Lyophilization Cycle Optimization

Development and optimization of a lyophilization cycle is a labor-intensive and re-iterative process. Several limiting factors need to be considered; in addition, the different process steps have individual requirements that need to be taken into account. Real-time monitoring of product temperatures with the Tempris system in all freeze-dryer scales offers versatile possibilities for optimization of all steps of the freeze-drying process. A lyophilization cycle is limited by the critical quality attributes of the product and the performance limitations of the equipment. For the design of an optimized process, both aspects need to be considered. In addition, the critical points to consider change within the various processing steps of a freeze-drying cycle. Formulation selection is typically based not only on the stabilizing effect but also on the critical formulation temperature during freeze-drying. An exemplary freeze-drying cycle, including freezing/annealing, primary drying, and secondary drying, is shown below.

Freezing Step

The importance of the freezing step for a lyophilization cycle optimization is often underestimated. One critical aspect that needs to be considered is the complete solidification of the formulation at the end of freezing, typically achieved by lowering the product temperature to at least below the critical formulation temperature, mostly to -40°C or less. If the final freezing temperature is too high upon the start of the vacuum pulldown, detrimental consequences for the product can arise. Another important point to consider is to ensure the quantitative crystallization of crystallizable components, e.g., bulking agents such as mannitol or glycine. This can be achieved by implementing an annealing step following initial freezing, comprising an increase in temperature over several hours. Tempris technology provides insight into the freezing properties of the formulation, including the nucleation temperature and the freezing profile, over different scales of freeze dryers. This information aids in the design of the freezing step to ensure that the product is fully solidified at the end of freezing by ensuring a sufficiently low product temperature. In addition, freezing variations within the batch can be investigated by applying multiple Tempris sensors at hot and cold spot positions.

Primary Drying Step

Practically all formulations subjected to a freeze-drying process have an inherent formulation-dependent critical formulation temperature and an upper-temperature limit for the product temperature during the primary drying process. For freeze-drying of simple crystalline one-component systems, this is the eutectic temperature (i.e., the temperature at which the formulation starts to form liquid domains within the frozen structure); product temperature exceeding this limit during primary drying will lead to severe damage to the cake structure. For partially or fully amorphous formulations, the critical formulation temperature is typically not related to the melting of ice but to structural loss of the dried cake matrix, mostly close to the ice sublimation interface. The critical formulation temperature can be measured by freeze-dry microscopy (optical determination of the ‘collapse temperature’, Tc) or by Differential Scanning Calorimetry (thermal measurement of the ‘glass transition temperature of the maximally freeze-concentrated solute, Tg’). For most pharmaceutical formulations, the product temperature during primary drying (i.e., until all ice has been removed) needs to remain below the critical formulation temperature. Tempris sensors can be used throughout process development to ensure that the primary drying process is designed appropriately to maintain the product temperature within the acceptable range. In turn, the product temperature can also be increased to reduce the drying time if the difference to the critical formulation temperature is sufficiently high. Since Tempris technology can be applied in different scales of freeze dryers with increased flexibility in loading and positioning, the temperature profiles in worst-case positions can also be considered for cycle optimization. In addition, Tempris data offers information regarding the endpoint of primary drying, which can be used to adapt the step time and avoid excessive soak times.

Secondary Drying Step

Optimization of secondary drying mostly concentrates on the determination of a suitable temperature and hold time to achieve a uniform target moisture content within the entire batch. In many cases, the optimum residual moisture content for stability is ‘as low as possible,’ but some formulations also show superior stability at an intermediate moisture content of, e.g., 2 – 3%. The exact product temperature profile can be measured in different product vials in real-time using Tempris technology, which facilitates optimization of the secondary drying conditions and direct comparison of different processing experiments.