PAT in Freeze Drying
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Transcript of PAT in Freeze Drying
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Application of PAT in Freeze-Drying of Biopharmaceuticals
Rakhi B. Shah, Ph.D .U.S. Food and Drug Administration
Disclaimer: The views expressed in this presentation are the personalopinions of the speaker and do not necessarily represent the views of FDA
AAPS National Biotech Conference 2010
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Overview
Process Analytical Technology (PAT)
Freeze-drying
Application of PAT in freeze drying
Case study
Conclusion
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Process Analytical Technology
A fundamental element of PAT is to increaseprocess understanding and control and to verifyproduct quality prior to release.
PAT offers the possibility to increase productquality consistency and to reduce product riskthrough increased process knowledge andunderstanding optimized process control with theuse of PAT tools
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Reducing Product Variability
Process(or Process Step)
DesignSpace
Monitoring of Parametersor Attributes
Process Controls/PAT
InputProcess
Parameters
InputRaw materials
Product(or Intermediate)
ProductVariability
ReducedProductVariability
ProcessVariability
Nasr, FDA
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Freeze-DryingLow-temperature drying process
Convert solut ions of heat-labile materials into sol ids
Heat and mass transfer
Steps in freeze-drying:i. Freezing: water converted to ice and the solutes are crystallized or
transformed into solid
ii. Primary drying: ice crystals removed by sublimation under vacuum
iii. Secondary drying: drying under vacuum where most of theunfrozen water is removed by desorption.
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Heat Transfer MeasurementsThermocouples
positioned bottom-center in the vial
-less robust ,difficult tohandle , sterilityproblems-Used mainly inlaboratory scale
Pikal et al., 2002; Scheind & Giessler, 2008; Chouvene et al., 2005; Schneid, SP Industries Webinar, 2009
wireless battery-freetemperature sensors
sterilizable and can be usedin both laboratory andmanufacturing scale optimal comparability of temperature profi les for scale up
Resistance thermaldetectors
TEMPRIS TM+ Reliable, easy tosterilize- s ize , accuratepositioning is difficult,limited validity due tomeasurement of temperature averageprimarily inmanufacturing scale
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Mass Transfer MeasurementsMicrobalance
Determines the loss of weight of a sample vial during freeze drying byintermittent or continuous weighing information about sublimationrate and process step endpoints
for research and development
Mayeresse & Veillon, 2006; Schneid, SP Industries Webinar, 2009
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Pressure MeasurementsCapacitance Manometer Thermal conductivity
sensor (Pirani)
Independent of the type of gas
Dependent on type of gas, calibrated for aspecific gas (usuallyN2 )
Dew point sensor
Determinationof concentrationof water vapor in a gas
Roy and Pikal, 1989; Jennings and Duan, 1995; Schneid, SP Industries Webinar, 2009
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Mass Spectrometer Plasma emissionspectroscopy
Measures water vapor, N2 alsoany additionalresidualsolvents,volatil es, etc
Lyotrack TM:Spectroscopicmeasurement of water concentration in thechamber atmosphereusing a cold plasmasource connected to thechamber
Manometric TemperatureMeasurement (MTM)
Pressure Rise Testsare performedperiodically by rapidclosing (
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Tunable Diode Laser Absorption Spectroscopy
NIR-spectroscopic method for the determination of trace concentrations of a gasNo contact to the product
Use in sterile processes (manufacturing) and in all scales of freeze dryers
Eg: SMART TM freeze dryer
www.tdlas.com ; Schneid, SP Industries Webinar, 2009
Pressure Measurements
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Spectroscopic Techniques
Near infra-red: for residual moisture measurements in vials throughcontinuous measurements dur ing secondary drying
Raman: for determination of physical product characteristi cs
Only one vial monitoredfor research and development
Near infra red/Raman Spectroscopy
Brulls et al., 2003;Liu; Bai et al., 2005; Lin & Hsu, 2005, Schneid, SP Industries Webinar, 2009De Beer et al., 2007; Romero-Torres et al., 2007
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Tools for Process DevelopmentFourier Transform Infra Red Spectroscopy Nuclear Magnet ic Resonance
Determination of secondary structure anddynamics of proteins during f reeze-drying
Kumar, et al., 2009; Bhuyan and Udgaonkar, 1999
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Tools for Process DevelopmentFreeze-drying microscopy
Lyostat TM
Differential ScanningCalorimetery
X-ray Diffraction
Determination of crtical temperatures(Collapse/Eutectic) for opt imized
process
Determination of crystalline-amorphous transitions
Taylor and Zhai, , ;Hatley and Franks, 1991; Pyne and Suryanarayanan, 2001
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A Case Study
Use of Near Infra-Red (NIR) to determine moisturecontent for Freeze-Drying Unit Operation
Design
Analyze Control
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Design
Noncontact probes buil t into the chamber through gaps made in the door of the freeze dryer chamber
Placement of sensor depends upon measurement attr ibute: NIR for residual moisture content and cake quality placed at the bottomof the vial
Calibration is set up with various levels of mois ture content of the productanalyzed with NIR. Calibration can be performed on-line or off-line andvalidation test samples are also run on the NIR instrument.
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Analyze
Principal Component Analysis (PCA) tocharacterize raw materials and processvariables
Parti al Least Square (PLS) regression toinvestigate the linkages betweenspectral information and other sourcesof data. Sometimes done after pretreatment (2 nd derivative or normalization of spectral data)
Build robust prediction model.Determine accuracy, precis ion, errors of
calibration and prediction
Y = f{x}+error
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ControlFeed incoming data into the computer
Pretreatment of data (if needed) done automatically by chemometric software
Calculate observed Y and compare with expected Y
Continuous feedback control is set
If obtained Y is on target, no need to change operating parametersIf outside the range, operating parameters are adjusted
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Drying Curve
Drying time
% w
a t e r
Design space
Knowledge space
Operating range
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Summary
Improve process control and deliver more consistentproduct quality and achieve higher operationalefficiency by use of PAT in biotech Freeze-dryingprocess
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Questions?