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Analytical Assessment Techniques

An overview on the analytical assessment techniques for biosimilar development

Successful biosimilar approval is determined by how well biosimilarity can be demonstrated between the proposed product and its innovator product. An analytical biosimilarity study provides the technical data that would confirm the similarity of critical quality attributes (CQAs) of the proposed product to its innovator in terms of safety, efficacy, and potency. This constitutes comprehensive characterization of the product’s structure and functional and validated analytical methods. Essentially, biosimilar development is significantly dependent on the analytical platform that is used [1]. Furthermore, orthogonal tools play a dynamic role in demonstrating biosimilarity particularly when one technique alone is not sufficient. The FDA stated that methods which utilize various biological and/or physicochemical concepts to assess and evaluate the same characteristics are invaluable in independently supporting the quality of the characteristic [2].
Analytical biosimilarity assessment techniques
Regulatory guidelines recommend using high-resolution, orthogonal analytical tools to characterize CQAs. These can be categorized into primary structure, high-order structures, glycosylation (for eukaryotic hosts), product- and process- related variants [1]. At least one assessment technique is mandated for each of these categories.
For primary structure sequence identify, mass spectrometry (MS) has emerged as a preferred technique due to various reasons including fast turnover, sensitivity, and more. Several MS platforms have been developed where orthogonal alternatives to MS-based methods have been used for biosimilarity assessments including biosimilar candidates of Cletrion’s infliximab, Amgen’s bevacizumab & infliximab, and Sun Pharma’s rituximab [3, 4, 5]. Orthogonal methods of assessment are more relevant for high-order structures i.e., secondary and tertiary, as multiple tools are needed for their characterization. Techniques such as far ultraviolet circular dichroism have helped identify secondary structures when demonstrating biosimilarity for products such as epoetin alpha and filgrastim to their reference product [6, 7]. For tertiary structures, the nuclear magnetic resonance has emerged as the “gold standard” as it is among the high-resolution techniques for collecting data regarding tertiary protein structure.
Support from the US FDA
The US FDA issued a draft guidance on ‘Statistical Approaches to Evaluate Analytical Similarity’ in 2017 for sponsors of biosimilar development that provided advice on evaluating the analytical similarity between the reference product and the proposed biosimilar that distinguished CQAs based on their risk and statistical tools. However, the guidance was withdrawn due to concerns regarding biosimilar cost, efficiency, and reference products landscape for evaluation. Thus, the US FDA plans on issuing a final guidance document that would address these issues as well as include all innovations and “state-of-the-art” technology for assessment of analytical data that would help support biosimilarity demonstration between the proposed and reference product. It would also include considerations on the appropriate methods for assessment as well as provisions for flexibility for biosimilar development [8].
The need for global harmonization
The need for harmonization of regulations surrounding biosimilars is evident as the number of biosimilar approvals continue to rise with various biosimilar guidelines being at different stages of development in different regions. This is true for several parameters including design of the clinical, non-clinical and/or analytical biosimilarity studies. However, all biosimilar guidance documents mandate the demonstration of biosimilarity by way of head-to-head comparison in terms of structure and function, and clinical, non-clinical, and pharmacokinetic studies. The extent of biosimilarity for a proposed product compared to its innovator determines the extent of what clinical and non-clinical data is required.
Conclusion
Delivering safe and effective biosimilars without compromising on compliance and quality requires collaboration from various stakeholders including, but not limited to, regulatory agencies and manufacturers. Indeed, as more technologies emerge that can be included in analytical similarity assessments for CQAs, the cost to incorporate them is also a challenge. Thus, MS and NMR are some of the preferred tools used to conduct similarity assessments for CQAs in biosimilar development.
References and Further Reading:

[1] Nupur N, Joshi S, Guillarme D, Rathore AS. Analytical similarity assessment of biosimilars: Global regulatory landscape, recent studies and major advancements in orthogonal platforms. Frontiers in bioengineering and biotechnology. 2022 Feb 9:36.

[2] US FDA. Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations Guidance for Industry. 2019

[3] Seo N, Polozova A, Zhang M, Yates Z, Cao S, Li H, Kuhns S, Maher G, McBride HJ, Liu J. Analytical and functional similarity of Amgen biosimilar ABP 215 to bevacizumab. InMAbs 2018 May 19 (Vol. 10, No. 4, pp. 678-691). Taylor & Francis.

[4] Saleem R, Cantin G, Wikström M, Bolton G, Kuhns S, McBride HJ, Liu J. Analytical and functional similarity assessment of ABP 710, a biosimilar to infliximab reference product. Pharmaceutical research. 2020 Jun;37(6):1-23.

[5] Hermosilla J, Sánchez-Martín R, Pérez-Robles R, Salmerón-García A, Casares S, Cabeza J, Cuadros-Rodríguez L, Navas N. Comparative stability studies of different infliximab and biosimilar CT-P13 clinical solutions by combined use of physicochemical analytical techniques and enzyme-linked immunosorbent assay (ELISA). BioDrugs. 2019 Apr;33(2):193-205.

[6] Deechongkit S, Aoki KH, Park SS, Kerwin BA. Biophysical comparability of the same protein from different manufacturers: A case study using Epoetin alfa from Epogen® and Eprex®. Journal of pharmaceutical sciences. 2006 Sep 1;95(9):1931-43.

[7] Skrlin A, Radic I, Vuletic M, Schwinke D, Runac D, Kusalic T, Paskvan I, Krsic M, Bratos M, Marinc S. Comparison of the physicochemical properties of a biosimilar filgrastim with those of reference filgrastim. Biologicals. 2010 Sep 1;38(5):557-66.

[8] US FDA. FDA withdraws draft guidance for industry: statistical approaches to evaluate analytical similarity. 2018