Transforming synthetic drug manufacturing: novel processes, methods and tools

Lead Research Organisation: Imperial College London
Department Name: Department of Chemical Engineering

Abstract

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

Planned Impact

The outputs of this prosperity partnership between Eil Lilly, Imperial, and UCL will have the potential to impact the pharmaceutical industry directly, as well as other industries and society. For example, the WP1 outputs, which will reduce cost and time-to market of drug substance synthesis, can produce not only economic but also environmental and broader societal benefits.
It will deliver novel methodologies for (i) drug substance synthesis (ii) drug substance purification and isolation (iii) drug product formulation and stability, and (iv) underpinning process systems engineering methods embodied in a range of tools. These will be demonstrated on a range of industrial case studies and demonstration projects supported by our partner.
The invention and development of such methods and their adoption by industry has the potential to lead to a step change in the manufacturing and quality control of advanced therapeutics. The new synthesis techniques for example will for the first time open up opportunities for larger peptide based therapies. The existing underpinning systems and modelling techniques have been shown in to have a 10-fold return in investment in the sector (Am Ende et al., AIChE An, 2010); We expect the next generation of tools to have at least the same impact.
The beneficiaries include:
Pharma industry and related academia: The recent UK Life Sciences Sector Deal states "The life sciences industry is one of the most important pillars of the UK economy, contributing over £70 billion a year and 240,000 jobs across the country" and highlights "advanced therapies" as one of the key platforms. We have aligned our programme with exactly this opportunity. The integrated work packages have the overarching objective of bringing cost-effective new therapies to market as quickly as possible.
Academics and software companies working on model-based systems engineering: The beneficiaries will be those working in the area of design of experiments, quality by desig, advanced thermodynamics, optimization and process analytics and control.
Wider industrial partners: The methods are generic and can be applied to a broad range of problems. The tools will have impact in the wider manufacturing sector ranging from consumer goods to agrochemicals and oil and gas; CPSE's industrial consortium includes representatives from these sectors.
Society: The improvements that will arise from our advancements should support faster development and manufacturing of advanced therapies. Our platform will reduce the time and cost of development for new drug production processes.
We shall ensure effective impact outcomes through:
Training: The researchers will gain career-relevant skills and will benefit from the cross-disciplinary interactions within the team as well as with the industrial partner, including secondment opportunities. Senior representatives from Eli Lilly will act as co-supervisors and provide advice, materials, data and analytical resources. They will also provide input on the quality, timeliness and relevance of the methods developed.
Software dissemination: A range of software tools will be developed in the course of the research and made available to the academic community to download and apply to their models.
Manufacturing technologies: we anticipate new manufacturing technologies (e.g. Nanostar sieving for liquid phase synthesis).
Project website and workshops: The core outputs developed herein will be advertised through a website dedicated to the project. We shall also hold dissemination workshops for end users and regulator representatives near the project end

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