Lyophilisation (or freeze drying) is the preferred process used by the pharmaceutical industry to preserve pharmaceutical products with minimum disruption to their formulation and preserve quality, while substantially increasing shelf life.

Lyophilisation works by freezing the material, and then reducing the surrounding pressure and adding enough heat to allow the frozen water in the material to sublime directly from the solid phase to the gas phase. Lyophilised products can be reconstituted quickly and easily, which is important for medical application.

However, pharmaceutical quality control and validation places significant demands on process reproducibility and product uniformity. New product formulations are increasingly putting more rigorous demands on the low temperatures and cooling rates that are crucial to the process.

Freeze drying is essentially a batch operation with complex cycles lasting for several hours or more, but until now technology has been limited when it comes to thermal control of the shelves and condensers of pharmaceutical freeze dryers, both integral components in the two-step lyophilisation process.

The rate of cooling and temperatures that must be achieved by the vials are critical parameters that affect batch-to-batch uniformity. Cooling must be carefully controlled, and at times during the process may be either very rapid or stopped altogether. At all times it must follow a precisely defined temperature profile that must be maintained within ±1°C.

Typical mechanical refrigeration systems struggle to achieve temperatures much below -50°C, and rapidly lose the capacity to provide rapid and accurate temperature control at low temperatures. Cryogenic systems have the promise of providing almost unlimited cooling capacity, but current technology limits the achievable temperatures to about -60 to -65°C.

New product formulations and processes are looking for improved temperature control and even lower temperatures down to -70 to -80°C.

Equally important is the second step of the lyophilisation process, when the product is dried through sublimation. This part of the process is equally complex and has unique thermal demands. The cooling requirements now shift from the shelves to the condenser. New products are placing even more demands on the low temperatures required to well below -120°C.

Current approaches to achieve these low temperatures, such as direct liquid nitrogen injection, flooding with refrigerants or using heat transfer fluids, either result in temperature extremes with little or no control, uniformity or flexibility, or cannot achieve the low temperatures necessary.

Cryogenic technology is able to achieve these temperatures with a high degree of cooling rate control and flexibility, so is becoming very attractive to the pharmaceutical industry.

Additionally, the industry is pushing new frontiers in biomedical research, incorporating a wide range of medicinal products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues and recombinant therapeutic proteins created by biological processes from human, animal or micro-organic sources.
These highly complex protein based formulations are ultra-sensitive to temperature changes and are therefore vulnerable to degradation.

Linde’s research on cryogenic lyophilisation is poised to surpass traditional approaches. The company’s proprietary cold gas cooling technique for condensers enable temperatures ranging from -60 to -170°C with a high level of control and uniformity.

The gas company’s latest technologies for shelf cooling will enable more optimal heat transfer delivering lower shelf temperatures than ever before – around five to 10°C colder than is currently possible – in turn enabling higher cooling rates and use of high viscosity fluids.

New cryogenic freezing methods will enable an improved degree of control that enables advanced pharmaceutical products to be handled without compromising quality or yield during their life cycle of production, formulation and storage.

Concluding, Beatrice Chinh, Applications Development Manager at Linde, said, “The increasing number of biologic drugs in the R&D pipeline gives industrial gas companies the opportunity to provide well-engineered solutions to improve process control.”

Boosting yield
“It is important to control the molecule’s microenvironment at every stage of the product lifecycle so that it maintains desired quality, and so the need for a consistently uniform cryogenic cooling process beyond present capabilities has become absolutely critical – this not only impacts quality, it also reduces manufacturing costs,” says Shivan Ahamparam, Linde’s Market Segment Manager.

“These high value products are expensive to produce and manufacturers could save millions by boosting their yield during the downstream lyophilisation phase.”