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

生物制药，如单抗，是制药业增长最快的部分。随着仿制生物药品或“生物仿制药”的出现，这一细分市场预计将更加显著地增长。生物制药现在被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，这严重限制了人们的可及性，即使在加拿大这样的发达国家也是如此。这项拟议的研究试图通过开发用于生产和分析生物药物的高效分离和纯化技术来应对这一挑战。这对于生产负担得起、具有治疗活性、符合法规、纯净和稳定、不含有害杂质的产品至关重要。树脂柱色谱广泛应用于生物制品的分离纯化，需要昂贵的资本设备，可扩展性差，生产效率低。近年来，从大型生物制造设备和设施转向较小的灵活生产，使用一次性设备。膜层析是一种快速、可扩展的纯化技术，它使用一堆膜作为层析介质，是一种灵活的、一次性使用的替代柱层析的生物药物纯化方法。然而，现有的径向膜色谱分离装置分辨率较低，严重限制了其应用。在我的团队中，我们设计了新型的横向馈电膜色谱(LFMC)设备，它将高分辨率与高速和可扩展性相结合，即提供了一个双赢的局面。用LFMC装置得到的分离度不仅优于膜色谱装置，而且也好于普通树脂基柱的分离度。我们的初步研究表明，使用LFMC可以在实验室规模非常有效地提纯生物相似的单抗。拟议研究的目标是进一步发展LFMC技术，并将其带入下一阶段，即证明其在更大规模的生物制药制造中的有效性。将进行几个涉及生物相似的单抗的案例研究。LFMC也显示出作为快速分析单克隆抗体的高效液相色谱的替代方法的重要前景。拟议的工作还包括了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发展为一种高效和灵活的生物制药生产纯化技术。

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.