FRESH PERSPECTIVES
Figure 1 - Uncontrolled Nucleation (-10.5°C to -13°C)
Figure 3 - Controlled Nucleation at -3°C
Figure 2 - Uncontrolled Nucleation and SMART™ Cycle Optimization
Figure 4 - Controlled Nucleation at -3°C Followed by SMART™ Cycle Optimization
Conclusion
Subsequent to the research in this paper, a number of biopharma research and production groups have scaled-up the ControLyoTM
Technology by temperature. Figure 4 shows the subsequent SMART™ cycle. There
are two signifi cant diff erences between this and the SMART™ cycle in the uncontrolled nucleation run. The fi nal shelf set-point determined by SMART™ was -9°C which is 12.5°C warmer than the uncontrolled run. The end point of primary drying, (again determined by Capacitance Manometer/Pirani gauge convergence), was approximately 17 hours.
The controlled nucleation cycle was more than 40% shorter than the cycle run without controlling nucleation. In the controlled nucleation run, larger ice crystals were formed that resulted in larger pores, less resistance to mass fl ow, and higher sublimation rates during the freeze-drying process, resulting in reduced cycle time. Additionally, because of the higher vapor fl ow, there is a greater “self-cooling” eff ect, allowing more heat to be put into the product without collapse. Hence the higher shelf set point was automatically determined and set by SMART™.
56 American Pharmaceutical Review | Fresh Perspectives 2013
retrofi t of existing production dryers. These groups have demonstrated that the technology is both scalable and can result in signifi cant commercial benefi ts. We believe the industry is moving rapidly to adopt controlled nucleation as a critical step in the freeze-drying process.
References 1.
2. 3. 4.
Tang, X., Nail, S.L., Pikal, M.J. (2005). Freeze-Drying Process Design by Manometric Temperature Measurement. Design of a Smart Freeze Dryer. Pharm. Res. 22(4), 685-700.
Sever, R.R., (2010). ControLyo™ Nucleation On-Demand Technology. SP Scientifi c Lyolearn Webinar. http://www.spscientifi
c.com/ControLyo-Improvement
Pikal, M. (2011). Quality by Design and Scale-Up Issues in Freeze Drying: The role of controlled ice nucleation. SP Scientifi c Lyolearn Webinar. QbD-and-Scale-Up
http://www.spscientifi
c.com/
Searls, J.A., Carpenter, T., Randolph, T.W. (2001). The Ice Nucleation Temperature Determines the Primary Drying Rate of Lyophilization for Samples Frozen on a Temperature Controlled Shelf. J. Pharm. Sci., 90:860-871.
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