Removing the Trial and Error From Developing Lyophilisation Cycles

Lyophilisation is a proven method for greatly increasing the shelf life and stability for a large variety of products, which are unstable in their native state. The growing prevalence of protein-based therapeutics is driving the increasing need for improved methods of freeze-drying process development. In order to streamline the drug development approval process, cycles must now be justified for each specific product. The goal is to have the most
efficient cycle possible designed around the formulations unique thermal properties. Smart™ Freeze-Dryer technology delivers the cycle optimisation technology to the formulation scientist so that the most efficient cycle can be derived in as little as one freeze-drying run.

FREEZE DRYING PROCESS DEVELOPMENT CHALLENGES
Major challenges in lyophilisation are development of an optimised lyophilisation cycle and the scale-up of the lyophilisation cycle from a laboratory to a pilot or production scale unit. Understanding the characteristics of
the product and the lyophiliser performance is a crucial prerequisite to successful freeze-drying. Many products that are candidates for freeze drying, such as protein based therapeutics, are in short supply and can be very expensive to produce. Lyophilisation is a time and energy intensive process that can take days and weeks to complete. Shortening the lyophilisation cycle development process to produce an optimised lyophilisation cycle, can increase efficiency, accelerate development time and thus reduce time to market and save valuable product. Transfer of an optimised lyophilisation cycle from the development stage to production scale should provide the most efficient drying cycle, thus furthering the return on investment.

The lyophilisation process consists of first freezing the product to a temperature at which all formulation components form a rigid solid. This is followed by primary drying, in which up to 95% of the frozen water or ice is
removed. During primary drying, controlled temperature shelves are utilised to provide the energy for sublimation of the ice. In-turn the pressure in the chamber must also be controlled in a way that heat can be added to the product to facilitate sublimation of the water, without causing melting or instability of the already dried product matrix. The sublimated water vapor from the product, travels into the product chamber and is transferred to the condenser due to the pressure differential between the product chamber and the condenser. The water vapour is then frozen onto the coils or plates in the condenser, thus helping the condenser to remain in a low pressure condition relative to the product chamber [1]. Any remaining water not removed during primary drying is removed during a secondary, desorption drying step.

Critical parameters in developing a lyophilisation cycle and to successful freeze-drying include knowing the collapse temperature of the formulation, the stability of the active pharmaceutical ingredient, and the properties of the excipients [2]. In addition to properties of the formulation, shelf temperature, chamber pressure, system geometry and the product container all play major roles in lyophilisation cycle development. Many lyophilisation processes are developed in a ‘trial-and-error’ manner that often results in unoptimised lyophilisation cycles that may not transfer well from the laboratory to production scale-up.