The Role of a Center of Excellence in Developing PAT Applications! Pittcon 2005 Orlando FL, March 2 nd 2005! Nils-Erik Andersson AstraZeneca R&D, Mölndal Sweden 1
Outline! Business needs and New ways of working! PAT tools and Process understanding! Conclusions 2
Business needs PAT benefits! Stocks! Cycle time! Waste Reduction! Variability! Quality by Design 3
Formulation Development R&D Operations Joint (Ad)Venture! Robust Process! Real Time Release? Manufacturing Analytical Development Regulatory Affairs Quality Risk Assessment Critical Control Points Design Space Control Loops Raw Material Characterisation Process Measurements PAT Tools Evaluation Multivariate Analysis PAT Tools Development PAT Tools Implementation Process Engineering Quality Assurance 4
PAT Definition FDA 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 5
PAT 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! 6
How can a PAT Center of 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 7
Old Truth... When you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot measure it, when you cannot express it in numbers, your knowledge is of a meager and unsatisfactory kind Lord Kelvin 8
PAT Tools...! 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 9
PAT Tools in use PAT Scheme Process control loops Advanced Process Control Assessment of material properties Real-Time Quality Control PAT Investigations Characterization of Process Chemistry/Dynamics Process optimization Process scale-up Trouble shooting Process validation 10
Process Understanding Natural Variability t[2] 0.30 0.20 0.10 0.00-0.10-0.20-0.30 90 81 20 Hpc_lf.M1 (PLS), Untitled, Work set Raw material quality Scores: t[1]/t[2] 147 146 21 28 86 105154 175 171 183 176 174 143 142 107 155189 185 104 126 179 82 182 85 23129 89 186 45 168 41 134 137 46 111 106 178 93 135 188 56 165 58 84 94 27 184 180 167 32 35 53 112 113 127 153 166162 3667 169 24 42 150 132 26 108 38 160 17 40 161 33 76 54 92 152116 181 110177 34 43 30 163 87 55 88 57 157 133 136 172 194 128 117 83 109 3 8 31 5 73 44 79 77 78 158 170 80 15 29 9 14 140 141 151 74 16 130 22 118 119 138164 187 195 396 37 7 4 139 173 190 75 192 10 68 156 149 124 71 191 19 72 131 193 70 25 159 69 91 Vendor 1 118 120 1252 123 121-2 -1 0 1 2 t[1] 122 47 66 62 61 95 65 59 99 100 12 1 64 96 63 144 60 102 97 98 48 51 145 148 13 49 52 103 101 50 Vendor 2 J. Vessman, Pharm. Anal., Overview, in Ellipse: Encyclopedia Hotelling of T2 Anal. (0.05) Sciences, Academic Press Limited, 1995, Simca-P 7.01 by Umetri AB 1998-11-10 17:21 p. 3807. O. Svensson, M. Josefson, F.W. Langkilde, Applied Spectroscopy, 51 (1997) 1826-1835. Principal Component Analysis (PCA) of NIR data for different batches of the same quality of raw material supplied from two different vendors. Note that all batches comply with pharmacopeial standards!
NIR Spectroscopy a PAT tool! Chemical information!! Physical information!! Selective? Sensitive?! Sampling?! Robust towards process or material changes?! Instrument variations?! Calibration transfer and maintenance? 12
Process Measurements: In-Situ NIR! 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! Spectral residuals SSQ / 10-4 B Scanning grating NIR 3.5 3 0 m/s 0.09 m/s 0.19 m/s 0.38 m/s 0.73 m/s 2.5 2 1.5 1 0.5 0 0 50 100 150 200 250 300 350 Measurement number 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. 13
Process Measurements: In-Situ NIR! 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 14
Process Understanding In-situ blend monitoring Statistical process control (SPC) Mixer Raw data Calibration 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 15
PAT - Process Understanding In-situ blend monitoring: Scale-up O Berntsson, S Folestad, L-G Danielsson, B Lagerholm, Powder Technology, 123 (2002) 187-195 16
Conclusions! 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! 17