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What does PAT, QbD, Modelling and Advanced Process Control mean to an SME?

An Observation. The EU provides 32% of the worlds chemicals manufacturing through some 25,000 enterprises of which 98% are SMEs which account for 45% of the sectors ‘added value’, and 46% of all employees are in SME. What does PAT, QbD, Modelling and Advanced Process Control mean to an SME?.

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What does PAT, QbD, Modelling and Advanced Process Control mean to an SME?

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  1. An Observation The EU provides 32% of the worlds chemicals manufacturing through some 25,000 enterprises of which 98% are SMEs which account for 45% of the sectors ‘added value’, and 46% of all employees are in SME What does PAT, QbD, Modelling and Advanced Process Control mean to an SME?

  2. Research Excellence in Process Analysis, Process Monitoring, Process Modelling, Process Control and Chemometrics Industrial Collaborations University Collaborations Technology Transfer Centre for Process Analytics and Control Technology

  3. The CPACT Membership and 8 Universities (1 in China)

  4. What Does CPACT do? CPACT advances manufacturing excellence to deliver business benefits across all sectors of the processing and manufacturing industries CPACT initiates leading edge R&D and technology transfer for the exploitation of process analytics and control technologies CPACT is managed by it’s industrial and academic partners with support from the Chemistry Innovation Knowledge Transfer Network CPACT’s role has been defined by its industrial partners as contributing to filling the growing gap in delivering leading edge R&D and Technology Translation in Process Analytics and related Control Technologies

  5. Products and Services • Leading Edge and Internationally Recognised Research and Development • Technology Translation • Training and CPD • Networking, Workshops and Conferences • A unique Annual Conference – “Advances in Process Analytics and Control Technologies” • A unique Triennial Conference – “Process Analytics and Control Technology” underpinned by DECHEMA • Distinctive Multidisciplinary skilled PhD and postdoctoral graduates

  6. CPACT R&D and Technology Transfer • 4 European Projects: • Sustainable Microbial and Biocatalytic Production of Advanced Functional Materials (Bioproduction) with CPI (Finished) • Reduction of Emissions and Energy Utilisation through Advanced Diagnostics and Control (ECOCARB) • Multiscale Modelling of Chemical and Biochemical Systems (MULTIMOD) • Model-based Optimisation & Control for Process-Intensification in Chemical and Biochemical Systems (OPTICO) • Knowledge Transfer Partnerships (KTPs) • The National Nuclear Laboratory • CPI • Johnson Matthey • Research Team (Newcastle and Strathclyde): • 16 Phds • 3 Postdoctoral Researchers

  7. CPACT Process Analytics • The development of at-line, on-line, in-line and non-invasive process monitoring procedures based on: • NIR, MIR, UV-visible, Raman scattering, NMR, Acoustics, … • Novel spectroscopic monitoring of emulsions; characterisation of biological suspensions (spores, bacteria growth) and fermentation broths – based on solving the Radiative Transfer Equation. • Industrial operations: • Crystallisation, drying, blending, tablet analysis, fermentation, chemical & bio-chemical reactions • Reactors: • Micro-reactors, Coflux batch reactor, OBR - continuous crystallisation, … • Advanced Chemometrics: • Correcting non-linear shift and broadening in spectral bands caused by temperature fluctuations. • Separating absorbance effects from multiplicative light scattering effects caused by the variations in optical path length • Robust calibration transfer algorithms

  8. Training Courses and CPD • 1-day, 2-day, 3-day courses; Tailored courses for industry …… • Process Analytics – NIR, MIR, UV-visible, Raman scattering, Fluorescence, NMR, Microwave, Acoustic, Mass spectrometry techniques, …. • Data analysis, data mining, data modelling • Data Pre-screening and Process Chemometrics • Process Performance Monitoring (Multivariate Statistical Process Control) • Process Modelling – data based modelling (statistical and neural networks); software sensors • PAT, Multivariate Data Analysis and Lean Six Sigma • Webinars - Training and CPD …. • A series of 1-hour tailored webinars for industry and academia

  9. Information and Knowledge from Multivariate Analysisof Process and Measurements Data • Sensor based Measurements are Multivariate • Considers all the variables simultaneously (measured and calculated) • Extracts information and knowledge of the directionality of process variations • From small amounts of data to huge amounts of data • Ill-conditioned, dynamic, temporal, collinear data, …… • Integrated spectroscopic and process data • Software sensors • A route to plant-wide performance (condition) monitoring • Benefits • Product and Process understanding – knowledge, know-how and IP • Early warning and identification of process variability and malfunctions • Tighter control over process variability, product quality and consistency • Reductions in emissions, energy usage and carbon footprint • Complements the experience of scientists, engineers, development & operational staff and plant managers

