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Biosimilars, like innovator biologics, raise challenges compared to SMDs, due to manufacturing complexity, presence of minor natural variations in the molecular structure (collectively known as microheterogeneity), and post‐manufacturing (post‐translational) modifications.^51,52 The production of innovator biologics and biosimilars comprises numerous steps and minuscule differences in the product may result in different clinical outcomes. Consistent drug discovery and manufacturing paradigm are likely to minimize product variations. Besides, drift (unnoticed and unplanned deviations) and evolution (planned changes) may lead to divergence, which can also lead to product variability and different product attributes. Divergence means that the biosimilar and the currently marketed innovator differ from the originator product that was first approved and marketed and the innovator product that was used in the comparability exercise.⁵³ Biotechnology process and manufacturing innovations, needed for regulatory reasons, production scale‐up, change in a facility or raw materials, and improving quality or consistency or optimizing production efficiency,⁵⁴ may lead to a higher quality biologic.

Identifying and controlling PTMs and demonstrating biosimilarity require specific and sensitive analytical techniques. Pharmacists need to be familiar with such techniques and issues; these are discussed in Chapter 6.