Batch-to-Batch Consistency of SB4 and SB2, Etanercept and Infliximab Biosimilars

Abstract

Background Biosimilars must meet stringent regulatory requirements, both at the time of authorization and during their lifecycle. Yet it has been suggested that divergence in quality attributes over time may lead to clinically meaningful differences between two versions of a biologic. Therefore, this study investigated the batch-to-batch consistency across a range of parameters for released batches of the etanercept biosimilar (SB4) and infliximab biosimilar (SB2). Methods SB4 (Benepali ® ) and SB2 (Flixabi ® ) were both developed by Samsung Bioepis and are manufactured in Europe by Biogen at their facility in Hillerød, Denmark. A total of 120 batches of SB4 and 25 batches of SB2 were assessed for consistency and compliance with specified release parameters, including purity, post-translational glycosylation (SB4 only), protein concentration, and biological activity. Results The protein concentration, purity, tumor necrosis factor-α (TNF-α) binding, and TNF-α neutralization of all batches of SB4 and SB2 were within the strict specification limits set by regulatory agencies, as was the total sialic acid (TSA) content of all batches of SB4. Conclusions Quality attributes of SB4 and SB2 batches showed little variation and were consistently within the rigorous specifications defined by regulatory agencies.As of August 2019, the Biogen Hillerød facility (Denmark) became Fujifilm Diosynth Biotechnologies Denmark ApS, a contract development and manufacturing organization (CDMO) for the manufacture of biosimilars developed by Samsung Bioepis. Key PointsBiosimilars are held to the same rigorous quality standards as any other biologic. SB4 and SB2 biosimilars demonstrated a high degree of batch-to-batch consistency.Quality attributes including purity, percentage of high molecular weight species, tumor necrosis factor-α (TNFα) binding, and TNF-α neutralization remained well within acceptance limits. 2

Type and Extent of Information on (Potentially Critical) Quality Attributes Described in European Public Assessment Reports for Adalimumab Biosimilars

“…Our observations reveal that minor differences in certain QAs between biosimilars and reference biological can occur at the same level of variability between pre-and postmanufacturing change batches of the reference biological [23,35,63], which reassures the biosimilar regulation system. Although EU regulators have focused on describing pCQAs, these critical attributes were not explicitly defined in EPARs.…”

A Systematic Review on Infliximab Biosimilar SB2: From Pre-Clinical Data to Real-World Evidence

“…Five of the identified references reported analytical studies with SB2 [9][10][11][12][13] (eAppendix 2).…”

“…An analysis of 25 different batches of SB2 demonstrated that the purity, protein concentration, TNF-α binding, and TNF-α neutralization capabilities of all batches were within the strict specification limits set by regulatory agencies, demonstrating batch-to-batch consistency [10]. The batch-to-batch consistency of SB2 is further supported by a study analyzing three lots of SB2, reconstituted as per EU Summary of Product Characteristics (SmPC) [36], diluted or undiluted and stored under different conditions (4°C and 25°C) [12].…”

“…In total, five studies characterizing the physicochemical and biological properties of SB2 were identified, two of these studies included head-to-head comparisons with the RP [9,11], one compared RP, SB2 and CT-P13 [13] whilst two comparing different batches of SB2 [10,12] (Supplemental Table 1).…”

Biosimilar-to-Biosimilar Switching: What is the Rationale and Current Experience?

“…At the same time, the authors caution that persistent antibodies to infliximab may be detected at least 1 year after therapy discontinuation, and drug batches could be subtly different (more or less immunogenic). However, considering manufacturers of biosimilars are compelled to vigilantly abide by rigorous quality standards in accordance with regulatory approval specifications, batch-to-batch drifting of the quality attributes of biosimilars is routinely precluded to any extent that is clinically meaningful [ 130 ]. For that reason, the proposed drug batch-to-batch–related limitation suggested in relation to the Fiorina et al, study seems improbable.…”