Creation of a process understanding of chromatographic performance loss during biotherapeutic manufacture: A UK-India partnership

国际合作在研究中的重要性得到了研究人员个人以及机构和政府的认可，研究表明，这些合作产生的出版物的平均影响显著高于国家合著的论文。这个由英国和印度的主要学术团体合作的项目致力于用于生产生物制药的纯化操作，例如抗体和胰岛素等激素。在这项活动中，它们得到了四个工业伙伴的支持，这些伙伴被选定为分析和制造方面提供支持(它们是各自领域的领先公司)，并提供将研究成果转化为实践的途径。许多最新的药物是基于蛋白质而不是传统的小分子(例如抗生素)。这些蛋白质药物是为治疗癌症等疾病而生产的。赫赛汀等抗体在这个市场占据主导地位。这里描述的研究合作的重点是研究生物制药生产中使用的核心纯化方法-层析的性能。具体地说，我们试图了解决定这一操作的制造寿命并可能导致性能变化的机制。这个问题是制造商面临的一个主要障碍。在寻求监管机构对这类药物的批准之前，他们必须建立一个强大的提纯工艺，生产成本可以接受。显然，导致延误的问题可能会延长患者获得药物的时间。这可能会影响新产品的制造商和那些寻求以更低的成本竞争并扩大这类药物(通常被称为生物仿制药的产品)可获得性的制造商。与其他制造领域相比，生物加工在几个方面是不寻常的。典型的产品数量很小(约250公斤/年)，但以极高的纯度和质量规格(杂质&lt；0.001%)制造。这些过程中常见的可变性导致了受到严格监管的制造业，其格言是“过程就是产品”。如果没有国际监管机构的详细和耗时的审查，就不能对获得许可的制造工艺进行重大改变。开发和验证用于生产的生物工艺需要大约10年的时间，成本为8亿GB。发展往往是经验性的，与其他制造业部门相比，很少使用建模。这些不同寻常的特征强调了对生物过程有更基本的理解的必要性。这项研究计划旨在建立对导致制造环境中色谱性能变化的事件的机械理解。有证据表明有几种机制，第一阶段是将这些机制组织成一系列拟议的机制。在咨询和研究了我们的工业伙伴的历史数据后，我们将着手进行实验研究。在这里，需要进行详细的分析测量，以确定与该机制的根本原因有关的特定关键物种。该项目将由伦敦的伦敦大学学院和德里的印度理工学院与印度理工学院孟买分校和肯特大学合作领导。这些学术团体得到了业界合作伙伴的支持：ABB、雷迪博士实验室、GE Healthcare、Genzyme、PerkinElmer和Regeneron。

The importance of international collaborations in research is recognised both by individual researchers and by institutions and government, with studies showing that the average impact of publications resulting from these collaborations is significantly higher than that of papers with national co-authorship. This collaborative project between leading academic groups in the UK and India addresses the purification operations used to manufacture biopharmaceuticals e.g. antibodies and hormones such as insulin. They are supported in this activity by four industrial partners selected to provide support to the analytical and manufacturing aspects (being leading companies in their respective areas) as well as to provide a route to transfer the findings of the research to practice. Many of the latest drugs are based upon proteins rather than traditional small molecules (e.g. antibiotics). These protein drugs are produced for the treatment of diseases such as cancer. Antibodies such as Herceptin dominate this market. The research collaboration described here is focused on the study of the performance of the core purification method used for the manufacture of biopharmaceuticals - chromatography. Specifically we seek understand the mechanisms which determine the manufacturing lifetime of this operation and can lead to changes in performance. This issue presents a major hurdle to manufacturers. They must establish a robust purification process with acceptable costs for production before seeking approval for such medicines from the regulatory agencies. Clearly problems leading to delays can lengthen the times before medicines can made available to patients. This can affect both manufacturers of new products and those seeking to compete at reduced costs and widen the availability of this class of medicines (products often termed biosimilars).In comparison to other areas of manufacturing, bioprocessing is unusual in several respects. Typical product quantities are small (~250 kg/year), but are manufactured to extremely high purity and quality specifications (impurities < 0.001%). The variability typically seen in these processes has led to extremely regulated manufacturing, whose dictum is that "the process is the product". No significant change can be made to a licensed manufacturing process without detailed and time-consuming review by the international regulatory authorities. Developing and validating a bioprocess for manufacture takes ~10 years at a cost of £800M. Development is often empirical, with little use of modelling compared to other manufacturing sectors. These unusual features emphasise the need for a more fundamental understanding of the bioprocess. This research programme is structured towards building mechanistic understanding of the events that lead to changes in chromatographic performance in the manufacturing setting. There is evidence for several mechanisms the first stage is to structure these into a series of proposed mechanisms. Following consultation and study of historical data from our industrial partners we will embark upon experimental studies. Here detailed analytical measurements are required to identify specific critical species that are associated with the root cause of the mechanism.The project is to be led by UCL in London and IIT in Delhi in collaboration with IIT Bombay and the University of Kent. These academic groups are supported by industrial partners; ABB, Dr Reddy's Labs, GE Healthcare, Genzyme, PerkinElmer and Regeneron.