ABSTRACT
Relevant stability-indicating assays are developed, and any potential stability issues or formulation challenges are identified. Preformulation studies should also characterize the impurities in the bulk protein as these will affect the stability of the product. For example, presence of a protease, even at very low concentrations, can destabilize the product.8 However, variants (which may result from the manufacturing process) with similar biological activity as the product are considered to be product-related substances rather than impurities. Impurities, when present, may be product related or process related. Process-related impurities may include host cell proteins, culture media components, lipids, polysaccharides, and viruses. These impurities can affect the immunogenicity of the protein as discussed in Chapter 1. Trace levels of deoxyribonucleic acid (DNA) from host cells may also be present and can be quantitated using a DNA hybridization test. The process history and purification history of a protein, such as its exposure to different pH, buffers, and contaminating proteases, may also affect its potency, stability, safety, pharmacokinetics, or immunogenicity and thus should be considered.9 However, a purified protein is not necessarily stable. Although the advances in biotechnology can now provide us with highly purified products, the purified protein may actually be more susceptible to processes such
as shear, agitation, and the like. This is because the purified protein does not have the natural environment that normally contributes to its stability. This environment may sometimes include other proteins, carbohydrates, lipids, or salts that help to stabilize the structure.10
