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


Figure 1. Typical shelf cool-down capability of large commercial freeze-dryers with >20 m2 shelf-space. Note the inferior performance of mechanical versus cryogenic liquid nitrogen refrigeration systems in terms of cool-down rate, cooling rate sustainability, and lowest temperature.
There are two key considerations in providing refrigeration to a process: 1) the refrigeration temperature required, and 2) the maximum cooling power required. First, the refrigeration temperature required by the process determines the type of refrigeration system needed. Commercially available refrigeration technologies have different fundamental thermodynamic limitations in terms of operating temperature, cooling rate capability, efficiency, and cooling power. Second, the peak and turn-down capacities of the chosen type of system are determined by the refrigeration load profile over time.

Lyophilization is a unique process from a refrigeration point of view, not only for requiring ultralow-temperature refrigeration (below –50 C),12 but also because the load is extremely variable, often requiring a system turn-down in excess of 10:1.7 Both these key requirements favor cryogenic refrigeration over mechanical systems.

Table 1. Overview of the properties of some low-temperature heat transfer fluids (HTFs)12,13
Chamber shelves (and sometimes walls) need to be cooled down to between –40 C to –60 C. The actual target temperature may vary from product to product, but it must always be set below the eutectic temperature of the solution to be lyophilized. The eutectic temperature is the lowest value at which a mixture of materials will melt. Meanwhile, the lowest temperature in the condenser typically needs to be between –60 C and –80 C, and sometimes as low as –100 C, to make sure the solvent condenses out at a rate that will maintain an appropriate vacuum in the chamber. These temperatures depart from the comfortable realm of "industrial refrigeration," defined as refrigeration from –35 C to –50 C.12 Thus, the requirements of lyophilization mainly reside in the "ultra low-temperature refrigeration" space, defined as –50 C to –100 C.12 The efficiency and reliability of mechanical systems deteriorates as refrigeration temperature drops. Cryogenic systems, in contrast, provide practically constant cooling power throughout the temperature ranges of any lyophilization cycle.

Depending on the effectiveness of the condenser, the condenser surface is kept at a temperature approximately 10–20 C lower than the shelves, i.e., –50 to –80 C during drying. It is critical to ensure that the temperature of the accumulating ice remains cold enough to condense out the solvent vapors. If not, the vacuum in the chamber can be lost, leading to loss of process control and possible destruction of valuable product. Meltdown of the cake occurs when the temperature of the product rises faster than the removal of the moisture or solvent. In addition, vacuum pump seal fluids may become contaminated by the solvent coming in through the condenser. Vacuum levels are typically controlled by adding refrigeration to the condenser, thus causing further condensation of the solvent vapors. Some experts therefore, view the condenser as a vacuum pump operated by refrigeration. Reliable and flexible cooling of the condenser is also crucial to lyophilization.

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