Fully Automated Platforms for Drug Nanocrystals Manufacturing via Continuous-Flow, Data-Driven Antisolvent Crystallization

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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.