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Introducing Lyostar III
 

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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    Introducing Lyostar III Introducing Lyostar III Presentation Transcript

    • Introductionofthenew
      FreezeDryer
      Enabling Maximum ProcessControl in FreezeDrying
      Emerging Technologies in FreezeDrying, Cambridge, UK, 11 May 2011
    • - 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
    • 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.
      • NowAvailable on thenewFTS/SP Scientific LyoStarTM3 developmentfreezedryer.
      3
    • 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
    • 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
    • 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
    • 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
    • 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
    • ControLyoTM-Nucleation on Demand-
      Nucleation on Demand Technology
      • Novel, patent pending approach
      • Uniformlyand instantaneouslyinduce
      nucleation at predefined temperatures.
      • Scalablefrom lab to production
      • Requires no formulation change or
      introduction of foreign materials into the
      vial.
      Why Nucleation Control?
      9
    • 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.
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 21
      Presented during “Emerging Technologies in Freeze Drying”, Cambridge, 11th May 2011. Event organised by BPS and BTL, www.biopharma.co.uk