i-PREDICT: Integrated adaPtive pRocEss DesIgn and ConTrol

英国在全球生命科学领域处于领先地位。在这个领域，生物制药发挥着主导作用，年营业额近810亿英镑（2020年生命科学竞争力指标，发布日期：2021年2月）。通过生命科学愿景2021，政府强调制造业创新和提升是英国的中心目标。“向净零排放过渡”首次将生命科学目标置于中心位置。为了使英国保持在生物制药制造的前沿，政府还鼓励数字创新，以实现时间/成本效益的流程（Made Smarter，2017年评论）。（生物）制药工艺对健康的重要积极影响可能超过该行业的环境足迹，与其他行业相比，该行业的产量要低得多。然而，累积起来，这仍然是一个迫在眉睫的挑战。使这些进程在环境和经济上可持续是一项复杂的任务，涉及相互冲突的目标。例如，需要确定最佳的分离循环次数，以满足药物的目标纯度，并产生尽可能少的环境足迹。计算机建模工具可以提供很大的帮助，帮助设计和解决多因素问题，以确定最合适的工艺设置和操作模式。在这方面，该项目旨在回答的研究问题是：“我们如何使用计算机建模工具将环境和经济可持续性嵌入生物过程，同时满足纯度限制？".从本质上讲，目标是采用工程思维和工具来开发系统框架和软件平台，以帮助：（a）定量杂质含量对下游分离性能的影响，（B）识别可行的和最佳的设计空间，在此范围内，流程绩效被认为是对所跟踪的关键绩效指标（KPI）满意的，以及（c）设计优化和控制策略，以确保最佳运行。拟议工作的新奇主要体现在两个方面。首先，环境可持续性KPI，如缓冲和能量消耗将首次在生物过程的设计中被系统地考虑。其次，将通过开发计算机建模框架和软件平台（i-PREDICT）来部署工程创新，利用不同建模方法的力量。在工程、制造、数字化和生物加工的结合点，i-PREDICT将通过持续监控实现生物过程数字化和集成。这是通过开发和实验验证与工业4.0一致的上游过程监测、优化和控制框架来实现“制药4.0”的首批计算尝试之一。这项工作将创建一个路线图，在生物工艺的设计产品质量的整合。支持工艺强化，该项目建议通过定量杂质在下游传播的影响来考虑上下游相互作用。这一新概念将允许设计可变性强的分离工艺，实现无缝单元集成和下游规模扩大。这里开发的数字和数学工具将通过实验验证，关闭从计算机到体外的循环。这个雄心勃勃的多学科项目将为（生物）制药过程中的集成设计，优化和控制的革命性研究领域带来一步变化。

The UK holds a leading position in the global life sciences scene. In this sector, biopharmaceuticals play a dominant role with almost £81bn in annual turnover (Life Sciences Competitiveness Indicators 2020, published: February 2021). Through the Life Sciences Vision 2021, the government is highlighting manufacturing innovation and ramp up as the UK's central aims. For the first time, Transition to Net Zero s brought at the centre of Life Sciences targets. For the UK to remain at the forefront of biopharmaceutical manufacturing, the Government is also encouraging digital innovation leading to time-/cost- efficient processes (Made Smarter, Review 2017). The crucial, positive health impact of (bio-) pharmaceutical processes may outweigh the environmental footprint of the sector that works with considerably lower volumes compared to other industries. Cumulatively, however, this remains to be an imminent challenge. Making those processes environmentally and economically sustainable is a complex task, involving conflicting objectives. For example, one would need to decide on the optimal number of separation cycles that meet both the target purity of the drug and create the least possible environmental footprint.Computer modelling tools can be of great help, lending themselves to the design and solution of multifactorial problems for the identification of the most suitable process setup and operating mode. In this respect, the research question this project aims to answer is: "How can we use computer modelling tools to embed environmental and economical sustainability in bioprocesses, while meeting the purity constraints?". In essence, the goal is to employ Engineering thinking and tools for the development of a systematic framework and software platform that will assist: (a) quantification of the impurity content on the downstream separation performance, (b) identification of a feasible and optimal design space, within which process performance is deemed satisfactory with respect to the tracked key performance indicators (KPIs) and (c) design of optimisation and control policies to ensure optimal operation. The novelty of the proposed work lies in two main aspects. Firstly, environmental sustainability KPIs, such as buffer and energy consumption will be considered for the first time systematically in the design of a bioprocess. Secondly, Engineering innovation will be deployed through the development of a computer modelling framework and software platform (i-PREDICT), harnessing the power of different modelling methodologies. In the junction of Engineering, Manufacturing, Digitalisation and Bioprocessing, i-PREDICT will enable bioprocess digitalisation and integration via continuous monitoring. This is one of the first computational attempts realising "Pharma 4.0" through the development and experimental validation of Industry 4.0-aligned frameworks for upstream in-process monitoring, optimisation and control. This work will create a roadmap towards the integration of product quality in the design of the bioprocess. Endorsing process intensification, this project proposes to consider upstream/downstream interplay through the quantification of the impact that impurity propagation in downstream. This novel concept will allow the design of variability-robust separation processes, enabling seamless unit integration and downstream scale-up. The digital and mathematical tools developed here will be validated experimentally, closing the loop from in silico to in vitro. This highly ambitious, multi-disciplinary project will create a step change towards a revolutionary research area of integrated design, optimisation and control in (bio-) pharmaceutical processes.