Scale‐Up Of Freeze‐Drying Cycles

By Stefan Schneid, Ph.D. Freeze-Drying Focus Group University of Erlangen, Germany

Laboratory scale freeze dryers are used for lyophilization of small amounts of product, either for simple preparation of relatively robust materials or for cycle development and subsequent transfer to a larger scale. If the lyophilization process developed is to be scaled up later on, it is beneficial if the freeze dryers employed on the various scales are constructed similarly. The relevant structural features include 2‐chamber vs. 1‐chamber design, cooling and heating rates of the shelves, condenser temperature and radiation effects from chamber door and walls. If vastly different freeze dryer setups are applied on the different scales (e.g. freezing outside the lyophilizer and primary drying without proper temperature control), a rational transfer to a larger scale is extremely difficult, and major additional experiments and optimization is required on the manufacturing scale freeze dryer which is much more expensive.

However, if equivalent or similar equipment with good instrumentation is used, it is possible to design an optimized cycle including determination of process robustness in the laboratory, and save time and money during the scale‐up process. This also applies to process control, for example use of identical sensor types for pressure control (Capacitance Manometer vs. Pirani vs. Thermocouple Vacuum Gauge) to ensure the same chamber pressure is used in all freeze dryers. Some major differences in freeze dryer construction cannot be avoided (i.e. ratio of vials in edge position to vials in center position, differences in radiation of walls and door, etc.), but can be compensated by process adaptations later on. In this context, environmental factors also play a large role, especially the particle‐free conditions in a manufacturing environment compared to the laboratory scale.