Readying Miniaturized Reactors for Flow Biocatalysis

项目描述在几乎所有的工程部门，都已成功地从批处理过渡到连续处理。生物化学工程中一个特别有前景的连续加工领域是活性药物成分(API)和增值化学品的生物催化合成。然而，大规模的连续生产尚未得到成功的论证。连续流生物催化提供了更好的反应条件控制，在产率和生产率水平上都有好处。这种效率的提高和随之而来的废物的最小化最终将导致更清洁的工艺和更低的总成本。此外，连续流程可以减少流水线和设施占地面积，从而减少前期资本投资。为了充分利用连续处理的好处，有必要对反应器的性能进行表征，并了解生物催化剂的限制和反应器运行之间的相互作用。只有到那时，这些过程才能被成功地利用到与工业相关的体积。为了实现这一目标，需要能够仔细评估反应器性能和生物催化剂行为的缩小模型。小型化连续流反应器是主要的候选对象。它们的尺寸小，与传统的间歇系统相比，可以用小得多的体积进行实验，当使用昂贵的底物或酶时，可显著降低成本。在这些反应器中，可以方便地控制反应参数，并展示了产品回收的在线净化。此外，由于强化了传质并伴随着反应时间的减少，反应可能会加速。因此，未来小型化的连续流动反应器将成为快速和高通量获取高质量数据的基础。项目目标-设计、制造和表征带有集成光学传感器和在线分析工具的小型连续流动反应器，用于在线监测化学和物理变量(pH、温度、氧气和二氧化碳)和在线反应分析(GC-和LC-MS)。-验证集成的微型连续流动反应器与工业相关的生物催化反应。-在评估工艺稳定性、产品工艺质量概况和可伸缩性的所有尺度上，比较间歇和连续系统中的反应器性能(例如，通过时空产率、(gproduct/(Lreac.h)和(gproduct/Genzyme)。产出和影响该项目与英国在工业生物技术领域的战略重点和EPSRC未来生物制造研究中心保持一致。由于这一研究方向的高度相关性和及时性，我们预计该项目的每个目标都将导致一份出版物产出。在整个项目中取得的成果将纳入本科生或研究生单元的教学。

Description of the projectIn almost all engineering sectors there has been a successful transition from batch to continuous processing. One particularly promising area for continuous processing in biochemical engineering is the biocatalytic synthesis of active pharmaceutical ingredients (APIs) and value-added chemicals. However, continuous production at large scale has not yet been successfully demonstrated. Continuous-flow biocatalysis offers an improved control over reaction conditions with benefits in yield and productivity levels. This increase in efficiency and concomitantly minimization of waste will ultimately result in cleaner processes with lower overall costs. Furthermore, continuous processes enable a reduction in process lines and facility footprints which in turn result in less up-front capital investment. To exploit the full benefits of continuous processing, it is necessary to characterise reactor performance, and to understand the interplay between the biocatalysts' constraints and the reactor operation. Only then can these processes be exploited to successfully at industrially relevant volumes.To achieve this aim, scale-down models that enable careful assessment of reactor performance and biocatalysts' behaviour are necessary. Miniaturized continuous-flow reactors are prime candidates. Their small dimensions allow experiments to be performed with much smaller volumes compared to traditional batch systems, offering significant cost reduction when using expensive substrates or enzymes. Within these reactors the control of reaction parameters is facilitated, and in-line purification with recovery of products has been demonstrated. Additionally, reactions can be potentially accelerated due to enhanced mass transfer with a concomitant decrease in reaction time. Therefore, miniaturized continuous-flow reactors will in the future form the basis to acquire high-quality data rapidly and with high throughput. Project Objectives- Design, fabricate, and characterize a miniaturized continuous-flow reactor with integrated optical sensors and at-line analytical tools for the on-line monitoring of chemical and physical variables (pH, temperature, oxygen and CO2) and for at line reaction analytics (GC- and LC-MS). - Validate the integrated miniaturized continuous-flow reactor with industrially relevant biocatalytic reactions. - Compare the reactor performance in batch and continuous systems (e.g. by space-time yields, (gproduct/(Lreactor.h), and (gproduct/genzyme)) at all scales assessing process stability, quality profile of the products process and scalability. Output & ImpactThis project aligns with UK strategic priorities in the area of Industrial Biotechnology and the departmental EPSRC Future Biomanufacturing Research Hub. Due to the high relevance and timeliness of this research direction, we anticipate that each objective of the project will lead to a publication output. The results obtained throughout this project will be included in teaching of undergraduates or postgraduate modules.