Spotlight Cooling & Freezing Technologies
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.
Removing the Trial and Error From Developing Lyophilisation Cycles
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.
“Lyophilisation is a time and energy intensive process that can take days and weeks to complete”
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.
ACCELERATING LYOPHILISATION CYCLE DEVELOPMENT
Author Details:
Leslie Mather, Product Manager R&D Lyophilisers Tel: +1-845-687-5315
Email:
Leslie.Mather@
SPindustries.com
FTS SMART Freeze-Dryer™ Technology from SP Industries is a breakthrough development tool for accelerating and streamlining the development of lyophilisation cycles. Developed through a partnership between the University of Connecticut and Purdue University and partially funded through the Centre for Pharmaceutical Processing Research (CPPR), SMART Freeze-Dryer Technology run on an FTS LyoStar II System (Figure 1) provides both experienced and new lyophilisation scientists a means of developing optimised lyophilisation cycles with a reduction in average cycle development time of up to 78%, based on independent testing results. SMART Freeze Dryer Technology reduces the average cycle development process to one or two runs, rather than the conventional series of six to eight runs, not only reducing development time, but also reducing materials costs by one-third or more. This leaves the development scientist more time for studying other factors contributing to an optimised lyophilisation cycle such as excipient choices and parameter extremes and their subsequent effect on the freeze dried product.
Figure 1. FTS LyoStar II running SMART Freeze Dryer™ Technology.
The principle behind SMART Freeze-Dyer Technology is the use of the manometric temperature measurement (MTM) technology. MTM delivers an accurate calculation of the product temperature at the sublimation interface without having to place thermocouples or other temperature sensors in the product vials. Measurement of the product temperature at the sublimation interface is critical for determining the correct parameters for preventing product collapse or ‘melt back’ during primary drying.
The conventional method for measuring product temperature during a freeze drying cycle is by placing a few selected temperature sensors in vials. Note that placing sensors in the vials may affect the freezing and drying behavior of the samples by inducing ice nucleation or acting as a thermal pathway. These issues make placing a thermocouple in a vial, a less than ideal representation of what is actually occurring in the majority of vials present in the product chamber. In addition, temperature sensors or thermocouples placed in vials are located toward the bottom of the vial, not at the sublimation interface, and therefore do not give as accurate a measurement of product temperature at the sublimation-ice interface [1]. Thermocouples are sometimes difficult to repeatedly place in the same position and have their own inherent inaccuracies across their temperature range.
With the MTM technique, an isolation valve is placed between the product drying chamber and the freeze dryer condenser. Input parameters prior to running a SMART lyophilisation cycle include the number of product vials, the fill volume of the vials, whether the product is amorphous or crystalline, and the collapse temperature or eutectic point of the product. During execution of the lyophilisation cycle using SMART the isolation valve is rapidly and automatically closed and the rise in pressure is measured for 25 seconds at regular intervals during primary drying. The raw data is accumulated and used in the MTM equation to calculate the product temperature at the ice surface interface, the dried layer resistance, the ice thickness, and the heat flow and mass transfer.
SMART applies this information to automatically adjust the shelf and vacuum set-points of the lyophiliser during freeze drying, thus achieving and maintaining the product temperature precisely at the target temperature throughout the lyophilisation cycle.
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