Readying Miniaturized Reactors for Flow Biocatalysis

Description of the project

In almost all engineering sectors there has been a successful transition from batch to continuous processing. One particularly promising area for continuous processing in biochemical engineering is the biocatalytic synthesis of active pharmaceutical ingredients (APIs) and value-added chemicals. However, continuous production at large scale has not yet been successfully demonstrated. Continuous-flow biocatalysis offers an improved control over reaction conditions with benefits in yield and productivity levels. This increase in efficiency and concomitantly minimization of waste will ultimately result in cleaner processes with lower overall costs. Furthermore, continuous processes enable a reduction in process lines and facility footprints which in turn result in less up-front capital investment. To exploit the full benefits of continuous processing, it is necessary to characterise reactor performance, and to understand the interplay between the biocatalysts' constraints and the reactor operation. Only then can these processes be exploited to successfully at industrially relevant volumes.
To achieve this aim, scale-down models that enable careful assessment of reactor performance and biocatalysts' behaviour are necessary. Miniaturized continuous-flow reactors are prime candidates. Their small dimensions allow experiments to be performed with much smaller volumes compared to traditional batch systems, offering significant cost reduction when using expensive substrates or enzymes. Within these reactors the control of reaction parameters is facilitated, and in-line purification with recovery of products has been demonstrated. Additionally, reactions can be potentially accelerated due to enhanced mass transfer with a concomitant decrease in reaction time. Therefore, miniaturized continuous-flow reactors will in the future form the basis to acquire high-quality data rapidly and with high throughput.

Project Objectives
- Design, fabricate, and characterize a miniaturized continuous-flow reactor with integrated optical sensors and at-line analytical tools for the on-line monitoring of chemical and physical variables (pH, temperature, oxygen and CO2) and for at line reaction analytics (GC- and LC-MS).

- Validate the integrated miniaturized continuous-flow reactor with industrially relevant biocatalytic reactions.

- Compare the reactor performance in batch and continuous systems (e.g. by space-time yields, (gproduct/(Lreactor.h), and (gproduct/genzyme)) at all scales assessing process stability, quality profile of the products process and scalability.

Output & Impact
This project aligns with UK strategic priorities in the area of Industrial Biotechnology and the departmental EPSRC Future Biomanufacturing Research Hub. Due to the high relevance and timeliness of this research direction, we anticipate that each objective of the project will lead to a publication output. The results obtained throughout this project will be included in teaching of undergraduates or postgraduate modules.

The CDT has a proven track record of delivering impact from its research and training activities and this will continue in the new Centre. The main types of impact relate to: (i) provision of highly skilled EngD and sPhD graduates; (ii) generation of intellectual property (IP) in support of collaborating companies or for spin-out company creation; (iii) knowledge exchange to the wider bioprocess-using industries; (iv) benefits to patients in terms of new and more cost effective medicines, and (v) benefits to the wider society via involvement in public engagement activities and impacts on policy.

With regard to training, provision of future bioindustry leaders is the primary output of the CDT and some 96% of previous EngD graduates have progressed to relevant bioindustry careers. These highly skilled individuals help catalyse private sector innovation and biomanufacturing activity. This is of enormous importance to capitalise on emerging markets, such as Advanced Therapy Medicinal Products (ATMPs), and to create new jobs and a skilled labour force to underpin economic growth. The CDT will deliver new, flexible on-line training modules on complex biological products manufacture that will be made available to the wider bioprocessing community. It will also provide researchers with opportunities for international company placements and cross-cohort training between UCL and SSPC via a new annual Summer School and Conference.

In terms of IP generation, each industry-collaborative EngD project will have direct impact on the industry sponsor in terms of new technology generation and improvements to existing processes or procedures. Where substantial IP is generated in EngD or sPhD programmes, this has the potential to lead to spin-out company creation and job creation with wider economic benefit. CDT research has already led to creation of a number of successful spin-out companies and licensing agreements. Once arising IP is protected the existing UCL and NIBRT post-experience training programmes provide opportunities for wider industrial dissemination and impact of CDT research and training materials.

CDT projects will address production of new ATMPs or improvements to the manufacture of the next generation of complex biological products that will directly benefit healthcare providers and patients. Examples arising from previous EngD projects have included engineered enzymes for greener pharmaceutical synthesis, novel bioprocess operations to reduce biopharmaceutical manufacturing costs and the translation of early stem cell therapies into clinical trials. In each case the individual researchers have been important champions of knowledge exchange to their collaborating companies.

Finally, in terms of wider public engagement and society, the CDT has achieved substantial impact via involvement of staff and researchers in activities with schools (e.g. STEMnet), presentations at science fairs (Big Bang, Cheltenham), delivery of high profile public lectures (Wellcome Trust, Royal Institution) as well as TV and radio presentations. The next generation of CDT researchers will receive new training on the principles of Responsible Innovation (RI) that will be embedded in their research and help inform their public engagement activities and impact on policy.