Abstract
Leading regulatory agencies recommend biosimilar assessment to proceed in a stepwise fashion, starting with a detailed analytical comparison of the structural and functional properties of the proposed biosimilar and reference product. The degree of analytical similarity determines the degree of residual uncertainty that must be addressed through downstream in vivo studies. Substantive evidence of similarity from comprehensive analytical testing may justify a targeted clinical development plan, and thus enable a shorter path to licensing. The importance of a careful design of the analytical similarity study program therefore should not be underestimated. Designing a state-of-the-art analytical similarity study meeting current regulatory requirements in regions such as the USA and EU requires a methodical approach, consisting of specific steps that far precede the work on the actual analytical study protocol. This white paper discusses scientific and methodological considerations on the process of attribute and test method selection, criticality assessment, and subsequent assignment of analytical measures to US FDA’s three tiers of analytical similarity assessment. Case examples of selection of critical quality attributes and analytical methods for similarity exercises are provided to illustrate the practical implementation of the principles discussed.
Highlights
Medicines of biological origin are complex mixtures containing a diversity of chemical variations of a therapeutic protein and other substances as a result of their production in living systems.The specific composition of such a product is controlled within carefully defined limits of variation by the design and control of its manufacturing process
Due to the inherent manufacturing variability associated with cell culture and the inability to precisely replicate the originator’s manufacturing process, even the best reproductions of protein therapeutics can at best be highly similar to a reference product based on current technologies
The selection and criticality ranking of quality attributes constitutes an essential step in early biosimilar development, informing both process development and controls as well as the design of the pivotal analytical similarity study
Summary
Medicines of biological origin are complex mixtures containing a diversity of chemical variations of a therapeutic protein and other substances as a result of their production in living systems. Because the details of product manufacture are proprietary knowledge, biosimilar product developers cannot precisely replicate the manufacturing process of a reference product. Due to the inherent manufacturing variability associated with cell culture and the inability to precisely replicate the originator’s manufacturing process, even the best reproductions of protein therapeutics can at best be highly similar to a reference product based on current technologies. A first iteration of quality attribute (QA) selection and ranking can be completed prior to product development. Detailed characterization of the reference product supports further attribute selection and ranking, and yields a precise quality target product profile (QTPP) for product and process development. The accumulating knowledge from structural and functional characterization studies provides
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