U.S. PHARMACOPEIA

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PRODUCT FORMULATION
The products of biotechnology are proteins and peptides that are relatively unstable molecules compared to most organic pharmaceuticals. Most biotechnology processes involve the transfer of proteins from one stabilizing or solubilizing buffer to another during the purification process. Ultimately, the protein is exchanged into its final solution dosage form where long-term stability is achieved. In addition, these products often require lyophilization to achieve long-term stability because of the potential for degradation by a variety of mechanisms, including deamidation, aggregation, oxidation, and possible proteolysis by trace levels of host cell proteases. The final dosage form of the protein usually contains stabilizing compounds that result in the optimal pH and solution conditions necessary for long-term product stability and/or the desired properties for administration of the product (tonicity). These compounds include proteins, polyhydric alcohols, amino acids, carbohydrates, bulking agents, inorganic salts, and nonionic surfactants. In addition, these excipients may be required for stable lyophilized cake formation. There are special requirements for lyophilized products, such as the control of moisture levels, that generally are defined in the individual USP monograph and that may be important to product stability. Significantly, the assessment of protein stability usually requires the use of multiple analytical methods, each of which may be used to assess a specific mode of protein degradation. Many of these assays are described in the following section. The use of accelerated stability studies to predict the shelf life of protein formulations is often complicated by the effects of temperature on protein conformation, resulting in non-Arrhenius behavior. Thus, reliance on real-time, recommended storage condition stability studies is often required for establishing the expiration dating of biotechnology-derived products.