Validation Of Ligand-binding Assays Research Articles

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.

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.

Immunogenicity and Pk/Pd Evaluation in Biotherapeutic Drug Development: Scientific Considerations for Bioanalytical Methods and Data Analysis

With the advent of novel technologies, considerable advances have been made in the evaluation of the relationship between PK and PD. Ligand-binding assays have been the primary assay format supporting PK and immunogenicity assessments. Critical and in-depth characterizations of the ligand-binding assay of interest can provide valuable understanding of the limitations, for interpreting PK/PD and immunogenicity results. This review illustrates key challenges with regard to understanding the relationship between anti-drug antibody and PK/PD, including confounding factors associated with the development and validation of ligand-binding assays, mechanisms by which anti-drug antibody impacts PK/PD, factors to consider during data analyses and interpretation, and a perspective on integrating immunogenicity data into the well-established quantitative modeling approach. Through recognizing these challenges, we propose some opportunities for improvements in the development and validation of fit-for-purpose bioanalytical methods.

Interview with Dr Bowsher

Dr Bowsher is currently a senior research advisor at AIT Biosciences advising on technical, regulatory and business development matters related to bioanalysis of biotherapeutics, as well as maintaining his consultancy and laboratory businesses at B2S Consulting® (IN, USA), and B2S Labs (IN, USA), respectively. Formerly working at EMD Millipore’s BioPharma Services for 10 years and at Lilly Research Laboratories for 30 years, Dr Bowsher brings more than 40 years of experience in the pharmaceutical/biotech and CRO industries. He received a bachelor’s degree in chemistry from Indiana University (IN, USA), and holds a master’s degree and doctorate in biochemistry from the Indiana University School of Medicine. He is an adjunct assistant professor of biochemistry and molecular biology at the Indiana University School of Medicine. Since 1980, he has published more than 100 research papers and monographs, and 105 abstracts, as well as holding three patents. In 2001, Dr Bowsher founded and organized the Ligand Binding Assay Bioanalytical Focus Group (LBABFG) within the American Association of Pharmaceutical Scientists (AAPS) and in 2004 he was elected as an AAPS Fellow, as well as being awarded an AAPS Presidential Citation for his work in establishing an educational program, and has served as the co-organizer for the past 6 years of the highly successful AAPS Immunogenicity Training Course. In 2012, Dr Bowsher received the Distinguished Alumnus Award, School of Science, Indiana University-Purdue University (IN, USA). In March 2013, Dr Bowsher spoke to Alexandra Sklan at Bioanalysis regarding his bioanalytical career, involvement in the AAPS and the future outlook relating to macromolecule bioanalysis. His primary research interests are the development and validation of ligand binding assays for the bioanalysis of macromolecules, endogenous compounds and conventional xenobiotic drugs to support regulatory-compliant assessments of PK/TK, PD and safety, and the ADME of biotherapeutics.

Bioanalytical Method Validation for Macromolecules in Support of Pharmacokinetic Studies

The development and validation of ligand binding assays used in the support of pharmacokinetic studies has been the focus of various workshops and publications in recent years, all in an effort to establish a guidance document for standardization of these bioanalytical methods. This summary report of the workshop from 2003 focuses on the issues discussed in presentations and notes points of discussion and areas of consensus among the participants.