Biotechnology has made significant advancements in the understanding of human genomics and proteomics revolutionising medical diagnosis, prevention and treatment. Advances and breakthroughs in target-oriented biotechnology research have been used to enhance the synthesis of a number of commercially significant products. It has been reported that there are over 6000 biopharmaceuticals currently in development, potentially worth in excess of $100's bn (£145bn in 2012). Despite the increasing successes in discovering protein-based medicines, their manufacture in a cost effective and reliable fashion remains a major industrial challenge, which currently limits the ability of the biopharmaceutical industry to deliver solutions to patients. The vision here is to develop a programme for process intensification and de-bottleneck of downstream bioprocessing (DSB), by implementation of Seeding and Continuous Biopharmaceutical Crystallisation (SCoBiC), for the separation and purification of biopharmaceuticals. The ambition of this proposed project to develop strategies for a continuous biocrystallisation process, including selective crystallisation directly from multicomponent fermentation broths by seeding, for whole antibodies and antibody fragments. The goal is to reduce manufacturing costs, provide for simpler processes while achieving the high purity of material achievable from multi step chromatography. This ambition is driven by the awareness that separation and purification processes represent one of the most time and cost-intense downstream operations in the manufacture of commercial biopharmaceutical products. This proposal will develop a continuous biocrystallisation platform as an alternative to conventional DSB, offering improvements to manufacturability, enabling higher throughput, lowering the product costs, an increase in product quality and stability, including opportunities for novel formulations and technologies.

Inorganic nanoparticles have the potential to dramatically modify existing materials while providing the capability to engineer a broad range of transformative new products. Exhibiting unique properties not encountered in bulk materials, inorganic nanoparticles present the opportunity to address, and the potential to overcome, some of the most pressing global challenges. This is leading to intense global competition to develop and commercialize nanoproducts with a variety of applications in healthcare, energy, transport and security, with the aim of acquiring a dominant market position in the nanotechnology sector. Nanoparticles offer ideal solutions for detecting and treating many diseases. They can be used as drug carriers, labelling and tracking agents, and vectors for gene therapy, hyperthermia treatment and magnetic resonance imaging contrast agents. Used as targeted drug-delivery systems, they can improve the performance of medicines already on the market. They enable the development of new therapeutic strategies such as anti-cancer drug delivery, extending product life cycles and reducing healthcare costs. In this proposal we focus on the manufacturing of gold nanoparticles (Au-NPs) and iron oxide magnetic nanoparticles (MNPs). These materials have existing applications in diagnostics and therapeutics. Bespoke monodispersed functionalised NPs offer new applications in antimicrobial surfaces (Au NPs plus dye) and in a new hyperthermia treatment for cancer (MNPs). UCL is at the forefront of the engineering approach to make nanoparticles as well as being world leading in magnetic hyperthermia and antimicrobial surfaces. Nanoparticles are conventionally synthesized in relatively small batch reactors. These systems are poorly controllable, leading to products that are hard to reproduce. Also, they do not lend themselves to expedient upscaling. Such problems are caused by the inefficient mixing and slow heat and mass transfer characterizing batch reactors, and by the difficulty of decoupling in time the various stages of the synthesis, particularly particle nucleation and growth. This research aims to design and demonstrate a new, sustainable and scalable approach for manufacturing high-value nanomaterials with advanced properties in a way that is controllable and reproducible and that does not involve significant upscaling issues. To attain this ambitious goal, we will integrate methods, skills and strengths of different disciplines (materials chemistry, engineering), seeking guidance from industrial partners and UK manufacturing centres. Giving us access to their state-of-the-art facilities, sharing their expertise and providing an application context for our work, they will further characterize the nanoparticles, evaluate their performance and facilitate pathways to manufacture and routes to market. There is currently a lot of research in developing novel materials, where the focus is on discovery but with little emphasis on manufacturing. Using chemical engineering principles and systems engineering methodologies within a multidisciplinary framework, our research will demonstrate not only the need to consider key physical phenomena (mixing, heat transfer etc.) in nanoparticles synthesis, but also how to account and address related manufacturing challenges from the outset. In this way, an important benefit of this project will be to provide a paradigm shift in nanoparticle synthesis and production and bridge the discovery-manufacturing divide.

