Development of an efficient single-step freeze-drying cycle for protein formulations.

Abstract

An efficient freeze-drying cycle for recombinant human interleukin-1 receptor antagonist (rhIL-1ra) formulations, which contained glycine and sucrose as excipients, was developed. Development was based on characterizing the frozen formulations by thermal analysis and by examining the effect of various lyophilization process parameters on the sublimation rate of ice. Thermal analysis showed that the metastable glass of glycine in frozen formulation could be devitrified by slowly warming the frozen product to -15 degrees C. During drying, the sublimation rate of ice was increased as a linear function of the difference between the vapor pressure of ice at the product temperature (PO) and the chamber pressure (PC). Therefore, the product temperature (Tp) was maintained as high as possible at temperatures below Tg' of the formulation, in order to maximize the PO without allowing the collapse of cake. Although various combinations of shelf temperatures and chamber pressures could be used to obtain the same Tp, the combination of higher shelf temperature and lower chamber pressure was used to maximize sublimation rate. A single-step drying cycle was developed to take advantage of these observations. The shelf temperature was set for the secondary drying and the product temperature during primary drying was maintained below Tg' by adjusting the chamber pressure. As the sublimation completed, the product temperature increased naturally to the shelf temperature for the secondary drying. This process resulted in successful drying of 1 ml of rhIL-1ra formulation to 0.4% moisture content within 6 hours.