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AstraZeneca PAT Center of Excellence1
The Role of a Center of Excellence in The Role of a Center of Excellence in The Role of a Center of Excellence in The Role of a Center of Excellence in The Role of a Center of Excellence in The Role of a Center of Excellence in The Role of a Center of Excellence in The Role of a Center of Excellence in Developing PAT ApplicationsDeveloping PAT ApplicationsDeveloping PAT ApplicationsDeveloping PAT ApplicationsDeveloping PAT ApplicationsDeveloping PAT ApplicationsDeveloping PAT ApplicationsDeveloping PAT Applications
! Pittcon 2005 Orlando FL, March 2nd 2005
! Nils-Erik AnderssonAstraZeneca R&D, Mölndal Sweden
AstraZeneca PAT Center of Excellence2
OutlineOutlineOutlineOutlineOutlineOutlineOutlineOutline
! Business needs and New ways of working
! PAT tools and Process understanding
! Conclusions
AstraZeneca PAT Center of Excellence3
! Stocks
! Cycle time
! Waste Reduction
! Variability
! Quality by Design
Business needs Business needs Business needs Business needs Business needs Business needs Business needs Business needs –––––––– PAT benefitsPAT benefitsPAT benefitsPAT benefitsPAT benefitsPAT benefitsPAT benefitsPAT benefits
AstraZeneca PAT Center of Excellence4
R&D R&D R&D R&D R&D R&D R&D R&D –––––––– Operations Operations Operations Operations Operations Operations Operations Operations Joint Joint Joint Joint Joint Joint Joint Joint (Ad)(Ad)(Ad)(Ad)(Ad)(Ad)(Ad)(Ad)Venture!Venture!Venture!Venture!Venture!Venture!Venture!Venture!
FormulationFormulationDevelopmentDevelopment
Analytical Analytical DevelopmentDevelopment
ManufacturingManufacturing
Process Process EngineeringEngineering
Quality Quality AssuranceAssurance
RegulatoryRegulatoryAffairsAffairs
Real Time Release?Real Time Release?Robust Process!Robust Process!
Process MeasurementsProcess MeasurementsMultivariate AnalysisMultivariate Analysis
Raw Material CharacterisationRaw Material Characterisation
Quality Risk AssessmentQuality Risk AssessmentCritical Control PointsCritical Control Points
Control LoopsControl LoopsDesign SpaceDesign Space
PAT Tools EvaluationPAT Tools EvaluationPAT Tools DevelopmentPAT Tools Development
PAT Tools ImplementationPAT Tools Implementation
AstraZeneca PAT Center of Excellence5
PAT DefinitionPAT DefinitionPAT DefinitionPAT DefinitionPAT DefinitionPAT DefinitionPAT DefinitionPAT DefinitionFDA Guidance for Industry, Sept 2004FDA Guidance for Industry, Sept 2004
PAT is a system
for designing, analyzing and controlling manufacturing
through timely measurements of critical quality and performance attributes
with the goal of ensuring final product quality
AstraZeneca PAT Center of Excellence6
PAT RealityPAT RealityPAT RealityPAT RealityPAT RealityPAT RealityPAT RealityPAT Reality
! Many technologies available
! However, few tools available off the shelf
! Use of technology is evolving
! Applications are product and unit specific
! Focus is on enhancing process understanding
! Scientifically based nomenclature needed
We need scientifically justified tools!
AstraZeneca PAT Center of Excellence7
How can a PAT Center of How can a PAT Center of How can a PAT Center of How can a PAT Center of How can a PAT Center of How can a PAT Center of How can a PAT Center of How can a PAT Center of Excellence contribute?Excellence contribute?Excellence contribute?Excellence contribute?Excellence contribute?Excellence contribute?Excellence contribute?Excellence contribute?
! Hub for corporate scientific and technical competence" Evaluate and advice on selection of PAT technology,
including IT systems" Congregate critical mass to develop cutting edge PAT
technology" Coordinate external scientific cooperation and internal work
! Increase speed of PAT implementation in all parts of the company" Provide the glue between formulation development and
analytical development, between R&D and Operations and between science and corporate experience
AstraZeneca PAT Center of Excellence8
“When you can measure what you are speaking about, “When you can measure what you are speaking about, and express it in numbers, you know something about it; and express it in numbers, you know something about it;
but when you cannot measure it,but when you cannot measure it,when you cannot express it in numbers,when you cannot express it in numbers,
your knowledge is of a meager and unsatisfactory kind”your knowledge is of a meager and unsatisfactory kind”
Lord KelvinLord Kelvin
Old Truth...Old Truth...Old Truth...Old Truth...Old Truth...Old Truth...Old Truth...Old Truth...
AstraZeneca PAT Center of Excellence9
! Vibrational Spectroscopy (NIR, Raman, midIR etc.)
! UV-Vis! Fluorescence! Acoustics (e.g. ultrasound)! NMR! MS! Imaging (e.g. Vision, Process Tomography)! Spectroscopic Imaging (e.g. NIR Imaging,
Raman microscopy, IR microscopy)! Accelerated Dissolution! Chemometrics
" Design of Experiments" Multivariate Analysis (PCA, PLS, NN etc.)" Multivariate SPC
PAT PAT PAT PAT PAT PAT PAT PAT ToolsToolsToolsToolsToolsToolsToolsTools........................
