VG09-171-0 Application of a TDLAS-based Water Vapor Mass Flow
Transcript of VG09-171-0 Application of a TDLAS-based Water Vapor Mass Flow
VG09-171-0
Application of a TDLAS-based Water Vapor Mass Flow Sensor for Monitoring
Pharmaceutical Freeze Drying
Flair 2009Flair 2009
W.J.Kessler, G.Caledonia, M.Finson, J.Cronin, D.Paulsen, K.L.Galbally-Kinney, P.A. Mulhall, S.J.Davis and D.M.Sonnenfroh
Physical Sciences Inc., Andover, MA
H. Gieseler, S. SchneidDepartment of Pharmaceutics, University of Erlangen (Germany)
M. J. PikalSchool of Pharmacy, University of Connecticut, Storrs, CT
A.SchaepmanIMA Edwards, Dongen, The Netherlands
September 6 – 11, 2009Garmisch-Partenkirchen, Germany
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LyophilizationLyophilization
Conversion of a liquid product to a freeze-dried solid state to improve chemical and physical stability
Freeze Drying primary steps:1. Freezing: Conversion of most of the solvent to solid (ice)2. Primary drying: Removal of frozen water by direct sublimation3. Secondary drying: Removal of bound water by desorption
Condenser ~ -70 CChamber
VacuumCondenser ~ -70 C
ChamberVacuum
Chamber pressure controlled to ~100 - 300 mTorr
Gases: water vapor and nitrogen
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Motivation for Sensor DevelopmentMotivation for Sensor Development
Pharmaceutical freeze-drying
Increasing usage with the development of new biotech productsManufacturing-scale product value in dryer $1M – $10MLack of adequate monitoring to fully understand and control the processLong process cycles (days) are often made longer by tentative operationWaste time and place product quality at riskLaboratory processes often do not scale to manufacturing due to dryer mass and heat transfer overload
Opportunity for the application of modern process monitoring andcontrol to improve manufacturing efficiency, production costs and product quality
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Pharmaceutical Product TemperaturePharmaceutical Product Temperature
Product temperature history is an important quality attribute:Product temperature must be maintained below a critical temperature to avoid collapseProduct structure may affect:– Appearance– Residual moisture content– Reconstitution time– Product stability
Product temperature indicates process endpoints (primary and secondary drying)Measurement of product temperature during a process deviation may be used to document product quality and avoid required disposal
During lyophilization product temperature is the most important process parameter influenced by:
Heat input by the shelvesCooling by ice sublimationResistances to heat and mass transport
Product temperature cannot be directly controlled but may be changed by:Shelf temperatureChamber pressure
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Product Temperature Measurement TechniquesProduct Temperature Measurement Techniques
Thermocouples placed in selected vials in 1st row of chamberTypically placed in first row vials due to sterility concerns Monitor a single vial out of thousands (may not be representative)Insertion into product results in a freezing bias and non-representative ice structureLess super cooling during freezing and faster drying timesNot compatible with automatic loading systemsNew wireless thermocouples have many of the same problems as wired thermocouples
Manometric temperature measurements (MTM)Non-intrusive pressure rise measurement typically carried out once an hourProduct temperature, resistance and mass flow determination based upon heat and mass transfer modelLimited to use in laboratory scale freeze dryers due to valve closing time requirementsMeasurement issues:
– Valve closing disrupts the drying process, limiting measurement frequency– Product temperature rises during measurement– Re-absorption of water vapor in the dried cake during measurement results in
inaccurate determinations
Mass Flux Sensor Technology:Mass Flux Sensor Technology:
Tunable Diode Laser Absorption Tunable Diode Laser Absorption Spectroscopy (TDLAS) Spectroscopy (TDLAS)
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Tunable Diode Laser Absorption Spectroscopy Tunable Diode Laser Absorption Spectroscopy (TDLAS) Sensor(TDLAS) Sensor
Scan Generator
Laser CurrentControl
LaserTemperature
Control
Laser Housing Optical FiberCoupled Laser Output
Fiber OpticSplitter
Detector
SignalDelivery
Fiber
ReferenceSignal
Signal Return Cable
J-7854
Noise Cancelling BalancedRatiometric Detector (BRD)
To DataAcquisitionSystem
Gas Flow
Sensor Control Unit Sensor Measurement Head
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TDLAS Measurements: TDLAS Measurements: LaboratoryLaboratory--Scale Scale LyophilizationLyophilization
Measurements performed at the UConn Department of Pharmacy
Research and DevelopmentLyostar II Freeze-Dryer
FTS Systems
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Sensor Measurement HeadSensor Measurement Head
Detector
to
VacuumPump
Condenser~ - 80°C
Chamber
Front Door
TestSection
θ
Vacuum
H-3236
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TDLAS Mass Flow MeasurementsTDLAS Mass Flow Measurements
