A Three-Arm, Tiered Comparability Strategy Bridging Post-Approval Process Changes for an Omalizumab Biosimilar...

Background: Post-approval manufacturing changes for biologics require rigorous comparability assessments to ensure uninterrupted quality and clinical performance. CMAB007 (Aomaishu^®), a China-approved (2023) omalizumab biosimilar, underwent process enhancements-including media optimization and anion-exchange chromatography substitution-yielding a 5-fold increase in production without altering the host cell line. Methods: A novel three-arm tiered strategy was adopted to compare post-change CMAB007, pre-change CMAB007, and reference (Xolair^®) products. Critical quality attributes (CQAs) were classified into tiers based on risk impact, with tier-specific acceptance criteria. Comprehensive analytics assessed structure, post-translational modifications, purity/impurities, activity, and Fc-mediated functions. Forced degradation (lyophilized/reconstituted states) and accelerated stability studies were evaluated. Based on the high degree of CMC similarity and to prevent "biological drift", the pharmacokinetic (PK) and safety comparability of the post-change CMAB007 versus the reference product (Xolair^®) was confirmed in a randomized, double-blind, two-arm study in healthy males (N = 114; single 150 mg subcutaneous administration). The pre-change product was not included in this clinical PK study. Results: Post-change CMAB007 exhibited analytical similarity within tiered acceptance criteria for all CQAs. Stability studies confirmed enhanced robustness under stress conditions. PK equivalence was demonstrated for AUC_0-inf (GMR: 99.82%; 90% CI: 91.46~108.94%), AUC_0-t (99.54%; 91.40~108.41%), and C_max (101.88%; 95.21~109.01%). Immunogenicity (ADA incidence: 10.5% vs. 12.5%, p = 0.742) and safety profiles were comparable. Conclusions: This study pioneers a tiered three-arm comparability strategy for post-approval changes, integrating advanced analytics, risk-based quality assessment, and clinical validation. The approach mitigates "biological drift" risks, ensuring biosimilar quality, efficacy, and safety while enabling sustainable production scalability.