Introducing Lyostar III


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Introducing the LyostarIII R&D freeze dryer, designed to maximise process control in freeze drying. Featuring SMART and Controlyo PAT systems.

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Introducing Lyostar III

  1. 1. Introductionofthenew<br />FreezeDryer<br />Enabling Maximum ProcessControl in FreezeDrying<br />Emerging Technologies in FreezeDrying, Cambridge, UK, 11 May 2011<br />
  2. 2. - Introduction -<br />Cuttingedge Research & Development freezedryerforlyophilizationscientists, developedby SP Scientific in conjunctionwithfreeze – dryingexperts.<br />Process Analytical Technology (PAT) Features:<br /><ul><li>SMARTTM</li></ul>FreezeDryer Technology<br /><ul><li>ControLyoTM</li></ul>Nucleation on Demand Technology<br />2<br />
  3. 3. SMARTTMandControLyoTM<br />Development Tool based on AdvancedProcess Analytical <br /> Technology: ManometricTemperature Measurement (MTM).<br /> Non-invasive <br /> Batch method<br />Available on FTS LyoStarTMFreezeDryersince 2006<br />Nowcompletedby an additional technology:<br /><ul><li>Allowscontrolofnucleationofproductsolutionatdefinedtemperaturesduringthefreezingphase.
  4. 4. NowAvailable on thenewFTS/SP Scientific LyoStarTM3 developmentfreezedryer.</li></ul>3<br />
  5. 5. SMARTTMFreeze Dryer was a joint development between UConn and Purdue University through the Center for Pharmaceutical Processing Research (CPPR).<br />WhatistheSMARTTMFreeze-Dryer?<br />Freeze Drying Process Development and Optimization by the Freeze Dryer during the First Laboratory Experiments.<br />SMARTTMis an expert system for freeze drying:<br />- Automatic determination of target product temperature<br /> - Selection of optimum chamber pressure(based on target product temperature)<br /> - Dynamic adjustment of shelf temperaturein primary drying<br />Based on somerequiredproductinformation (SMART settings)<br />SMARTTMandControLyoTM-SMARTTM – An Expert System-<br />NOTE: it is absolutely critical to precisely determine the critical formulation temperature of the product (e.g. by Freeze-Dry Microscopy )  this greatly affects the cycle design!!!<br />4<br />
  6. 6. SMARTTMFreeze-Dryer Technology-The Technical Conceptof MTM-<br />MTM – Core Technology of SMARTTM<br />The “MTM procedure”: <br /> Isolate chamber from condenser for a short period of time (i.e. 25 sec):<br />Monitor pressure rise,<br />collect pressure rise data (10 points/sec).<br /> Fit raw data to a pressure rise model function derived from heat and mass transfer theory (MTM equation) by non-linear regression analysis.<br />DIRECT evaluation of: <br />Vapor pressure of ice at the sublimation interface (Pice), <br />Dry product layer and stopper resistance (Rp+Rs).<br />INDIRECT evaluation of additional critical product and process parameters:<br />Software uses fundamental steady state heat and mass transfer equations to calculate (from Pice and Rp data) derivative parameters (Tp, dm/dt, Lice, Tb …). <br />5<br />
  7. 7. SMARTTMFreeze-Dryer Technology-The Operation Modes-<br />Two operation modes:<br />SMART Freeze Dryer:<br /> Use of "direct" and "indirect" parameters, automatic adjustment of shelf temperature or chamber pressure.<br />Auto-MTM:<br /> User pre-defined recipe, no automatic adjustment, requires less input parameters to SMART software.<br />6<br />
  8. 8. SMARTTMFreeze-Dryer Technology-Smart Cycle Design-<br />automaticallycalculatedby SMART TM (including a safetymargin)<br />SMART Tsauto-adjustmentstokeepTpinsidethedefinedboundaries<br />predefined SMARTTMsettings<br />Excellent agreement between Tb-TC and Tb-MTM for “typical” formulations [1].<br />[1] Gieseler et al. 2007, J. Pharm. Sci. 96(12):3402-3418. Full investigation of critical equipment and experimental factors for SMART technology.<br />7<br />
