Intelligent Decision Support and Control Technologies for Continuous Manufacturing of Pharmaceuticals and Fine Chemicals

Lead Research Organisation: University of Strathclyde
Department Name: Electronic and Electrical Engineering

Abstract

Although continuous crystallisation provides significant benefits to innovative manufacture, the key challenge of real time, robust monitoring of quantitative attributes (form, shape, size) of particulate products still remains a massive challenge. While particle attributes are crucial for downstream processing of products, no current solution allows the processing of data from in-line sensors to reliably extract these attributes in real time across multiple manufacturing steps and the subsequent use of this knowledge for IDS and control of processes. The development of solutions for the sector requires expertise across many technologies driven by end user requirements. Industrial co-creators will provide the requirements, the range of expertise within the applicants ensuring that the goals of the programme are met. The grant will enable the establishment of a process test-bed which as the project matures, will be made available to a range of national and international user and application communities. This activity will support the creation of a requirement and technology roadmap, in so doing informing both the research and commercial communities on future opportunities. The project will also yield the following added value to the community:
- the cross-disciplinary nature of the project and participating teams will stimulate new solutions and promote creativity through sharing best practice in executing research from different perspectives
- the PDRAs will be applying their know-how to joint development tasks, allowing them to gain comprehensive knowledge and expertise across a range of field and in so doing provide trained, talented engineers that will fuel the deployment of these innovative solutions
- the project addresses the integration of a number of distinct architectural layers to transform a physical infrastructure into a flexible platform which supports a range of applications whilst accessible to users

Planned Impact

The project contains the following elements of a strategic impact strategy;
- fostering the global economic competitiveness of the UK. As the industrial co-creators will have first access to the technology, and since dissemination will be carried out initially within the UK, the project will enhance economic competitiveness.
- increasing the effectiveness of UK business by engaging with industries across the supply chain, in so doing promoting future commercial partnerships aimed at capturing the massive global market opportunities for these solutions.
- increasing practical engagement - most notably through the pilot process test-bed - with key researchers in academia who can evaluate new concepts within a controlled environment
and contains the following key people-based activities;
- collaboration with industrial partners
- exchange/sustaining/exploration of knowledge
- cross-disciplinary collaborations/cross-sector learning
- engagement with wider community of beneficiaries (public demonstrations)
- new collaborations/research activities to enhance exploitation
In order to reach the widest possible impact and outreach, the plan is focussed on cross-disciplinary learning based on strong engagement with a wide range of beneficiaries including ICT hardware and software suppliers, ICT exploitation providers and users involved in pharmaceutical and fine chemicals manufacturing.

The project combines a range of disciplines in academia and the private sectors and consequently the outputs of the project will bring benefit to all communities and the economy. The industry co-creators contributing to the activities range from end users, to data management providers through to SMEs offering technology solutions to the sector. The Academic institutions have established strong knowledge exchange programmes to transmit the relevance of their research to the public. The knowledge exchange within the project between the disciplines will enhance the project and the partners, particularly between the pharmaceutical specialists and engineers.The project will deliver highly skilled people to a key sector whilst meeting the needs of industry for researchers to address their environmental challenges that have increased over the recent past.

Publications

10 25 50
 
Description Development and validation of multi-sensor models for variable particle shapes.
Successfully completed:
Algorithm to estimate particle size distribution (PSD) and aspect ratio from chord length distribution (CLD) data.
Algorithm to incorporate aspect ratio estimate from images in PSD estimation from CLD data.
Algorithm to estimate PSD from laser diffraction data.
Algorithm to estimate PSD from combined laser diffraction and CLD data.
Implementation of robust inversion of multi-sensor data to identify particle size and shape distributions.
Successfully completed:
Implementation of CLD inversion algorithm in a wet milling process.
Software package for near real-time CLD inversion.
Implementation of CLD forward model in gCRYSTAL.
Implementation of CLD inversion algorithm on industrial data.
Implementation of combined CLD and Laser diffraction inversion algorithm on data from different particle suspension.
Algorithm to detect fouling and determine nucleation induction times in crystallisation processes
Algorithm for particle size and shape characterisation from in-line imaging (PVM)
Validation on standard systems
Evaluation on a range of applications
Implementation in real time monitoring and control
Engagement with CMAC academic and industrial communities through demonstrations and dissemination of tools (ImagingApp)

Various mathematical model have been developed for crystallization: single- and multi-stage MSMPR crystallization, antisolvent crystallization, tubular-loop crystallization, COBC;
Mathematical models for screen- and dry-milling;
Model-based predictive control for anti-solvent crystallization; and polymorphic transformation;
Model for particle breakage by using novel moment closure technique;
Experimental investigation and model validation of crystallization including polymorphic transformation;
Fully automated control system (including data transfer) by using multi-sensor PAT.
Exploitation Route Given the project had a spectrum of industrial partners, that grouping represents a viable route to commercilisation of the software developed under the project. In addition the close working relationship with CMAC and its body of researchers also guaranteed ready adoption of these outputs.
Sectors Digital/Communication/Information Technologies (including Software),Pharmaceuticals and Medical Biotechnology

