Liquid chromatography has become an indispensable tool in the pharmaceutical and biotechnology industries for preparative and large‐scale purifications to obtain high purity biopharmaceutical products. However, imperfect packing of the column bed and complex rheological behaviors of resin particles pose a great challenge for any modeling effort.
A systematic study, based on rigorous physics, which attempts to understand the intrinsic complicated interrelationships between column packing, hardware design, flow distribution, and separation efficiency would be of great help to chromatography practitioners. Seeing this need, this article makes an effort to perform a systematic study of the chromatography processes from start to finish and to provide mathematical models and case studies for each stage. First, the author discusses the challenges in scaling up chromatography column packing and examines the wall effect through a dimensional analysis, then follows it by introducing a one‐dimensional model, describing column packing and scale‐up. Next, the author presents a case study on a commercial scale column with a special headplate design and investigates the impact of hardware design on flow distribution, using the technique of computational fluid dynamics (CFD). Finally, this article presents simulations on the transport of elute and computation on the height equivalent to a theoretic plate (HETP) in a modeled, large column set for no retention, ion exchange, and affinity systems. The author discovers that the hardware design exerts a great impact on the flow distribution in the columns and thus affects the column separation efficiency to a large extent.