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This study evaluates Morphologically Directed Raman Spectroscopy (MDRS) for detecting and characterizing VPs in therapeutic protein DPs. MDRS combines morphological and chemical analyses, which are essential for root cause analysis (RCA) during incident investigations of VP formation. We evaluated MDRS using polystyrene (PS) microsphere standards, candidate reference materials from the US National Institute of Standards and Technology (NIST), and stressed therapeutic protein DPs, insulin lispro and rituximab. Using MDRS, VPs were imaged and chemically characterized in insulin or rituximab drug products with varying morphologies and ranged from 100 to 400\u00a0\u03bcm in diameter. The intensity of Raman spectral peaks varied with VP size, transparency, morphological complexity, and between therapeutic protein drug classes. Principal component analysis (PCA) of morphological features (e.g., size, shape, and transparency) revealed that NIST ethylene tetrafluoroethylene (ETFE) particles displayed a range of morphologies, akin to stressed therapeutic protein VPs. 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Certain commercial equipment, instruments, or materials are identified in this manuscript to foster understanding. Such identification does not imply recommendation or endorsement by FDA or the National Institute of Standards and Technology, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose. This work was carried out in part in the NIST Center for Nanoscale Science and Technology NanoFab.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclaimer"}}],"article-number":"42026"}}