Column chromatography is undeniably the industry standard for the purification of biotherapeutics beginning with the production of the first FDA-approved recombinant human insulin in 1982. Conventional column chromatography, traditionally a batch operation, comprises discreet steps such as column equilibration, sample loading, column washing, and product elution. Batch operations are simpler to execute but are inefficient and costly due to several reasons: 1) the purity-yield trade-off; 2) low resin utility, that is, ∼60–80% of the resin capacity can be used before breakthrough occurs; 3) dilution of the product from gradients; 4) low efficiency associated with operating a single column; and 5) the requirement of increasing facility footprint with increasing scale.

Owing to these shortcomings of batch chromatography, mature industrial sectors eventually transition from batch to continuous mode of chromatography [1]. In the 1960s, the first continuous chromatography operation was designed as a competitive alternative for petrochemical separation methods. This system used a chromatographic resin bed that remained fixed in space, but the outlet and inlets moved, simulating a moving bed chromatography [2]. This technology was appropriately termed simulated moving bed (SMB) chromatography. SMB processes mimic the counter-current flow used in continuous distillation processes by connecting numerous columns in series in a loop and switching the inlet and outflow streams periodically. The periodic movement of the flow streams with respect to the stationary resin simulates a counter-current operation that significantly overcomes the purity-yield trade-off that is inherent to batch chromatography. The productivity, resin utility, and buffer consumptions are also improved at a reduced cost [3]. This technique was readily adopted by the food industry for the first industrial-scale SMB process for sugar processing in the 1970s [4]. Later, the pharmaceutical industry employed SMB processes starting in the 1990s to separate enantiopure drug compounds, leading to improvements in drug product quality 5, 6. More recently, the increasing demand for biotherapeutics and the rise of biosimilars has incentivized the reduction of manufacturing expenses with an emphasis on chromatography-based downstream unit operations. There has been an increasing focus on designing continuous chromatography and filtration methods as an alternative to current platform purification processes.

Continuous chromatography methods are costly to implement, however, the increase in productivity and lower manufacturing costs lead to long-term highly competitive processes. Such an early trade-off is expected when transitioning from a batch to a continuous technology. Current continuous chromatography approaches stem from the general SMB technology framework, the use of two or more columns coupled with a counter-current switching of columns opposite the direction of flow. Though SMB chromatography is termed continuous, a steady-state operation is never reached due to the periodic valve switching. The modern-day multicolumn chromatography approaches are also better described as semicontinuous due to the cycling and output of the product in a periodic manner. For simplicity, this review will refer to multicolumn approaches as continuous.

Continuous multicolumn chromatography (CMCC) approaches are more complex than their batch chromatography counterparts due to the presence of multiple columns and valves. A process requiring the simultaneous operation of multiple columns needs real-time monitoring, feedback, and feed-forward control strategies. Valve switching should be synchronized, and failure-mitigation strategies are necessary should one of the multiple columns fail. As such, the successful operation of continuous chromatography demands greater process understanding extending beyond what can be experimentally determined. Mathematical models can assist not only in improving process understanding but can also be implemented as process analytical technology (PAT) tools. In addition, low-cost and low-maintenance PAT such as microfluidics approaches are highly desired to monitor process quality attributes in real time. This review will discuss continuous chromatography approaches, key technical challenges facing their industrial adoption in the biopharmaceutical industry, and potential mitigation strategies.