Reference Standard Calibration Challenges in the Case of Erythropoietin: Impact on Potency and Biosimilarity...

International reference standards have been established as gold standards for several biological products. Use of international units can drive consistency and standardization for biosimilar products across manufacturers. However, our research and development for Retacrit® (epoetin alfa-epbx), the first and only biosimilar FDA approved for all indications of Epogen®/Procrit® (epoetin alfa), showed that use of a compendial reference standard overestimated the potency of both the biosimilar and the originator product. Possible causes are or imprecision in the methods used to assign potency, or differences in the isoform composition between the compendial reference standard and product. Tracing the history of international reference standard potency assignment for erythropoietin provided insight into this issue. An internal product specific reference standard and process for qualifying and maintaining future replacements are recommended. Use of specific activity as compared to percent potency or units/mL was a useful tool and can provide a means to normalize data from multiple methods and samples with differences in labelled activity from various manufacturers.