Primary Drying: The Sublimation of Ice - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 112

as an indication of the complete removal of ice. The necessary period of
monitoring will depend on the time taken to fill the chamber with water
vapour, and therefore on the total number of vials in the drier.
Other more refined methods that rely on pressure difference include
the combination of different types of pressure probes, e.g. a combination
of a capacitance pressure probe and a Pirani gauge. 115 The former device
measures the total pressure, whereas the Pirani reading is affected by the
thermal conductivity of the gas, e.g. water vapour. Completion of
sublimation is indicated when both pressure readings coincide.
Anemometers (wind mills) have been described as particularly sensi-
tive methods of detecting gas flow in freeze-drier chambers. Such devices
cannot, of course, discriminate between different gases.
The incorporation of mass spectrometers in freeze-driers, even in
production equipment, is a recent development. Their use offers a
particularly sensitive method for monitoring the completion of subli-
mation. As an added advantage, they will also detect the onset of any
product deterioration and/or decomposition.
8.10 Summary
In summary, the practical considerations and conditions for effective ice
sublimation are:
temperature difference between product ice front and condenser;
chamber pressure;
structural continuity of the ice phase throughout the frozen solu-
tion;
volume of water to be removed;
total solid content and chemical composition of the product;
liquid fill depth (i.e. container geometry);
design and performance efficiency of the freeze-drier.
For reasons of economy, short drying cycles are of course highly
desirable, and much time and effort are often devoted by the pharma-
ceutical industry to improve (shorten) historical drying cycles. A mature
consideration of these seven factors must, however, lead to the impor-
tant conclusion that for any given product formulation and vial type,
there is a limit to any process cycle reduction that can be achieved,
without putting the quality of the dried product at risk.