BRIC 2008: Bioprocess intensification by microcapillary separations systems

生物柴油制造商需要新的下游处理技术，其与当前制造方法的纯化能力和可靠性相匹配，但提供显著更高的通量、易用性和经济性。目前的技术（灌注和整料色谱，膜过滤）与早期的方法（超离心，沉淀）的比较突出了材料科学发展的核心作用。分离技术的先前进展已经利用了微结构材料，并且尽管在开始时很复杂，但是这些材料的制造技术已经发展，使得现在可以以合理的成本、质量和体积可靠地和可重复地制造过滤膜和灌注吸附剂。此外，模块设计和自动化已经并行发展，以实现方便，快速和一次性。我们的概念是在挤出的平膜内实现高清晰度的微通道分离，使用新的微结构化材料，微毛细管膜（MCF），其由共同申请人在该实验室中发明。MCF在平坦的聚合物膜内含有任何数量的均匀、平行的毛细管。它们可以重复制造，毛细管直径可低至100微米，并且可以使用高通量挤出工艺由一系列低成本聚合物树脂（PMMA、MBS、聚苯乙烯共混物）制成。它们可以精确、廉价和批量生产。MCF内的毛细管表面可以被化学修饰以结合复杂混合物内的靶生物产物。结合的生物保留在MCF上，而混合物中的其他化合物可以被洗掉。在随后的步骤中，结合的生物可以从毛细管的表面分离，并在流出处以纯状态从MCF收集。MCF可以制造成适用于生物制造操作的微流装置（MFD）。即使在高通量下，MFD中流动的停留时间分布也非常窄，这提供了理想的活塞流行为，这是在高液体流速下尖锐的色谱柱突破所需的。由于这种理想的流动行为，MFD已被用于广泛的分离规模的精细化学合成，并且在本发明的上下文中，它们代表了用于生物分离的当前聚合物整料和膜色谱系统的明确替代方案。

Biotherapeutic manufacturers have a need for new downstream processing techniques that match the purification ability and reliability of current manufacturing methods but which provide significantly higher throughput, ease of use and economy. Comparisons of current techniques (perfusion and monolith-based chromatography, membrane filtration) with earlier methods (ultracentrifugation, precipitation) highlight the central role of developments in materials science. Previous advances in separations technology have exploited microstructured materials and though complex at inception, the manufacturing technology for these materials has evolved so that filtration membranes and perfusion adsorbents can now be made reliably and reproducibly, at reasonable cost, quality and volume. Furthermore, module design and automation have evolved in parallel to enable convenience, speed and disposability. Our concept is to implement high definition micro-channel separations within an extruded flat film, modular format using a novel microstructured material, a MicroCapillary Film (MCF), which has been invented in this laboratory by the co-applicant. MCFs contain any number of uniform, parallel capillaries within a flat polymer film. They can be made reproducibly with capillary diameters down to 100 microns and they can be fabricated from a range of low-cost polymer resins (PMMA, MBS, polystyrene blends) using a high-throughput extrusion process. They can be manufactured precisely, cheaply and in bulk. The surface of capillaries within an MCF can be chemically modified to bind to target biological products within a complex mixture. The bound biological remains held on the MCF whilst other compounds in the mixture can be washed away. In a subsequent step the bound biological can be detached from the surface of the capillary and collected at the outflow from the MCF in a pure state. MCFs can be fabricated into MicroFlow Devices (MFDs) that are suitable for use in biomanufacturing operations. Residence time distributions for flows in MFDs are remarkably narrow, even at high throughput, and this provides the ideal plug-flow behaviour that is needed for sharp chromatography column breakthrough at high liquid flow rates. As a result of this desirable flow behaviour MFDs have been used for a wide range of preparative-scale fine-chemical syntheses and in the present context they represent a clear alternative to current polymer monolith and membrane chromatography systems for bio-separations.