FRESH PERSPECTIVES
Figure 4 - Once the product is nucleated, crystal growth begins in the equilibrium freeze concentrate. The graph below shows the radical changes in heat fl ux as the shelf temperature is lowered at 0.5°C/min. Although FreezeBooster controlled nucleation created a common starting point for the entire batch, the crystal structure inside the vial is heterogeneous due to the changes in heat fl ux as the shelf temperature decreases.
Post-controlled nucleation, the shelf is typically cooled at a controlled rate of 0.50C/min. As the shelf is cooled, the heat fl ow out of the vial changes dramatically. Although controlled nucleation produces a uniform initial ice crystal structure across the batch, the crystal growth inside the vial is not uniform resulting in a non-uniform ice crystal structure inside the vial.
Controlling the heat fl ow between the shelf and the vial post-nucleation is necessary to create a uniform and porous structure intra-vial. Using AccuFlux, the shelf temperature can be adjusted to produce a consistent level of heat fl ow to/from the vials. Controlling the heat fl ow throughout the entire freezing process, including super-cooling soak, crystallization of the freeze concentrate and solidifi cation of the maximal freeze concentrate, the ice crystal structure can be controlled and a uniform structure intra-vial is achieved. Controlling the freezing process in this fashion eliminates the
Measurement and Control of Heat Flow into the Vial
The challenge to monitoring for a proper crystal structure post-nucleation still exists due to minimal product temperature change as the water changes phase from liquid to solid. Measuring product temperature provides no signifi cant information about crystal growth. Measurement of the heat leaving the vials (heat fl ux) provides the information needed to monitor and control the ice crystal growth rate. Millrock Technology’s AccuFlux™ technology provides a method to measure the heat fl ow between the shelf and the vial. Measuring the heat fl ux provides a new level of information previously unavailable to the freeze-drying community about both the freezing and drying processes.
Figure 5 - The combination of FreezeBooster providing a common nucleation event across the batch and using AccuFlux to control the heat fl ow during freezing results in a homogeneous ice structure inter-vial and intra-vial. A consistent and repeatable ice structure improves yields and reduces overall freeze-drying process times. Monitoring and controlling the heat fl ux, using AccuFlux technology, in each of these stages produces a consistent and repeatable crystal structure both inter-vial and intra-vial.
Prior to nucleation, the product temperature is lowered to a predetermined super-cooled level and held for a period of time to achieve thermal equilibrium. When the measured heat fl ow to the vials stabilizes, the product is ready to be nucleated. Measuring the heat fl ow eliminates the guesswork of the time required to reach thermal equilibrium and reduces processing time.
71 American Pharmaceutical Review | Fresh Perspectives 2013
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