Aluminum in Erythropoietin Formulations: Lyophilized versus Liquid Forms

Abstract

Background: Erythropoietin (EPO) formulations may comprise aluminum (Al) as a contaminant. Due to the toxicity of Al in chronic kidney disease patients, possible sources of Al were investigated. Since EPO formulations are stored in container-closure systems made of glass and rubber, and both contain Al, formulation ingredients may enable its leaching into the solution during shelf-life. Methods: Individual solutions of formulation ingredients were stored in new glass vials and in contact with the rubber stopper and kept at 4 ± 2°C. For 12 months, aliquots of each solution were collected for analysis. Fifteen commercial samples of EPO were analyzed for their Al content. Aluminum was determined by atomic absorption spectrometry. Results: Glass and rubber are sources of Al for EPO formulations. Storage assay showed that citrate and phosphate (used as buffers) extracted high amounts of Al from the container/closure parts. The most important difference, however, was found when comparing liquid and lyophilized samples. While in liquid forms the Al level reached 943 μg/L, in lyophilized forms the level did not exceed 20 μg/L. The container system was also confirmed as a source of Al in reconstituted lyophilized samples. Al in reconstituted samples stored in their own vials increased 19-fold in 12 months. Lyophilized powders stored for 2 years in glass vials contained less Al than in 1 month after dissolution. Conclusion: The difference in the Al measured in liquid forms of EPO and in lyophilized powders suggests that the latter would be the best pharmaceutical form for CKD patients.