Future Continuous Manufacturing and Advanced Crystallisation Research Hub

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

Abstract

Our Hub research is driven by the societal need to produce medicines and materials for modern living through novel manufacturing processes. The enormous value of the industries manufacturing these high value products is estimated to generate £50 billion p.a. in the UK economy. To ensure international competitiveness for this huge UK industry we must urgently create new approaches for the rapid design of these systems, controlling how molecules self-assemble into small crystals, in order to best formulate and deliver these for patient and customer. We must also develop the engineering tools, process operations and control methods to manufacture these products in a resource-efficient way, while delivering the highest quality materials.

Changing the way in which these materials are made, from what is called "batch" crystallisation (using large volume tanks) to "continuous" crystallisation (a more dynamic, "flowing" process), gives many advantages, including smaller facilities, more efficient use of expensive ingredients such as solvents, reducing energy requirements, capital investment, working capital, minimising risk and variation and, crucially, improving control over the quality and performance of the particles making them more suitable for formulation into final products. The vision is to quickly and reliably design a process to manufacture a given material into the ideal particle using an efficient continuous process, and ensure its effective delivery to the consumer. This will bring precision medicines and other highly customisable projects to market more quickly. An exemplar is the hubs exciting innovation partnership with Cancer Research UK.

Our research will develop robust design procedures for rapid development of new particulate products and innovative processes, integrate crystallisation and formulation to eliminate processing steps and develop reconfiguration strategies for flexible production. This will accelerate innovation towards redistributed anufacturing, more personalisation of products, and manufacturing closer to the patient/customer. We will develop a modular MicroFactory for integrated particle engineering, coupled with a fully integrated, computer-modelling approach to guide the design of processes and materials at molecule, particle and formulation levels. This will help optimise what we call the patient-centric supply chain and provide customisable products. We will make greater use of targeted experimental design, prediction and advanced computer simulation of new formulated materials, to control and optimise the processes to manufacture them.

Our talented team of scientists will use the outstanding capabilities in the award winning £34m CMAC National Facility at Strathclyde and across our 6 leading university spokes (Bath, Cambridge, Imperial, Leeds, Loughborough, Sheffield). This builds on existing foundations independently recognised by global industry as 'exemplary collaboration between industry, academia and government which represents the future of pharmaceutical manufacturing and supply chain R&D framework'.

Our vision will be translated from research into industry through partnership and co-investment of £31m. This includes 10 of world's largest pharmaceutical companies (eg AstraZeneca, GSK), chemicals and food companies (Syngenta, Croda, Mars) and 19 key technology companies (Siemens, 15 SMEs) Together, with innovation spokes eg Catapult (CPI) we aim to provide the UK with the most advanced, integrated capabilities to deliver continuous manufacture, leading to better materials, better value, more sustainable and flexible processes and better health and well-being for the people of the UK and worldwide. CMAC will create future competitive advantage for the UK in medicines manufacturing and chemicals sector and is strongly supported by industry / government bodies, positioning the UK as the investment location choice for future investments in research and manufacturing.

