Lyophilization of pharmaceutical and biopharmacetical products

Freeze-drying is a dehydration process in which water is removed by sublimation of ice. The resulting substance, the lyophilisate, is a friable, highly porous solid. As a result, it has a very high affinity with a solvent (usually water). This property is probably the origin of the name of the lyophilization process, the word lyophile meaning "friend of solvents" from the Greek "lyophile". Originally, it was a natural phenomenon that enabled certain foods to be preserved by populations benefiting from the combination of different climatic conditions (cold, dry winds, solar heat and rarefied atmosphere) found in mountainous regions. Freeze-drying began to be used on an industrial scale during the Second World War, to transport human blood over long distances when demand became critical. Today, it has become a particularly widespread industrial operation in the agri-food and pharmaceutical sectors. Despite this industrialization and increasing use, the technology based on keeping a product under vacuum at low temperature for long periods remains very costly and is used for high value-added products. In the pharmaceutical field, freeze-drying is used to preserve vaccines, and many pharmaceutical and biopharmaceutical products, which are highly labile in solution, stemming from the intensive development of biotechnologies for the latter.

In order to reduce the costs of a freeze-drying cycle, and to obtain a freeze-dried product that meets the standards required for marketing, it is necessary to optimize the various parameters associated with ice formation, and with the transformation of ice into water vapor, in order to reduce the duration of the ice sublimation operation. Optimizing these parameters to reduce sublimation time requires an understanding of the physical phenomena associated with heat transfer, matter transfer and phase transformation of water and water-solute mixtures. Freezing and sublimation operations must be controllable, so that they can be stopped as soon as necessary to avoid unnecessarily extending the duration of a freeze-drying cycle.

When freeze-drying biopharmaceutical products (peptides, proteins), they are exposed to various sources of stress (such as ice formation, high pH variation, low temperature, dehydration...), which can induce a loss of biological activity and render the active ingredient ineffective. Excipients are often used in complex, empirically developed formulations.

This article shows the various physical phenomena involved in the freeze-drying technique, and presents the main parameters (both in terms of operating mode and formulation) that need to be optimized and/or controlled so that the pharmaceutical product meets the standards required to be marketable and cost-effective.