Foam Cake Structures
Much of the improvement in lyophilization technology has come through a thorough understanding of the basic material science of pharmaceutical solids and the “thermal history” or processing conditions that the product is subjected to during the drying process.
“We seek to improve the survivability of proteins through the process that typically may include loss of secondary, tertiary, and quartenary protein structures,” according to Vu Truong, Ph.D., vp, R&D, Aridis Pharmaceuticals (www.aridispharma.com). “Complex, large proteins such as the antihemophilic Factor VIII are a particular challenge.”
Because of the poor performance of traditional lyophilization procedures, Dr. Truong looked for other drying processes, settling on foam drying. “Foamy cake structures, or foam drying, is a half-century-old drying process dismissed as an unconventional and poorly designed freeze-drying strategy because the resulting material looked like a collapsed cake,” Dr. Truong comments.
“By altering the freeze-drying parameters slightly we are able to achieve the collapsed cake structures, which give the material a white-transparent look,” he explains. Given the right formulation, the foam-dried material adopts an amorphous, glassy structure that is found to be lower in stored energy as compared to the same formulation when freeze-dried or spray-dried. In this condition, both the global glassy-state motions and local molecular motions of the dried structure, as measured by neutron scattering, are lowered. This means longer glass relaxation time.
In scanning electron microscope pictures, the foam-dried material takes on a thick vitreous appearance that exhibits less specific surface area, so that the encased protein is less exposed at the air-solid interface as compared to the thinner, honeycomb structures of a typical freeze-dried cake.
These findings translate into longer shelf life, especially at room temperature. But in cases that still require refrigeration (at 2–8ºC or below), like with vaccines, there is great interest in improving storage stability to simplify product distribution.
Dr. Truong’s approach of foam-drying along with the addition of sugars as a cryo- and dessicoprotectant greatly improves product stability. His team was guided in this respect by Mother Nature. Bacterial species such as thermophilic bacteria produce thermoprotectants, unusual polysaccharides that enable them to resist extremely warm conditions and also help avoid formation of ice crystals inside the membrane of the virus or bacterium cell, which is the prime source of lowered viability.
Aridis has introduced other processing improvements, since the cake structures formed by foam drying are extremely nonuniform and inconsistent. For this reason, steps are taken to control the foaming action, and the material is thoroughly milled and mixed to generate product consistency.
The application of these approaches allowed Aridis to realize room temperature preservation of live viruses, effective powderization of live viral vaccines, and greatly improved overall stability.