A Practical Review of Technical Barriers and Solutions on Mass Spectrometry-Based Multi-Attribute Method (MAM) in Biotherapeutics

The multi-attribute method (MAM) is a liquid chromatography–mass spectrometry (LC–MS) platform that combines site-specific quantitation of critical quality attributes (CQAs) with non-targeted new peak detection (NPD) in a single workflow, and can consolidate several conventional chromatographic and electrophoretic assays used to control biotherapeutics. More than a decade after the introduction of MAM, the method is widely used for characterization, yet adoption for release and stability testing in current Good Manufacturing Practice (cGMP) quality control (QC) laboratories remains limited, primarily by technical rather than conceptual or regulatory barriers. In this review, we examine method-induced artifacts and their control during sample preparation, the role of automation, chromatographic and mass spectrometric requirements, software-dependent variability, and the parameter setting and false-positive management required for robust NPD. In addition, we summarize applications across the product lifecycle and the regulatory framework for QC implementation. For each barrier, we assess the readiness of the reported solutions for implementation and identify the gaps where further innovation is most needed. Within the literature identified, most barriers have documented solutions, although only a subset have been demonstrated across independent laboratories. This review is intended as a practical reference for laboratories developing, qualifying, or transferring MAM workflows.