Optical measurement of :1) Gas (water vapor) temperature (K)
2) Gas concentration [molecules/cm3]
3) Gas velocity [m/s]
→ Calculate the water vapor absorption linestregth using the measured temperature
→ Calculate the water vapor flow rate, dm/dt [grams/s], from the concentration & gas velocity data
→ Integrate the water removal rate during the process to predict the total amount of water removed (mass balance)
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Data Point Index
Nor
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ized
Abs
orpt
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Process Ref Cell
FWHM
Frequency shift, ∆νTemperature α FWHMConcentration α Area & TVelocity α ∆ν
MeasurementMeasurement PrinciplesPrinciples –– Basic Basic Physics IPhysics IWater Vapor Absorption LineshapesWater Vapor Absorption Lineshapes
Process ≡ water vapor absorption measurement in lyophilizer ductRef Cell ≡ absorption measurement in sealed, low pressure reference cell
≡ frequency standard
Simultaneousmeasurement of two
water vaporabsorption lineshapes
Critical Data Analysis IssuesCritical Data Analysis IssuesGas Flow DevelopmentGas Flow Development
Zero Velocity OffsetZero Velocity Offset
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Development of the Gas Profile within the FD DuctDevelopment of the Gas Profile within the FD Duct
Gas velocity profile develops due to gas viscosity and drag along the walls of the duct connecting the FD chamber and condenser:– Gas velocity and temperature profiles evolve from a “top hat” to a parabolic
profile with fully developed gas flow
– The centerline velocity of a fully developed flow is two times faster than the average flow velocity
– The gas temperature profile is influenced by the gas temperature entering the duct, the duct wall temperature and the development of the velocity profile
The gas velocity, temperature and density profiles can be calculated from:– Duct dimensions (L/D)
– Gas composition
– Pressure drop between the chamber and condenser
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Example Fluid Flow CFD:Example Fluid Flow CFD:Water Vapor Density Flow ProfileWater Vapor Density Flow Profile
FDChamber
FDCondenser
IsolationValve
MeasurementWindow ports
MeasurementWindow ports
Gas Flow
Knudsen number Kn ~ 5.5e-03, Kn<<1 low-pressure boundary slip conditionPinlet= 100 mtorrPoutlet= 97.8 mtorrTgas= 265 KTwall= 296 K (steel)
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Example Fluid Flow CFD:Example Fluid Flow CFD:Gas Temperature ProfileGas Temperature Profile
FDChamber
Tgas = 265K
Gas Flow
MeasurementWindow ports
MeasurementWindow ports
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Example Fluid Flow CFD:Example Fluid Flow CFD:Flow Velocity ProfileFlow Velocity Profile
MeasurementWindow ports
MeasurementWindow ports
Gas Flow
FDChamber
FDCondenser
Sensor reports line-of-sight average velocity
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TDLAS Mass Flux Sensor Data AnalysisTDLAS Mass Flux Sensor Data Analysis
Sensor provides line-of-sight water vapor absorption measurements across the lyophilizer duct
Line-of-sight measurements are interpreted to provide a determination of the mass flow rate (goal: 95% accuracy)– Analysis algorithm developed through absorption lineshape modeling over
the limits of flow profile development
Sensor continuously (0.5 seconds) calculates the development of the gas flow within the measurement duct: flow parameter
A calculated flow parameter used with the analysis model scales the measured gas temperature, density and flow velocity
Instantaneous mass flow rate measurements are calculated using the density and velocity measurements
The instantaneous mass flow rate measurements are integrated to provide a measurement of total water removed
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Zero Velocity DeterminationZero Velocity Determination
In the absence of bulk gas flow the mass flow sensor should measure zero velocity
There are a number of sensor hardware and basic physics effects which result in non-zero velocity readings under no-flow conditions (typically <2 m/s)
A zero velocity offset factor is determined at the start of eachdrying batch and subtracted from all velocity measurements to account for the offset
Parameters affecting the zero velocity offset:1. Data acquisition board multiplexing
2. Detector electronic circuit phase shifts
3. Optical noise
4. Gas collision-induced pressure shifts in the absorption feature
Application of the Mass Flow Sensor forApplication of the Mass Flow Sensor forBatch Averaged Batch Averaged
Product Temperature DeterminationsProduct Temperature Determinations
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Heat transfer
Heat flow
Product temperature
Tb determined for comparison to thermocouple data
Milton, N., Pikal, M.J., Roy, M.L., and Nail, S.L., Evaluation of ManometricTemperature Measurement as a Method of Monitoring Product Temperature During Lyophilization, PDA Journal of Pharmaceutical Science and Technology, 51, 7-16(1997).
