MOPP. Made to Order Process Plants

Lead Research Organisation: University of Strathclyde
Department Name: Inst of Pharmacy and Biomedical Sci


New reactor technologies are set to change the operation of batch manufacture in the process industries into the "new
wave" of semi-continuous Make to Order Processing Plants (MOPP). These have the potential to transform these sectors
by reducing the environmental burden, inventories and cost of manufacture and distribution. This project develops an
adaptive 'Dial a Product' control system to deliver the precise control required for these unique high value low volume
manufacturing systems. Bringing together control design and analytical techniques to complement these reactors will
enable the system to reach optimum performance and have commercial impact. The solution will offer the chance to
change the very way the industry operates. Instead of investing in a number of product specific batch reactors, a single
reactor will be used for a number of applications, allowing companies to reduce CAPEX or even work on a rental basis,
bringing in reactors as required.

Planned Impact

The outcomes of the proposed research will lead to broad ranging impact. New process control capabilities will open up
opportunities for those concerned with the scale-up and manufacture of novel, high-value particulate products. Improved
control combined with the new reactor technology will reduce manufacturing waste product by 8-15% and energy
consumption by 40-70% by significantly reducing non value added activities such as storage costs and transporting
unnecessary volumes of materials with their associated energy and environmental costs. The reactor being developed in
this research typically has less than 5% of the solvent hold-up compared to a batch reactor, and involves less manual
intervention enhancing safety. The use of the new technologies would allow more cost effective and affordable drugs to be
developed, improving quality of life and it's associated economic benefits. The project would open up links with the wider
process industries and promote the work done at the EPSRC Centre in Strathclyde and at the Catapult CPI facility on
Teesside. This project will deliver the opportunity for the UK to create HVM related jobs in the UK, as the benefits of
transporting a product half way around the world are greatly reduced when it is possible to make it in the UK for a
competitive delivered costs without the problems associated with global delivery routes and import regulations. A
successful outcome would be to generate ca. 20 jobs in the technology companies involved in the project and their supply
chain. In addition manufacturing jobs could be brought back to the UK through the "Patent Box" tax regime, and end-user
supply chain jobs would be created. AstraZeneca would reduce OPEX and gain the ability to make product with shorter
development times, allowing more bespoke run sizes. Advanced control typically reduces off-spec production by 40% and
re-work by 10%. The operating companies will benefit from lower delivered costs to the customers offering the potential to
increase market share and profits plus more sustainable operations. New opportunites to manufacture a wider variety of
small volume, high-value drug products will be enabled through flexible small to medium scale manufacturing thus allowing
companies new opportunites to take new drugs or existing drugs for new applications to market more cost effectively. UK
intensified reactor and agile equipment design companies will exploit the learning for their commercial benefit. The UK will begin to be perceived as a cost competitive environment to manufacture HVM process product sand the potential for the
UK to re-establish itself as a location for the design, manufacture and supply of process HVM processing plants.


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Description The Make to Order Processing Plants (MOPPs) project was conceived to deliver the full benefits of advanced process control to the new generation of continuous reactor/crystalliser systems that have recently been developed for use in High-Value/Low-Volume manufacturing. This report describes the technical delivery of the project, broken into Work Packages (WP). It describes both the work performed to develop transferable control systems on both continuous reactor and continuous crystalliser systems. It then goes on to describe the application of these control methodologies on a second reaction in the same reactor system and on a second crystalliser for the same product for the crystallisation system.

The main technical challenges faced in this project were:
• Integrating automation systems onto the reactor rigs, allowing computer operated control to be implemented on such systems
• Gaining an understanding of the processes involved in transferring a reaction from the batch to continuous domain and defining a suitable, repeatable work procedure for the efficient implementation of this work
• The transfer of control concepts from the time profile basis used in batch reactions to the spatial profile present in continuous reactors.
• The integration of on-line PAT into these reactor systems and the challenges of moving from their use in batch where their output is available through all stages of a reaction to continuous, where only point measurements are available.

