LyoFlux-100-SalesTraining冻干技术

1、Lyoflux 100A Revolutionary Mass Flux Monitor for Pharmaceutical Freeze Dryers29-Feb-2008Confidential: Internal Sales Presentation2Commercial Section3General terms Units, manufactured by Physical Sciences, Inc. (PSI), are supplied to IMA Edwards on an OEM basis and exclusively sold by IMA Edwards und

2、er our own label. PSI has the right to sell Lyoflux for use on non-IMA Edwards pharmaceutical freeze dryers in service prior to December 2005. IMA Edwards is responsible for marketing, sales, and service of Units sold by us. PSI will provide continuing support as required and charge us for their ser

3、vices. IMA Edwards warrants the units under our standard warranty clause.4Price and availability Integrated units must be ordered (and are delivered) with the freeze dryer and include spool piece, optics, Lyoflux 100, control system integration. Selling price $159,950 Stand-alone units have a 6 week

4、 delivery and consist of: Lyoflux 100 (stand-alone version) $128,875 Spool piece modification: consult the factory5Lyoflux 100 Technical Specification ParameterSpecificationStand aloneIntegratedMeasurement rangeH20 densityH20 velocityH20 Mass FluxTotal H20 removed1014 to 3.5x1016 cm-3 (equals 3 mTor

5、r to 1 Torr at 273K)0 to Mach 0.9n.a.n.a.Accuracy *)Relative error H2O Mass FluxRelative error Total H2O Removed5.0%=500 sccm=500 sccm*) When H20 Velocity = 20m/s and H2O pressure 500mTorr7Technical Section8 What is the Lyoflux? Lyoflux applications Comparison with other PAT technologies Working pri

6、nciple Installation Lyoflux versions CalibrationContents9What does the Lyoflux 100 do?Measures mass flux of water vapor (note: mass flux = mass flow = sublimation rate = kg/hr)first and only one on the marketreal-time monitornon-intrusive sensorspecifically developed for the pharmaceutical marketThe

7、 Lyoflux 100 measures additionally:water vapor density (note: density = pressure = molecules /cm3)water vapor velocity (in the spool piece, m/s)total water removed (kg, for mass-balance determinations)FDA PAT tool:measures one of the most important characteristic of a drying process: the drying rate

8、10Why measure mass flux? Mass flux is equal to sublimation rate (speed of drying) Key parameter for cycle development (temperature, pressure, time) Enables cycle comparisonGives insight into the effect of freezing parametersDirectly related to shelf temperature Gives detailed information on the comp

9、lete drying processDrying rate vs. timeSupporting data for regulatory batch disposition11Lyoflux applications 1) Process monitoring (quality assurance) 2) Cycle development (pressure - temperature optimum) 3) Cycle transfer (scale-up and process equivalency) 4) Endpoint monitor (productivity improve

10、ment) 5) Future promise: product temperature12Process monitor I Gain additional and detailed process knowledgeProcess diagnostics (try to understand what is going on)Compare cycles (even if you dont understand the details)Verify performance over time (constant quality)Provide critical data during pr

11、ocess irregularities00.511.522.533.5400.050.1Runtime hrMass Flux g/sMass Flux and Spool Density 23-Jan-2007 00.511.522.533.54024x 1015Density molec/cc Mass FluxSpool Density13Process monitor IICorresponds with 98 mTorr H20 vapor pressureTemperature cycling of the shelves (PID loop mistuned)Chamber f

12、lash-offAdsorbed water on shelves desorbs0.050.1Run time hrMass Flux g/s 00.511.522.533.54024 x 1015Spool Density molecules/cc 14Process monitor IIIActivation shelf coolingAmount of water absorbed water on shelfsTotal water removed00.511.522.533.5400.050.1Runtime hrMass Flux g/s 00.511.522.533.54050

13、01000Water removed g 15Cycle development I Mass flux gives direct information on the effect of different process parameters on drying Determine optimum process parameters efficientlyQuantify the effect of P,T on drying timeQuantify the effect of different freezing cycles on drying time Real time mea

14、surement allows efficient exploration of P,T parameter space Reduces cost and lead time16Cycle development IIMass Flux Ts=0CHigher density due to lower gas Temp Ts=0CMass Flux Ts=40CLyomax 3: Pc=130mTorr, at shelf temperatures of 0C and 40C Density lowers due to increasing gas temp Ts=40C4Runtime hr

15、Mass Flux g/sLyomax run comparisons 00.511.522.533.5456 x 1015Density molecules/cc 17Cycle Transfer and Process Equivalency I Faster cycle transfers at reduced cost and lead time:Between lab and manufacturing dryers (process scale-up)Between manufacturing dryers (moving or expansion of validated pro

16、duction) Mass flux is the only parameter which scales with the size of the load (partially loaded freeze dryers) Lyoflux demonstrates equivalency of critical process attributes (change management: change vials, change stoppers, new shelves, etc.)18Cycle Transfer and Process Equivalency IIThere is a

17、direct correlation between the water vapor flux and the temperature of the sublimation front. This temperature is determined by the many details of the heat transfer process: shelf temperature, heat conduction, gas pressure, radiation, etc.Flux equivalency gives reasonable assurance of product tempe

18、rature equivalency.Flux deviations have been modeled and can be calculated back to temperature excursions of the product.T19Endpoint monitor I Quantifies primary drying endpoint Can detect the slowest vials in a batch Based on H20 density Enables shorter cycles Reduces operational cost510152025Runti

19、me hrH2O Density5Laggard vials20Endpoint monitor IIMinifast 10, 4% Mannitol, Pc=200mTorr, Ti=0C, 200 vials with 2ml, 2 vials with 4ml Nominal filled vialsOverfilled vials05101520250510 x 1015Runtime hrH2O Density molecules/ccPrimary drying endpoint detection (4% Mannitol) 0510152025-50050Temperature