Planned Impact

The CMAC Future Manufacturing Hub team actively engage and collaborate with a wide range of research beneficiaries: leading pharmaceutical companies (e.g. AZ, GSK, Bayer, Pfizer, Lilly); companies in the process industries (e.g. Mars, AB Sugar, Syngenta, Croda); technology and supply chain companies (e.g. Siemens and 15 SMEs). It has a vibrant innovation landscape with partners including; HVM Catapult (CPI); the National Formulation Centre; medical charities (e.g. CRUK), Medicines Manufacturing Industry Partnership (MMIP) of the UK pharma manufacturing industry; Chemical Growth Partnership; International academic partners (Rutgers, Graz, Singapore) through the newly formed International Institute of Advanced Pharmaceutical Manufacturing. This strong, active and influential network of collaborators, stakeholders and business leaders (contributing £31.2m to translate the research into impact), maximises the potential to achieve the Hub vision will create substantial associated impact and benefits including:
1. Economic Impact: contributing to the UK economy by increasing the competitiveness of companies across the £50Bn Pharmaceutical and Chemicals sector. The Hub programme will impact on business innovative capacity and revenues by giving industry access to a 'particle production toolbox' which will increase competitiveness by enabling flexibility of product supply delivered through integrated multi-step continuous manufacturing processes. The Hub will accelerate development and scale up of products with improved costs, energy and material usage, delivering regeneration and economic development opportunities through creation and growth of new companies and jobs through the exploitation and commercialisation of novel processing and platform formulation technologies (potential licensing, spin-out formation) attracting direct inward R&D investment investments from global businesses.
2. Wider Societal Impacts: delivering improvements to life quality and health & webeing through improvements to the speed and agility of drug development, manufacture and supply required to meet current unmet customer and patient needs and future demand; availability of a wider range of effective, safe and economically viable products will impact on health across the population. Through smaller plant footprint and reduced energy consumption, continuous manufacturing will deliver lower production costs and significant positive environmental impacts. Engaging with policy-makers and influencing future regulatory frameworks will be a key activity to realise the full potential of these transformative innovations in highly regulated sectors. The manufacturing technology developments will also impact internationally - small modular reconfigurable manufacturing capability with automated, intelligent control has the potential to enable distributed manufacture with units positioned close to the point of need, tackling global priority problems; opportunities for anti-malarial or anti-retroviral products at low cost in developing economies for local distribution to patients will improve access to safe and effective healthcare.
3. Academic Impacts: an interdisciplinary approach to developing new and innovative methodologies and technologies will deliver worldwide academic opportunities in addressing the challenges facing global pharmaceutical and chemicals industries. A unique focus on manufacturing technology and connectivity across multiple stakeholders will enhance the profile of manufacturing research in key sectors of the UK economy, increasing research activity and capacity. Through training highly skilled researchers and attracting talent, a pipeline of knowledge and skilled people will be created for businesses, international collaboration, engagement and research impact (e.g. through co-authored research papers) and new opportunities for UK researchers to obtain international experience via researcher exchanges through CMACs global network.

Organisations

Publications

10 25 50
 
Description Integrated Paracetamol Process
The CMAC Future Manufacturing Research Hub launched its research program with the development of an end-to-end process for the synthesis, purification, isolation and formulation of Paracetamol, an analgesic medicine. In Parallel a prototype digital twin was developed using PSE's gFormulate software. This short project ran from January to June 2017 and built upon the outputs of the CMAC Centre for Innovative Manufacturing (CIM). This short project assessed the current capabilities in development workflows, equipment and modelling to inform future research and it also acted as a platform for developing the new research partnership.
Prototype Lovastatin Microfactory and Digital Twin
Over the period July 2017-October 2019, CMAC has developed and tested a novel prototype integrated continuous crystallisation, spherical agglomeration, filter, wash and dry process for the manufacture of Lovastatin. This is a drug where the active ingredient forms difficult to process needle-like crystals that make the traditional manufacture process difficult and expensive. The new process can be implemented in a laboratory setting using our Microfactory platform with the benefits of a very small space footprint. For the first time, the material from this process was successfully made into tablets using direct compression to produce an oral solid dose form with improved manufacturability.
A digital twin of the new Lovastatin process has been developed. It coupled predictive models for solvent screening and selection, crystal growth, and spherical agglomeration to enable simulation of possible conditions of these integrated processes. A set of visualisation tools are being developed to support the digital twin. The prototype versions of these were also demonstrated alongside the Lovastatin Microfactory at the CMAC Open Day 2018.
Research outputs from this work and the underpinning research supporting it are being written up and will be added to the common outcomes as they are disseminated during 2019.
Exploitation Route The pre-competitive CMAC Future Manufacturing Research Hub programme has been co-created with our industry partners (AstraZeneca, Bayer, GSK, Lilly, Novartis, Pfizer, Roche, Takeda). The research outputs have been demonstrated at CMAC Open Day 2018 via live demonstrators, talks and posters. Research outputs are being disseminated via publications and internal reports. Learnings form this project are expected to be translated to industry partners through routes including researcher placements, and knowledge applied to proprietary industry projects run by CMAC in parallel with this programme.
The academic team working on the pre-competitive CMAC Future Manufacturing Research Hub programme will take the learnings developed through the Paracetamol and Lovastatin projects and incorporate these into the planning for the programme and specifically into the next digital twin and Microfactory currently under development. This work will also link directly to the research being done on the aligned EPSRC ARTICULAR project (EP/R032858/1).
Sectors Chemicals,Digital/Communication/Information Technologies (including Software),Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description ARTICULAR: ARtificial inTelligence for Integrated ICT-enabled pharmaceUticaL mAnufactuRing
Amount £1,965,119 (GBP)
Funding ID EP/R032858/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 07/2018 
End 06/2022
 
