PAT Tools for the Optimization of the Freeze-Drying Process

1. Freezing: the product to be dried is put over shelves in a chamber and its temperature is lowered so that the water (or the other solvent) is frozen. Unfortunately, not all the solvent freezes forming ice crystals, but a certain amount (sometimes significant) remains bonded to the product and must be finally desorbed. In some cases the product (the drug and the excipients) does not crystallize, but forms an amorphous glass which can retain a high amount of moisture. 2. Primary drying: the pressure of the chamber where the product is placed is reduced to a low value, thus causing ice sublimation. This process is carried out at very low temperatures (typically in the range -40°C to -10°C), but it requires energy that is generally supplied through the shelves. 3. Secondary drying: the amount of residual water, strongly bonded to the partially dried product, is reduced to a low value by using high vacuum and moderate temperatures, e.g., 20°C to 40°C. This step is required to ensure the long term preservation of the product.