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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.

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

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