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


Calculating the exact cycle specifications for product cool-down rate, freezing, and temperature profiles to be delivered by the refrigeration and heating system depend heavily on the particular characteristics of the product. These profiles may differ radically depending on the product formulation. The more flexible the design of the refrigeration system, the more versatile the unit will be. Additional flexibility and control will better position the owner for processing new formulations with new requirements. Cryogenic refrigeration using LN2/GN2 enables manufacturers to operate across a broad range of processing parameters, both at cool-down and at constant cooling to temperatures lower than –80 C. Using a cryogenic system, the lowest temperature on the shelves is limited by the thermo-physical properties of the HTF, not the refrigerant. Direct expansion of cryogens in the condenser or a nonfreezing cryogenic heat exchanger with a high performance HTF can provide temperatures below –100 C in the condenser.


A cryogenic refrigeration system requires fewer and less complex components. Typically, a cryogenic refrigeration skid only requires approximately one-half to one-third the space of a comparable mechanical compressor-based skid.

Environmental Impact

Nitrogen is an inert molecule that is nontoxic and nonflammable, with no ozone-depleting or global warming potential. It comes from, and returns to the atmosphere after giving off its refrigeration. Most HFC-based refrigerants are either toxic, flammable, or both. LN2/GN2 refrigeration of the lyophilization operation reduces space requirements and noise, and is environmentally friendly.


The growth of LN2/GN2 freeze drying is particularly driven by the need for 1) increased reliability for high-value products, 2) enhanced flexibility, 3) increasing number of formulations containing biologics and 4) dosages with high-fill depth and high volume. The users of lyophilization technology and related equipment are just starting to realize many of its benefits. Many decision makers, still unaware of the benefits associated with LN2/GN2 systems, are also surprised at the lower cost of ownership of a well-designed LN2/GN2 system offering high LN2 efficiency at a low capital expenditure. These features are also worth considering for manufacturers aiming to increase the efficiency, operating flexibility, and profitability of lyophilization systems while controlling costs.

Balazs Hunek, PhD, is a senior manager of technology, 630.320.4242,
Alan Cheng, PhD, is a senior development associate, R&D, and John Capettini is a manager of global applications market development, all at Praxair, Inc.


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3. Cheng ATY, Devack DL. (Praxair) Nonfreezing heat exchanger. US Patent 5,937,656. 1999;Aug 17.

4. Stewart P. Liquid nitrogen: why is progress slow? economic and environmental factors. Pharm Technol Europe 1997;3:44.

5. Telstar. GN2-Tech. Product brief;2005.

6. Liu J, Rouse D. Using liquid nitrogen to maximize lyophilization manufacturing capacity. BioProcess Int. 2005 Feb.

7. Based on Praxair analysis of actual customer experience.

8. Usifroid. Liquid nitrogen applied to freeze drying: performance, reliability, flexibility. 2006. Available from: http://

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