  10. CPACT Predictive Modelling Process Performance Monitoring • Multivariate Statistical Process Control (MSPC – Process Performance Monitoring) • Multi-recipe, Multi-formulation, Multi-product and Multi-site modelling and Performance Monitoring • Data Fusion and the integration of spectroscopic and process data • Rapid Prototyping / Rapid Scale-up from minimal numbers of batch runs • Neural network modelling and prediction • Eg Modelling and Control of Reactive Distillation unit with Solvay

  11. CPACT R&D and Technology Translation • 4 European Projects: • Sustainable Microbial and Biocatalytic Production of Advanced Functional Materials (Bioproduction) with CPI (Finished) • Reduction of Emissions and Energy Utilisation through Advanced Diagnostics and Control (ECOCARB) • Multiscale Modelling of Chemical and Biochemical Systems (MULTIMOD) • Model-based Optimisation & Control for Process-Intensification in Chemical and Biochemical Systems (OPTICO) • Knowledge Transfer Partnerships (KTPs) • The National Nuclear Laboratory Sellafield • Centre for Process Innovation (CPI) • Johnson Matthey • Research Team • 16 Phds • 3 Postdoctoral Researchers

  12. Some Process Analytics Challenges Spectra from different probes show distinct Inter-probe variability ‘Product Quality’ across lab, pilot & production scales (Staffan Folestad AstraZeneca, APACT09) 20 20 • • P1 P1 - - 2343.0 2343.0 • • P1 P1 - - 2225.0 2225.0 P2 P2 P3 P3 • • P1 P1 - - 2401.0 2401.0 • • P1 P1 - - 2303.0 2303.0 • P2 - 5649.0 • P2 - 5649.0 • • P1 P1 - - 2322.0 2322.0 P1 P1 • • P1 P1 - - • • P2 P2 - - 5919.0 5919.0 • • P2 P2 - - 5507.0 5507.0 • • P1 P1 - - 2629.0 2629.0 • • P3 P3 - - 2748.0 2748.0 10 10 • • • • • • P2 P2 P2 P2 P2 P2 - - - - - - 5420.0 5420.0 5629.0 5629.0 5805.0 5805.0 • • P3 P3 - - 3002.0 3002.0 P 2 P 2 • • P1 P1 - - 2552.0 2552.0 • • P2 P2 - - 5937.0 5937.0 • • P2 P2 • • P2 P2 - - 5610.0 5610.0 - - 0227.0 0227.0 • • P3 P3 - - 3059.0 3059.0 • • P2 P2 - - 5440.0 5440.0 • • P2 P2 - - 5537.0 5900.0 • • P2 P2 - - 5537.0 5900.0 • • P1 P1 - - 2420.0 2420.0 • • P3 P3 - - 2651.0 2651.0 • • P2 P2 - - 0150.0 0150.0 • • P3 P3 - - 2844.0 2844.0 • • P2 P2 - - 0208.0 0208.0 • • • • P2 P2 P2 P2 - - - - 0744.0 0744.0 0858.0 0858.0 • • P3 P3 - - 5213.0 5213.0 • • P2 P2 - - 0304.0 0304.0 • • P3 P3 • • P3 P3 - - 3020.0 3020.0 - - 2806.0 2806.0 • • P2 P2 - - 0803.0 0803.0 • • P3 P3 - - 3233.0 3233.0 • • P1 P1 - - 2648.0 2648.0 • • P2 P2 - - 0033.0 0033.0 • • P3 P3 • • P3 P3 - - 3137.0 3137.0 - - 2710.0 2710.0 • • P2 P2 - - 5708.0 5708.0 • • P2 P2 - - 0839.0 0839.0 • • P3 P3 - - 3446.0 3446.0 • • P3 P3 - - 2940.0 2940.0 • • P1 P1 - - 2534.0 2534.0 • • P3 P3 - - 4941.0 4941.0 P2 0707.0 • • P2 - - 0707.0 • • P2 P2 - - 0322.0 0322.0 • • P3 P3 - - 2921.0 