Inhomogeneous Distribution of Components in Solid Protein Pharmaceuticals: Origins, Consequences, Analysis, and Resolutions

Abstract

Successful development of stable solid protein formulations usually requires the addition of one or several excipients to achieve optimal stability. In these products, there is a potential risk of an inhomogeneous distribution of the various ingredients, specifically the ratio of protein and stabilizer may vary. Such inhomogeneity can be detrimental for stability but is mostly neglected in literature. In the past, it was challenging to analyze inhomogeneous component distribution, but recent advances in analytical techniques have revealed new options to investigate this phenomenon. This paper aims to review fundamental aspects of the inhomogeneous distribution of components of freeze-dried and spray-dried protein formulations. Four key topics will be presented and discussed, including the sources of component inhomogeneity, its consequences on protein stability, the analytical methods to reveal component inhomogeneity, and possible solutions to prevent or mitigate inhomogeneity.