Abstract
Recommended best practices in monitoring of product status during pharmaceutical freeze drying are presented, focusing on methods that apply to both laboratory and production scale. With respect to product temperature measurement, sources of uncertainty associated with any type of measurement probe are discussed, as well as important differences between the two most common types of temperature-measuring instruments—thermocouples and resistance temperature detectors (RTD). Two types of pressure transducers are discussed—thermal conductivity-type gauges and capacitance manometers, with the Pirani gauge being the thermal conductivity-type gauge of choice. It is recommended that both types of pressure gauge be used on both the product chamber and the condenser for freeze dryers with an external condenser, and the reasoning for this recommendation is discussed. Developing technology for process monitoring worthy of further investigation is also briefly reviewed, including wireless product temperature monitoring, tunable diode laser absorption spectroscopy at manufacturing scale, heat flux measurement, and mass spectrometry as process monitoring tools.
Highlights
Pharmaceutical scientists and engineers recognize the importance of respecting the intellectual property of other organizations, proprietary information regarding specific drug products and associated processes
We focus on two types—thermal conductivity-type sensors and the capacitance manometer
Capacitance manometers are not useful here because they will not give a reading until the pressure reaches the upper limit of the range of that gauge, usually either 1 or 10 T. Having both a Pirani gauge and a capacitance manometer on both the chamber and the condenser could enable use of the connecting duct as a mass flow meter, with the aid of computational fluid dynamics. This is currently an active project in the LyoHub consortium, and it could prove useful for measurement of equipment capability curves, for large freeze dryers not equipped for tunable diode laser absorption spectroscopy
Summary
Pharmaceutical scientists and engineers recognize the importance of respecting the intellectual property of other organizations, proprietary information regarding specific drug products and associated processes. In many production operations, temperature probes are placed only in vials on the front row of the freeze dryer, since this can be done without reaching over the tops of partially open vials of product While this is good practice from the standpoint of sterility assurance, the front row is a very non-representative location because of the Bedge-effect^, where vials on the edge of an array of vials, the edge near the door, receive additional heat via thermal radiation (5). RTDs are better than thermocouples in terms of accuracy, precision, linearity, and stability For this reason, temperature measurement at fixed points in a freeze dryer, such as in the heat transfer fluid at the inlet manifold to the shelves, on the condenser, and in the drain lines are usually RTDs. An attribute of thermocouples that makes them useful for product temperature measurement, is that the thermocouple measures temperature at the point where the two wires are joined; that is, it is a Bpoint^ measurement. The logger must be positioned in such a way that it does not interfere with freeze drying operations, such as stoppering
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