2921.0 • • P2 P2 - - 0534.0 0534.0 • • P3 P3 • • P3 P3 - - 2902.0 2902.0 - - 2729.0 2729.0 • • • • P2 P2 P2 P2 - - - - 0418.0 0418.0 0649.0 0649.0 • • P2 P2 - - 5400.0 5400.0 • • P1 P1 - - 2710.0 2710.0 • • P2 P2 • • P2 P2 • • P2 P2 - - 5746.0 5746.0 - - 0359.0 0359.0 - - 0916.0 0916.0 • • P3 P3 - - 3039.0 3039.0 • • P2 P2 - - 5727.0 5727.0 • • • • P3 P3 P3 P3 - - - - 4401.0 4401.0 4050.0 4050.0 • • P2 P2 - - 0245.0 0245.0 • • • • P2 P2 P2 P2 - - - - 0553.0 0553.0 0821.0 0821.0 • • P3 P3 - - 3350.0 3350.0 • • • • P2 P2 P2 P2 - - - - 0725.0 0725.0 1129.0 1129.0 • • P2 P2 - - 1206.0 1206.0 • • P3 P3 - - 3505.0 3505.0 • • P1 P1 - - 2746.0 2746.0 • • P3 P3 - - 3603.0 3603.0 • • P1 P1 - - 2805.0 2805.0 • • P2 P2 • • P2 P2 - - 0612.0 0612.0 - - 1748.0 1748.0 • • • • P3 P3 P3 P3 - - - - 5038.0 5038.0 3155.0 3155.0 • • P1 P1 - - 2611.0 2611.0 • • P1 P1 - - 3341.0 3341.0 • • P2 P2 - - 1843.0 1843.0 • • P3 P3 - - 3816.0 3816.0 • • P1 P1 - - 3014.0 3014.0 • • P3 P3 - - 4109.0 4109.0 • • P1 P1 - - 3208.0 3208.0 • • P2 P2 - - 1920.0 1920.0 • • • • P3 P3 P3 P3 - - - - 4730.0 4730.0 5135.0 5135.0 • • • • P3 P3 • • P3 P3 P3 P3 - - - - 4845.0 4845.0 - 4535.0 4535.0 - 3118.0 3118.0 • • • • P2 P2 P2 P2 - - - - 0437.0 0437.0 0630.0 0630.0 • • • • P3 P3 P3 P3 - - - - 3408.0 3408.0 3621.0 3621.0 • • P2 P2 - - 1939.0 1939.0 • • P1 P1 - - 2728.0 2728.0 • • P3 P3 - - 4631.0 4631.0 • • P2 P2 - - 1727.0 1727.0 • • P3 P3 - - 5232.0 5232.0 P3 P3 4554.0 4420.0 • • • • P3 P3 - - - - 4554.0 4420.0 • • • • • • P3 P3 P3 P3 P3 P3 - - - - - - 4438.0 4438.0 4242.0 4242.0 4127.0 4127.0 • • P2 P2 - - 1825.0 1825.0 • • P3 P3 - - 4612.0 4612.0 • • P3 P3 - - 4321.0 4321.0 • • P3 P3 - - 3427.0 3427.0 t[2] t[2] • • P1 P1 - - 2823.0 2823.0 • • • • P3 P3 P3 P3 - - - - 5154.0 5154.0 4301.0 4301.0 • P3 - 5000.0 • P3 - 5000.0 • • P1 P1 - - 2956.0 2956.0 • • P2 P2 - - 2053.0 2053.0 • • P1 P1 - - 2900.0 2900.0 • • P3 P3 - - 3544.0 3544.0 • • • • • • P2 P2 P2 P2 P2 P2 - - - - - - 1440.0 1440.0 1147.0 1147.0 2148.0 2148.0 • • • • • • P2 P2 P2 P2 P2 P2 - - - - - - 1650.0 1650.0 2111.0 2111.0 1708.0 1708.0 • • P3 P3 - - 4340.0 4340.0 • • P2 P2 - - 2400.0 2400.0 • • • • P3 P3 P3 P3 - - - - 4650.0 4650.0 4708.0 4708.0 • • P1 P1 - - 2842.0 2842.0 • • P2 P2 - - 2323.0 2323.0 • • • • P3 P3 P3 P3 - - - - 3835.0 3835.0 4922.0 4922.0 • • P3 P3 - - 3640.0 3640.0 • • • • P2 P2 P2 P2 - - - - 1421.0 1421.0 2342.0 2342.0 • • • • P2 P2 P2 P2 - - - - 1806.0 1806.0 2244.0 2244.0 • • • • P3 P3 P3 P3 - - - - 5117.0 5117.0 5019.0 5019.0 • • P1 P1 - - 3400.0 3400.0 • • P3 P3 - - 5058.0 5058.0 • • P3 P3 - - 4457.0 4457.0 • • P1 P1 - - 2919.0 2919.0 • • P2 P2 - - 1902.0 1902.0 0 0 • • • • P3 P3 P3 P3 - - - - 4516.0 4516.0 3701.0 3701.0 • • P1 P1 - - 3150.0 3150.0 • • P1 P1 - - 3437.0 