Abstract
Controlling ice nucleation during lyophilization of parenteral drug products increases the homogeneity of critical quality attributes, such as residual moisture, across drug product batches and shortens lyophilization cycle time. In the present study, we compare three mechanistically different techniques to control ice nucleation during the freezing step of lyophilization, which are referred to as “depressurization”, “partial vacuum”, and “ice fog” techniques. The techniques are compared with respect to their operational limitations and challenges. Installation considerations are also discussed. Using the aforementioned nucleation techniques, we investigated a monoclonal antibody formulation and an enzyme formulation at different protein concentrations using feasible nucleation temperatures and different vial formats and fill volumes. Samples were compared for solid state properties and other critical quality attributes on stability. When nucleated at the same temperature, the three techniques produced products with the same quality attributes and stability behavior. Under conditions resulting in micro-collapse, stability behavior can be different. We found that each technology had considerations for achieving robust nucleation. The present comparison may serve as guidance in selecting a nucleation method.
Highlights
Controlled ice nucleation during lyophilization has been shown to result in improvements to lyophilization cycle time, product consistency, and transfers from lab scale to production scale dryers [1]
The objective was to identify the nucleation conditions required for robust nucleation with each technology and to determine whether the three technologies produce comparable drug product when using similar freezing protocols and lyophilization conditions
A balance must be struck between ensuring robust nucleation and achieving warm nucleation temperatures to produce product with smaller specific surface area and shorter primary drying time
Summary
Controlled ice nucleation during lyophilization has been shown to result in improvements to lyophilization cycle time, product consistency, and transfers from lab scale to production scale dryers [1]. Controlling ice nucleation results in a much tighter distribution of nucleation temperatures with warmer average nucleation temperatures, and greater process consistency which does not change with scale [2]. Since nucleation temperature has been observed to directly impact critical quality attributes like residual moisture as well as important product attributes like cake surface area, which impacts primary drying time, it is desirable to better control nucleation temperature through the use of controlled ice nucleation [3,4,5]. ControLyo TM (SP Scientific) [6] and SynchroFreeze (Hof) [7] rely on rapid
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