07.03.2017 |

LOGFILE No. 09/2017 - The Process of Freeze-Drying

Temperature monitoring and control

An excerpt from the GMP Series The Process of Freeze-Drying

(3 min. reading time)

by Dr. Margit Gieseler


Temperature monitoring and control

The components of a freeze dryer being subject to an accurate temperature control are shelf fluid inlet and outlet, and condenser. The main types of probes used for measuring the temperature of these components are resistance temperature detectors (RTDs), e.g. Pt100, or thermocouples, with the RTD having an accuracy of ±0.1 °C and a thermocouple of ±0.5 to ±1 °C.

Measurement principle of a RTD is a change in resistance of a metal filament (usually platinum) as a function of temperature. A thermocouple consists of two thin wires (e.g. copper/constantan, nickel/chrome/nickel) which are brazed together at the tip. The different materials show a different warming profile upon temperature changes which results in a thermal voltage that can be translated into temperature.

The same sensors can also be used for monitoring the product temperature during the freeze-drying process. It might be intuitive that RTDs are the sensors of choice because of their accuracy but it should be noted that there are some more differences between the two types of probes. A RTD is a relatively large sensor because the measuring filament needs to be encapsulated. Additionally, the temperature output value is an average of the total filament length. Considering the progress of drying in the product (Figure 1), a large probe can lead to erroneous results and might, for example, indicate the endpoint of primary drying too early.


Figure 1 
Drying behavior of a product in a vial (source: Pikal et al. PDA J. Pharm. Sci. Technol., 1997)

Thermocouples measure the temperature at their tip, i.e. they give a more reliable indication of the actual product temperature at the point of measurement. Independent of the type of temperature sensor used, a correct positioning in the vial is of utmost importance: center, with the tip touching the bottom.

Generally, temperature sensors do not reflect the “true“ drying situation of the total batch because they are invasive and influence the freezing behavior which, in turn, affects drying performance. Additionally, RTDs and thermocouples are heat sources themselves, resulting in a faster drying of sensor vials compared to non-sensor vials. The electrical current flow in RTD sensors is higher than in thermocouples. In general, thicker probes tend to heat up more compared to thinner ones. Thermocouples have one main disadvantage: they cannot be used in production due to sterility concerns. Recently developed wireless passive transponders rule out most of the issues mentioned above. Some of them can be sterilized and are even compatible with automatic loading and unloading systems.

There are various technologies available to monitor and (by some) even control product and process at different stages of the freeze-drying cycle. For more information, it is referred to the relevant PAT (Process Analytical Technology) literature.


In this PDF-download The Process of Freeze-Drying you will find answers to the following questions:

  • How is freeze-drying performed?
  • What are the relevant process parameters to be measured?
  • What are the quality-determining physical principles/processes?
  • What are the technical requirements of a freeze-drying system and how is the system qualified?
  • How is a freeze-drying cycle validated?


Dr. Margit Gieseler




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