Systematic Verification of Bioanalytical Similarity Between a Biosimilar and a Reference Biotherapeutic: Committee Recommendations for the Development and Validation of a Single Ligand-Binding Assay to Support Pharmacokinetic Assessments

Abstract

Abstract. For biosimilar drug development, it is critical to demonstrate similar physiochemical characteristics, efficacy, and safety of the biosimilar product compared to the reference product. Therefore, pharmacokinetic (PK) and immunogenicity (antidrug antibody, ADA) assays that allow for the demonstration of biosimilarity are critical. Under the auspices of the American Association of Pharmaceutical Scientists (AAPS) Ligand-Binding Assay Bioanalytical Focus Group (LBABFG), a Biosimilars Action Program Committee (APC) was formed in 2011. The goals of this Biosimilars APC were to provide a forum for in-depth discussions on issues surrounding the development and validation of PK and immunogenicity assays in support of biosimilar drug development and to make recommendations thereof. The Biosimilars APC's recommendations for the development and validation of ligand-binding assays (LBAs) to support the PK assessments for biosimilar drug development are presented here. Analytical recommendations for the development and validation of LBAs to support immunogenicity assessments will be the subject of a separate white paper.

Recommendations for the Development and Validation of Neutralizing Antibody Assays in Support of Biosimilar Assessment

“…With regard to using a one-assay approach (usually using biosimilar reagents) or a two-assay approach (i.e., each assay optimized for the respective drug) for immunogenicity assays (2,4,25,26), the industry trend is now leaning towards the oneassay approach for immunogenicity assays (communications among multiple AAPS biosimilar subcommittees and regulatory agencies). The AAPS Biosimilar committee recommends using one assay for Biosimilar NAb evaluation (Table I).…”

“…One important explanation to this point is that since the regulatory agencies (FDA and EMA) only require that the biosimilar product is Bno more immunogenic^than its originator (1,3), using biosimilar reagents in a one assay will be the most conservative approach ensuring the most optimal detection of immunogenicity (4,25,26) to the Biosimilar product.…”

“…The subcommittee for biosimilars also recognized the importance of assessing comparable immunogenicity of the biosimilar products to their originator products. In 2014, a white paper from the AAPS Ligand Binding Assay Bioanalytical Focus Group (LBABFG) Action Program Committee (APC) subcommittee was published with a focus on PK assays to support biosimilar comparability studies (4).…”

A Liquid Handling Robot for Robust and Reproducible Preparation of Standard and Quality Control Samples in Bioanalysis

“…The idea is to avoid variabilities from the preparation as much as possible, in order to keep the reference substances the only relevant variable. For a biosimilar ELISA method, we used our robotic approach and prepared these standard curves, via several dilution steps, and sorted them in alternating order on the assay plate as recommended by Marini et al [6]. The standard curves yielded from these independent robotic preparations were found to be well in accordance to each other, not only within the preparations from one reference substance but also when curves were compared between originator and biosimilar ( Figure 4).…”

Demonstrating Biosimilar and Originator Antidrug Antibody Binding Comparability in Antidrug Antibody Assays: A Practical Approach

“…However, similarity must also be demonstrated through nonclinical and clinical studies; hence, the bioanalytical assays (pharmacokinetic [PK] assay, antidrug antibody [ADA] assay and neutralizing antibody assays) must be able to detect both the biosimilar and originator drug molecules in a comparable manner in order to be able to accurately assist in demonstrating that there are no meaningful differences in PK and immunogenicity. Bioanalytical biosimilar testing recommendations for the PK assay are extensively discussed in literature, and most of the industry take inspiration from the practical recommendations of Marini et al [7]. For the immunogenicity assays, the practical approach is neither yet well defined nor is there a full consensus in the industry.…”