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Equipment and Processing Report
Efficient freeze-drying processes result in time and energy savings, reduced failure rates, and improved batch consistency.
In a typical freeze-drying cycle, a product is placed in vials and dried on a shelf in a freeze dryer by first lowering the temperature sufficiently to ensure that the product is completely frozen. In the subsequent primary drying phase, the chamber pressure is reduced to induce sublimation of the frozen solvent (see Figure 1). A secondary drying phase is performed to achieve the required dryness. The key characteristics of a freeze-drying cycle are the temperature and pressure gradients. The behavior of a product as it dries, however, is affected by many additional factors, such as vial size, condenser volume, product purity, batch size, and equipment specifications. The following aspects should be considered when designing a freeze-drying cycle and choosing freeze-drying equipment. Optimize freezing conditions There are three main factors to consider when optimizing the freezing stage of the cycle: the product must be fully frozen; the ice crystal structure should be open to aid sublimation; and complete freezing should be achieved at as high a temperature as possible to save time and energy. Annealing and controlled nucleation can help create optimal freezing conditions. Annealing. Freeze dryers can be programmed to incorporate multiple ramp and hold functions to achieve the required frozen structure. Some programs use an annealing process, which is a technique of raising and lowering the temperature over a range of a few degrees to control the freezing. Controlled nucleation. Studies have shown that with uncontrolled nucleation, the drying time for the last vial to nucleate could be almost 20% longer than the first vial and 45% longer than a vial made to freeze close to its thermodynamic freezing point by controlled nucleation (1). Controlled nucleation techniques (e.g., ControLyo by Praxair) make it possible to induce freezing at the maximum safe temperature for the product. For every 1°C increase in the nucleation temperature, primary drying time can be reduced by as much as 3-4%, and the overall time to freeze the product can be reduced (1). Supercooling. Supercooling is a phenomenon in which the product is cooled below its freezing temperature without ice forming, resulting in unpredictable freezing behavior that may be several tens of degrees below the measured thermodynamic freezing temperature. Because ice crystals require a nucleating point in order to form, supercooling is likely to occur in ultra-filtered pharmaceutical formulations. Controlled nucleation is a useful method for controlling this behavior. Choose the right vacuum pump Most common laboratory pumps, such as single-stage pumps, diaphragm pumps and central vacuum systems, are powerful enough for freeze-drying applications. Most freeze dryers require a pump with an achievable vacuum of the order of <1 Mtorr, measured directly at the pump, according to pump manufacturer data. This vacuum will provide close to 100% of the pumping-speed performance across the typical working range of freeze-drying vacuum requirements. If the freeze-drying system is specified correctly, then the condenser will trap all condensable vapors, and the pump will provide initial pulldown and maintain set vacuum. Vacuum-pump maintenance is often overlooked, but it is one of the more important day-to-day tasks that users can complete simply and easily to ensure the long-term performance of the freeze dryer.
Balance vacuum and temperature
The sublimation of ice crystals during the primary drying phase occurs due to the combination of vacuum pressure and temperature (see Figure 1). The system must achieve a vacuum lower than the vapor pressure of the frozen product temperature to begin the sublimation process. Getting the balance right is the key to achieving the fastest possible rates of sublimation. A common misconception about the drying phase is that the vacuum sucks the moisture out of the sample. If this were the case, then a lower pressure (i.e., a higher vacuum) could speed the process. In freeze drying, however, the purpose of the vacuum is to achieve sublimation of the frozen solvent. Increasing the vacuum further does not speed up this process; in fact, it actually slows it down, because fewer air molecules are available to provide heat to drive sublimation.
Consider condenser parameters
The temperature of the condenser isn’t as important as trapping rate. To condense and freeze the solvent, the condenser needs only to be colder than the product in the chamber. Trapping rates are related to the design (i.e., size and shape) of the condenser. As the ice builds up, the temperature on the surface of the ice will not be as cold as on the condenser surface, and trapping rate might fall. If the deposition rate is exceeded, the risk is that vapor will bypass the condenser and potentially contaminate the vacuum pump, thus reducing its useful lifespan and increasing maintenance. A common misconception is that a colder condenser will improve freeze drying and ‘suck the water out faster,’ whereas specifying colder condensers for straightforward applications will simply increase the cost and complexity of the equipment. Colder condensers are best employed when processing solvents other than water that may have lower freezing points. The actual rate at which drying can progress is far more influenced by the product itself and is highly dependent on the formulation’s parameters, the type of container (e.g., bulk trays or vials), and the fill depth per container. All of these data are used to calculate the total shelf area required to accommodate that load and the optimum choice of freeze-dryer design. On larger production dryers, it is increasingly common to employ automated loading and unloading systems, and shelf spacing also needs to accommodate mechanisms of such equipment.
Choose the right container size
A cycle that has been prepared and adopted for a 10-mL vial with a particular fill depth will not necessarily be suitable for a differently sized vial, even with the same fill volume of the same product. Clearly, changing the vial size changes the product depth. This change may result in the product drying more quickly, therefore, requiring additional thermal energy from the shelf to counteract sublimation cooling, or more slowly, requiring less heat energy and extended primary drying. A small change in fill volume could also increase the overall vapor load of the batch, thus decreasing the drying rate or even overloading the condenser. Different vial dimensions will affect the rate at which vapor can leave the product, which affects the speed of drying. This characteristic can be useful. For example, a cycle time can be decreased by choosing a larger vial with a shallower fill depth, but conversely the maximum number of vials per batch will also be reduced. It is important to find the right balance between vial size, batch size, and cycle duration.
Tailor cycles to formulas
Different formulations of product will freeze dry differently. Concentration alone can significantly affect the processing characteristics of a product, which will consequently affect drying time and batch parameters. Different excipients have different thermal characteristics, so alterations to a formulation’s make-up can affect the freeze-drying cycle. Even small changes in formulation, batch parameters, and equipment can all have an impact on the process requirements. It is therefore not advisable to re-use an existing freeze-drying cycle for a reformulated product. It is essential to know the critical freeze-drying parameters of a formulation, particularly when submitting for regulatory approval. Formulations for freeze drying often exhibit complex and unpredictable behavior, and detailed knowledge of this behavior is vital for effective cycle development. Significant thermal events include collapse, glass transitions, eutectic melting, and crystallizations. The most important critical temperature is the point below which the formulation must be cooled for complete solidification and maintained during primary drying to prevent processing defects. A variety of analytical techniques, including differential scanning calorimetry, differential thermal analysis, impedance analysis, and freeze-drying microscopy, can be used to identify freeze-drying parameters. It is advisable to use several analyses to ensure that a complete and accurate picture is formed. When changing a formulation, for whatever reason, the product’s changing characteristics should be kept in mind. Not only will this prevent unexpected process failures later down the line, it may be possible to reformulate to provide a more favorable thermal profile and improve efficiency.
1. J.A. Searles, T. Carpenter, and T.W. Randolph,
J Pharm Sci.
90 (7) 860-871 (2001).
About the Author
Katriona Scoffin is a freelance science writer working for Biopharma Technology Ltd (BTL), a CDMO with expertise in freeze drying;
Vol. 39, No. 4
When referring to this article, please cite it as K. Scoffin, “Designing Trouble-Free Freeze-Drying Processes,”
39 (4) 2015.