Japanese Study Provides Postapproval Insights Into Biosimilar Quality Attributes

Japan’s slow uptake of therapeutic monoclonal antibody (mAb) biosimilars—despite more than a decade of regulatory approval—has led researchers to examine whether quality concerns are a factor.1 In a recent study, scientists analyzed the quality characteristics of biosimilar mAbs and their reference products approved in Japan, assessing multiple product lots to measure variation and lot-to-lot consistency.2 The findings aimed to inform clinically acceptable quality ranges and strengthen public confidence in biosimilars.

Biosimilars are cost-effective alternatives to reference biologics that match their efficacy and safety but differ in cell lines and manufacturing processes. Japan’s Ministry for Health, Labour, and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) introduced biosimilar guidelines in 2009, modeled on the European Union’s similarity concept.3 While 35 biosimilars have been approved since then, adoption of mAbs has lagged, with 2020 replacement rates at roughly 70% for rituximab, 40% for etanercept, and just 20% for infliximab—figures experts attribute partly to limited awareness of biosimilar quality and clinical evidence for certain indications.2

The study examined reference products and biosimilars for infliximab, trastuzumab, rituximab, bevacizumab, and etanercept, purchased between 2019 and 2022. Key quality attributes measured included glycosylation profiles, charge heterogeneity, binding affinities to antigens and Fcγ receptors, high-molecular-weight species, and subvisible particles. Higher-order structures were also assessed. Similarity was evaluated against quality ranges defined by the reference product's standard deviation. Patient demographic information was not part of this product-focused characterization study.

The study confirmed that the degree of similarity in quality attributes varied for each biosimilar product when compared to its reference. Significant differences in overall glycan profiles were noted, particularly for infliximab, where different cell substrates influenced glycosylation. Some biosimilars (eg, specific infliximab, trastuzumab, rituximab, bevacizumab, and etanercept products) showed glycan content outside the reference product's quality range. Similarly, charge heterogeneity differed, with infliximab biosimilars exhibiting notable variations in basic variants. While lot-to-lot variation was present, no clear upward or downward drifts were observed among lots.

Regarding biological activities, no biosimilar products exhibited binding affinities to antigens outside the reference product's quality ranges. Differences in FcγRIIIa binding affinity correlated with glycosylation variations; for instance, certain infliximab and rituximab biosimilars had lower FcγRIIIa 158F affinity, while etanercept biosimilars showed higher affinity.

In terms of aggregation, some biosimilars had higher high-molecular-weight species content, but no products exceeded pharmacopoeial acceptance criteria for subvisible particles. Crucially, despite variations in glycan and charge profiles, all biosimilar products demonstrated similar higher-order structures to their corresponding reference products.

Researchers concluded that the observed quality differences, often consistent with prior regulatory review reports, were not considered to impact efficacy or safety at the time of approval. The absence of significant post-marketing adverse events for these products further suggests these observed ranges are clinically acceptable. The study underscores the importance of ongoing monitoring of quality attributes throughout a product's lifecycle to ensure continued safety and efficacy. This comprehensive post-approval analysis offers valuable information for healthcare providers, fostering a deeper understanding of biosimilar quality and supporting their continued integration into patient care.

References

1. Avhad VR, Patil SB. A comparison of US, Europe, Japan and India biosimilar regulation. Int J Drug Reg Affairs. 2025;13(1):34-39. doi:10.22270/ijdra.v13i1.745

2. Shibata H, Harazono A, Kiyoshi M, Saito Y, Ishii-Watabe A. Characterization of biosimilar monoclonal antibodies and their reference products approved in Japan to reveal the quality characteristics in post‑approval phase. BioDrugs. 2025;39:645-667. doi:10.1007/s40259-025-00722-4

3. Biosimilars approved in Japan. Generics and Biosimilars Initiative (GaBI Online). Published March 7, 2014. Updated October 24, 2023. Accessed June 24, 2024. https://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Japan