Controlling Ice Nucleation During the Freezing Step of Lyophilization - Pharmaceutical Technology

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Controlling Ice Nucleation During the Freezing Step of Lyophilization
Lyophilization technologies for controlled nucleation.

Pharmaceutical Technology
Volume 37, Issue 5, pp. 36-40

Ice-fog technologies

Millrock's patented FreezeBooster controlled nucleation technology combined with the company's patent pending AccuFlux technology is an ice-fog approach that allows the crystal structure to be consistently created, monitored, and controlled. According to Thompson, the combined methods of FreezeBooster and AccuFlux produce a consistent and repeatable ice formation resulting in a highly uniform finished product with reduced primary drying times.

"To reduce drying times and produce a consistent product, control of the entire freezing process is required," explains Thompson. "Millrock's AccuFlux technology enables crystal growth to be monitored and controlled even though the temperature of the product is not changing. It provides the tool necessary to accurately and repeatedly transfer protocols from the laboratory to production. It also provides a tool for simulating production protocols in the laboratory, which is useful for determining production problems."

The Veriseq nucleation technology, developed by Linde Gases in cooperation with IMA Life North America, offers a commercially viable technique for cryogenically generating a uniform dispersion of microscopic ice crystals as a result of contact between liquid nitrogen (produced from sterile-filtered gaseous nitrogen) and steam in a mixing device outside the lyophilization chamber. Upon introduction into precooled vials containing the product to be freeze dried, these ice-fog crystals serve as nucleation sites, which cause rapid and uniform nucleation of the product in a vial as well as between vials of the same batch at very low degrees of supercooling.

"A key challenge for the commercial implementation of Veriseq nucleation technology was to generate sufficient amount of ice-fog and ensure its penetration inside the vials given various lyophilizer volumes," observes Brower. "Efficient ice-fog generation and distribution were achieved using the ejector assembly, providing an extremely efficient way of quickly forming the ice fog and circulating it throughout the freeze chamber."

A recent case study involved the use of Veriseq nucleation technology on a product that required a long (120-hour) lyophilization cycle (17). Conservative cycle parameters had to be employed because of the thickness and concentration of the frozen material. Attempts to reduce cycle time by adding more heat to the process resulted in broken containers. By using Veriseq nucleation technology to increase the crystal size, it was possible to accelerate drying with no breakage and reduce cycle time to 80 hours (17).


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