In vitro stability of two formulations of recombinant activated factor viia reconstituted in inappropriate solvents or at inappropriate volumes

Abstract

Background: Recombinant activated factor VIIa (rFVIIa) is indicated for on-demand treatment of bleeding and the prevention and treatment of surgical bleeding in patients with hemophilia A or B who have antibodies to coagulation factors VIII or IX. The currently approved single-use formulation of rFVIIa is freeze dried and is stable for up to 3 years when stored at 2°C to 8°C (36°F-46°F). A new formulation has been developed that is stable for up to 2 years when stored at temperatures up to 25°C (77°F). This formulation does not require refrigerated storage and does not have to be brought to room temperature before use. Both formulations must be reconstituted before use. The original formulation is reconstituted with sterile water for injection (SWFI), whereas the new formulation is reconstituted with a solvent containing histidine. Objective: This study examined the stability of the 2 formulations of rFVIIa after being dissolved in inappropriate types or volumes of solvent. Although the new formulation is expected to take the place of the original formulation, inappropriate reconstitution may accidentally occur in the transition period during which both products are available. Methods: A series of in vitro experiments was designed to determine the chemical and physical stability of the 2 formulations under 4 sets of conditions. In part 1, the new formulation was reconstituted with appropriate volumes of inappropriate solvent (SWFI or physiologic saline) and in the appropriate histidine solvent. In part 2, the new formulation was reconstituted in inappropriate volumes of saline, histidine solvent, or a mixture of saline and histidine solvent. In part 3, the original formulation was reconstituted with histidine solvent. In part 4, the new formulation was mixed with the original formulation, each correctly reconstituted but subsequently pooled. Results: The active substance, rFVIIa, remained chemically and physically stable for up to 6 hours of storage at 25°C (77°F) or for up to 24 hours of storage at 5°C (41°F) in the experiments in which an inappropriate type or volume of solvent was used. However, the concentration of rFVIIa stated in the product labeling was not achieved when the product was reconstituted in the incorrect volume of solvent. No changes in rFVIIa concentration, rFVIIa aggregates (dimers, oligomers, or polymers), degradation products, oxidized forms, coagulation activity, clarity, or pH were seen after storage of the reconstituted products. Conclusion: Based on the results of these experiments, the 2 rFVIIa products should be reconstituted using the appropriate solvent at the correct volume.