BRIC 2008: Bioprocess intensification by microcapillary separations systems

生物治疗制造商需要新的下游处理技术，这些技术与当前制造方法的净化能力和可靠性相匹配，但提供显著更高的生产能力、易用性和经济性。当前技术(灌注法和整体层析法、膜过滤)与早期方法(超速离心法、沉淀法)的比较突出了材料科学发展的中心作用。以前在分离技术方面的进展利用了微结构材料，虽然最初这些材料的制造技术很复杂，但这些材料的制造技术已经发展到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滤膜和灌流吸附剂。此外，模块设计和自动化并行发展，以实现便利性、速度和一次性。我们的概念是使用一种新的微结构材料--微毛细管膜(MCF)，在挤出的平板薄膜中实现高清晰度微通道分离，这是一种模块化格式，由共同申请者在本实验室发明。MCFs在平面聚合物膜中包含任意数量的均匀、平行的毛细管。它们可重复制造，毛细管直径小至100微米，并可由一系列低成本聚合物树脂(PMMA、MBS、聚苯乙烯混合物)使用高通量挤出工艺制造。它们可以精确、廉价和批量地制造。可以对MCF内的毛细血管表面进行化学修饰，以结合到复杂混合物中的目标生物产品。结合的生物残留物保留在MCF上，而混合物中的其他化合物可以被冲洗掉。在随后的步骤中，结合的生物可以从毛细管表面分离，并在从MCF流出时以纯状态收集。MCF可以被制造成适合于生物制造操作的微流器件(MFD)。即使在高流量的情况下，MFD中流动的停留时间分布也非常窄，这为高液体流速下的色谱柱突破提供了理想的推流行为。由于这种理想的流动行为，MFD已被用于广泛的制备规模的精细化学合成，在目前的上下文中，它们代表着用于生物分离的当前聚合物整体柱和膜层析系统的明显替代。

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.