 
Description Findings have been implemented in commercial software after publication. These include both SMEs and large multinational organisations. The possibilities of new types of process measurement have also been demonstrated to project partners.
First Year Of Impact 2014
Sector Digital/Communication/Information Technologies (including Software),Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Imapct Accelerator Account / Direct Industrial Funding
Amount £31,592 (GBP)
Organisation University of Strathclyde 
Sector Academic/University
Country United Kingdom
Start 07/2016 
End 03/2017
 
Description Impact Acceleration Account
Amount £14,000 (GBP)
Organisation University of Strathclyde 
Sector Academic/University
Country United Kingdom
Start 03/2016 
End 07/2016
 
Title CLD Inversion Software 
Description "This is the software for converting a measured chord length distribution (CLD) data to particle size distribution (PSD). The CLD is measured with the Mettler Toledo focused beam reflectance measurement (FBRM) sensor immersed in a particle suspension, for example, crystalline particles in a crystallisation process. The software then performs the necessary calculations to estimate the PSD and the aspect ratio for the particles. Details on the use of the software are contained in the user guides. The software was developed under the EPSRC funded ICT-CMAC project (grant number EP/K014250/1). Details of the workings of the algorithm behind the software are given in the publications: [1] O. S. Agimelen et al., "Estimation of particle size distribution and aspect ratio of non-spherical particles from chord length distribution", Chemical Engineering Science, 123, pp. 629-640, 2015. [2] O. S. Agimelen et al., "Integration of in situ Imaging and Chord Length Distribution for Estimation of Particle Size and Shape", Chemical Engineering Science 144, pp. 87-100, 2016. We would greatly appreciate your feedback on your experience using the software. For further details or help using the software please contact the software developer Stephen Agimelen at the email address okpeafoh.agimelen@strath.ac.uk. " 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact Unknown 
 
Title Data for "Monitoring crystal breakage in wet milling processes using inline imaging and chord length distribution measurements" 
Description This is the dataset associated with the article titled 'Monitoring crystal breakage in wet milling processes using inline imaging and chord length distribution measurements'. The dataset consists of images obtained with the Mettler Toledo Particle Vision and Measurement (V819) sensor, as well the Malvern Morphologi G3 instrument. It also contains the chord length distribution data obtained with the Mettler Toledo focused beam reflectance measurement (G400) sensor. Various particle statistics obtained from the Morphologi G3 instrument are also contained in the dataset. The data were collected at various stages of different wet milling processes using the following crystalline materials: 1. Benzoic acid 2. Paracetamol 3. Metformin hydrochloride The data from the Morphologi G3 instrument were obtained before and at the end of each wet milling process. The MagicLab rotor stator wet mill was employed in all the processes. The file 'Read me' contains more details of this dataset. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact Unknown 
 
Title Data for: "Engineering of Acetaminophen Particle Attributes Using a Wet Milling Crystallisation Platform" 
Description "This dataset is for the article titled 'Engineering of Acetaminophen Particle Attributes Using a Wet Milling Crystallisation Platform'. Mettler Toledo focused beam reflectance measurement (G400) and particle vision and measurement (V819) sensors were used for capturing inline counts, chord length distributions and images. Chord lengths were further inverted for an estimation of inline particle size distributions through a CLD-inversion app. A Malvern Morphologi G3 instrument was also used which provided various particle size and shape statistics and distributions from particles undergone a wet milling process. In addition, an inverse gas chromatography measured various surface properties such as surface areas and surface energy distributions. This is all shown in the dataset. The data collected was for acetaminophen. Various wet milling configurations were used which produced particles exhibiting different attributes and features. " 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? No  
Impact
 
Title Data for: "Fusion of laser diffraction and chord length distribution data for estimation of particle size distribution using multi-objective optimisation" 
Description "This is the dataset for the articl titled ""Fusion of laser diffraction and chord length distribution data for estimation of particle size distribution using multi-objective optimisation"". The preprint of the article is available at: arXiv:1804.05633. Full details of the materials and measurement proceedure can be found in the preprint." 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact
 
Title Data for: "In situ characterisation of particle size and shape attributes through image-based analysis" 
Description This dataset contains a set of in-line microscopy images analysed in the manuscript ""In situ characterisation of particle size and shape attributes through image-based analysis"". The Particle Vision and Measurement (PVM) images were captured by the PVM V819 probe for two different materials: - standard polystyrene microspheres of 150, 300, 400 and 500 microns at solid loadings ranging from 1 to 5 wt.%. - standard silicon particles of elongated shape of 20x20x160, 20x20x60, and 20x20x20 microns. This dataset is freely available, however due to its size access should be requested using the contact email provided on this page. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? No  
Impact Unknown 
 
Title Data for: "Integration of in situ imaging and chord length distribution measurements for estimation of particle size and shape" 
Description This is the dataset for the article titled Â"Integration of in situ imaging and chord length distribution measurements for estimation of particle size and shapeÂ" [Chemical Engineering Science 144 (2016) pp. 87Â-100]. The dataset was produced with the focused beam reflectance measurement (FBRM) and particle vision and measurement (PVM) sensors both from Mettler Toledo Ltd. Details of measurement procedure are given in [Chemical Engineering Science 144 (2016) pp. 87Â-100]. More details of the dataset are contained in the PDF file included. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact
 