3437.0 • • P2 P2 - - 2129.0 2129.0 • • P1 P1 - - 3708.0 3708.0 • • • • P2 P2 P2 P2 - - - - 2305.0 2034.0 2305.0 2034.0 • • P1 P1 - - 3418.0 3418.0 • • P2 P2 - - 1957.0 1957.0 • • P1 P1 - - 3532.0 3532.0 • • P1 P1 - - 3227.0 3227.0 • • • • P2 P2 P2 P2 - - - - 2225.0 2015.0 2015.0 2225.0 • • P1 P1 • • P1 P1 - - 3245.0 3245.0 - - 3514.0 3514.0 • • P2 P2 - - 2206.0 2206.0 • • P1 P1 - - 3131.0 3131.0 • • P1 P1 - - 3304.0 3304.0 • • P1 P1 - - 3455.0 3455.0 • • P4 P4 - - 5854.0 5854.0 • • • • P1 P1 P1 P1 - - - - 3840.0 3859.0 3840.0 3859.0 • • P1 P1 - - 3726.0 3726.0 • • P1 P1 - - 3744.0 3744.0 • • P4 P4 - - 5835.0 5835.0 • • P4 P4 • • P4 P4 - - 0007.0 0007.0 - - 5912.0 5912.0 • • P1 P1 - - 3803.0 3803.0 • • P4 P4 - - 0026.0 0026.0 • • P4 P4 • • P4 P4 - - 0044.0 0044.0 - - 5949.0 5949.0 • • P1 P1 - - 4225.0 4225.0 • • P1 P1 - - 4646.0 4646.0 • • P1 P1 • • P1 P1 - - 4015.0 4015.0 - - 4244.0 4244.0 • • P4 P4 - - 0140.0 0140.0 • • P1 P1 - - 4705.0 4705.0 • • P4 P4 • • P4 P4 - - 0158.0 0158.0 - - 5931.0 5931.0 • • P1 P1 - - 4628.0 4628.0 P4 P4 • • P1 P1 - - 4819.0 4819.0 - - 10 10 • P1 - 4742.0 • P1 - 4742.0 • • P1 P1 - - 4609.0 4609.0 Position 1 Position 1 • • • • P4 P4 P4 P4 - - - - 0238.0 0238.0 0220.0 0220.0 • • P1 P1 - - 4532.0 4532.0 • • P1 P1 - - 4551.0 4551.0 • • P1 P1 - - 4837.0 4837.0 • • P4 P4 - - 1217.0 1217.0 • • P1 P1 - - 4514.0 4514.0 • • P1 P1 - - 4800.0 4800.0 • • P1 P1 - - 4723.0 4723.0 • • P4 P4 - - 1236.0 1236.0 • • P4 P4 - - 1254.0 1254.0 • • P4 P4 - - 1621.0 1621.0 • • P4 P4 - - 2330.0 2330.0 • • • • P4 P4 P4 P4 - - - - 2006.0 2006.0 1658.0 1658.0 • P4 - 1603.0 • P4 - 1603.0 • • • • • • P4 P4 P4 P4 P4 P4 - - - - - - 2619.0 2619.0 2849.0 1313.0 2849.0 1313.0 • • • • P4 P4 P4 P4 - - - - 2157.0 2157.0 1544.0 1544.0 P4 1849.0 • • P4 - - 1849.0 • • P4 P4 - - 1409.0 2542.0 • • P4 P4 - - 1409.0 2542.0 • • • • P4 P4 P4 P4 - - - - 1427.0 1427.0 2253.0 2253.0 • • P4 P4 - - 2446.0 2446.0 • • P4 P4 - - 2926.0 2926.0 • • P4 P4 - - 1331.0 1331.0 • • P4 P4 - - 2216.0 2216.0 • P4 - 1350.0 • P4 - 1350.0 • • P4 P4 - - 2348.0 2348.0 • • • • P4 P4 P4 P4 - - - - 2409.0 2409.0 2311.0 2311.0 • • P4 P4 - - 2504.0 2504.0 • • • • P4 P4 P4 P4 - - - - 1640.0 1640.0 2523.0 2523.0 • • P4 P4 - - 2234.0 2234.0 • • P4 P4 - - 2945.0 2945.0 • • P4 P4 - - 1831.0 1831.0 • • P4 P4 - - 2908.0 2908.0 • P4 - 3040.0 • P4 - 3040.0 • • P4 P4 - - 2600.0 2600.0 - - 20 20 • • P4 P4 - - 2427.0 2427.0 - - 100 100 - - 80 80 - - 60 60 - - 40 40 - - 20 0 20 40 60 80 100 20 0 20 40 60 80 100 t[1] t[1] Different formulations/recipes showing within & between group variability Sensing space direction PCA of spectra collected for over 1 hr L1 L2 L2 L3 L3 L4 L4 Agitator Probe Location Probe Location Courtesy R O’Kennedy et al (GSK & Univ Strathclyde)

