Some Practical Aspects - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 129

Figure 4 Amount of ice sublimed at the same temperature in 3 h, scaled to unstoppered
vials ( ¼ 100%); stopper 1 ¼ 77%, stopper 2 ¼ 75% and stopper 3 ¼ 66%.
Data from Willemer 13
temperature and/or the chamber pressure. Preferably, the product tem-
perature should be monitored directly by probes placed in vials at
predetermined locations within the freeze-drier. Probes consisting of
thin wire thermocouples are preferable to resistance thermometers
(RTD sensors), but any probe must remain in close contact with the
product throughout the drying cycle. However, any probe will liberate
heat; hence, product temperature readings will not correspond exactly to
the temperature of the vast majority of vials that do not carry a probe.
In practice, the heating effect of the thin wire thermocouple is negligible,
compared to that of the RTD probe; also sample contact is more easily
maintained. It should also be remembered that the presence of any solid
temperature sensor in a vial will increase the ice nucleation probability in
that vial. The detection of a freezing event is therefore not representative
of the average freezing temperature, taken over all the vials in the freeze-
drier.
The temperature of the advancing ice front can be determined using
a barometric temperature measurement, via a pressure rise test (PRT)
(see later), using a water vapour-temperature diagram, as shown in
Figure 5. In practice, this requires an interruption of the cycle and lacks
the convenience of the continuous output from a thermocouple.
In some commercial equipment, a conductimetric method is employed
to measure the so-called eutectic temperature. In practice, where super-
saturated solutions are the rule, eutectic temperatures are rare, and
where they do occur, they are unrelated to the physical state of the drug
substance. Such measurements are of little value other than indicating a
change in conductance with temperature. In this role, they might give a
warning of abnormal conditions.