Freeze Drying of l -Arginine/Sucrose-Based Protein Formulations, Part I: Influence of Formulation and Arginine Counter Ion on the Critical Formulation Temperature, Product Performance and Protein Stability

The objective of this study was to investigate product performance of freeze dried l-arginine/sucrose-based formulations under variation of excipient weight ratios, l-arginine counter ions and formulation pH as a matrix to stabilize a therapeutic monoclonal antibody (MAb) during freeze drying and shelf life. Protein and placebo formulations were lyophilized at aggressive primary drying conditions and key attributes of the freeze dried solids were correlated to their thermal properties and critical formulation temperature. Stability (physical) during processing and long-term storage of the MAb in different formulations was assessed by SE-HPLC. Thermal properties of the mixtures were greatly affected by the type of l-arginine counter ion. High glass transition temperatures were achieved by adding multivalent acids, whereas the temperature values significantly decreased in the presence of chloride ions. All mixtures were stable during freeze drying, but storage stability varied for the different preparations and counter ions. For l-arginine-based formulations, the protein was most stable in the presence of chloride ion, showing no obvious correlation to estimated global mobility of the glass. Besides drying behavior and thermal properties of the freeze dried solids, the counter ion of l-arginine must be considered relevant for protein shelf life stability