Development of efficient and flexible purification technologies for manufacturing and analyzing biopharmaceuticals

生物制药，如单克隆抗体，是制药行业增长最快的部分。随着非专利生物制药或“生物仿制药”的出现，这一细分市场预计将进一步大幅增长。生物制药现在用于治疗严重的病毒感染、自身免疫性疾病、神经退行性疾病和癌症。然而，它们的开发和制造都非常昂贵，这严重限制了可获得性，即使在加拿大这样的发达国家也是如此。拟议的研究试图通过开发用于制造和分析生物药物的有效分离和纯化技术来应对这一挑战。这对于生产经济实惠、具有治疗活性、符合法规、纯净稳定且不含有害杂质的产品至关重要。广泛用于分离和纯化生物产品的树脂基柱色谱法需要非常昂贵的资本设备，具有可扩展性差的缺点，并且生产率低。近年来，已经从大型生物制造设备和设施转向使用一次性设备的小型灵活生产。膜色谱法是一种快速且可扩展的纯化技术，其使用一叠膜作为色谱介质，已被提出作为用于生物制药纯化的柱色谱法的灵活的一次性替代方案。然而，现有的径向流膜色谱装置的分辨率差，这严重限制了它的应用。在我的团队中，我们设计了新颖的横向进料膜色谱（LFMC）设备，该设备将高分辨率与高速和可扩展性相结合，即提供了双赢的局面。用LFMC装置获得的分离度不仅优于用膜色谱装置的类型，而且优于用普通树脂基柱获得的分离度。我们的初步研究表明，生物类似物单克隆抗体可以非常有效地纯化在实验室规模使用LFMC。拟议研究的目标是进一步开发LFMC技术并将其带入下一阶段，即证明其在大规模生物制药生产中的有效性。将进行涉及生物类似物单克隆抗体的几个案例研究。LFMC还显示出作为HPLC的替代品用于单克隆抗体的快速分析的显著前景。拟议的工作还将涉及理解基于计算流体动力学（CFD）分析的LFMC的工作原理。总体而言，目标是将LFMC开发为用于制造生物制药的高效且灵活的纯化技术。

Biopharmaceuticals such as monoclonal antibodies comprise the fastest growing segment in the pharmaceutical industry. With the emergence of generic biopharmaceuticals or “biosimilars”, this segment is expected to grow even more significantly. Biopharmaceuticals are now used for the treatment of serious viral infections, autoimmune disorders, neurodegenerative diseases and cancer. However, they are very expensive to both develop and to manufacture, and this seriously restricts accessibility, even in developed countries like Canada. The proposed research attempts to address this challenge through the development of efficient separation and purification technologies for manufacturing and analyzing biopharmaceuticals. This is critical for producing affordable, therapeutically active, regulatory-compliant, pure and stable products, which are free from harmful impurities. Resin-based column chromatography which is widely used for separation and purification of biological products requires very expensive capital equipment, suffers from poor-scalability, and gives low-productivity. In recent years, there has been a move away from large bio-manufacturing equipment and facilities towards smaller flexible production, employing single-use equipment. Membrane chromatography, a fast and scalable purification technique, which uses a stack of membranes as chromatographic media has been proposed as a flexible, single-use alternative to column chromatography for biopharmaceutical purification. However, currently available radial-flow membrane chromatography devices give poor resolution and this severely restricts it application. In my group we have designed novel laterally-fed membrane chromatography (LFMC) devices which combine high-resolution with high-speed and scalability, i.e. provides a win-win situation. Resolution obtained with LFMC devices is not only better than that with type of membrane chromatography devices, but also better than resolution obtained with common resin-based columns. Our preliminary studies have shown that bio-similar monoclonal antibodies can be very efficiently purified at a laboratory-scale using LFMC. The objective of the proposed research is to develop the LFMC technology further and take it to the next stage, i.e. demonstrate its effectiveness in larger-scale biopharmaceutical manufacturing. Several case studies involving bio-similar monoclonal antibodies will be undertaken. LFMC has also shown significant promise as an alternative to HPLC for rapid analysis of monoclonal antibodies. The proposed work will also involve understanding the working principles of LFMC based on computational fluid dynamic (CFD) analysis. Overall, the objective is to develop LFMC as an efficient and flexible purification technology for manufacturing biopharmaceuticals.