Chapter 11: Particles in Biopharmaceuticals: Causes, Characterization, and Strategy

Biopharmaceutical companies are required to control subvisible and visible particles in their products to ensure a consistent manufacturing process, assess product quality, as well as address potential safety concerns. Subvisible particles cover the size range between 1 and 100 μm, while particles >100 μm are generally considered to be visible [1]. According to USP guidelines, particles are classified into three different categories, namely, extrinsic, intrinsic, and inherent particles [1]. Extrinsic particles are defined as foreign particles unrelated to the manufacturing process, while intrinsic particles arise from the manufacturing process or primary packaging. Inherent particles can result from drug product degradation and can contain proteinaceous and/or other formulation components [2]. These three particle types are associated with different risk profiles, and an appropriate risk and safety assessment must be performed in order to set up an appropriate control strategy. In general, occurrence of extrinsic particles should be eliminated, and intrinsic particle types must be monitored/controlled to minimize their occurrence, while potential inherent particles must be well characterized and their presence justified and monitored/controlled over the product shelf life [3]. Thus, unless otherwise stated, hereafter the main focus will be given to the inherent particle type. In the last few years, more occurrences of inherent particles such as proteinaceous or fatty acid particles have prompted companies to develop more complex and risk-based control systems to control levels of these specific particle types. For this, general safety assessments based on prior knowledge and clinical experience with such inherent particles are required to demonstrate patient safety and guarantee product quality.