Advance Understanding of Buffer Behavior during Lyophilization

Abstract

The formulation of monoclonal antibodies, antibody drug conjugates, fusion proteins, and enzymes for administration typically requires lyophilization to maintain biologic activity. The control of pH throughout the lyophilization process is critical to maintaining biologic activity and an acceptable shelf life. In this chapter, the critical aspects of selecting a buffer that achieves optimal stability throughout the freeze-drying process and on subsequent storage are presented. Acidic and basic components that can be used to moderate pH to maintain the therapeutic activity of biological molecules during processing by lyophilization are reviewed. Throughout this chapter we focus on what properties of the buffer are important for achieving acceptable stability in both the solution and dry states, and minimizing the potential for pH changes that may accompany temperature changes and freeze concentration throughout the lyophilization process. One critical attribute of the buffer system is potential for crystallization during freeze concentration. The potential for crystallization of different buffers is highlighted in this chapter, including the role that other components in the formulation, such as sugars, can either promote or retard buffer crystallization. It was further demonstrated that freeze-drying can result in significant changes in apparent acidity even without buffer crystallization. The changes in the apparent acidity, which were monitored by measuring ionization of probe molecules and expressed as Hammett acidity function, depend both on buffer type and co-solutes (such as sugars and polymers) and were shown to correlate with degradation rates of acid-sensitive compounds. The chapter concludes with a case study that illustrates the criticality of selecting the appropriate buffer system to achieving a stable formulation.