Preformulation studies as an essential guide to formulation development and manufacture of protein pharmaceuticals

Preformulation generally refers to a process in which a bulk drug material is characterized to a sufficient extent that it can be converted to a pharmaceutically acceptable drug substance. In the case of conventional, small-molecule (nonmacromolecular) pharmaceuticals, this procedure can usually be accomplished to a high degree of scientific rigor. For example, the atomic level structures of these compounds are usually known from a combination of X-ray crystallography, nuclear magnetic resonance (NMR), and mass spectrometry. Furthermore, the sensitivity of modern high-performance chromatography systems coupled to mass spectrometric detectors often permits altered forms of these molecules to be simply detected and identified. Unfortunately, the increased complexity of proteins, arising from a combination of their large size and higher order forms (secondary, tertiary, quaternary) of structure does not yet permit the more straightforward type of analysis utilized for small molecules to be simply applied. Nevertheless, it is still possible to treat proteins primarily as chemical (rather than biological) entities through an understanding of their structure and stability and use of a more complex array of lower resolution methodologies.