20、 C T of over-filled vialT of 2 nominally filled vialsT shelf inlet21Commentary on previous slide The results demonstrate how sensitively the Lyoflux, now operated as a pressure meter and not as a flux monitor, detect the presence of 2 overfilled vials out of 200 vials. As an aside and general commen

21、t, pressure is a more sensitive indicator of end-point than flux.22Current developments, future applications Increased accuracy: 1% instead of 5% Shorter spool pieces: 30 instead of 45 incidence angle Expansion to non-aqueous solvent-based processesLyoflux 100 is presently only suitable for water va

22、por Secondary drying endpoint monitorBased on mass flux and vapor density in the chamberThis requires the higher 1% accuracyNot: residual moisture but time integrated water vapor flux Lyoflux for process control Estimate of the product temperature based on mass flux and vapor pressure (being develop

23、ed by PSI and UConn)Control of shelf temperature based on this modeled product temperature23 Comparison to other PAT-technologiesPirani-capacitance gauge comparisonPressure rate-of-rise measurement and MTMRelative humidity monitoring (LyoTrack, mass spectrometer)Thermocouples and RTDsMicrobalance No

24、ne of the above techniques measure the mass flow rate directly and are end point detection methods at best.Comparison with other PAT tools24 To measure mass flux (mass flow) in a gas directly (not a derivative measurement), one needs to know 2 things:how many molecules are there (density)and how fas

25、t do they move (drift velocity)mass flux is the product of these two Tunable Diode Laser Absorption Spectroscopy (TDLAS) can measure both pressure and speed Direct measurement, no calibration necessary (excepting the annual calibration of the tunable diode laser wavelength covered in a later slide)H

26、ow does Lyoflux work?25Working principle I Tunable Diode Laser Absorption Spectroscopy (TDLAS) is an optical method for detecting trace concentrations of one or more selected gases mixed with other gases.26Beer-Lambert Law:Measurement:H2O density determined by integrating the area under the absorpti

27、on peakWorking principle IIdIISNo,ln1knownmeasuredI = Io, exp S(T) (,T,P) N Io,= incident intensityI= transmitted intensity= optical absorption path length S= absorption line strength = lineshape functionN = molecular density27Doppler shiftVelocity: mass flux :Working principle IIIqvapor flowLaserDe

28、tector1.21.00.20.0-0.40.4-Relative Frequency cm-1 Normalized Amplitude frequency shiftD D w wqwwcosocvDAvdtdm/28Working principle IV Physical principlesBeer-lambert law (vapor density)Doppler shift (vapor speed) Combined with knowledge of :Duct area cm2 Allows determination of:Mass

29、 flux grams/sIntegration of mass flux provides a determination of the total amount of water removed from the product grams29Data Recorded during a Valve OpeningH2O density area under curve Velocity peak shiftIllustration of Doppler Shifting30 qDetectorFiber opticcable from laser diodeDiagnostic duct

30、 as assembled in IMA Edwards Minifast freeze dryerInstallation on a freeze dryerRequires special spool piece to mount the optical windows31Two available versionsStand-aloneNo controls interaction between FD and sensorSensor must be operated manually (starting / stopping / alarming)No pressure profil

31、es available during dryingAvailable for all freeze dryers (IMA Edwards and non- IMA Edwards )Not 21 CFR, Part 11 compliant IntegratedIntegrated within freeze dryer control systemCan be used for end-point monitoring / auto step advanceAutomatic operation, no operator intervention requiredSimultaneous

32、 logging of Lyoflux and FD dataOnly available on IMA Edwards dryers (Lyomax, Lyofast, Minifast)32Stand-alone version of the Lyoflux 100 Manual actions required from operator:Enter the chamber pressure (cycles with pressure profiles are not automatically possible)Zero the sensor (velocity) when the c

33、hamber is under vacuum and the main valve is closed Start/Stop data loggingStart the H20 mass flux integration to calculate total H2O removed at start of primary drying Monitor sensor alarm conditions 33Sensor validation Units are calibrated at the factory (TDLAS wavelength verification). The optica

34、l absorption path length is known and pre-programmed. There are no further adjustable parameters. Hardware and software has been extensively pre-tested. Test protocols and results have been documented and are available upon request.34Calibration CalibrationLyoflux measurement based on well known phy

35、sical principlesBeer-Lambert law and Doppler shift Gas molecules absorb energy at very specific wavelengths. At wavelengths even slightly different than these absorption lines, there is essentially no absorption Therefore: only laser wavelength needs to be calibratedCalibration interval: once per ye

36、arCalibration executed with a confocal etalon (Fabry-Perot cavity) Advised to run sublimation test after calibration35BACK UP MATERIAL and SUPPLEMENTAL INFORMATION36Minimum Required Sales Numbers To retain exclusivity with PSI for this product, we need to sell the following quantities:2008: 12009: 5

37、2010: 92011: 102012: 1137Comparison with other PAT toolsBatch methodsMethodPrincipleLimitationsPirani-Capacitance gauge comparisonPressure difference between the two gauges is an indication for the vapor density the chamberIndirect measurement Limited process informationOnly end point indicatorPress

38、ure Rise TestMeasures rise in chamber pressure after main valve closing. Requires process interruptionCan only be executed at certain intervalsRisk of product damageOnly end point indicatorHumidity monitoringMeasures the water vapor density in the chamberGives only process information at end of primary drying (no variation in humidity during first part of 1st drying) MTMPredicts the product temperature after main valve closingRequires process interruptionLimited to first part of primary dryingLimited to lab FD due to valve closing requirements38Comparison wit