Description Multi-User Facility for SAXS/WAXS Studies on Nanoscale Structures in Controlled Environments.
Amount £1,183,496 (GBP)
Funding ID EP/R042683/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 06/2018 
End 05/2023
 
Description 03 April 2017 edition of Chemistry World. "The flow revolution" 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Article in Chemistry World Magazine that includes CMAC
Year(s) Of Engagement Activity 2017
URL https://www.chemistryworld.com/feature/the-flow-revolution/2500496.article
 
Description 16 November , The Scotsman, "Fast-track medicine base in Scotland could be a game changer" . 
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 Public/other audiences
Results and Impact Article about CMAC in Scotsman newspaper / online
Year(s) Of Engagement Activity 2017
URL https://www.scotsman.com/business/fast-track-medicine-base-in-scotland-could-be-a-game-changer-1-461...
 
Description 18 December 2017 - CMAC Welcomes Pfizer as Newest Partner 
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 Media (as a channel to the public)
Results and Impact Press release to announce that Pfizer joined CMAC as tier 1 Industry Partners
Year(s) Of Engagement Activity 2018
URL http://www.strath.ac.uk/whystrathclyde/news/cmacwelcomespfizerasnewestpartner/
 
Description 24 May 2017 , Pharmaceutical Online "Developing Mobile Continuous Process Technology: A Collaborative Innovation Case Study" . 
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 Public/other audiences
Results and Impact Press release about CMAC and REMEDIES project
Year(s) Of Engagement Activity 2017
URL https://www.pharmaceuticalonline.com/doc/developing-mobile-continuous-process-technology-a-collabora...
 
Description 26 January 2017 edition of Chemical Engineer Magazine "Continuous Collaboration" . 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Article in Chemical Engineer Magazine that outlines the CMAC activities including research, training, facilities and translation into industry.
Year(s) Of Engagement Activity 2017
URL https://www.thechemicalengineer.com/features/continuous-collaboration/
 
Description 28th November , featured in the Herald, "Alastair Florence: 'The key to success is working pre-competitively with industry' 
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 Public/other audiences
Results and Impact Article about CMAC in the Herald newspaper and online
Year(s) Of Engagement Activity 2017
URL http://www.heraldscotland.com/business_hq/15687920.Alastair_Florence___The_key_to_success_is_working...
 
Description 3rd ISCMP Conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact The 3rd CMAC-MIT International Symposium on Continuous Manufacturing of Pharmaceuticals (ISCMP) brought together pharmaceutical company end users, suppliers, regulators and academics building on how research groups, globally, might collaborate more to help drive continuous manufacture and guide the way in which new technologies and approaches in the pharmaceutical industry can transform quality, cost and service for the benefit of the patient.

A key objective of the 2018 meeting was to address business, regulatory and technological barriers to increase the rate of integration of continuous manufacturing into process development. Thus, emphasis placed upon regulatory with modelling and process validation as high priority areas, in addition to business cases.

The London based event had excellent attendance across the board with 300 delegates and attracted many regulatory bodies including FDA, EMA and PMDA with Dr Janet Woodcock, M.D., Director, Center for Drug Evaluation and Research delivering the keynote.

