SCILS - Systematic consideration of inhomogeneity at the large scale: towards a stringent development of industrial bioprocesses

该提案涉及英国对已批准的ERA-IB第三个跨国项目（在欧盟第七框架计划的ERA-NET计划内）的贡献，该项目由生物和地球科学研究所Marco Oldiges教授领导，IBG-1：生物技术，Forschungszentrum j<s:1> lich， FRG。大型生物反应器中的生物技术生产是一项最先进的技术。然而，由于生物反应器不均匀性的增加，与实验室规模条件相比，全规模生产往往伴随着性能的下降。例如，当细胞在大型生物反应器周围的流动中对流时，它们会经历不同的溶解氧（DO）浓度；相比之下，在小型生物反应器中，更容易确保均匀的DO浓度，因此细胞在整个发酵罐中以相同的方式呼吸和生长。在大规模环境中的不均匀性，可能导致细胞的异质群体，这是不希望的。应用传统的放大准则来匹配不同尺度之间的水动力条件是相当困难的；由于所需的能源投入在经济上是不可行的，因此在生产规模上不能简单地通过更强烈地混合来克服不均匀性的存在。这些不均匀性问题通常不会在工程的早期阶段和选择适合生物生产的生物菌株时被考虑，也不会在实验室规模的生物工艺开发中被考虑。不足为奇的是，这会导致放大过程中的关键点和故障，需要额外的应变或工艺工程迭代，以实现成功和经济的生产性能。尽管在菌株工程和对细胞调控过程的理解方面取得了巨大进展，但对生物系统的振荡环境等规模效应的考虑大多缺失。缩小这一差距可以在经济效率和低效率之间产生差异，并可以在大规模上提供更有效的流程。

The proposal relates to the UK contribution to an approved ERA-IB 3rd Transnational project (within ERA-NET Scheme of the 7th EU Framework Programme) led by Professor Marco Oldiges, Institute of Bio- and Geosciences, IBG-1: Biotechnology, Forschungszentrum Jülich, FRG.Biotechnological production in large scale bioreactors is a state-of-the-art technology. Nevertheless, full scale production is often accompanied by loss of performance compared to lab scale conditions, due to the effects of increasing bioreactor inhomogeneity. For example, cells experience a varying dissolved oxygen (DO) concentration as they are convected in the flow around a large scale bioreactor; in contrast, in small scale bioreactors it is much easier to ensure uniform DO concentrations and hence cells respire and grow in the same way throughout the fermenter. The inhomogeneities in the large scale environment, can lead to heterogeneous populations of cells, which is undesirable. Application of conventional scale-up criteria to match hydrodynamic conditions between different scales is rather difficult; the presence of inhomogeneities cannot simply be overcome at production scales by mixing more intensely, since the required energy inputs are not economically feasible. These inhomogeneity issues are not usually considered at the early stages of engineering and selecting suitable strains of organism for bioproduction, nor during lab-scale bioprocess development. Not surprisingly, this leads to critical points and failures during scale-up, necessitating additional iterations of strain or process engineering to achieve successful and economic production performance. Despite the great advances in strain engineering and understanding of cellular regulatory processes, the consideration of scale up effects such as an oscillatory environment for the biological system is mostly missing. Closing this gap can make the difference between economic efficiency and inefficiency and can provide more efficient processes at large scale.