Scientific Article: Structural Analytical Challenges in Biosimilar and Generic Drug Development

As the biosimilars market grows and experiences are drawn from years of product development, the process of getting this class of drugs to market, especially in terms of testing and approval requirements, is being continually examined. Questions are being asked regarding the need for clinical trial analysis and if it is more appropriate to front-load biosimilar drug investigations with risk-based structural analyses of innovator vs biosimilar in comparability exercises. Technological advances in the hardware and software required for structural analysis, such as in mass spectrometry and techniques for higher order structural investigations, mean that detailed investigations can take place covering all aspects of structure, both at the primary but also secondary and tertiary levels. Investigations into properties of the molecule which are a function of structure, such as levels of aggregation, are also possible. These detailed investigations, as part of a comparability exercise, can give great confidence in the nature of the biosimilar, providing information from which risk-based assessments can be made. Furthermore, since the regulatory guidelines invoke ICH Q6B, there is a commonality of analytical expectation and thus subsequent investigation into the same molecular aspects of the biosimilar structure.

Biopharmaceuticals take many forms, ranging from pure recombinant proteins and glycoproteins, through partially chemically modified forms such as PEGylated products and conjugates, to those that are fully chemically synthesised such as glatiramer acetate. Some are relatively simple products with limited heterogeneity, such as monoclonal antibodies, but others are much more complex and heterogenous (e.g. glatiramer acetate and LMWHs). Biological molecules and the chemistry we perform upon them to tailor them more precisely for our own needs, give rise to challenges in structural analysis that will frequently require unique solutions in order to perform meaningful comparability studies. The technology, experience and tools are available to structurally dissect these different classes of drugs and provide high quality in-depth analysis for data led product development and licencing decisions to be taken. The portfolio of analytical techniques will undoubtedly continue to grow as, over time, new products and new chemical modifications make their way into the biosimilars and generics markets, with new analytical solutions developing to meet these structural challenges and provide insightful data for product licencing decisions.

In this article, BioPharmaSpec’s Technical Director for Structural Analysis, Dr. Richard L. Easton, considers disulfide bridges, PEGylation, heterogeneity and drug conjugation (e.g. ADCs) as structural features in biopharmaceuticals that present particular analytical challenges. Richard goes on to describe the technologies, knowledge and experience that are available to investigate these structural features and obtain meaningful comparative data.

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