Visible and Subvisible Protein Particle Inspection Within a QbD-Based Strategy

In spite of significant progress in many analytical technologies, nondestructive particle characterization remains a challenge. Guidance on foreign particle matter in conventional therapeutics dates back many years in contrast to protein aggregate particles present in the relatively recent biotechnology protein therapeutic products. In this chapter the focus will be on protein aggregates that manifest themselves as both visible and subvisible particles. Protein aggregation is undesired and when unavoidable must be controlled. This requires the ability to characterize this attribute, ideally by size and number and its distribution amongst a manufactured drug product lot as a function of time. Once quantitation is available, in-process controls can be established to ensure that those aggregation levels observed in the manufacture of clinical materials are not exceeded in the commercial product during its shelf life.