Lyophilization: A Primer - Pharmaceutical Technology

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Lyophilization: A Primer
Optimized freeze-drying cycles can offer scientific and business advantages.


Pharmaceutical Technology
Volume 37, Issue 5, pp. 42-45, 93

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 for troubleshooting.

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.

References

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.


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