Variability of intended copies for etanercept (Enbrel®): Data on multiple batches of seven products

Abstract

Fusion protein and monoclonal antibody-based tumor necrosis factor (TNF) inhibitors represent established treatment options for a range of inflammatory diseases. Regulatory authorities have outlined the structural characterization and clinical assessments necessary to establish biosimilarity of a new biotherapeutic product with the innovator biologic drug. Biologic products that would not meet the minimum World Health Organization's standard for evaluation of similar biotherapeutic products are available in some countries; in some cases relevant data to assess biosimilarity and appropriate regulatory approval pathways are lacking. Batches of seven intended copy (IC) products for etanercept (Enbrel®) were subjected to a subset of test methods used in the routine release and heightened characterization of Enbrel®, to determine key attributes of identity, quality, purity, strength, and activity. While a number of quality attributes of the IC lots tested met the release specifications for Enbrel®, none fell within these limits across all methods performed, and there were no IC lots that satisfied the criteria typically applied by the innovator to support comparability with Enbrel®. Although the consequences of these differences are largely unknown, the potential for unanticipated clinical outcomes should not be overlooked.

Keywords: biosimilar; characterization; comparability; etanercept; intended copy; quality attribute.

Figure 1.

Stacked Tryptic peptide map HPLC profile for single batches of Altebrel™, Qiangke, and Intacept versus Enbrel® RS. (Presence of additional peaks, and absence of expected peaks versus Enbrel® RS). HPLC, high-performance liquid chromatography; RS, reference standard.

Figure 2.

(A) Stacked HIC profiles for single batches of Yisaipu, Etanar®, Etacept, and Qiangke versus Enbrel® RS. (Similarly atypical profiles were obtained for all batches of each product and are not comparable to Enbrel® RS). (B) Stacked SE-HPLC profiles for single batches of Yisaipu, Etanar®, Etacept, and Qiangke versus Enbrel® RS. (Higher levels of aggregate were observed in all batches of each IC). (C) Stacked N-linked oligosaccharide HPLC profiles for Altebrel™, Infinitam, Intacept, and Qiangke versus Enbrel® RS. (Atypical profiles with new N-glycan species observed). (D) Stacked anion exchange HPLC profiles for overall negative charge heterogeneity of Yisaipu, Etanar®, Etacept, Altebrel™, Qiangke, and Intacept. (Shift in overall charge profiles versus Enbrel® RS). AU, absorbance units; HIC, hydrophobic interaction chromatography; HPLC, high-performance liquid chromatography; IC, intended copy; RS, reference standard; SE, size-exclusion.

Figure 3.

Isoelectric focusing gel of multiple intended copies versus Enbrel® RS. Image is a composite of three individual gels assembled for illustrative purposes. White bars indicate isoelectric point range for principal etanercept species. RS, reference standard.