Multi-Attribute Methods for Biotherapeutics: A Decade of Evolution

Over the past decade, the liquid chromatography–mass spectrometry (LC-MS)-based Multi-Attribute Method (MAM) has successfully transitioned from development laboratories into Quality Control (QC) environments. Driven by pharmaceutical Quality by Design (QbD) principles, MAM enables the direct, site-specific monitoring of Critical Quality Attributes (CQAs), effectively replacing multiple conventional profile-based assays. This review chronicles the 11-year evolution of MAM, highlighting key milestones such as the first-in-industry implementation of MAM in QC, FDA’s acceptance of MAM as a replacement for multiple conventional assays, and the establishment of the United States Pharmacopeia (USP) MAM General Chapter <1060>. The article details changes to MAM scope, technological advancements across the MAM workflow, and expanding applications across novel modalities. Substantial progress has been made in new peak detection (NPD) validation with the reduction of false-positive detections and practical validation strategies have been reported. Global implementation still faces logistical challenges related to import testing and worldwide regulatory alignment. Ultimately, end-to-end MAM implementation offers superior specificity, accuracy, and data depth compared to conventional profile-based assays, enabling manufacturers to streamline QC release testing, reduce costs, and consistently deliver high-quality biotherapeutics. This narrative historical review provides a chronological perspective on the evolution and implementation of MAM and is not intended as a systematic or comprehensive critical evaluation of individual MAM technologies.