Abstract
Formation of aggregates and particulates in biopharmaceutical formulation continues to be one of the major quality concerns in biotherapeutics development. The presence of large quantities of aggregates is believed to be one of the causes of unwanted immunogenic responses. Protein particulates can form in a wide range of sizes and shapes. Therefore, a comprehensive characterization of particulates in biologics formulation continues to be challenging. The quantity of small size aggregates (e.g., dimer) in a stable biologics formulation is well controlled using precision analytical techniques (e.g., high-performance liquid chromatography). Particulate in clinical and commercial formulations is monitored using visual inspection and subvisible particulate counting assays. While visual inspection (by human eye or automated systems) is intended to detect particulates (intrinsic and extrinsic) of ~100 μm or larger, the subvisible counting methods cover smaller size ranges down to 10 μm. It is well recognized that research of particulates in the submicron (<1 μm) and low-micron (1–10 μm) ranges may provide important clues to understand the mechanism of particulate formation. The recent years have seen a significant increase in the development of newer technologies for more comprehensive characterization of particulates. This is attributed to increased awareness in this field of research over the past 5 years, stimulated by scholarly articles, commentaries, and robust discussions in various forums. This article provides an overview of emerging detection technologies that provide complementary characterization data encompassing a wider size range of particulates. It also discusses their advantages and limitations in the context of applications in biotherapeutics development.
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Notes
The terms “biologics”, “biopharmaceutical”, and “biotherapeutics” are used interchangeably in this article; whereas “protein” or “protein pharmaceutical” refer to a sub-class of biologics that are protein-based. Also, “particle”, “particulate matter” (PM), and “particulate” are used interchangeably.
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The author thanks Dr. Kevin King for review of the manuscript.
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Das, T.K. Protein Particulate Detection Issues in Biotherapeutics Development—Current Status. AAPS PharmSciTech 13, 732–746 (2012). https://doi.org/10.1208/s12249-012-9793-4
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DOI: https://doi.org/10.1208/s12249-012-9793-4