Practical approaches to protein formulation development.

Abstract

As is the case with other pharmaceuticals, formulation development is one of the critical steps in developing a protein as a therapeutic product. Development of stable protein formulations may require even more resources and effort than conventional small molecule pharmaceuticals. Proteins typically have more stability issues as a result of their complexity and delicate structural stability. Fortunately, a great deal of research regarding protein stability has been conducted and this information is readily available in the literature (reviewed by Manning et al., 1989; Chen, 1992; Ahern and Manning, 1992a; Ahern and Manning, 1992b; Arakawa et al., 1993; Cleland et al., 1993; Wang and Pearlman, 1993; Pearlman and Wang, 1996; Volkin and Middaugh, 1997). Ultimately, it would be ideal to be able to develop a pure pharmaceutical containing only the native protein. However, it is not practical to have only the native form of a protein in the formulation because the protein must be purified from a complex biological mixture containing a pool of other proteins which includes misfolded, denatured, and degraded forms of the same protein. Furthermore, a major challenge is to maintain the integrity of the purified protein during routine pharmaceutical processing, storage, handling, and delivery to the patient. One could envision achieving this goal by developing a formulation with perfect stability, i.e., no physical and chemical change in the protein. Becauise proteins are complex molecules composed of numerous reactive chemical groups and delicate three-dimensional structures, identifying a set of conditions to keep all components stable is virtually impossible. In general, commercial therapeutic protein formulations are developed under the assumption that some degree of physicochemical changes will occur during storage and handling.