  9. 9. SMARTTMFreeze-Dryer Technology-Return on Investment-<br />SMARTTM Return on Investment<br />Delivers freeze-drying expertise to scientists new to freeze drying.<br />Ensures freeze drying cycle development is based on sound scientific principles rather than trial and error approach.<br />Reduces / eliminates dependency on thermocouple product temperature measurement:<br />Batch method,<br />non-invasive determination of product temperature and product resistance.<br />Provides consistent, automated MTM process data which saves even experts in the field of freeze drying significant time and money.<br />8<br />
  10. 10. ControLyoTM-Nucleation on Demand-<br />Nucleation on Demand Technology<br /><ul><li> Novel, patent pending approach
  11. 11. Uniformlyand instantaneouslyinduce </li></ul> nucleation at predefined temperatures.<br /><ul><li>Scalablefrom lab to production
  12. 12. Requires no formulation change or </li></ul> introduction of foreign materials into the<br /> vial.<br />Why Nucleation Control?<br />9<br />
  13. 13. ControLyoTM-Basics ofNucleation-<br />Basic Principles of Nucleation<br />Tf = ThermodynamicFreezing Point<br />Nucleation temperature is the temperature at<br /> which ice crystal formation begins.<br />Nucleation rarely occurs at the<br /> thermodynamic freezing point of the solution.<br />(Significant differences between lab and production environment!) <br />The degree of super-cooling has a great impact on drying behavior!<br />Degree of supercooling<br />Tn = Temperatur ofOnsetofNucleation<br />10<br />M. Shon, L. Mather, 2010. The Importanceof Controlling NucleationTemperatureDuringtheFreezeStep. IntorductionofControLyoTMNucleation on Demand Technology on the New FTS/SP Scientific TMLyoStarTM 3 FreezeDryer, SP Scientific, 3538 Main Street, Stone Ridge, NY.<br />
  14. 14. ControLyoTM-Basics ofNucleation-<br />SAMPLE<br />FREEZING<br />POINT<br />Low degree of supercooling:<br /> Larger ice crystals<br /> larger pores in the dried matrix<br /> decrease of Rp<br />High degree of supercooling:<br /> Smaller ice crystals<br /> smaller pores in the dried matrix<br />increase of Rp<br />SAMPLE<br />FREEZING<br />POINT<br />TEMPERATURE<br />TEMPERATURE<br />For every 1 degree increase in nucleation temperature, drying times are reduced by 3%. [1]<br />[1] Searls JA, Carpenter T, Randolph, TW., 2001. The IceNucleationTemperatureDeterminesthe Primary Drying Rate ofLyophilizationfor Samples Frozen on a TemperatureControlledShelf. JpharmSci 90: 860-871.<br />11<br />
  15. 15. ControLyoTM-UncontrolledNucleation-<br />Common uncontrolled nucleation during freeze drying<br />random nucleation occurred within a temperature range of 10°C and a timeframe of 48 min in this case.<br />Adverse effects of uncontrolled nucleation:<br />Problems in scale up and process transfer<br />colder nucleation  higher Rp  longer process time  higher costs<br />longer cycle  less throughput  more facility capacity required<br />vial to vial uniformity impossible (cycle time )<br />M. Gieseler, L. Mather, 2011. Unpublished Data, SP Scientific.<br />Example: 5% Sucrose, 3 mL in 10 mL vials, 1 tray LyoStar3, 3 shelf unit<br />12<br />
  16. 16. ControLyoTM-The NucleationProcedure-<br />How does ControLyoTMwork?<br />A typical sequence for controlled nucleation:<br />Equilibration of the samples at the nucleation temperature.<br />Pressurization of the system with an inert gas (N2, Ar) to approximately 25 - 28 psi (1.7 - 1.9 bar).<br />Equilibration of the samples. <br />Rapid depressurization (from 28 psi to 1 - 2 psi/0.07 - 0.14 bar).<br /> Nucleation<br />Hold at nucleation temperature to allow ice crystal growth (Ostwald ripening).<br /><ul><li>Reduce shelf temperature to complete the freezing step.</li></ul>Video<br />13<br />
