Therapeutic biologics such as monoclonal antibodies possess substantial structural complexities in comparison with small-molecule drugs.
Biologics represent the fastest growing segment of the pharmaceutical market; to gain regulatory approval of these agents, developers of these products are required to perform in-depth characterization to ensure batch-to-batch consistency. In addition to new products developed by innovators, the market will also see the introduction of follow-on biologics (also known as biosimilars), and regulatory agencies (including the US Food and Drug Administration in 2012) have been prompted to develop specific guidelines for this class of drugs.
The regulatory pathways for follow-on versions of complex biologics require the comparison of a reference (innovator) product to the biosimilar version. Analytical technologies provide vital product characterization data that can help establish the degree of comparability and similarity. Such data are likely to have impact on the product approval process, including the scope of required clinical trials, the shelf life of the approved version and the requirements for post-market assessment of the product.
This Review discusses the current state of the art in the analytical technologies used to structurally characterize complex biologics, and also addresses properties of biologics that regulatory authorities have identified as being important in any development strategy for biosimilar versions.
Specific emphasis is placed on the analysis of post-translational protein modifications, three-dimensional protein structures, protein aggregates and subvisible particles that are present in formulated products.
Biologics such as monoclonal antibodies are much more complex than small-molecule drugs, which raises challenging questions for the development and regulatory evaluation of follow-on versions of such biopharmaceutical products (also known as biosimilars) and their clinical use once patent protection for the pioneering biologic has expired. With the recent introduction of regulatory pathways for follow-on versions of complex biologics, the role of analytical technologies in comparing biosimilars with the corresponding reference product is attracting substantial interest in establishing the development requirements for biosimilars. Here, we discuss the current state of the art in analytical technologies to assess three characteristics of protein biopharmaceuticals that regulatory authorities have identified as being important in development strategies for biosimilars: post-translational modifications, three-dimensional structures and protein aggregation.
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J.R.E. acknowledges research funding from the US National Institutes of Health (NIH) (R01-GM086507) and a research collaboration with the Waters Corporation. G.B.J. acknowledges research funding from the NIH (R01 CA111985-04), US Department of Energy (DE-SC0001781) and the US National Science Foundation (HRM 0811170). This is contribution 979 from the Barnett Institute.
Jeffrey R. Mazzeo is an employee of Waters Corporation, which manufactures chromatography and mass spectrometry instrumentation that can be used for protein analysis.
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Berkowitz, S., Engen, J., Mazzeo, J. et al. Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars. Nat Rev Drug Discov 11, 527–540 (2012). https://doi.org/10.1038/nrd3746
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