Increasing Lyophilization Productivity, Flexibility, and Reliability Using Liquid Nitrogen Refrigeration–Part 1 - - BioPharm International


Increasing Lyophilization Productivity, Flexibility, and Reliability Using Liquid Nitrogen Refrigeration–Part 1

BioPharm International
Volume 20, Issue 11

Refrigeration Temperature and Cool-down Rate

Operating temperatures below –50 C negatively affect the performance, efficiency, and reliability of mechanical systems. However, such operating temperatures have no impact on cryogenic systems driven by liquid nitrogen (which has a normal boiling point of –195.8 C). The cooling rate and efficiency of a mechanical compressor-based system starts to deteriorate below –20 C.7,8 Figure 1 shows the typical shelf cool-down of large commercial freeze-dryers equipped with mechanical compressors versus cryogenic heat exchangers. Cryogenic systems are capable of providing a rapid, constant cool-down rate throughout the entire ultralow temperature range. Mechanical refrigeration systems, on the other hand, cannot maintain their initial cool-down rate. This is probably the reason why original equipment manufacturers (OEMs) of freeze-dryers relying on mechanical compression equipment typically specify the cool-down rate in terms of overall time to reach a certain temperature. Citing an average rate can mask a deteriorating cooling rate over time. Only cryogenic systems can maintain cool-down rates of 1 C per minute or higher over the entire temperature range of a lyophilization cycle.

Figure 1 also shows that LN2 systems can reach –55 to –70 C setpoint for the heat transfer fluid (HTF) inlet temperature to the shelves one to two hours faster than comparable mechanical units reaching a –50 C setpoint. If the lyophilization cycle requires rapid cooling, this means increased productivity in terms of cycle time reduction. The manufacturers of sensitive products, such as vaccines, attain product viability benefits from rapid cooling. In addition, LN2/GN2 systems can easily go to even lower temperatures if required. Their lowest operating temperature is limited by the characteristics of the HTF, not those of the refrigeration system.

In summary, LN2 systems offer a wider processing window of operation leading to added flexibility and productivity benefits. They do not suffer from the fundamental thermodynamic limitations of mechanical refrigeration systems, such as deterioration of efficiency and cool down rate, or limits on operating temperatures.

Refrigeration Load Profile

Lyophilization has special demands due to the extreme variability of the refrigeration load requirements. There are two main cooling circuits in a freeze-dryer: one for the shelves and another for the condenser. The shelf cooling circuit needs high-peak refrigeration power for the relatively short time (two to three hours) required to cool down the freeze-dryer and its contents, and to freeze the entire batch. This peak load on the shelf circuit is followed by a relatively longer period (one to three days) requiring significantly lower refrigeration power for the condenser circuit, but at a lower temperature. This load serves mainly to condense out the ice, which is slowly sublimating and desorbing from the product during primary and secondary drying. The corresponding refrigeration power required to run the condenser circuit is typically an order of magnitude lower than that required by the shelves for initial cool down and freezing.

This type of highly variable refrigeration at temperatures between –40 C and –80 C is best served by cryogenic refrigeration. LN2/GN2 systems are much more flexible in this temperature range, and are capable of efficient turn-down. Mechanical refrigeration systems are better suited to meeting steady demands. Compressors are ill-suited for short duration peak loads followed by extended operation at low load and ultralow temperatures. Under such conditions, compressors run inefficiently, using a lot of power while providing minimal cooling. They are designed to meet the short period peak load, yet are operated under suboptimal efficiency conditions for most of the lyophilization cycle time. Cryogenic systems, on the other hand, easily meet the variable refrigeration demands of lyophilization. Unlike mechanical systems, cryogenic systems operate with only small changes in thermal efficiency during the entire process cycle.


All lyophilization refrigeration systems feature an HTF loop, which is the passive component from a refrigeration point of view. The HTF loop includes the fluid, piping, and pumping system with controls. The main differences between refrigeration systems are in 1) the active component(s) that drive the system, and 2) the necessary auxiliary systems. The active refrigeration system cools the low temperature HTF, which in turn refrigerates the shelves. Typically, a separate active circuit needs to provide the cooling for the condenser by direct expansion of a refrigerant, except in some advanced designs.

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