QbD in Biopharmaceutical Manufacturing and Biosimilar Development

Abstract

Over the last ten years, the development of biosimilars has transitioned from concept into approved products. The mechanisms of action of the molecules had been proven, clinical efficacy and safety profiles established, with large markets and sales margins, making them attractive targets for many biopharmaceutical companies, both large and small. However, inherent properties of the molecules result in higher levels of risk in the eyes of regulatory bodies. Therefore, a major component of the demonstration of biosimilarity is the thorough analytical characterization of the biosimilar in comparison to the reference product. The establishment of analytical biosimilarity can reduce the number of clinical studies required to support product approval. The application of Quality by Design (QBD) in early product stages can both reduce risk to patients and streamline the development path for any biologic. The concepts become even more critical with the development of biosimilar molecules, where decisions that are made at very early stages with respect to cell lines, fermentation parameters, and purification strategy will impact the chemical and physical properties of the product. A thorough analytical tool kit is key to establishing critical quality attributes for the product across fermentation and purification development. Critical quality attributes for a biosimilar must take into account both the knowledge gained during early manufacturing and formulation development work and also properties of the reference product. Characterization of the reference materials must occur in parallel with process development. The application of more advanced analytics during early development will allow for the selection of clones that are closest to matching the reference product in terms of glycosylation patterns. Information on the impurity profile of the reference product can be utilized to establish the target product profile as well as to gain an understanding of sensitivities of the molecule to different stresses that may be encountered during processing. The application of QBD does not end at the drug substance stage, but should also be applied during formulation development and also in the selection of container/closure components. Understanding the sensitivity of the product to certain stresses should influence decisions for fill/finish processing equipment as well as placing limitations on exposure to light and time out of refrigeration. The ultimate goal is patient safety, and in the world of Biosimilars, that means applying the correct tools to ensure that the product will match the reference product.