Key issues with biosimilars: variability problems

Biosimilars/Research | Posted 30/07/2009 post-comment0 Post your comment

Analytical studies have revealed the extent of heterogeneity of biopharmaceuticals produced by different manufacturing processes around the world. Key differences have been found in the structure, stability, composition, concentration and activity of manufactured erythropoietins (epoetins or EPOs).

Erythopoietin is a 165-amino-acid glycoprotein that stimulates erythropoiesis and erythropoiesis-stimulating agents (ESAs) based on recombinant human erythropoietin have been used successfully for more than 17 years for the treatment of anaemia associated with chronic kidney disease or cancer therapy.


There are a number of first-generation ESAs available in the US and Europe: Epogen (epoetin alfa) and Procrit (epoetin alfa), manufactured by Amgen and currently available in the US; Eprex (epoetin alfa), manufactured by Ortho Biologicals LCC and marketed by Johnson & Johnson, is available outside the US; NeoRecormon (epoetin beta), manufactured by Roche, is available in Europe; Aranesp (darbepoetin alfa), manufactured by Amgen, is available in the US, Europe, Canada and Australia; and Mircera (methoxy polyethyleneglycol-epoetin beta), manufactured by F Hoffmann-La Roche, is available in Europe.


For Eprex, it was shown that it was not structurally identical to Amgen’s Epogen: small differences were found in the hydrodynamic structure, the degree of alfa helicity and the stability of the products. Furthermore, for three non-innovator products of epoetin alfa manufactured in Korea – Eporon (Dong-A Pharmaceutical Company), Espogen (LG Life Sciences) and Epokine (CJ Corporation) – it was shown to differ from Amgen’s Epogen, with variations in the bioactivity, concentration and isoforms of the products.


Also in other studies it was found that, compared to the reference product, non-innovator epoetins differed in composition, did not consistently meet declared specifications and displayed variation between batches. Additional compounds were detected in three of 11 products analysed and additional epoetin isoforms in nine of 11 cases, while bioactivity was higher than specified in four cases and lower in two cases. In addition, few of the clinical studies were competitor-controlled and they were not thorough enough to show equivalent safety and efficacy.


Though these branded non-innovator products are not biosimilars, they illustrate the difficulties facing regulators to ensure the quality and safety of biosimilar products. The variation between products manufactured by different companies underscores the challenge in producing biopharmaceutical proteins to consistent standards.

Source: Huub Schellekens, NDT Plus. 2009;2(Suppl 1):i27-i36.

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