A key output from this is a White Paper, which will be published in the forthcoming year (2019/2020).
Year(s) Of Engagement Activity 2018
URL https://www.iscmp2018.org/
 
Description Accelerating the delivery of new drugs to patients 
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 Media (as a channel to the public)
Results and Impact 25 June Accelerating the delivery of new drugs to patients - ARTICULAR announced.
Year(s) Of Engagement Activity 2018
URL https://www.strath.ac.uk/whystrathclyde/news/acceleratingthedeliveryofnewdrugstopatients/
 
Description CMAC Open Day 2018 
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 CMAC Open Day 2018 showcased the research outputs of the Future CMAC Hub through a packed programme of talks, posters, interactive demonstrations, a VR/AR demo and a tour that included a live demo of a prototype Lovastatin Microfactory and digital twin devloped as part of the CMAC Future Manufacturing research Hub research programme. Additionally, there were keynotes from Prof Marianthi Ierapetritou, Rutgers University and Prof Jon-Paul Sherlock, AstraZeneca and Chair of the CMAC Advisory Board. There were 260 delegates from 76 organisations in attendance including 22 exhibitors from technology companies.

All CMAC researchers presented a poster during the poster session.

The talks and posters related directly to the Lovastatin Microfactory and digital twin were:
Talks
Arjmandi-Tash, O.; Tew, J.D.; Yusoff, S.N.M.; Pitt, K.; Smith, R.; Litster, J. Mechanistic Modelling of Spherical Agglomeration. CMAC Open Day, Glasgow 25-26th October 2018
Brown, C.J.; Application of Process Models to Microfactories. CMAC Open Day 2018, Glasgow 25-26th October 2018
Hatcher, L. E.; Control of Lovastatin Crystal Shape and Size by Additive Crystallisation Methods CMAC Open Day. University of Strathclyde, Glasgow, 25-26th October 2018
Robertson, J.; Overview of CMAC Hub Microfactories. CMAC Open Day 2018, Glasgow 25-26th October 2018
Turner, T; The Intermolecular Synthon Analysis Associated with the Morphology and Surface Properties of the API Lovastatin. CMAC Open Day 2018, Glasgow 25-26th October 2018

Posters
Arjmandi-Tash, O.; Tew, J.D.; Yusoff, S.N.M.; Pitt, K.; Smith, R.; Litster, J. Mechanistic modelling of spherical agglomeration for continuous manufacturing of pharmaceuticals. CMAC Open Day. University of Strathclyde, Glasgow, 25-26th October 2018
Hatcher, L. E.; Influence of Temperature and Additive Crystallisation Methods on Lovastatin Crystal Size and Shape; CMAC Open Day: University of Strathclyde, Glasgow, 25-26th October 2018
Jolliffe, H.G., Papathanasiou, F., Prasad E., Robertson J., Brown C.J., Halbert G., Florence A.J.; Predicting multi-component tablet properties from pure component parameters. CMAC Open Day. University of Strathclyde, Glasgow, 25-26th October 2018
McGinty, J.; Developing a Workflow for Continuous Antisolvent Crystallisation. CMAC Open Day. University of Strathclyde, Glasgow, 25-26th October 2018
Pallipurath, A.; Advanced Characterisation of Lovastatin: A Theoretical and Experimental Perspective. CMAC Open Day. University of Strathclyde, Glasgow, 25-26th October 2018
Prasad, E.; Evaluation of gFormulate Modelling Tools for Tablet Compression. CMAC Open Day, University of Strathclyde, Glasgow, 25-26th October 2018
Robertson, M.; The CMAC Digital Platform. CMAC Open Day, University of Strathclyde, Glasgow, 25-26th October 2018
Tew, J.D.; Arjmandi-Tash, O.; Pitt, K.; Smith, R.; Litster, J. Wetting & Nucleation: Developing the Mechanistic Understanding of Spherical Agglomeration. CMAC Open Day. University of Strathclyde, Glasgow, 25-26th October 2018
Vassileiou, A.; Using Machine Learning to Enhance Mechanistic Solubility Predictions. CMAC Open Day, University of Strathclyde, Glasgow, 25-26th October 2018
Watson, O. L.; Galindo, A.; Jackson, G.; Adjiman, C. S. Computer-aided design of solvent blends for the cooling and anti-solvent crystallisation of lovastatin and ibuprofen. CMAC Open Day, University of Strathclyde, Glasgow, 25-26th October 2018
Year(s) Of Engagement Activity 2018
 
