Transforming synthetic drug manufacturing: novel processes, methods and tools

制药业是英国制造业的关键参与者，在将有前途的新分子转化为负担得起的药物方面面临巨大挑战。虽然合成药物占制药公司药物组合的最大部分，但肽代表了越来越重要的一类药物，从发现药物分子到使患者受益的商业产品的道路仍然令人沮丧地漫长而艰难，开发总成本达到26亿美元，每个新化学实体（NCE）需要10年。由于难以实现合成中所需的分子精度或产率、难以确保纯化期间的高产率以及难以生产具有使患者益处最大化的稳定性和功效的最终产品，制造和配制可能是限速且昂贵的步骤。此外，制药工业正面临着提高其制造工艺的经济和环境性能的驱动力，目前这些制造工艺的材料效率极低，系数为0.01至0.1并不罕见，产生大量废物，并且缓慢采用设计质量（QbD）概念，特别是对于更复杂的产品。这种繁荣伙伴关系建立在领先的工业和学术研究人员之间的现有合作基础上，以解决我们以成本和时间有效的方式制造合成药物的能力中的关键问题。我们共同确定了阻碍成功生产和向患者提供关键药物的科学障碍，并制定了一项雄心勃勃的研究方案来克服这些障碍。我们的方法的一个独特和令人兴奋的特点是利用小分子制造的专业知识和进步，使更大的肽类药物的合成制造取得根本性进展，考虑到从原料药到制剂的整个链。因此，我们的计划将提供基本的理解，模型，技术和设计方法，以加速合成，分离，纯化和不同大小的合成药物的配制，从小分子到肽，并推动与肽药物有关的可行性边界。除了科学成就，繁荣伙伴关系将使英国在高价值合成药物制造方面处于专业知识和创新的领先地位，为创造价值的创新生态系统的发展做出贡献。礼来公司和两家学术合作伙伴共同创建了一个全面的研究计划，其目标是从根本上降低合成药物制造的成本、时间和风险，为英国带来健康和经济效益。因此，我们的研究愿景是提供新型的基于系统的工程设计方法，用于先进合成药物和药物产品制造工艺的快速开发，这些方法深深植根于科学理解并建立在最先进的制造技术、可解释的人工智能、建模和实验方法的基础上。我们的计划围绕5个相互作用的工作包1进行设计。原料药（活性成分）的新合成方法，包括非常有前途的新兴疗法2的复合肽。基于基本热力学模型的原料药结晶先进技术3。原料药纯化的先进技术，包括肽色谱的新兴领域4。药品的先进制造和稳定性分析。原料药必须配制成制剂，必须证明其在有效期内稳定。这里将探讨设计、制造和稳定性之间的相互作用。基于模型的设计和操作优化的交叉系统工程方法

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 packages1. Novel synthesis methods for drug substances (active ingredients), including complex peptides which are a very promising emerging therapy2. Advanced techniques for drug substance crystallisation based on fundamental thermodynamic modelling3. Advanced techniques for drug substance purification, including the emerging area of peptide chromatography4. 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