The major outcomes from the project include:
• Model Predictive Control system and work flow on a continuous flow reactor that has been shown to be transferable between reaction types.
• Control system on Model Predictive Control system and work flow on continuous oscillatory baffled crystallisers that has been shown to be transferrable across different crystallisers that are producing the same product.
• A work procedure for the efficient transfer of crystallisation systems from the batch to continuous domains.
• A software tool that combines and automates two of the most time consuming activities performed during the development of a new reactor and its associated control system. These are the performing of a DoE trial and the controller development step test.
• A methodology to convert process from batch to continuous or produce new on continuous.
• Continuous, automated systems to measure MSZW and solubility curves
• Automated control of continuous oscillatory baffled crystallisers
• Automatically adjust processes to react to changes in both conditions and feedstock quality in real-time.
• Utilisation of assay information and in-line PAT measurements to assess process performance.
• Reduced need for staff to perform low value-adding work (manually adjusting process, reacting to basic events).
• Can automatically move process from product one grade to another without the need to stop the process and re-configure reducing waste and energy use.
• Speeds up development time and Scale-up.
• Perform automated DoE runs by feeding in a DoE plan and moving the process automatically between the respective factors to deliver significant development savings.
• Information outputted by one control system can be used as input to next, allowing the process to be adjusted in a pro-active rather than reactive manner.
• Proven ability to run for 5 days and 26% higher yield (vs batch) in continuous crystallisation in COBC => improved yield
• 2 fold reduction in span of PSD vs stirred tank reactor => higher quality
• Reduction in Lactose crystallisation time from 16 hour to 5 hours => intensified process
• A successful predictive model for concentration control in COBC system
• Successful transfer of concentration control strategy from one crystalliser to the other
Exploitation Route Model predictive control implemented on both continuous reactor (Corning Plate reactor) at CPI and continuous crystallisers (CRD's rattlesnake and Nitech DN15) at University of Strathclyde as part of the collaborative project.
Sectors Agriculture, Food and Drink,Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

Description Pharmaceuticals and speciality chemicals are key sectors with an interest in this technology and a business need to adopt more flexible manufacturing techniques. Under this project the EPSRC national centre, has demonstrated a technologically innovative crystallisation system targeted towards actual industrial operation. The platform is now available within the National Centre facilities for access by other UK companies. A systematic approach has been developed and optimised for an easy adoption of automated continuous system from an existing industrial batch system. This project provides the facility to develop a better process understanding using advanced technologies to optimise an existing process efficiently. As a direct result of this project, with support from UK-RPIF funding, the EPSRC Centre and crystallisation has purchased and owns both fully automated continuous crystallisation platforms developed under the MOPPS project. This has of course led to a direct financial benefit to the equipment manufacturers. In addition as these platforms are now available for research and collaboration with all of UK industry for open access testing, development and production of new molecules at CMAC's new facility in the Technology Innovation Centre, further economic impact may be generated from demonstration of the technology to other potential users. This extra advanced manufacturing capability at small scale is expected to result in an additional 2-3 company specific projects per annum using this equipment (value estimated at 100k). As a further direct consequence of the project EPSRC centre has (outwith the project) commissioned Perceptive Engineering to install APC systems on a further 5 different continuous processing platforms at CMAC to extend the advanced real time control approach to other platforms including spray drying, cascade of stirred tanks (CSTR). Perceptive Engineering have commercialized some of the software models developed during the project and now incorporate it into their platform software package for advanced control (PharmaMV). This has led to 3 specific projects for perceptive. CMAC have used the capabilities to manufacture a >3 pharmaceutically relevant compounds at a higher quality than was previously possible including one that is in late stage evaluation and is likely to be manufactured at >10 tonne scale in the next 5-10 year. The publications, posters and presentations emerging from the work will significantly enhance the EPSRC Centre's international reputation as a world-class manufacturing research centre accelerating the uptake of continuous processing. It is expected that this will lead (indirectly) to funding for an additional 2 PhD and one PDRA post at the EPSRC Centre and will form a key technical aspect of future Centre funding proposals. The collaboration and excellent relationship with the partners has resulted in further externally funded collaborations including; all partners being part of the REMEDIES project, a £23M AMSCI funded project ; an additional funding application as part of InnovateUK's Flexible Manufacturing call (AZ, Perceptive and EPSRC Centre); collaboration in National Formulation centre with CPI and scoping work is being funded with CPI through the Manufacturing Medicines Industry Partnership for a new medicines manufacturing innovation centre. Through these activities the project has contributed to job creation and increased R&D economic activity in the short term and has the potential to contribute to more signicant economic impacts through MMIP ( with CMAC leading the Skills agenda in that partnership. Peer-reviewed Literature Publications 1. Establishment of continuous sonocrystallisation process in oscillatory baffled crystalliser, Humera Siddique, Ian Houson, Alastair Florence. OPRD, Manuscript ID: DOI: 10.1021/acs.oprd.5b00127 2 Continuous seeded crystallisation of lactose to Control particle size distribution in an oscillatory baffled crystalliser, H. Siddique, V. Raval, F. Mabbott, J. Mack, K. Krzemieniewska, I. Houson, E. Mercer, A. Florence. Manuscript to be submitted March 2017 to Chem. Eng. 3. Control of product attributes in continuous crystallisation using model predictive control, H. Siddique, I. Houson, J. Mack, K. Krzemieniewska, E. Mercer, A. Florence. Manuscript In progress 4. Comparison of product from two continuous crystallisation platforms operated under predictive control, H. Siddique, I. Houson, J. Mack, K. Krzemieniewska, E. Mercer, A. Florence. Manuscript in progress 5. Design of crystallisation process using direct control from lab to manufacturing scale, H. Siddique, V. Raval, T. McGlone, Q. Yuan, I. Houson, J. Mack, E. Mercer, A. Florence. Manuscript submitted to Chemical Engineering Science 6. Tahir, F., K. Krzemieniewska-Nandwani, J. Mack, D. Lovett, H. Siddique, F. Mabbott, V. Raval, I. Houson, and A. Florence. "Advanced control of a continuous oscillatory flow crystalliser." Control Engineering Practice 67 (2017): 64-75. 6. Advanced Control of a Continuous Oscillatory Flow Crystalliser, K. Krzemieniewska-Nandwani, F. Tahir, J. Mack, D. Lovett, H. Siddique, F. Mabbott, V. Raval, I. Houson, A. Florence, submitted to Control Engineering Practice (awaiting final approval) Poster Presentations at Conferences 1. Dial a molecule, Process-ability Workshop Proctor and Gamble UK, 19-20th of October 2014. Best poster prize. 2. Poster presentation in Manufacturing the Future Conference, Glasgow, United Kingdon, 23-24th of September 2014. 2nd best poster prize 3. Poster presentation in International Symposium on Industrial Crystallisation (ISIC), Toulouse, France, 16-19th September 2014 4. Poster presentation in EPSRC centre for continuous manufacturing and crystallisation internal research day, 25th September 2014 5. Poster presentation in EPSRC centre for continuous manufacturing and crystallisation internal research day, 21st March 2014 6. Poster presentation in RSC Continuous Flow Technology in Industry II, from Research to Manufacturing, Cambridge, United Kingdom, 17-18th March 2014. 7. Poster presentation in Annual open day of EPSRC Centre for continuous manufacturing and crystallisation, 12th September 2013. 4.1.3 8. Poster presentation at CMAC Internal research Day, 10th October 2017 Presentations 1. Control of product attributes in seeded cooling crystallisation, Technical Committee meeting EPSRC centre for continuous manufacturing and crystallisation, 20th February 2015 2. Control of product attributes in continuous crystallisation using model predictive control and process analytical tools, Community of Practice EPSRC Centre for continuous manufacturing and crystallisation, 06th January 2015 3. Mixing and flow characterisation of continuous oscillatory baffled crystalliser, Technical Committee meeting EPSRC centre for continuous manufacturing and crystallisation, 2014 4. Joint CMAC - Perceptive Engineering presentation to Pfizer R&D group, Grotton, USA in 2014. 5. Mixing and flow characterisation of continuous oscillatory baffled crystalliser, CMAC Community of Practice EPSRC Centre for continuous manufacturing and crystallisation, 2014 6. "Dial-a-particle" Capability using Advanced Process Control in Continuous Crystallisers, RSC Flow Processing Confernece, 17 March 2016 7. Two presentations: Emerging Technology "Improving process performance through integrated PAT, Advanced Process Control and Monitoring." and "Improving continuous manufacturing processes using Calibration Modelling and Model Predictive Control." both presented at IFPAC 2016 8. " Direct Design Approach to Dial-a-Particle Size Capability in Continuous Crystallisation of Lactose" " Abstract submitted for ISIC, 3-6, September 2017 Training Courses Core professional development training course developed and delieverd at least twice in 2016 "Introduction to Pharmaceutical Production Control Course": ADDoPt project training and then also run at CMAC for 14 DTC students and PDRA reserachers This project has identified that teh modelling to predict the crystallisation of lactose is inadequate a PhD reseracher has started work at teh University of Strathclyde to investigate this work with Prof Alastair Florence.
Sector Agriculture, Food and Drink,Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

