Published on May 23, 2011
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: SMARTTMFreezeDryer Technology ControLyoTMNucleation 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
NowAvailable on thenewFTS/SP Scientific LyoStarTM3 developmentfreezedryer.
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 .  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 approachUniformlyand 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
Novel, patent pending approach
Scalablefrom lab to production
Requires no formulation change or
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%.   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
Reduce shelf temperature to complete the freezing step.
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
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