Impact case study database

Through the establishment, growth and global influence of CMAC, Strathclyde’s demand-led research and expertise in forming particles with controlled attributes, in workflow design, on advanced continuous platform technology and development of digital tools has improved pharmaceutical development and manufacturing processes globally. By demonstrating the viability and benefits of advanced continuous manufacturing techniques, Strathclyde’s innovative approach to integrated development and operating platforms has enabled adoption within the pharmaceutical industry and created business opportunities for technology providers. As evidenced by the following examples, this has resulted in improved processes which have lowered development time and production costs, increased yields, reduced risk and enhanced product quality to the benefit of manufacturers, suppliers and end-users. Upskilling of staff in new techniques and methods has also been achieved. Since August 2013, CMAC’s research has enabled approximately GBP45,000,000 of savings and improvements for the 22 multinational and SMEs who have invested directly in proprietary analytical and process improvement projects.

Contributing more broadly to technology translation for societal and economic benefit, CMAC’s work has generated 54 highly-skilled individuals, 31 of whom have gone on to employment in industry (e.g. AZ, Pfizer, GSK, Lilly, Novartis, Roche, Perceptive Engineering, National Physical Laboratory (NPL), Solid Form Solution, Process Systems Enterprise (PSE) Ltd, Mettler Toledo) and 23 to academia (e.g. Strathclyde, Imperial, Loughborough, Massachusetts Institute of Technology (MIT)).

Improved Industrial Process Development:

• CMAC research workflow outcomes [ R3, R5] were applied by AstraZeneca (AZ; 2016-18) to improve a commercial process for a pharmaceutical product delivering GBP10,000,000 saving [ S1]. The improved process understanding led to reduced waste and increased product quality.

• In 2014, Novartis adopted CMAC Strathclyde’s novel methodology for introducing seed crystals into a continuous crystallisation [ R2, R3] in their continuous pilot plant in Basel, Switzerland. This approach has been applied to the development of an anti-cancer product and at least 2 other active ingredients in development. As noted by the Novartis Development Engineer, ‘this effective application of CMAC research reduced chemical exposure risk to operators, minimised plant down time and improved product quality’ [ S2].

• CMAC doctoral placements (2013-19) installed a novel continuous nucleation and crystallisation platform at AZ which has since been used on 10 live medicinal compounds, 4 of which are in commercial manufacture [ R2, R3, R5]. This led to a 90% time reduction to generate the existing amount and quality of information compared to previous approaches. AZ’s Principal Scientist confirmed that, ‘Without the CMAC collaboration and student placements we would not have had the laboratory continuous crystallisation facilities established in this time frame or have been able to test the feasibility of continuous crystallisation on multiple AZ compounds. Using this new capability AZ scientists are be able to develop continuous crystallisation processes for APIs in-house in a much shorter timescale’ [ S1].

• The application of CMAC’s workflow approaches for particle attribute control at Eli Lilly in 2017 resulted in an improved particle size control from the use of high shear wet milling in the continuous crystallisation of the final active pharmaceutical ingredient for an oncology asset which was then in Phase IIb clinical trials [ R3, R6]. According to a Senior Engineering Advisor at Eli Lilly, by enabling the removal of a post processing dry milling step, this work ‘reduced fouling on the crystalliser walls (reducing plant cleaning and down time) and improved the physical product properties improving the product manufacturability. The removal of a milling step has reduced cycle times of each lot of product by 3 days and development time by 3 months. This is now a platform capability embedded at Lilly’ [ S3].

Enhanced workforce understanding and skills:

• The benefits of process insights from CMAC’s multivariate analysis (MVA) and data visualisation approaches were demonstrated on plant data at Lilly’s manufacturing plant in Ireland as part of a PhD project. These learnings enhanced process understanding and operations engagement with data analytics tools [ R1, R3, R6]. The project delivered real-time data cleansing, organisation and visualisation enabling a reduction in plant downtime and product losses. The work demonstrated the benefits of MVA to senior management and resulted in investment in digitisation of manufacturing processes. As noted by the Eli Lilly Team Leader for Small Molecule Technical Services/Manufacturing Sciences, in Cork, Ireland, this ‘really raised awareness of the benefits to manufacturing when data and technology are combined with people with the right skillsets…this work was a significant factor in convincing the site to expand the use of these tools’ [ S4].

