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 Wang and Hansen, 1988; Manning et al., 1989; Chen, 1992; Ahern and Manning, 1992a, 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. Because 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.
Realizing that it is impossible to develop a perfectly stable formulation, especially while meeting an aggressive product development timeline, the main objective then becomes one of maintaining the appropriate safety and efficacy of the product. In order to achieve this objective, it is imperative to understand the broad spectrum of degradation pathways affecting proteins, and to have available equipment and expertise in an extensive repertoire of analytical methods. Formulation development focuses on determining the potential degradation pathways, assessing the significance of each and optimizing variables to minimize the degradation products that are clinically significant.
Regulatory guidelines also are critical elements for guiding formulation development. They provide information about how to conduct studies and obtain useful results for evaluating formulations. The results obtained allow formulation scientists to write an appropriate developmental pharmaceutics section in regulatory filings. The guidelines also help to evaluate the significance of some inevitable degradation products that are produced during manufacturing, shipping and storage. For example, if the degradation products have properties comparable to those of the desired product with respect to activity, efficacy, and safety, they can be classified as product-related substances. This classification is significantly different from considering the degradation product as an impurity when there is not sufficient supporting evidence to justify classification as a product-related substance (Appendix, Regulatory Document 1). Understanding of these practical issues of regulatory requirements is critical for formulation scientists during design, implementation, evaluation and reporting of their studies.
In addition to insight into the scientific and regulatory issues, developing commercial formulations requires a clear understanding of the potential market. For example, indication, patients, method of delivery, frequency of dosing, typical dose requirement, market distribution and other business-related information will provide directions for the design of a successful formulation. Also, it is important to consider the competitiveness of the formulation as compared to other products available in the market.
In this chapter, an overview of critical factors affecting the design of therapeutic protein formulations and a general guide to developing commercially viable dosage forms for protein pharmaceuticals will be discussed. Since the majority of practical issues are not covered very well in the scientific literature, this chapter also includes information from regulatory guidance documents (see Appendix), labels from marketed products and routine industrial experience.