Real time flux modelling in biopharmaceutical bioprocessing

生物制药，如用于乳腺癌治疗的赫赛汀(Trastumazab)，使许多严重疾病的治疗发生了革命性变化，如实体瘤、白血病、阿尔茨海默氏症等退行性疾病，以及其他具有复杂因素的疾病，如哮喘。然而，除了是人类有史以来部署的最有效的药物外，这些药物也是最复杂的。这意味着漫长的开发周期，以及非常高的治疗成本。赫赛汀治疗一个疗程的费用约为每个患者27,000英镑。这导致了人们对这些强效药物的获取和可获得性的严重关切。为了制造这些复合剂，专门开发的(基因改变的)微生物或动物细胞系统(表达系统)被培养在发酵罐或生物反应器中。但我们对我们引入的遗传变化以及我们在其中培养细胞的发酵罐或生物反应器环境之间的相互作用如何影响细胞代谢的了解相当有限，特别是在发育的早期阶段。缺乏对细胞代谢的清楚了解是这些药物开发周期长、成本高的一个主要原因。我们的方法是专注于尖端技术，在开发阶段的早期实现对这些表达系统行为的更好理解。我们计划在培养容器中实际使用非侵入性监测技术(近红外和中红外光谱)，以及以前的非实时代谢分析工具(流量平衡)，以实时了解这些特殊细胞在培养时的新陈代谢。这项技术将在过程周期的早期增加对细胞新陈代谢的了解，有助于加快产品开发，从而使患者更快地获得成本更低的疗法。这将有助于提高整个社会的健康水平。它还将为参与制造这些药物的英国生物制药行业提供竞争优势。在不久的将来，这种方法可以极大地帮助开发和部署专门的基于细胞的疗法(例如干细胞)。这一点尤其重要，因为这些药物比生物制药更复杂，在不久的将来有巨大的潜力促进社会的健康和福利。实现

Biopharmaceuticals, such as herceptin (trastumazab) which is used in breast cancer treatment, have revolutionised the treatment of many serious diseases, such as solid tumours, leukaemias, degenerative illnesses such as Alzheimer's, and other diseases having complex contributors, such as asthma. However, in addition to being the most potent drugs humanity has ever deployed, these are also the most complex. This implies lengthy development cycles, and very high costs for therapy. A course of herceptin treatment costs around £27,000 per patient. This has led to serious concerns over access to, and availability of these potent drugs. In order to make these complex agents, specially developed (genetically altered) microbial or animal cell systems (expression systems) are cultured in fermenters or bioreactors. But our understanding of how the interaction of the genetic alterations we introduce, and the fermenter or bioreactor environment we culture the cells within, impact upon the cell metabolism is quite limited, especially in early development phase. This lack of clear knowledge about cell metabolism is one major cause of the long, costly drug development cycle of these agents. Our approach is to focus cutting edge techniques upon achieving better undertsanding of the behaviour of these expression systems early in the development phase. We plan to use non-invasive monitoring techniques (near and mid infrared spectroscopies) actually in the culture vessels together with a previously non real time metabolic analysis tool (flux balancing) to gain real time understanding of the metabolism of these specialised cells when in culture. This technology would give increased knowledge of cell metabolism early in the process cycle, helping accelerate product development, leading to reduced cost therapeutics reaching patients more speedily. This would contribute to increased health in society in general. It would also provide a competitive advantage to the UK biomanuafturing sector involved in making these drugs. In the very near future, this approach could greatly help the development and deployment of specialised cell based therapies ( e.g. stem cells). This is especially important as these agents are even more complex than biopharmaceuticals, and have tremendous potential to contribute to enhancing the health and welfare of society in the immediate future. Achieving