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

VG09-171-1

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

VG09-171-2

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

VG09-171-3

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

VG09-171-4

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)

VG09-171-6

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

VG09-171-7

TDLAS Measurements: TDLAS Measurements: LaboratoryLaboratory--Scale Scale LyophilizationLyophilization

Measurements performed at the UConn Department of Pharmacy

Research and DevelopmentLyostar II Freeze-Dryer

FTS Systems

VG09-171-8

Sensor Measurement HeadSensor Measurement Head

Detector

to

VacuumPump

Condenser~ - 80°C

Chamber

Front Door

TestSection

θ

Vacuum

H-3236

VG09-171-9

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)

VG09-171-10

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1000 1500 2000 2500 3000 3500 4000

Data Point Index

Nor

mal

ized

Abs

orpt

ion

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

VG09-171-12

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

VG09-171-13

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)

VG09-171-14

Example Fluid Flow CFD:Example Fluid Flow CFD:Gas Temperature ProfileGas Temperature Profile

FDChamber

Tgas = 265K

Gas Flow

MeasurementWindow ports

MeasurementWindow ports

VG09-171-15

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

VG09-171-16

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

VG09-171-17

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

VG09-171-19

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

VG09-171-20

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

VG09-171-21

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))

VG09-171-22

LyophilizerLyophilizer Operating Parameters during aOperating Parameters during aRepresentative Representative KvKv Determination SublimationDetermination Sublimation

0 1 2 3 4 5-45

-40

-35

-30

-25

-20

-15

-10

-5

0

150

200

250

300

350

400

Tem

pera

ture

(°C

)

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

VG09-171-23

Corresponding TDLAS Mass FluxCorresponding TDLAS Mass Flux

0 1 2 3 4 50.000

0.005

0.010

0.015

0.020

TDLAS calculated mass flux (dm/dt)

Mas

s Fl

ux (g

/sec

)

Primary Drying Time (h)

removal of frozen water from the shelves(not included into calculation)

Non-steady state operationduring shelf temperature ramp

Steady statesublimation

VG09-171-24

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

VG09-171-25

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

VG09-171-26

TDLASTDLAS--based Product Temperature Determinationbased Product Temperature DeterminationProduct: 10% Product: 10% GlycineGlycine

-45

-40

-35

-30

-25

-20

-15

-10

-5

0 4 8 12 16 20 24 28 32 36 40

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

VG09-171-27

TDLASTDLAS--based Product Temperature Determinationbased Product Temperature DeterminationProduct: 7.5% Product: 7.5% MannitolMannitol

-50

-40

-30

-20

-10

0

10

20

0 2 4 6 8 10 12 14 16 18 20

Drying Time (hours)

Tem

pera

ture

(C)

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

VG09-171-28

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