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Figure 2. The SMART Freeze-Dryer Technology Process.
Figure 3. A graphical representation of an actual Smart cycle showing how tightly controlled the product temperature is 3° below its collapse temperature throughout primary drying.
In practice, in order to get good MTM data, a minimum product surface area of greater than 300 square centimeters or three quarters of a sample tray is required. Other requirements include that the lyophilisation system be relatively leak free, the sample be in an aqueous solvent, the recommended solids content be between three and 15% and the optimal vial fill is ideally no more than one-third the volume of the selected product container.
CRITICAL PARAMETERS IN CYCLE DEVELOPMENT
One of the critical parameters for successful cycle development using SMART Freeze Dryer Technology is the critical temperature at which the product needs to be maintained throughout the primary drying phase. This critical temperature is determined from either the glass transition temperature of the product (Tg’) or the collapse temperature (Tc) [3]. These values are most commonly determined by Differential Scanning Calorimetry (DSC) or Freeze-Dry Microscopy. The precision of the input parameters for set up of a SMART lyophilisation cycle will determine the quality of the MTM fit and therefore the resultant lyophilisation process design.
Figure 2 summarises the steps in SMART Freeze Dryer Technology operation. Based on user input, an initial temperature and pressure are automatically chosen by the SMART Freeze Dryer software. After transitioning to primary drying, MTM measurements begin and are fed into the SMART algorithms to determine the product temperature at the sublimation surface. The SMART software provides real time data on the product resistance, ice thickness, and heat transfer flow during primary drying (Figure 3). Using these process measurements, SMART automatically adjusts the shelf temperature and drying chamber pressure to maintain the optimal product temperature throughout primary drying.
SMART detects the end of primary drying and automatically proceeds into secondary drying. At the end of the process, SMART delivers an optimised lyophilisation cycle along with all the process data.
Figure 4 gives results from two case studies of process development savings that were achieved by applying SMART Freeze Dryer Technology. Both laboratories reported breaking even on their investment in new technology in less than three months. Primary savings were achieved through SMART’s ability to deliver an optimised lyophilisation cycle after just a few experimental runs. The average cycle development time was reduced by 62 days or 78%. Development savings, primarily in labour and active ingredient material costs, averaged $40,029. With an average of eight development programs per year, the average annual savings is $320,232.
CONCLUSIONS
SMART Technology has proven benefits in field use. Even the most experienced Lyophilisation scientists have achieved gains in cycle efficiency using Smart. The calculated data of dried layer resistance, ice thickness, heat flow and mass transfer and product temperature at the ice surface has proven extremely valuable in providing a never before available window into what is happening in the product while it is in the freeze-dryer.
In response to user feedback, the original Smart Technology has been enhanced to also offer Smart data collection on pre-existing recipes. This additional feature delivers the capability for the scientist to perform robustness testing, show equivalence or trouble shoot existing cycles while generating additional invaluable data from which to make informed decisions.
This tremendous improvement over the legacy method of trial and error cycle design is clear. Smart Technology delivers the capability to safely and quickly auto-optimise freeze-drying cycles based the specific requirements of each unique formulation. Thus, Smart Freeze-Dryer is truly the break- through method of choice for today’s Lyophilisation scientists.
REFERENCES
[1]. Tang, X; Nail, S.L; Pikal, M.J. Evaluation of Manometric Temperature Measurement, a Process Analytical Technology Tool for Freeze-Drying: Part I, Product Temperature Measurement. AAPS PharmeSciTech 2006, 7(1), E1-E9.
[2]. Tang, X; Pikal, M.J. Design of Freeze-Drying Processes for Pharmaceuticals: Practical Advice. Pharmaceutical Research 2004, 21(2), 191-200.
[3]. Gieseler, H; Lee, H; Mulherkar, B; Pikal, M.J. Applicability of Manometric Temperature Measurement (MTM) and SMART Freeze Dryer Technology to Development of an Optimised Freeze Drying Cycle: Preliminary Investigations of Two Amorphous Systems. 1st European Congress on Life Science Process Technology 2005, October 11-13, Nuremberg, Germany.
[4]. U.S. FDA Centre for Drug Evaluation and Research,
http://www.fda.gov/Cder/OPS/PAT.htm
[5]. Gieseler, Henning; PAT for freeze drying: cycle optimisation in the laboratory. European Pharmaceutical Review 2007, Issue 1, 62-67.
Figure 4. SMART Freeze-Dryer Technology Delivers Robust ROI - Case Study Details.
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