Preformulation and stability studies of biotherapeutics using DSC

The use of biotherapeutics, such as antibodies and other protein molecules, to treat diseases is a rapidly growing field in the pharmaceutical industry. Biotherapeutics are often required at high concentrations and multiple doses, hence a manufacturer must produce kilogram quantities or more of the protein drug. The manufacturing process for biotherapeutics involves protein expression in thousands of liters of bioreactor medium followed by a purification process using large-scale chromatography columns and filtration systems.

The stability of the protein to process conditions, reversibility of conformational changes, and any propensity to form aggregates depends on factors such as pH and buffer composition. A thorough understanding of these factors is important for the selection of process conditions, formulation and development of analysis methods. Steps in the antibody purification process that could render a protein unstable include low pH elution step from protein A column, low pH hold step for viral inactivation and any stage involving pH and/or ionic strength adjustment, including final formulation.

Differential Scanning Calorimetry (DSC) provides information on the thermal stability of a protein under conditions of different pH and cosolutes, by monitoring thermal transition midpoints, Tm. A higher Tm reflects higher thermal stability, which correlates well with long term stability. This application note describes how Diosynth Biotechnology uses thermal stability data obtained from DSC to characterize the stability of an antibody during initial pH and buffer screening for preformulation development and for optimization of the low pH viral inactivation used in the manufacturing process. Low pH viral inactivation is desirable for protein manufacturing provided it does not cause any decrease in protein stability.

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