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When evaluating a drug’s risk assessment for elemental impurities, one must consider all aspects of its lifecycle.
A crucial step in achieving approval of a biosimilar is establishing analytical and clinical biosimilarity with the innovator biologic (i.e., reference product). Analytical biosimilarity studies therefore aim to demonstrate a highly similar profile taking into account variations in critical quality attributes (CQAs) of the biosimilar product. Such variations, however, must fall within a range set by the innovator.
Biosimilarity studies should consist of detailed comparative structural and functional characterizations, the data for which must be gathered using appropriate, validated analytical methods. These analytical methods must not only fingerprint the molecule in question but must also help reduce the cost (economic burden) that would otherwise be incurred in meeting regulatory requirements for extensive preclinical/clinical similarity data (1). In reducing cost at the biosimilarity study stage, it makes sense that the biosimilar product can thus be more affordable than its innovator.
Luckily for the biopharma industry, biosimilar manufacturing processes and the regulations associated with getting approval for them have become more well established in the past decade, as evidenced by the number of biosimilar drug approvals during that timeframe. It has also been helpful that biosimilarity studies that have been conducted (with an eye toward gaining regulatory approval) are being published more frequently and being made public, making access easier. As a result, some technical advancements that have been made in analytical sciences have found their way into techniques used for biosimilar assessment (1).
BioPharm International® delved into the challenges and advancements made in analytical methods for biosimilar characterization with Stephen Pagnotta, executive director and biosimilar commercial lead at Boehringer Ingelheim.
BioPharm: What is meant by ‘implementation of orthogonal tools’, and why are orthogonal tools important for biosimilar studies?
Pagnotta (Boehringer Ingelheim): Orthogonal tools or techniques are laboratory methods used to characterize the structure of a molecule or protein. To build a complete physiochemical profile of a biotherapeutic, multiple orthogonal assessments are used to capture different aspects of a molecular structure. These techniques include, but are not limited to, peptide mapping, mass spectrometry, circular dichroism, and analytical ultracentrifugation.
Orthogonal tools are important for biosimilar studies because researchers must establish that the biosimilar is structurally like the reference product so that there is no clinically meaningful difference in terms of safety, efficacy, purity, and potency.
BioPharm: What analytical advancements have been made that have boosted the ability to conduct biosimilar studies?
Pagnotta (Boehringer Ingelheim): Biosimilar development requires extensive analytical comparison of medicine structure and function to ensure biosimilarity to the reference product. Analytical method development is a procedure for reliable detection of analytes of interest. High-grade method development ensures that the method is suitable for full validation and high-quality analysis of medicines, metabolites, and biomarkers in biological matrices. Advances in analytical techniques have resulted in more rapid results, increased reproduction validation, and higher selectivity and specificity.
During research, the developed analytical methods are utilized to measure and define the required dosage, acceptable impurity, observed stability, and bioavailability of the medicine overall.
BioPharm: Why is it so challenging to demonstrate biosimilarity with respect to CQA variations between the biosimilar product and its innovator?
Pagnotta (Boehringer Ingelheim): Biotherapeutics are more structurally complex compared to small-molecule medicines, and this complexity requires manufactures to use advanced analytic methods to verify structural similarity between the biosimilar and its reference product.
BioPharm: Industry dialogue revolves around the two concepts: biosimilarity and interchangeability. What are the differences between the two terms and what is the impact on a biosimilar product’s trajectory on the regulatory pathway to approval?
Pagnotta (Boehringer Ingelheim): A biosimilar is a version of a biologic medication that is made by a different company than the one that invented it, with no clinically meaningful differences in terms of safety, potency, and purity.
An interchangeable biosimilar first must meet the high FDA standards of a biosimilar. Then, to achieve the interchangeable designation, the biosimilar must be supported by additional FDA-required data, generally through one or more studies of multiple substitutions in patients, known as an interchangeability study.
An interchangeability study shows how patients do when they are switched back and forth from a reference product to the interchangeable biosimilar. The interchangeability study is designed to demonstrate that patients can be switched with no increased risk in terms of safety or diminished efficacy, as compared to remaining on the reference product. The FDA interchangeability designation enables auto-substitution at the pharmacy level. Individual state laws control how and whether providers must be notified.
BioPharm: Why is it important to develop new analytical methodologies not traditionally used in biosimilar studies?
Pagnotta (Boehringer Ingelheim): Biosimilar development follows the regulatory authority guidelines such as those from the FDA and EMA [European Medicines Agency]. As the number of medicines released in the market is increasing by the day, so is the need for method development and validation. These new medicines may be compounds never used before or modifications of existing medicines. An inability to relay analytical procedures, as well as reference and internal standards for new medicines, could hinder thorough R&D. Hence, it becomes necessary to develop new analytical methods for studying the effect of medicinal compounds. These methods are designed to understand the identity, characteristics, purity, and potency of medicinal compounds.
1. Nupur, N.; Joshi, S.; Gulliarme, D.; Rathore, A. S. Analytical Similarity Assessment of Biosimilars: Global Regulatory Landscape, Recent Studies and Major Advancements in Orthogonal Platforms. Front. Bioeng. Biotechnol. 2022, 10. DOI: 10.3389/fbioe.2022.832059.
Feliza Mirasol is science editor for BioPharm International.