FRESH PERSPECTIVES
LyoPAT™: Real-Time Monitoring and Control of the Freezing and Primary Drying stages During Freeze-drying for Improved Product Quality and
Reduced Cycle Times T.N. Thompson Millrock Technology, Inc.
Freeze-drying consists of three major process stages: freezing, primary drying (sublimation), and secondary drying. Primary drying is the longest stage of the freeze-drying process. Most of the eff ort for process improvement has focused on measuring and controlling the product temperature as close to its critical point as possible to shorten the cycle. However, to produce a better product in a shorter period of time the focus needs to be on developing a suffi cient pore size and uniformity in the frozen product. Producing a better ice crystal structure, using an optimized freezing protocol, can result in both higher yields due to more uniform cake structures and shorter primary drying cycles due to reduced cake resistance.
Freezing Process
Freezing of solutions occurs in three major stages; (a) nucleation, (b) crystallization of the equilibrium freeze concentrate, and (c) solidifi cation of the maximal freeze concentrate. The fi rst two stages are crystal growth events. Each of these stages has its own unique challenges since the heat transfer from shelf to product changes dramatically and is not truly controlled.
Nucleation is the initial process of formation of a crystal in a super-cooled solution in which a small number of molecules become arranged in a stable structure upon which additional molecules are more easily deposited.
Once nucleation occurs, a portion of the water in the pre-lyophilized solution crystalizes. The amount of water that initially crystalizes depends on the degree of super-cooling and is typically between 3% and 19% (Figure 1). The initial ice propagation is limited to the capacity of solution and vial to absorb the latent heat of fusion of ice generated by the crystallization of water. As the ice grows from the nucleation sites, heat is released raising the temperature of the vial contents to approximately -0.50C and crystal growth signifi cantly slows.
Mr. Thompson is president of Millrock Technology, a manufacturer of high tech freeze dryers. Millrock Technology focuses on
improving freeze-drying equipment and control systems and has developed several recent
patents for new technologies. Mr. Thompson was previously the President of FTS Systems.
Post-nucleation, the remaining unfrozen water, up to 97%, begins to crystalize as heat is further removed from the vial. Ice crystalizes from the equilibrium freeze concentrate as the shelf temperature is reduced and further energy is removed. The rate of crystal growth during this freezing stage is not well-controlled and the ice forms at diff erent rates creating a heterogeneous
68 American Pharmaceutical Review | Fresh Perspectives 2013
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