Automated and digitalised RNA process-in-a-box for rapid outbreak-response disease-agnostic RNA vaccine/therapeutic development and manufacturing at high-quality and low cost

核糖核酸（RNA）疫苗平台技术已经开发了二十多年，并在COVID-19大流行期间得到了很大程度的验证。尽管RNA疫苗的第一次迭代在临床上取得了成功，但仍有很大的改进生产过程的空间，以将生产率和产量提高10倍，并将制造成本降低6-7倍，同时保持一贯的高产品质量。研制和生产用于大规模人类使用的X病疫苗的速度往往受到化学、制造和控制（CMC）的限制。为了消除这一CMC瓶颈，并释放RNA技术的疾病诊断平台潜力，我们正在采取一种独特的创新方法，将以下两个协同成分结合起来：1)设计和建造一个全自动连续RNA-foundry-in-a-box (RNAboxTM)，允许制造研发级和GMP级材料；2)开发一个基于数字设计质量（QbDD）框架的定制设计空间，允许使用相同的自动化和连续RNAbox生产不同的RNA序列（转化为不同的产品）。启用qbdd的RNAbox将为以下方面提供RNA材料：1)研究分子机制、生化和细胞信号通路以及疾病机制的基础研究；2)配方科学研究；3)动物模型研究；4)临床试验。此外，它还将为监管批准的产品提供商业规模的GMP生产。这将有助于流行病/大流行的防范以及针对各种疾病的众多疫苗的开发和生产。上述将大大提高英国在RNA疫苗/治疗开发和制造方面的地位。此外，这种自动化制造技术将不需要大量的操作员培训，并将提供高质量和低成本的RNA材料。它也将适用于中低收入国家（LMICs）的疫苗生产，因为低成本（由于有效的原材料使用）和低技能（由于自动化）的低级别洁净室（例如欧盟GMP D级，由于密封过程）。客户将包括疫苗制造商、生物技术公司、制药公司、合同（开发）制造组织、研究机构和学术团体。启用qbdd的RNAbox的全球部署将建立一个分布式疫苗和治疗药物制造网络，这将导致流行病/大流行的准备工作，并通过预防和治疗疾病改善健康。

The ribonucleic acid (RNA) vaccine platform technology has been developed for over two decades and has been largely validated during the COVID-19 pandemic. Although this first iteration of RNA vaccines was clinically successful, there is still substantial room for improving the production process to increase production rates and volumes 10-fold, and to reduce manufacturing costs 6-7-fold, whilst maintaining consistently high product quality. The rate at which vaccines against Disease X can be developed and manufactured for large-scale human use is often limited by Chemistry, Manufacturing and Controls (CMC).To remove this CMC bottleneck and to unleash the disease-agnostic platform potential of the RNA technology we are taking a unique and innovative approach which combines the following two synergistic components: 1) design and construct a fully automated continuous RNA-foundry-in-a-box (RNAboxTM) that will allow the manufacturing of both R&D grade and GMP grade materials and 2) develop a bespoke design space based on the Quality by Digital Design (QbDD) framework that will allow the production of the different RNA sequences (translating into different products) using the same automated and continuous RNAbox.The QbDD-enabled RNAbox will provide RNA material for: 1) basic research to study molecular mechanisms, biochemical and cellular signalling pathways as well as disease mechanisms, 2) formulation science studies, 3) studies in animal models and 4) clinical trials. Moreover, it will also provide commercial-scale GMP manufacturing of regulatory-approved products. This will help with epidemic/pandemic preparedness as well as with the development and manufacturing of numerous vaccines against a wide range of diseases.The above will substantially enhance UK's position in RNA vaccine/therapeutic development and manufacturing. In addition, this automated manufacturing technology will not require substantial operator training and will provide high-quality and low-cost RNA material. It will also be suitable for vaccine manufacturing in low- to middle-income countries (LMICs), because of the low-cost (due to efficient raw material use) and lower-skilled manufacturing (due to automation) in lower-grade clean rooms (e.g. EU GMP Grade D, due to the hermetically sealed process). Customers will include vaccine manufacturers, biotechnology companies, pharmaceutical companies, contract (development) manufacturing organizations, research institutes, and academic groups. The global deployment of the QbDD-enabled RNAbox will establish a distributed vaccine and therapeutics manufacturing network which will lead to epidemic/pandemic preparedness and improved health through prevention and treatment of diseases.