Steady State Vial Heat and Mass Transfer ModelSteady State Vial Heat and Mass Transfer Model
( )bSVV TTKAdtdQ −⋅⋅=/
dtdmHdtdQ S // ⋅∆=
( )( )⎥⎦
⎤⎢⎣
⎡⋅
⋅∆−=
VV
SSb KA
dtdmHTT /
dQ/dt : heat flow (cal/s)Av : cross sectional area of vialsKv : vial heat transfer coefficientTs : shelf temperatureTb : product temperature at vial bottom∆Hs : water heat of sublimationdm/dt : sublimation rate
•• Possible to convert to product sublimationinterface temperature using model
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TDLASTDLAS--based Product Determinationbased Product Determination
TDLAS mass flow (dm/dt) measurements combined with model:– Provides average product temperature of all vials
Requires knowledge of:– Freeze dryer shelf temperature, Ts
– Vial heat transfer coefficient, Kv
Shelf temperature:– Thermocouple attached to shelf (lab scale) or
– Average shelf fluid inlet and outlet temperatures (pilot & manufacturing scale)
Average vial heat transfer coefficient determined as a function of:– Vial type and dimensions– Chamber pressure– Vial array configuration and dryer size
ratio of “edge vials” to “interior vials” is an important scale-up issue
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Vial Heat Transfer DeterminationVial Heat Transfer Determination
Vial heat transfer coefficient: three heat transfer mechanisms1. Direct conduction from the shelf to the vial bottom, Kc
2. Radiative heat transfer, Kr-higher for “edge vials”
3. Gas conduction, Kg
Method for determining vial heat transfer, Kv
– Vial-based water sublimation tests: for given vial array configuration
1. Weigh water added and water remaining following sublimation2. Thermocouple based “product” temperature (representative vial locations)3. Gravimetric measurement of average mass flow rates4. TDLAS measurement of instantaneous and average mass flow rates
Kv = ∆Hs (dm/dt)/( Av (Ts - Tp))
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LyophilizerLyophilizer Operating Parameters during aOperating Parameters during aRepresentative Representative KvKv Determination SublimationDetermination Sublimation
0 1 2 3 4 5-45
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Tem
pera
ture
(°C
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Primary Drying Time (h)
Shelf Setpoint TC Front TC Back TC Left TC Right
TC C1 TC C2 TC C3 TC Shelf Surface
CM Chamber Pirani Chamber
Pre
ssur
e (m
Torr
)
Conditions: Pc = 200 mTorr, Ts = -5°C
Shelf Temperature
Pirani GuageChamber Pressure
Capacitance ManometerChamber Pressure
Vial ProductTemperatures
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Corresponding TDLAS Mass FluxCorresponding TDLAS Mass Flux
0 1 2 3 4 50.000
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TDLAS calculated mass flux (dm/dt)
Mas
s Fl
ux (g
/sec
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Primary Drying Time (h)
removal of frozen water from the shelves(not included into calculation)
Non-steady state operationduring shelf temperature ramp
Steady statesublimation
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LabLab--Scale Freeze Dryer KScale Freeze Dryer Kvv DeterminationsDeterminations
Determined position dependent vial heat transfer coefficient, KvCalculated a weighted average Kv using the ratio of edge to center vials
Kv = Kc + Kr + KgKc : direct conduction heat transferKr : radiative heat transferKg : gas conduction heat transfer
Gravimetric
Average TDLAS
Real Time TDLAS
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Application of TDLAS to Determine Application of TDLAS to Determine Product TemperatureProduct Temperature
Freeze drying runs in a laboratory scale dryer (FTS Lyostar II) using partial and full loads (Glycine, Mannitol and Sucrose)
Continuous measurements of water mass flow rates combined with the heat and mass transfer model enable the determination of average product temperature
A comparison of TDLAS product temperatures and thermocouple data show excellent agreement throughout primary drying
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TDLASTDLAS--based Product Temperature Determinationbased Product Temperature DeterminationProduct: 10% Product: 10% GlycineGlycine
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Drying Time (hours)
Tem
pera
ture
(C)
TC top front TC mid front
TC mid left TC low right
TC top C1 TC top C2
TC mid C1 TC mid C2
TC low C1 TC low C2
Tss average Tb TDLAS
Tb MTM
Procuct = 10% Glycine
Shelf Temperature
Center Vial Product TemperaturesEdge Vial
Product Temperatures
MTM ProductTemperature Determination
TDLAS ProductTemperature Determination
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TDLASTDLAS--based Product Temperature Determinationbased Product Temperature DeterminationProduct: 7.5% Product: 7.5% MannitolMannitol
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Drying Time (hours)
Tem
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T shelf surface
TC Edge 1
TC Edge 2
TC Edge 3
TC Edge 4
TC Center 1
TC Center 2
TC Center 3
TDLAS ProductTemperature
Product = 7.5% Mannitol(crystalline)
ShelfTemperature
Edge VialProduct Temperatures
Center VialProduct Temperatures
TDLAS ProductTemperature Determinations
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SummarySummary
LyoFlux: gas temperature, water vapor density and gas flow velocities
Data analysis algorithm includes the development of the gas flow profile and the interpretation of line of sight measurements across the duct
Zero velocity offset factor continuously updated and applied
LyoFlux dm/dt used to determine vial heat transfer coefficients providing results in agreement with gravimetric-based determinations
LyoFlux dm/dt used in combination with Kv and heat and mass transfer model to predict batch average product temperatures
LyoFlux-based product temperature determinations show great potential to achieve enhanced process monitoring and control during freeze drying cycles