Because lyophilization dries a product from the frozen state under temperature controlled conditions, the refrigeration system's process capabilities and performance are critical to a successful commercial lyophilization operation. Part 1 of this article outlines recent trends in pharmaceutical manufacturing and their impact on the evolution of refrigeration technology in lyophilization. It also explains the advantages and disadvantages of choosing a refrigeration system that uses liquid nitrogen instead of mechanical compressors, and its affect on the overall operation. Part 2 of this article, to be published in the December 2007 issue of BioPharm International, will detail design and performance considerations for cryogenic nitrogen refrigeration in a freeze-dryer. The relative cost affect of choosing a cryogenic versus a mechanical refrigeration system will also be discussed as related to the lyophilization process.
Key advantages driving the growth of lyophilization as a preferred fill-and-finish step include the enhanced stability of freeze-dried powder, the ability to remove solvent with minimal heating and concentration effects, the relative ease of aseptically processing a liquid in a freeze-dryer, and rapid and easy dissolution of the product upon reconstitution. All these advantages facilitate minimizing the time to market of a novel therapeutic agent, establishing an early marketing lead, and collecting increased revenues. Disadvantages of this method include increased handling and processing time, the need for a sterile diluent upon reconstitution, and the cost and complexity of related equipment, including its operation and maintenance.1,3,5,6
REFRIGERATION TRENDS IN FREEZE-DRYERS
However, since the early 1990s, cryogenically refrigerated freeze-dryers have been claiming an increasing market share.7–11 These reliable, flexible, and well-proven systems use liquid nitrogen (LN2) or cold gaseous nitrogen (GN2) to cool the components of the freeze-dryer.
In recent years, both the efficiency and flexibility of cryogenic refrigeration systems for freeze-drying have further increased, and their cost of ownership has decreased.8–11 With these improvements, LN2/GN2 systems are ready for mainstream processes. In this article and the subsequent cryogenic lyophilization article, we outline key considerations to help users make informed decisions about what type of refrigeration is best for a particular lyophilization situation.