Refining the cycle
Once initial cycle parameters have been defined, the next step is to run a test batch on a research freeze dryer with product
monitoring capabilities. Monitoring process conditions such as chamber pressure and product temperature enable the endpoints
of primary drying and secondary drying to be determined.
Where primary drying should end and secondary drying begin is dependent on the individual properties of the product and the
stated process requirements. But as the two stages are so different in processing terms, when and how the change should occur
is of vital importance to the success of the process and minimizing cycle time.
The end of secondary drying, and the freeze-drying process overall, is difficult to define and pinpoint. A range of tolerance
for final moisture content must be decided upon, weighing the desired stability and activity of the product against the cost
of continuing the process for further hours or days.
A conservative freeze-drying cycle that has been arrived at by trial and error might produce satisfactory product reliably
and repeatably. However, there will be no scientific evidence of the suitability of the process other than exhaustive quality
assurance testing. By providing evidence of the analysis, cycle feedback and overall process of cycle development, the suitability
of the cycle can be easily verified by internal and external auditors.
In the instance that previously robust batches lose consistency or product stability slips, the original data can be used
Freeze-drying cycles are optimized not only with regards the formulation, but also the freeze drying equipment and batch parameters
such as fill depth, batch size, and container type. For optimum efficiency in manufacturing scale-up, the cycle should be
designed for the specific process equipment used.
The following real example of how this technology has been used to improve efficiency speaks volumes about how much of a difference
characterizing a freeze-drying cycle makes.
A vaccines manufacturer had a 70-hour freeze-drying cycle for a product, which was limiting manufacturing capability. Freeze-drying
company Biopharma Technology Ltd was asked to analyze the product's thermal characteristics. The cycle had been designed to
freeze the product below -45 °C and maintain the product below -40 °C throughout primary drying. FDM analysis showed a collapse
temperature at -18.2 °C; DTA/impedance analysis showed a significant softening event at -23 °C. Raising the designated freezing
temperature to a still-conservative -28 °C enabled the freezing step to be significantly shortened, as well as saving the
cost in energy of cooling the chamber and product through unnecessary extra degrees. The temperature setpoint of primary drying
could also be raised to increase the rate of sublimation. Process monitoring subsequently indicated that the product was being
left in primary drying conditions for much longer than necessary and the duration of this stage was cut by 40%.
Analysis of the product dried using the new cycle demonstrated that while the total process time was reduced by 15 hours,
the product was just as good as before.
1. Tang, X.; Pikal, M., J. Pharm. Res. 21(2), 191–200, (2004).
2. Formulation Characterisation 2: Thermal and Other Methods, Biopharma Technology Ltd.
Katriona Scoffin is a science writer and Laura Ciccolini, PhD, is commercial director of Biopharma Technology Ltd, Winchester, England.
All figures courtesy of the authors.