  17. 17. ControLyoTM-ControlledNucleation-<br />Controllednucleation<br />Example: 5% Sucrose, 3 mL in 10 mL vials, 1 tray LyoStar3, 3 shelf unit<br />DEPRESSURIZATION<br />NUCLEATION<br />M. Gieseler, L. Mather, 2011. Unpublished Data, SP Scientific.<br />14<br />
  18. 18. ControLyoTM-Adaptation toyour System-<br />Praxair’s ControLyoTMTechnology <br />Implementation:<br />Praxair:0.6, 1 and 5 m2freeze-dryers<br />Lyophilization Services of New England: 1 and 5 m2freeze-dryers<br />Retrofitable for SIP-rated freeze-dryers<br />Nucleation control at temperatures up to -1 °C <br />Batch sizes up to 3.150 vials (5 m2 full load)<br />No limitations in choice of container systems <br />No contaminants or changes to drug formulation<br />15<br />
  19. 19. SMARTTMandControLyoTM-LyoStarTM 3 Innovations-<br />New functions implemented in LyoStarTM 3<br />ControLyoTM (optional)<br />Allen Bradley PLC<br />2Capacitance Manometer (1 in chamber, 1 in condenser)<br />TDLAS readiness<br />Pirani / CM Differential Control software<br />Barometric Endpoint Control software<br />Vacuum ramping during primary drying<br />Vacuum pre-seal feature<br />Product driven mode<br />Ability to control with Pirani<br />Heat transfer fluid: Silicone oil<br />SMARTTM Freeze-Dryer Technology available as option!<br />16<br />
  20. 20. ControLyoTM-Experimental Results-<br />Benefits of ControLyoTMTechnology<br />Acceleration of 1°drying<br />To achieve comparable results PRCM Diff mode was used ( Setpoint: 5 mTorr) for all runs performed.<br />24% (avg.) reduction in 1°drying time was achieved for Controlled Nucleation.<br />M. Gieseler, L. Mather, 2011. Unpublished Data, SP Scientific.<br />Example: 5% Sucrose, 3 mL in 10 mL vials, 1 tray LyoStar3, 3 shelf unit, processed with and without controlled nucleation.<br />17<br />
  21. 21. ControLyoTM-Experimental Results-<br />Benefits of ControLyoTM Technology<br />Reduction in protein aggregation<br />Human growth hormone (hGH) known to be sensitive to aggregation at gas-liquid interfaces.<br />Good model to test whether ControLyo™ technology creates bubbles during depressurization. <br />ControlledNucleation<br />UncontrolledNucleation<br />Experiments: 2 mg/mLhGH+ 2 mMsodiumphosphate + 6 mg/mLsucrose<br />1 mL fill in 5 mL vial<br />Assay hGH aggregation via HPLC <br />(pre-& post-freeze drying and after 14 days at 50°C)<br />Michael J. Pikal, School of Pharmacy, University of Connecticut, “Understanding The Importance of Ice Nucleation Temperature in Freeze Drying”, Lyophilization of Biologicals Conference, 24th January 2011, Brussels<br />18<br />
  22. 22. SMARTTMandControLyoTM-Conclusion-<br />Conclusion<br />Over the last few years since SMART Freeze Dryer technology became available on the market, the concept of MTM and the SMART Freeze Dryer evolved as an important and valuable PAT tool for freeze-drying.<br />ControLyoTMallows access to a so far nearly uncontrollable part of the Freeze-Drying Process. Controlled Nucleation clearly proved to optimize batch uniformity and reduce primary drying time due to higher nucleation temperatures.<br />Combining both technologies in one development freeze dryer enables maximum process control for freeze drying!<br />19<br />
  23. 23. SMARTTMandControLyoTM-IntroductionofLyostar 3-<br />THANK YOU FOR <br />YOUR<br />ATTENTION<br />Would you like to learn more about freeze drying ? Go to the following site to discover more about our free LyoLearn webinar series:<br />20<br />
  24. 24. 21<br />Presented during “Emerging Technologies in Freeze Drying”, Cambridge, 11th May 2011. Event organised by BPS and BTL,<br />