- Chapter 1: Current regulatory landscape for biosimilars approval
- Chapter 2: Overview of biosimilars development
- Chapter 3: Case Studies: EU Regulatory Guidelines and how to interpret them
- Chapter 4: Analytical Comparability (chemistry, manufacturing and controls related product attributes)
- Chapter 5: Key factors that influence biosimilar in vitro and in vivo nonclinical testing strategies
- Chapter 6: Immunogenicity assessment for biosimilars: assay development, validation and interpretation
- Chapter 7: Case studies: challenges of developing and validating PK and immunogenicity assays to support pre-clinical and clinical comparability studies for biosimilars
- Chapter 8: Biosimilar monoclonal antibodies
Associate Director, Biological Assays, MMTech, Global Biologics QC
About the Authors
James Munday gained his D.Phil at the University of Oxford working in the field of cellular and molecular immunology. He then went onto to do his postdoctoral studies at the Mount Sinai School of Medicine in New York where he published his work on transcription factor regulation of hematopoiesis and vasculogenesis. Following on from his academic career he moved into industry posts at Celltech, UCB and Quotient Bioresearch. His current role is a Senior study director at Covance where he has gained extensive experience with a variety of analytical assays for assessing immunogenicity of biosimilars and other novel biopharmaceutical products. James has had an active role in European Bioanalysis Forum working with other members of this group to build a consensus amongst the analytical community on how to perform immunogenicity assessment of biosimilars.
Camille Dycke conducted her PhD at the Commissariat à l’Energie Atomique (CEA) in Grenoble, France, where she studied iron homeostasis in eukaryotic cells. She then joined Covance as a study director before becoming the Manager of the Bioassay group at Covance. Her current role is Associate Director in the Biological assay group at Genentech. During her career she has gained extensive experience with optimising and validating cell-based assays to support biologics development and market release. She also has extensive experience with developing cell-based methods to investigate and characterise immunogenicity of novel biopharmaceutical products as well as biosimilars.
Immunogenicity assessment for biosimilars: assay development, validation and interpretation
Immunogenicity is the ability of a biological entity to elicit an immune response, which can be humoral and/or cell-mediated. Immunogenicity can have serious consequences for both safety and efficacy of biopharmaceutical products. For biosimilar development, the goal for drug approval is to demonstrate similarity of efficacy, safety and quality. Immunogenicity assessment for biosimilars therefore plays a significant role in demonstrating overall similarity. Due to differences in the manufacturing process involved for the production of the biosimilar and the approved biopharmaceutical, the presence, type and level of immunogenicity can be significantly different between the two products. Secondary, tertiary and quaternary structure, as well as unexpected process-related impurities can all lead to differences in immunogenicity. The expectation of the regulatory authorities is that a biosimilar product should have no meaningful difference in the immune response observed, when compared with the approved biopharmaceutical product. Therefore, the assays used to assess immunogenicity can play a significant role in determining the success or failure of a new biosimilar product. The ways in which immunogenicity assays are developed and validated must be carefully considered. In contrast with PK bioanalytical assays in which a specific analyte is measured, immunogenicity assays must be able to detect a broad range of immunoglobulins that differ in affinity, specificity and structure. Despite the significant industry and regulatory concern regarding the need to understand immunogenicity of biosimilars, there are currently no specific bioanalytical guidelines that detail how to develop, validate and interpret immunogenicity assays set up to evaluate new biosimilars. There is therefore a responsibility for any company developing a biosimilar, to justify the approach taken and validity of the bioanalytical tests performed. This Chapter will review the challenges in developing and validating biosimilar immunogenicity assays to support pre-clinical and clinical trials.
Immunogenicity assessment of biosimilars
Consequences for safety & efficacy
The complex nature of the immune response to biological entities (immunogenicity) such as biosimilars can manifest itself in a variety of ways. Therefore, the consequence of an immune response in terms of efficacy and safety can range from no overt symptoms at all, to death of a patient . As part of the normal immune response, humans produce antibodies in response to many things on a daily basis. Generally this has no effect on the individual and is an important mechanism for fighting infection. There are many instances where the host immune response can develop antibodies, including against biopharmaceuticals. These are typically referred to as anti-drug antibodies (ADAs). Differences for induction of ADA between the approved biopharmaceutical product and biosimilar can result in differences in the safety profile, efficacy, PK and PD (See Table 1).