DETERIORATION OF LYOPHILIZED PHARMACEUTICAL PROTEINS

The successful use of proteins in pharmaceutical and other commercial applications requires close examination of their relative fragility. B ecause of the resultant enhanced stability, proteins are often formula ted in the solid state, even though dehydration tends to alter their s tructure. Even in the solid form, however, proteins may become inactiv ated due to various deleterious processes, e.g., aggregation. This rev iew focuses on such mechanisms, with an emphasis on case studies condu cted in our laboratory. Proteins which have both disulfide bonds and f ree thiols may aggregate via thiol-disulfide exchange, and this proces s may be facilitated by lyophilization-induced structural perturbation s. For proteins possessing disulfides but not free thiols, aggregation also may occur when native disulfides are beta-eliminated, thus givin g rise to thiol species which can catalyze disulfide scrambling. Other deleterious processes have also been uncovered, including a formaldeh yde-mediated aggregation of formalinized vaccines. It is illustrated h ow knowledge of such deterioration pathways makes possible the rationa l development of stable solid protein formulations.