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。尽管合成药物在制药公司的药品组合中占据了最大份额，其中多肽代表着一个日益重要的药物类别，但从发现药物分子到开发造福患者的商业产品的道路仍然漫长而艰辛得令人沮丧，研发总成本高达26亿美元，每个新的化学实体(NCE)需要10年时间。制造和配方可能是一个限速和昂贵的步骤，因为在合成过程中难以达到所需的分子精度或产率，难以在纯化过程中确保高产率，并在生产最终产品时具有最大限度地提高患者利益的稳定性和有效性。此外，制药业正面临着改善其制造过程的经济和环境绩效的动力，目前这些过程的材料效率极低，0.01至0.1倍并不罕见，产生大量废物，按设计质量(QbD)概念的采用缓慢，特别是对于更复杂的产品。这一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方面的关键问题。我们共同确定了阻碍关键药物成功制造和向患者提供的科学障碍，并制定了一项雄心勃勃的研究方案来克服这些障碍。我们方法的一个独特和令人兴奋的特点是，考虑到从药物物质到药物产品的整个链条，我们利用小分子制造方面的专业知识和进展，使更大的多肽药物的合成制造取得根本进展。因此，我们的方案将提供基本的理解、模型、技术和设计方法，以加速合成、分离、提纯和配制从小分子到多肽的各种大小的合成药物，并推动多肽药物的可行性界限。除了其科学成就，繁荣伙伴关系将使英国在制造高价值合成药物的专业知识和创新方面处于领先地位，为创造价值的创新生态系统的增长做出贡献。礼来公司和两个学术合作伙伴共同创建了一个全面的研究计划，雄心勃勃地从根本上减少合成药物制造所固有的成本、时间和风险，为英国带来健康和经济利益。因此，我们的研究愿景是为先进的合成药物和药物产品的制造工艺的快速开发提供基于系统的新颖工程设计方法，牢固植根于科学理解和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。我们的方案是围绕5个相互作用的工作包1设计的。药物物质(活性成分)的新合成方法，包括复合肽，这是一种非常有前途的新兴疗法2。基于基本热力学模型的药物物质结晶的先进技术3。药物提纯的先进技术，包括新兴的多肽层析领域4。药品的先进制造和稳定性分析。药品必须作为药品来配制，并且必须证明其在保质期内是稳定的。这里将探讨设计、制造和稳定性之间的相互作用。基于模型的设计和运行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