Increasing Lyophilization Productivity, Flexibility, and Reliability Using Liquid Nitrogen Refrigeration–Part 2 - - BioPharm International


Increasing Lyophilization Productivity, Flexibility, and Reliability Using Liquid Nitrogen Refrigeration–Part 2

BioPharm International
Volume 20, Issue 12

Figure 6.
To avoid two-phase flow and the related nonuniform performance of the condenser, a so-called fluid condenser option is also available. In this case, one or more dedicated compressors or cryogenic heat exchangers may cool a separate HTF loop, which in turn cools the fluid condenser. The downside of a fluid condenser is the potential for frictional heat generation. If a cryogenic heat exchanger is applied, a low HTF velocity helps minimize the parasitic heat generation. The efficiency benefits gained from more uniform use of the condenser surface often outweigh the minor increase in frictional heat generation. A simplified process flow diagram of the refrigeration system for a freeze-drying application developed by Praxair is shown in Figure 6. In place of separate dedicated refrigeration systems for the shelves and condenser, we recommend a unique configuration with a single nonfreezing cryogenic heat exchanger. This heat exchanger cools two HTF loops with differing temperature setpoints and refrigeration demands. The warmer HTF loop cools the shelves, the colder one the condenser. Major advantages of the single-heat-exchanger configuration include significantly reduced capital cost for the refrigeration system and lower LN2 consumption compared to cryogenic refrigeration systems that use both a heat exchange system and a LN2 DX condenser to meet the cooling requirements of the lyophilization process.


Table 1. Comparison of estimated cost of ownership for mechanical versus cryogenic refrigeration of a typical commercial freeze-dryer operating in North America.7
Table 1 illustrates the key components of the cost of ownership of the refrigeration part of a freeze-dryer. Both the capital items and operating costs were considered. Overall, if one considers the cost of auxiliary systems and maintenance for mechanical refrigeration, LN2 units are less expensive. After many years of operation of commercial mechanical units, the same conclusion was drawn by Liu.6

The amount of nitrogen required for refrigeration will depend largely on the thermal efficiency of the cryogenic heat exchange system. High efficiency, nonfreezing systems that operate at low pressure use 15–30% less nitrogen than high-pressure nonfreezing systems and systems that do not use a nonfreezing design. LN2 costs can account for as much as 50% of the overall costs to operate a cryogenic freeze-drying system. Therefore, LN2 refrigeration efficiency should be considered while selecting the cryogenic refrigeration system.



The inherent reliability of cryogenic refrigeration systems is important to manufacturers of high-value and sensitive products, such as protein therapeutics and vaccines. Lyophilization production managers often worry about the breakdown of the mechanical compressors on their freeze-dryers, which would lead to the loss of entire batches. A cryogenic refrigeration skid contains no moving parts unlike compressor-based mechanical refrigeration skids. Properly used and maintained, LN2/GN2-based refrigeration systems can run for decades with minimal maintenance requirements and a low chance of failure. The resulting savings in maintenance and repair of both parts and labor can amount to hundreds of thousands of dollars over the life of a commercial freeze-dryer. In addition, the value of the significant reduction in the risk of mechanical failure and subsequent loss of a batch due to catastrophic compressor or power failure can often be measured in excess of a million dollars, depending on the product.

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