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

单克隆抗体等生物制药是制药行业中增长最快的部分。随着仿制生物制药或“生物仿制药”的出现，这一细分市场预计将增长得更加显著。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制药的有效分离和纯化技术来解决这一挑战。这对于生产负担得起的、治疗活性的、符合法规的、纯净和稳定的、不含有害杂质的产品至关重要。树脂基柱色谱法广泛应用于生物制品的分离纯化，其设备造价昂贵，可扩展性差，生产效率低。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。膜色谱是一种快速、可扩展的纯化技术，它使用一堆膜作为色谱介质，已被提出作为一种灵活的、一次性的替代柱色谱法用于生物制药纯化。然而，目前可用的径向流膜色谱装置分辨率较差，这严重限制了它的应用。在我的小组中，我们设计了新型的横向馈入膜色谱（LFMC）设备，该设备将高分辨率与高速和可扩展性相结合，即提供双赢的局面。LFMC装置的分辨率不仅优于普通膜层析装置，而且优于普通树脂基柱。我们的初步研究表明，使用LFMC可以在实验室规模上非常有效地纯化生物相似的单克隆抗体。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，即证明其在大规模生物制药生产中的有效性。将进行几个涉及生物类似单克隆抗体的案例研究。LFMC作为快速分析单克隆抗体的高效液相色谱（HPLC）的替代方法也显示出巨大的前景。建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。总的来说，目标是发展LFMC作为一种高效和灵活的纯化技术，用于生产生物制药。

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.