Stability and Sterility of Sucrose-Formulated Recombinant Factor VIII (Kogenate® FS/Bayer) for Use during Continuous Infusion.

Continuous infusion of factor VIII (FVIII) is an alternative treatment approach to bolus dosing for providing hemostatic control in patients with hemophilia A undergoing surgery. Continuous infusion maintains consistent circulating FVIII, thus avoiding wastefully high or dangerously low levels. Potential advantages of continuous infusion include improved protection from excessive bleeding, reduced factor consumption, and easier monitoring. Continuous infusion requires FVIII usage parameters that are typically outside of the tested and approved ranges for the product, including extended time in an aqueous state at room temperature and exposure to a large surface area of tubing. Here we present in vitro data on the stability and sterility of a sucrose-formulated recombinant FVIII product (Kogenate^® FS/Bayer; rFVIII-FS) under conditions comparable to those that would be experienced during the continuous infusion of patients. Three lots for each of 3 vial sizes (250, 500, and 1000 IU) were tested. Twenty vials of each size were reconstituted in Water for Injection, pooled into a 50 mL volume (100, 200, or 400 IU/mL for the 250, 500, and 1000 IU vial sizes, respectively), and aseptically transferred to pump reservoirs. Two mini-pumps were evaluated (WalkMed 350 Ambulatory Infusion Pump and CADD-Legacy PLUS Ambulatory Infusion Pump Model 6500) using a flow rate of 0.6 mL/hr. Reservoir bags containing reconstituted rFVIII-FS, pumps, and tubing were incubated at 30°C and samples were withdrawn to test coagulation activity via one-stage and chromogenic assays after 0.5, 1, 2, 3, 6, 12, 24, and 48 hours. Sample remaining in the reservoir after 48 hours was tested for sterility. The reservoirs and tubing used in this study were made from polyvinyl chloride (PVC), which has a high FVIII adsorption potential. Results for all 1000 IU lots based on the recoveries obtained at the first time point demonstrated >80% activity at the end of the study using both the one-stage and chromogenic assays on both pumps. Results for all 500 IU lots showed similar recoveries (≥80%) for both pumps at study end using the chromogenic assay. However, the one-stage assay gave higher recovery values for the WalkMed pump (>90%) compared to the CADD pump (>75%). Results for all 250 IU lots demonstrated ≥79% activity at the end of the study using both pumps and both assays. All lots passed the sterility test. These findings indicate that rFVIII-FS is stable in both the WalkMed and CADD pumps and that sterility of rFVIII-FS is maintained for at least 48 hours. This suggests that rFVIII-FS is suitable for use in continuous infusion.