AstraZeneca PAT Center of Excellence10
PATScheme
PATInvestigations
Advanced Process Control
Characterization ofProcess Chemistry/Dynamics
Real-Time Quality Control
Process optimizationProcess scale-up Process validation
Trouble shooting
PAT PAT PAT PAT PAT PAT PAT PAT Tools in use…Tools in use…Tools in use…Tools in use…Tools in use…Tools in use…Tools in use…Tools in use…
Process control loops Assessment of material properties
AstraZeneca PAT Center of Excellence
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t[2]
t[1]
Hpc_lf.M1 (PLS), Untitled, Work setScores: t[1]/t[2]
Ellipse: Hotelling T2 (0.05)
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Simca-P 7.01 by Umetri AB 1998-11-10 17:21
Principal Component Analysis(PCA) of NIR datafor different batches of the same “quality” of raw material supplied fromtwo different vendors. Note that all batches comply withpharmaco-peialstandards!
Vendor 1
Vendor 2
• J. Vessman, Pharm. Anal., Overview, in Encyclopedia of Anal. Sciences, Academic Press Limited, 1995, p. 3807.• O. Svensson, M. Josefson, F.W. Langkilde, Applied Spectroscopy, 51 (1997) 1826-1835.
Raw material quality
Process UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingNatural VariabilityNatural Variability
AstraZeneca PAT Center of Excellence12
NIR Spectroscopy NIR Spectroscopy NIR Spectroscopy NIR Spectroscopy NIR Spectroscopy NIR Spectroscopy NIR Spectroscopy NIR Spectroscopy –––––––– a PAT toola PAT toola PAT toola PAT toola PAT toola PAT toola PAT toola PAT tool
! Chemical information!
! Physical information!
! Selective? Sensitive?
! Sampling?
! Robust towards process or material changes?
! Instrument variations?
! Calibration transfer and maintenance?
AstraZeneca PAT Center of Excellence13
Measurement number
Spec
tral r
esid
uals
SS
Q /
10-4
0 50 100 150 200 250 300 350
B
0
0.5
1
1.5
2
2.5
3
3.50 m/s 0.09 m/s 0.19 m/s 0.38 m/s 0.73 m/s
Measurement number
Spec
tral r
esid
uals
SS
Q /
10-4
0 50 100 150 200 250 300 350
B
0
0.5
1
1.5
2
2.5
3
3.50 m/s 0.09 m/s 0.19 m/s 0.38 m/s 0.73 m/s
Scanning grating NIR
M. Andersson, O. Svensson, S. Folestad, M. Josefson, K.-G. Wahlund, “NIR Spectroscopy on Moving Solids Using a Scanning Grating Spectrometer – Impact on Multivariate Analysis”, Chemometrics and Intelligent Laboratory Systems, 75 (2005), 1-11.
! ”Sampling” on moving solids by scanning grating NIR exhibit spectral artefacts
! Artefacts interfere in qualitative and quantitative analysis
! Emanate from varying sample scattering properties
! Can not be mathematically deconvoluted!
Process Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: In--------Situ NIRSitu NIRSitu NIRSitu NIRSitu NIRSitu NIRSitu NIRSitu NIR
AstraZeneca PAT Center of Excellence14
! ”Sampling” on moving solids by FT NIR exhibit spectral artefacts in interferograms
! Transformation to frequency domain → artefacts well outside NIR spectral region
! FT NIR is a suitable technique for qualitative and quantitative analytical process applications
FT-NIR
O. Berntsson, L.-G. Danielsson, S. Folestad, “Characterization of Diffuse Reflectance Fiber Probe Sampling on Moving Solids using a Fourier Transform NIR Spectrometer, Analytica Chimica Acta , 431 (2001) 125-131
Process Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: InProcess Measurements: In--------Situ NIRSitu NIRSitu NIRSitu NIRSitu NIRSitu NIRSitu NIRSitu NIR
AstraZeneca PAT Center of Excellence15
• O Berntsson, L-G Danielsson, M O Johansson, S Folestad. Analytica Chimica Acta 419 (2000) 45-54• O Berntsson, L-G Danielsson, B Lagerholm, S Folestad. Powder Technology 123 (2002) 187-195
Mixer
Raw data
Calibration
Statistical process control (SPC)
Process UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingInIn--situ blend monitoringsitu blend monitoring
AstraZeneca PAT Center of Excellence16
O Berntsson, S Folestad,L-G Danielsson, B Lagerholm, PowderTechnology, 123 (2002) 187-195
In-situblendmonitoring:Scale-up
PAT PAT PAT PAT PAT PAT PAT PAT -------- Process UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess UnderstandingProcess Understanding
AstraZeneca PAT Center of Excellence17
ConclusionsConclusionsConclusionsConclusionsConclusionsConclusionsConclusionsConclusions
! PAT tools are not available off the shelf
! A PAT scheme is built upon a high level of process understanding
! PAT implementation requires extensive cross functional working
! PAT is not only techniques, it is a mind set!
! A Center of Excellence can make the difference between failure and success when implementing meaningful PAT!