Current trends in freeze-drying
This article reviews the trends in freeze drying highlighted at recent Parenteral Drug Association (PDA) conferences
Controlled nucleation is one of the most topical trends in the industry, as the freezing step is of paramount importance for stability of products. The temperature range between 0°C and the real crystallisation temperature is called supercooling, spanning over 10°C in a freeze-dryer. Unfortunately, the lack of control of nucleation temperature can affect product uniformity and lead to suboptimal freeze-drying cycles.
Controlled nucleation technology allows for a significant decrease in the nucleation temperature variability. Different technical solutions are available; one is the ice fog technology, which consists of introducing small water crystals into the chamber. Another example is a method that creates an important pressure difference inside the freeze-dryer through a carefully timed depressurisation event. The question for the pharmaceutical industry relates to the advantage of controlled nucleation in terms of product stability compared to a more classical, well-established freezing protocol. The product data have now started to emerge and some of them will be reviewed during this edition of the PDA conference.
Process analytical technology (PAT) has been supported by authorities for more than 10 years. New analytical devices can now be added to freeze-dryers. Mass spectrometers can be adapted to check for absence of silicone oil. These devices are also used to analyse the different gas concentrations during freeze-drying cycles, allowing precise end-point determination of primary drying. This helps to assess reproducibility between cycles and during cycle development.
The Pirani probe, a pressure gauge using a hot wire system, is sensitive to different gases. This probe is used in combination with a capacitance diaphragm vacuum gauge, measuring the whole quantity of gases in the freeze-drying chamber. The system is also able to determine the end-point of primary drying. This kind of gauge has existed for years, but its recent capacity to sustain sterilisation allows it to become a PAT tool on industrial freeze-dryers.