Description RE-configuring MEDIcines End-to-end Supply (REMEDIES) project
Amount £22,100,000 (GBP)
Organisation Birmingham City Council 
Sector Public
Country United Kingdom
Start 09/2015 
End 03/2018
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. CMAC poroducced kgs of material for pharmaceutical research for AZ of specified particle size distribution
Collaborator Contribution CMAC use approach and equipment developed through the project to make material that would have required significantly more time and effort to make before the project occurred.
Impact Continuned reserach programmes and agreements with AZ ~ 5 confidential proujects have resulted form teh partnership developed during the MOPPs project
Start Year 2016
Description IChemE GlobalResearch Award 2015 shortlisted 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact IChemE GlobalResearch Award shortlisted in Research Project category for Make-to-order Product Properties - Perceptive Engineering Ltd; University of Strathclyde; Centre For Process Innovation; AstraZeneca, UK
A new generation of continuous reactors is coming onto the market, aimed at traditionally batch-manufactured high-value, low-volume processes. These units have a high level of operational flexibility, enabling a single reactor to manufacture multiple products over a wide range of operating conditions. The MOPPs project developed an automation system to automatically derive the maximum possible benefits from these units. Analytical modelling tools and control strategies can be transferred rapidly between reactors, allowing agile, short-run and multi-product manufacture in sectors such as such as next-gen pharmaceuticals and speciality chemicals. Demonstrator Systems were developed for both flow chemistry and continuous crystallisation systems.
Year(s) Of Engagement Activity 2015