Title ImagingApp: image analysis framework for particle size and shape characterisation 
Description "This is a software to extract particle size and shape distributions from image analysis. The implementation of a focus classifier allows the user to apply this tool to both off-line and inline imaging. For more details on this image analysis framework, please visit the following publications: [1] J. Cardona et al., ""Image analysis framework with focus evaluation for in situ characterisation of particle size and shape attributes"", Chemical Engineering Science, 191, pp. 208-231, 2018. [2] O. S. Agimelen et al., Â"Integration of in situ Imaging and Chord Length Distribution for Estimation of Particle Size and ShapeÂ", Chemical Engineering Science, 144, pp. 87-100, 2016. We would greatly appreciate your feedback on your experience using the software. For further details or help using the software please contact the data creators using the contact details contained within the user guides provided." 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact
 
Description Consultancy with AZ 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution The consultancy was to provide specialist analysis on a specific project for which the need had been identified within the company.
Collaborator Contribution The partners provided access to data and experienced personnel to facilitate understanding of the data and the problem to be solved.
Impact The output was a short consultancy report.
Start Year 2015
 
Description Joint research with Loughborough University 
Organisation Loughborough University
Country United Kingdom 
Sector Academic/University 
PI Contribution University of Strathclyde researchers worked on this project with researchers from Loughborough University
Start Year 2013
 
Description Mettler Toledo project partnership 
Organisation Mettler Toledo Safeline Ltd
Country United Kingdom 
Sector Private 
PI Contribution Mettler Toledo Ltd worked with the research team and assisted/contributed to the project outcomes
Collaborator Contribution Mettler Toledo provide technical information and in-kind support.
Impact Working with Mettler Toledo has accelerated understanding of the subject area and therefore accelerated research. This is a multi-disciplinary collaboration, covering crystallisation, imaging, data acqusition and signal processing.
Start Year 2014
 
Description Project partnership with Astra Zeneca 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Astra Zeneca worked with the research team and assisted/contributed to the project outcomes
Start Year 2013
 
Description Project partnership with Glaxo Smithkline (UK) 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Glaxo Smithkline (UK) worked with the research team and assisted/contributed to the project outcomes
Start Year 2013
 
Description Project partnership with Perceptive Engineering Ltd 
Organisation Perceptive Engineering Ltd
Country United Kingdom 
Sector Private 
PI Contribution Perceptive Engineering Ltd worked with the research team and assisted/contributed to the project outcomes
Start Year 2013
 
Description Project partnership with Process Systems Enterprise (PSE) 
Organisation Process Systems Enterprise Limited (PSE)
Country United Kingdom 
Sector Private 
PI Contribution Two of the five Work Packages work closely with PSE to develop models using their software, and to integrate other models to PSE software
Collaborator Contribution Expertise and software licenses.
Impact Publications arising from using the collaboration are: DOI: 10.1021/acs.oprd.5b00110 10.1016/j.cep.2015.01.001 10.1109/ACC.2015.7172001
Start Year 2013
 
Description Project partnership with Siemens 
Organisation Siemens AG
Country Germany 
Sector Private 
PI Contribution Results from the ICT CMAC project are applicable to be demonstrated using Siemens hardware and software.
Collaborator Contribution Expertise, software licenses and hardware.
Impact Multidisciplinary collaboration. A demonstration project with Siemens and Perceptive Engineering as partners with CMAC and ICT CMAC is under way to demonstrate capabilities and add functionality to CMAC.
Start Year 2016
 
Description CMAC Summer School - Particle Sizing Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact CMAC Summer School - Particle Sizing Workshop
Year(s) Of Engagement Activity 2017
 
Description Engage with Strathclyde: CMAC Tier 2 Partners event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact The ICT CMAC project was represented at the CMAC Tier 2 partners event through a flash presentation. Discussions during the day led to a number of new contacts.
Year(s) Of Engagement Activity 2016
URL http://www.strath.ac.uk/workwithus/engage/
 
Description Engage with Strathclyde: ICT CMAC and Hyperspectral Imaging 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Industrial visitors to Engage with Strathclyde Week attended short workshop sessions explaining the purpose of the ICT CMAC project and also the use of Hyperspectral Imaging in the context of crystallisation and mixing processes. The event led to a number of follow up activities and new industrial links.
Year(s) Of Engagement Activity 2016
URL http://www.strath.ac.uk/workwithus/engage/
 
Description Invited presentation and poster at 'Embracing Industrie 4.0' workshop at University of Nottingham 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The event was targetted at senior policymakers and practitioners, academics and professionals involved in Industrie 4.0 and Digital Manufacturing. Presentations were invited from EPSRC grant holders in the area.
Year(s) Of Engagement Activity 2015
URL https://www.nottingham.ac.uk/conference/fac-eng/dtmi2015/index.aspx