  13. Faster Sustainable Chemistry / Bio-Processing Scale-up • Knowledge Transfer Partnership (KTP) with CPI To implement innovative monitoring, modelling and control technologies within CPI Advanced Processes in order to increase process understanding which will accelerate process scale-up, development and optimisation for CPI’s customers.

  14. Process Analytics in Bio-pharmaDevelopment and Production Multivariate plots of culture parameters: substrates, metabolites, viability, …. (coloured by Batch number) Multivariate plots on Pre-processed NIR Spectra (coloured by Batch number) “Process Signatures” Courtesy José C. Menezes, EUROPACT 2011 – Glasgow (Scotland) April 27-29, 2011

  15. Process Analytics in Chemicals and Materials Processing • Intelligent MSPC: Performance monitoring integrated into the G2 real time expert system – significant operational cost savings (Corus and now SSI). • (Presently being applied to Tata Steel Coke Ovens for energy savings and emission reductions)

  16. Scale-up from Lab to Manufacture through PAT and Smart Chemometrics From ½ and 20 litre to 250 litre Plant Scale (Probably the first application of PAT from the lab to closed loop crystallisation control) (2002-2005)

  17. Crystal Chemistry versus Morphology: L-Glutamic Acid α-form β-form Metastable α-form: produced under kinetic control, separated to avoid solvent mediated transformation. α-form more form more soluble than β-form, i.e. less stable

  18. In-Process Analytics, PAT-based Reactor Scale-upand Process Control PAT from 1/2 to 20 to 250l Scales 250l Pilot Scale Syngenta Switzerland ½ and 20l lab scale Leeds UK

  19. Temperature monitors Temperature readers System provides capability to monitor polymorphic form “in-process”, i.e. that unaffected by product separation prior to analysis. Typically circa 1 wt % detectable via in-process XRD, much lower with advanced chemometric analysis (Smoothed PCA) Bede MONITORTM In-process XRDCrystal Polymorph Monitoring & Control

  20. Münchwilen Foxboro Control System as Set-Up for CBBII Trial on 250 Litre Reactor R-122

  21. PAT-based Supersaturation Control of L-Glutamic Acid250 litre Plant Crystalliser

  22. Some Business Benefits from the Technologies • Savings in catalyst usage in a commercial scale fluidised bed reactor ~ £1M / annum (BASF). • Assured monitoring of chemical reactions ~ £800,000 (BP). • Detection and Diagnosis of a bio-intermediate impurity problem, its solution and how to ensure minimal levels in future production (GSK). • Introduced the whole concept of Process Performance Monitoring using Multivariate Statistical Process Control to GSK. • Multi-site transfer of development and production models using generic modelling technologies. • Unexplained variability in fermentation production processes, expected benefits ~ £4.5M / annum (GSK). • Early detection of faulty reactor dosing ~ £250K / annum (Unilever). • Modified recycling of fluidised bed catalytic bed reactors ~ £250K per Bed (Shell). • The first application of PAT-based scale-up from a UK lab to 250l pilot in a different country (Syngenta) – 2002/2005. • Significant benefits to NNL/Sellafield Ltd have been realised through the involvement with CPACT.

  23. Some Comments from Reviewers ….. CPACT is . . . “. . . one of the few multidisciplinary platforms for process analytics in the world.” The international standing of CPACT is recognised as being, besides CPAC in the USA, the only multidisciplinary platform for Process Analytics in the world. There is no other team with this record in the UK in this field. It is an outstanding example of how to integrate industry into long term strategic research in PAT

  24. All researchers and staff in CPACT – past and present The EPSRC, DTI, EU and CPACT member companies for research funding. The collaborating companies for access to their plant data and expertise The PhD students and Post-Doc Researchers’ for their contributions Acknowledgements THANK YOU FOR LISTENING I WOULD BE PLEASE TO ANSWER QUESTIONS

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