Transforming synthetic drug manufacturing: novel processes, methods and tools

The pharmaceutical industry, a key player in UK manufacturing, faces huge challenges in turning promising new molecules into affordable medicines. While synthetic drugs make up the largest part of pharmaceutical companies' drug portfolios, with peptides representing an increasingly important class of drugs, the road from the discovery of a drug molecule to a commercial product that benefits patients remains frustratingly long and arduous, with the total cost of development reaching $2.6bn and 10 years per new chemical entity (NCE) . Manufacturing and formulation can be a rate-limiting and costly step due to the difficulty in achieving the required molecular precision or yield in synthesis, in ensuring high yields during purification, and in producing final products with the stability and efficacy that maximise patient benefit. Furthermore, the pharmaceutical industry is facing a drive to improve the economic and environmental performance of its manufacturing processes, which currently suffer from extremely low material efficiency, with factors of 0.01 to 0.1 not unusual , the production of a large amount of waste and a slow adoption of quality by design (QbD) concepts, especially for more complex products. This Prosperity Partnership builds on an existing collaboration between leading industrial and academic investigators to address critical issues in our ability to manufacture synthetic drugs in a cost and time effective way. Together, we have identified scientific hurdles that prevent the successful manufacture and delivery to patients of key medicines and we have devised an ambitious research programme to overcome them. A unique and exciting feature of our approach is to draw on expertise and advances in the manufacture of small molecules to enable radical progress in the synthetic manufacture of much larger peptide drugs, considering the entire chain from drug substance to drug product. Our programme will thus deliver fundamental understanding, models, technologies and design methodologies in order to accelerate the synthesis, isolation, purification and formulation of synthetic drugs of varying sizes, from small molecules to peptides, and to push the boundary of feasibility in relation to peptide drugs. Beyond its scientific achievements, the Prosperity Partnership will positioning the UK at the leading edge of expertise and innovation in the manufacturing of high-value synthetic drugs, contributing to the growth of a value-creating innovation ecosystem. Eli Lilly and the two academic partners have co-created a comprehensive research programme with the ambition to reduce radically the cost, time and risk inherent in the manufacturing of synthetic drugs, bringing health and economic benefits to the UK. Our research vision is thus to deliver novel systems-based engineering design methods for the rapid development of manufacturing processes for advanced synthetic drugs and drug products, strongly rooted in scientific understanding and building on state-of-the-art manufacturing technologies, explainable AI ,modelling and experimental approaches. Our programme has been designed around 5 interacting work packages 1. Novel synthesis methods for drug substances (active ingredients), including complex peptides which are a very promising emerging therapy 2. Advanced techniques for drug substance crystallisation based on fundamental thermodynamic modelling 3. Advanced techniques for drug substance purification, including the emerging area of peptide chromatography 4. Advanced manufacturing and stability analysis of drug products. Drug substances must be formulated as drug products which must be proven to be stable over their shelf life. Here will explore the interactions between design, manufacturing and stability. 5. Cross-cutting systems engineering methods for model-based design and operational optimisation