Description Cambridge Crystallographic Data Centre (CCDC) has joined CMAC as a Tier 2 Member 
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 Public/other audiences
Results and Impact 23 October Cambridge Crystallographic Data Centre (CCDC) has joined CMAC as a Tier 2 Member.
Year(s) Of Engagement Activity 2018
URL https://www.ccdc.cam.ac.uk/News/List/2018-10-23-ccdc-joins-future-manufacturing-initiative-to-help/
 
Description Chemical Engineer Article May 2018 "Continuous crystallisation workflow enables high precision manufacturing of pharmaceuticals" 
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 09 May Chemical Engineer Article May 2018 "Continuous crystallisation workflow enables high precision manufacturing of pharmaceuticals" link below. Features C J Brown et al, Mol. Syst. Des. Eng., 2018, DOI: 10.1039/c7me00096k
Year(s) Of Engagement Activity 2018
URL https://www.thechemicalengineer.com/news/continuous-crystallisation-workflow-enables-high-precision-...
 
Description Chemistry World "The Case for Lab Management Systems" 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 03 July edition of Chemistry World "The Case for Lab Management Systems"
Year(s) Of Engagement Activity 2018
URL https://www.chemistryworld.com/opinion/the-case-for-lab-management-systems/3009220.article
 
Description Chemistry World Article March 2018 "Solving the Crystal Maze" by Laura Fisher 
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 26 March Chemistry World Article March 2018 "Solving the Crystal Maze" by Laura Fisher (26th March 2018) link below (subscribers only). Highlights the CMAC publication C J Brown et al, Mol. Syst. Des. Eng., 2018, DOI: 10.1039/c7me00096k
Year(s) Of Engagement Activity 2018
URL https://www.chemistryworld.com/news/solving-the-crystal-maze/3008812.article
 
Description Doctoral Training Centre for Continuous Processing and Crystallisation 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Cambridge programme lead on the Doctoral Training Centre for Continuous Processing and Crystallisation involving some 50 plus PhD students
Year(s) Of Engagement Activity 2016,2018
 
Description Looking back to look forward 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact 22 June Looking back to look forward - ReMEDiES article.
Year(s) Of Engagement Activity 2018
URL https://remediesproject.com/2018/04/16/looking-back-to-look-forward-craig-johnston/
 
Description Microfactory and Digital Twin Video 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact 24 October EPSRC CMAC Future Manufacturing Research Hub - Microfactory and Digital Twin video.
Year(s) Of Engagement Activity 2018
URL https://www.youtube.com/watch?v=MttQ-nAs3VM
 
Description Siemens released a video of Alwyn Jones, Siemens UK & Ireland Head of Pharmaceutical & Life Sciences, in conversation with CMAC's Industry Director Craig Johnston 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact 26 February Siemens released a video of Alwyn Jones, Siemens UK & Ireland Head of Pharmaceutical & Life Sciences, in conversation with CMAC's Industry Director Craig Johnston
Year(s) Of Engagement Activity 2018
URL https://www.youtube.com/watch?v=kbzSgHFn_w4&__prclt=DZb25HTl
 
Description Strathclyde in Medicines Manufacturing Innovation Centre - press release 
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 Media (as a channel to the public)
Results and Impact 15 June Strathclyde in Medicines Manufacturing Innovation Centre Full press release link below.
Year(s) Of Engagement Activity 2018
URL https://www.strath.ac.uk/whystrathclyde/news/strathclydeinmedicinesmanufacturinginnovationcentre/