• Working pre-competitively with its 8 large pharma Tier 1 members, CMAC developed an industrially-relevant workflow with 7 case studies providing methods to avoid the incorporation of impurities in crystals [ R4, R5]. Between Jan and Nov 2020, tailored training was provided to over 130 industry staff who subsequently applied the approaches directly into the process development of all their Active Pharmaceuticals Ingredients (APIs) [ S5].

Advanced process technology and industry adoption:

• An Advanced Process Control (APC) system for continuous reaction and crystallisation was developed and demonstrated in collaboration with Perceptive Engineering, Centre for Process Innovation (CPI) and AstraZeneca [ R1]. The Managing Director of Perceptive Engineering said, ‘The commercialisation of this software directly led to one new client with follow-on sales of GBP207,700, GBP400,000 of related projects, employment of 1 new FTE to support applications on continuous manufacturing and publication of 4 peer-reviewed papers and 2 articles significantly increasing our visibility and reputation’ [ S6].

• In collaboration with Alconbury Weston Ltd (AWL), CMAC developed and delivered a platform for continuous isolation (filtration, washing and drying) of APIs bridging from process development to manufacturing and reducing scale up risk [ R3, R6]. The platform is now in commercial production. As confirmed by AWL’s CEO, ‘Continuous isolation systems are rare at this scale and coupled with the demonstrated benefits of rapid processing times of less than 15 minutes, no particle shear or attrition, precise, repeatable dosing and consistent product, the unit has been demonstrated on >10 commercial molecules (including vitamins, pharmaceuticals, Cannabidiol (CBD) and an energetic material) with more than 15 companies. To date, 8 units have been sold with a further 3 on order, including 2 production scale systems for processing CBD and 2 systems are on hire around the world. The success of the new products based on the outstanding direction and input from Prof. Chris Price has allowed us to refine and commercialise a range of lab, pilot and production scale continuous filtration and drying systems for multiple industries’ [ S7].

Enhanced the global manufacturing landscape:

• At the request of Janet Woodcock, Head of the U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research, CMAC collaborated with the Novartis Centre for Continuous Manufacturing at MIT to initiate biennial symposia to advance continuous pharmaceutical manufacturing. Since 2014, the International Symposium for Continuous Manufacturing of Pharmaceuticals (ISCMP) has been held 5 times (2014, 2016, 2018, 2020 and 2021), demonstrating sustained interest in its potential impact on the global medicines manufacturing landscape. Due to the Covid-19 pandemic, the 2020/21 events were delivered as webinars which attracted over 500 delegates and facilitated discussion between key stakeholders: US and UK regulators (FDA, MHRA), industry bodies (Medicines Manufacturing industry Partnership, MMIP) and the UK Government (Office for Life Sciences and Business Enterprise Innovation and Science, BEIS). By bringing the wider international industry, regulatory and academic communities together to share case studies, develop and share practical guidance on continuous manufacturing (further embedded through the publication of a series of whitepapers and reports) CMAC has accelerated the pace of innovation and change in this strategically important industry sector. Attesting to this, the Chair of the Medicines Manufacturing Industry Partnership (MMIP) notes: ‘CMAC, on the basis of its research and recognised expertise, has strengthened international cooperation around continuous pharmaceutical manufacturing through the ISCMP. By facilitating discussion and focusing attention on key developments and issues to be addressed, this initiative has enhanced global relations and positioned the industry well to respond to current and future challenges’ [ S8].

Strengthened UK Research and Innovation:

• CMAC’s critical mass as a collaborative research centre has highlighted the success of the ‘triple helix’, coupling the power of industry, government and academia working together to accelerate change in the form of the adoption of continuous manufacturing. By working together with the Centre for Process Innovation (CPI Ltd), AZ and GSK, Strathclyde University helped to secure investment of GBP56,000,000 to create the Medicines Manufacturing Innovation Centre (MMIC) in 2018. This new facility, owned by CPI, will be built in 2021 and create 80 high value jobs by 2023 [ S9].