Quality by Design–Based Assessment for Analytical Similarity of Adalimumab Biosimilar HLX03 to Humira®

Abstract

Quality by design (QbD) is an efficient but challenging approach for the development of biosimilar due to the complex relationship among process, quality, and efficacy. Here, the analytical similarity of adalimumab biosimilar HLX03 to Humira® was successfully established following a QbD quality study. Quality target product profile (QTPP) of HLX03 was first generated according to the public available information and initial characterization of 3 batches of Humira®. The critical quality attributes (CQAs) were then identified through risk assessment according to impact of each quality attribute on efficacy and safety. The anticipated range for each CQA was derived from similarity acceptance range and/or the corresponding regulatory guidelines. Finally, a panel of advanced and orthogonal physicochemical and functional tests and comparison of 6 batches of HLX03 and 10 batches of the reference standard demonstrated high similarity of HLX03 to Humira®, except for slightly lower percentage of high mannosylated glycans (%HM) in HLX03 which had no effect on FcγRIII binding and antibody-dependent cell-mediated cytotoxicity (ADCC) activity in human peripheral blood mononuclear cell (PBMC). All above demonstrated the feasibility and efficiency of QbD-based similarity assessment of a biosimilar monoclonal antibody (mAb).

Physicochemical and biological similarity assessment of LBAL, a biosimilar to adalimumab reference product (Humira®)

“…In the ADCC reporter bioassay, LBAL showed a slightly lower ADCC activity than Humira®, and the mean ranges of relative ADCC activity of LBAL (78–93%) were marginally outside the QR of Humira® (80–115%) ( Figure 5 B). In this highly sensitive, artificial test system, the ADCC activity can be much higher than under normal physiological conditions due to overexpression of both FcγRIIIa on surrogate effector cells and tmTNF-α on target cells (Zhang et al 2020 ). In contrast to the ADCC reporter assay, LBAL exhibited similar ADCC activity in an ex vivo ADCC assay using PBMCs ( Figure 5 C), which was thought to be a more appropriate test system, more closely representing in vivo conditions.…”

Pharmacokinetics, safety, and immunogenicity of HLX03, an adalimumab biosimilar, compared with reference biologic in healthy Chinese male volunteers: Results of a randomized, double‐blind, parallel‐controlled, phase 1 study

“…18 In an extensive analytical comparison, HLX03 demonstrated structural and functional similarity to the China (CN)sourced adalimumab product. 19 In vitro, the effective concentration of HLX03 was equivalent to that of adalimumab, with a similar in vitro neutralizing activity. In vivo, HLX03 and adalimumab showed equivalent efficacy in inhibiting the pathology of arthritis in mice:…”

“…The active ingredient, recombinant anti‐TNFα fully human monoclonal antibody, was obtained by designing the gene sequence based on the protein sequence of adalimumab and overexpressed in Chinese hamster ovary cells system through transfection of an expression vector 18 . In an extensive analytical comparison, HLX03 demonstrated structural and functional similarity to the China (CN)‐sourced adalimumab product 19 . In vitro, the effective concentration of HLX03 was equivalent to that of adalimumab, with a similar in vitro neutralizing activity.…”

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

“…Subsequently, a list of pCQAs was defined in a two-step process. First, the pCQAs of adalimumab were identified from scientific publications presenting comparability or biosimilarity studies of adalimumab products, including the reference biological (Humira ® ) and corresponding biosimilars [23][24][25][26][27][28][29][30][31][32]. The publications were selected from an updated search of our previous systematic review [46].…”

“…Some pCQAs apply to all biologicals, but some pCQAs are specific to a biological and information about these may (d)evolve over time as more knowledge of the product and manufacturing process becomes available. The pharmaceutical industry generally defines which QAs are considered pCQAs based on the available information and the manufacturer risk assessment [23][24][25][26][27][28][29][30][31][32]. For biosimilars, the test results of all QAs must remain within the range of variability set by analyzing different batches of the reference biological.…”