Inorganic nanomaterials are widely used in diverse applications such as oil refining, food, coatings, cosmetics, textile, transport, healthcare and electronics and communication, with a global market worth 20 billion EURO. A recent inventory has documented >1800 consumer products that contain nanomaterials and many more non-commodity products such as industrial catalysts and separation media. However, there are limitations in terms of the sustainability of and the attainable product quality from current manufacturing. Industry uses wet (chemical precipitation) and dry (flame or plasma) processes for manufacturing nanomaterials. Despite the advances in the latter, it has been shown that the wet processes are lot more efficient than the dry processes. Anastas and co-workers performed a sustainability analysis for wet processes, which revealed that nanomaterials manufacturing is significantly wasteful when compared to the production of bulk chemicals. This creates an enormous burden on the environment and results in unsustainable manufacturing. Further, some of the key properties of nanomaterials cannot be obtained with existing manufacturing methods. Lab-based methods exist for synthesising nanomaterials of desired properties, however, these methods are very wasteful and uneconomical to scale-up. Hence such high value materials remain at small scales and commercially inaccessible. A World Technology Evaluation Center report, commissioned by the USA's National Science Foundation, explicitly recommended that achieving green manufacturing by 2020 is the "holy grail" and that future research should focus on emulating natural designs to develop scalable processes for manufacturing nanomaterials [Ref. Roco et al., Nanotechnology Research Directions for Societal Needs in 2020, NSF and WTEC, 2010]. I have developed fully synthetic novel bioinspired approaches to nanomaterials, with rapid reactions (takes only 1-5 minutes) at room temperature in water, producing almost no waste, yet providing superior control of product properties. This method can reduce the energy usage of the reaction step by ~95% when compared with a traditional precipitation process and the materials would as cheap as the lowest grade commercial counterparts, yet provide significantly better quality and properties. However, the bulk of research on bioinspired synthesis has been performed at small scales. The bioinspired method cannot be scaled-up yet because there is a critical gap in our knowledge on its scale dependence. This fellowship aims to apply bioinspired routes to deliver sustainable ("green"), low cost and scalable technologies for manufacturing high value functional nanomaterials. I will develop scale-up rules by modelling and experimentally measuring mixing mechanisms. I will design process chemistry to produce bespoke nanomaterials and demonstrate pathways for larger-scale manufacturing. This fellowship has a great potential to take the UK to the world leading stage in sustainable manufacturing of bespoke nanomaterials.

The pharmaceutical industry is undergoing a period of unprecedented change in terms of product development, with increased digitization, greater emphasis on continuous manufacture and the rapid advent of novel therapeutic paradigms, such as personalized medicines, becoming more and more business critical. This change is amplified by Quality by Design considerations and the now routine use of the Target Product Profile approach to the design of patient-centred dosage forms. The recent advances in the range of available therapeutic strategies, alongside the breadth of diseases that can now be successfully treated, has resulted in the need for both new dosage forms and manufacturing approaches. Crucially, there has been a shift from high volume, low cost manufacture towards a more specialized, higher value product development. Consequently, ever more sophisticated approaches, not merely to producing medicinal products, but also to controlling their quality at every stage of the manufacturing process, have become paramount. These would be greatly facilitated by the emerging technologies, based on artificial intelligence and machine learning techniques, for enhancing online process analysis as well as real-time responsive process control. These technologies are particularly important for products where the financial and practical margins for manufacturing error are low, as is the case for an increasing proportion of new therapies. In this proposal, we focus on a new way of screening, manufacturing and quality controlling drugs in the form of nanocrystals, that is, drugs prepared as nanosized crystalline particles stabilized by surface-active agents. In particular, we will combine continuous-flow processing, online advanced process analytical technology, real-time process control and quality assurance, design of experiments, advanced data analysis and artificial intelligence to deliver fully automated, self-optimizing platforms for screening and manufacturing drugs as nanocrystals via antisolvent precipitation. These dosage forms have attracted substantial interest as a means of delivering poorly water-soluble (and thus poorly bioavailable) drugs, a persistent and increasing problem for the pharmaceutical industry. While nanocrystals offer a suitable test system for our approach, our methodology and the manufacturing platform we intend to deliver can be applied to other drug delivery systems. We focus on nanocrystals because they are of considerable therapeutic and commercial significance both nationally and internationally. We intend to use continuous-flow small-scale (i.e. millifluidic) systems. These offer excellent process controllability, can generate crystals of nearly uniform size, and as the process is continuous, the product characteristics are more stable than in batch systems. Millifluidic systems are flexible (one platform can produce a larger variety of products) and agile - reacting rapidly to changes in market demands; they reduce the manufacturing time, speed up the supply chain and, being smaller, can be portable. These systems also expedite screening, curtailing the quantities of material required, benefits that design of experiments will amplify. This data-driven technique allows identifying the most informative experiments, maximizing learning while minimizing time and costs, advantages not fully exploited by the pharmaceutical industry. These technologies, coupled with online advanced process analytical methods, real-time process control, cutting-edge data analysis and machine learning methods, have the potential to disrupt the status quo, accelerate process development and deliver transformative platforms for the cost-effective and sustainable manufacturing of active pharmaceutical ingredients in solid dosage form, reducing the timeline from drug discovery to patient, and contributing to placing the UK at the forefront of innovation in the pharmaceutical sector.