Lyophilization of High-Concentration Protein Formulations

High-concentration protein formulations are in the focus of current pharmaceutical development because the required therapeutic doses of biologics, especially monoclonal antibodies, are extremely high, ranging between 5 and 750 mg per patient. Considering applications via the sub-cutaneous route, protein concentrations much above 300 mg/mL are often requested. At present, commercialized high-concentration biologics, with protein concentrations between 150 and 200 mg/mL, are launched as lyophilized (freeze-dried) products, while liquid protein formulations are available with concentrations around 100 mg/mL. The current chapter will address specific topics linked to high-concentration lyophilized protein formulations. The term "high-concentration protein formulation" (HCPF) is often used, but hardly ever defined. We have therefore asked, how highly concentrated can a protein formulation become? We consider this question, particularly for monoclonal antibody drugs, along with the rationale for developing HCPF and the issues encountered during formulation. Lyophilization is the technique of choice for stabilizing labile molecules. However, for the development of high-concentration, freeze-dried protein formulations (HC-FDPFs), new challenges appear, such as extremely prolonged reconstitution times or even stability issues. Therefore, new technologies such as controlled nucleation are introduced and presented as one option for reducing these unfavorable reconstitution times.