Lyophilization of Therapeutic Proteins in Vials: Process Scale-Up and Advances in Quality by Design

The quality-by-design (QbD) approach enables the robust development of the lyophilization cycle in an effective manner where deep understanding is gained through building a scalable freezing step in terms of ice nucleation along with the generation of a primary drying design space. Applying QbD to the design of the cycle allows for the consideration of scalability up front, removing the traditional “trial-and-error” approach, while understanding the performance of the large-scale freeze-dryer. To achieve this, the heat transfer coefficient (K v) of the vial and the product cake resistance (R p) are needed for the mathematical modeling in order to obtain an accurate design space. This chapter explores the latest development and scale-up of the lyophilization process for protein therapeutics in the vial using a QbD approach. Ice nucleation, heat and mass transfer, lyophilization cycle design, and scalability are discussed. A case study is presented for a protein product using both theoretical modeling and experimental scale-down model approach to obtain a wide design space.