FRESH PERSPECTIVES
Simply put, all the researcher has to do is load the dryer and click the “SMART™” icon on the software to achieve an optimized cycle without ever touching the dryer again. When SMART™ was developed, companies showed a reduced cycle development time from an average of 60 days to an average of 13 days.
Another key cycle optimization technology was introduced by Praxair in 2011. This technology is called ControLyo™ Nucleation on Demand Technology, and is also incorporated in SP Scientifi c’s Lyostar 3 Freeze Dryer [2]. Its function is to control the nucleation of the product solution in the freeze dryer, i.e. the solution in all vials (or bulk, syringes, etc.) nucleates at the same time and temperature, which is predefi ned by the researcher. This is important to reducing cycle times as nucleation temperatures determine the ice/product morphology. Until the advent of the technology, all freeze dryers exhibited a phenomenon called “supercooling”. When a product supercools, it freezes at a temperature that is below its thermodynamic freezing point [3]. The greater the supercooling, the lower the temperature at which freezing begins (termed nucleation). In a development freeze dryer, nucleation commonly occurs in the temperature range between -10° and -15°. In a clean Class 100 cGMP environment, it may be as low as -40°C. Again, the inherent problem with supercooling is the greater the supercooling, the smaller the ice crystals that form during freezing. As the drying progresses, small ice crystals lead to small pores and greater resistance to mass fl ow. Therefore, it is more diffi cult to get the sublimed water vapor out of the freeze-dried cake, and the process of primary drying takes longer. Research has shown that for each 1°C warmer nucleation can take place, primary drying time can be reduced
by 3% [4]. Another advantage of the Praxair technology is that it eliminates the random nature of typical uncontrolled nucleation, where vials nucleate at diff erent times and temperatures as the temperature is ramping during the freezing phase. This can lead to a variety of process and product problems. In an industry where vial-to-vial uniformity and product homogeneity is critical, uncontrolled/random nucleation leads to vial-to-vial diff erences.
Given the availability of these two critical Process Analytical Technology (PAT) tools on one development freeze dryer, SP ran a series of experiments where the nucleation temperature was controlled during the freezing phase and allowed SMART™ to automatically optimize the primary drying cycle. They then compared those results with a run where nucleation was uncontrolled and SMART™ optimized the primary drying cycle.
Figure 1 illustrates the freezing phase in an uncontrolled nucleation of vials containing 5% sucrose. Due to the eff ect of supercooling, nucleation temperatures ranged from -10.5°C to -13°C. Self-adhesive thermocouples were attached to the outside of the vials to prevent the thermocouple itself from aff ecting the nucleation event. The subsequent SMART™ cycle is shown in Figure 2. Two points are worth noting. First, after the initial few shelf adjustments, SMART™ held the shelf temperature at -21.5°C throughout primary drying. Secondly, by using Capacitance Manometer/ Pirani diff erential pressure control to determine the end of primary drying, it was delineated at about 27 hours.
Figure 3 shows a graph of the freezing phase in a run where nucleation was controlled at -3°C. All vials nucleated at exactly the same time and
Rapid and Rational Development of Stable Lyophilized Protein Formulations: A Hands On Training Course
March 11-14, 2014
Warminster, Pennsylvania Limited Space Available
Presented by:
Dr. Jeff Schwegman: Founder and CEO, AB Biotechnologies
Dr. John Carpenter: Professor of
Hands On Learning Opportunities:
• Formulation development and optimization using the TA Instruments Microcalorimeter.
• Lyophilization of protein formulations using a variety of SP Scientific Development Freeze Dryers.
• Evaluate the structural differences between native and formulated proteins using the Biotools PROTA Analyzer.
• Measure and characterize nano-scale particles, such as protein aggregates, using Nanosight instruments.
• Utilize the Affinity Biosensors Archimedes to measure particle aggregation and agglutination.
Pharmaceutical Sciences and Co-Director of the Center for
Pharmaceutical Biotechnology, University of Colorado
Course Objectives:
This course has been designed in collaboration with leaders in the academic and industrial communities to address the issues of optimal formulation and stabilization of protein molecules. By getting involved early in the development phase of the drug, vaccine or diagnostic protein, and understanding the keys to successful formulation and stabilization, the development scientist is able to deliver a product on time that is safe, effective, has a long shelf life and meets the FDA’s established guidelines for this type of molecule.
In Collaboration With:
To Learn More or Register Visit:
www.SPScientific.com/ProteinHandsOn Course fee of $4900 USD includes hotel accommodations, meals, lab fees and materials.
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v2.indd 1 55 American Pharmaceutical Review | Fresh Perspectives 2013 12/11/2013 1:09:26 PM
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