developments, including chromatographic hyphenation, online buffer exchange (OBE), improved automation, and charge-detection MS (CDMS), are beginning to address these constraints. We argue that the future impact of native-MS in biopharma will depend on integrating these technological advances with platformed analytical workflows and software capable of supporting high-throughput characterization across therapeutic pipelines. We hope that the ideas raised in this article spur debate on when, how, and if native-MS would or should see increased adoption.