In a classic batch process, a quantity of the desired product is manufactured within a single production run – meaning a single injection in the case of chromatography – characterized by a well-defined start and endpoint. Once a batch is completed, a new production cycle or run can begin.

During continuous processes, sample injection remains uninterrupted throughout the chromatographic separation, and the process operates without distinct start or endpoint markers. Production is ongoing, resulting in a continuous inflow of raw materials and a constant outflow of the product.

With continuous sample feeding and product discharge, maintaining product quality and minimizing potential failures are critical. This is achieved through continuous monitoring of both the process and equipment, requiring a high degree of automation. Automation not only ensures process stability but also minimizes human intervention, thereby reducing errors. Additionally, continuous processing improves efficiency by increasing throughput, while reducing solvent consumption, raw material requirements, and downtime, leading to lower operational expenditures (OPEX) compared to batch processing. However, the initial investment is substantial, increasing capital expenditure (CAPEX).

Despite the higher upfront costs, continuous processing enhances production yield and allows the same equipment to be used for both small- and large-scale operations, minimizing the need for scale-up studies. It is also more energy- and labor-efficient, requires a smaller footprint, and is a more environmentally friendly alternative to traditional batch processing.

In summary continuous chromatography enables higher throughput, improved solvent utilization, and reduced waste generation, making it a more sustainable and cost-effective solution.

Liquid-liquid chromatography can be applied in continuous manufacturing. By using one or two CPC units in multiple dual-mode (MDM), continuous operation is possible, enabling significantly more effective scale-up and increased productivity.

However, once compound B reaches the rotor’s outlet, we switch the valve to pump the lower phase in the opposite direction (descending mode, Fig. 2.). This pushes the partially separated mixture of A and B back into the system. In this step, compound B becomes the faster-moving one (reciprocal Kd values govern their speeds), and we can collect pure compound B at the “inlet” of the rotor, while the co-elution band is pushed back.

This cycle can be repeated until both compounds are fully separated using the CPC system (Fig. 3.). This clever technique allows us to effectively resolve compounds with very similar partition coefficients.

Continuous CPC implements the unique MDM-CPC approach in which two CPC devices are interconnected. Sample injection can be positioned at the front of the rotors, effectively increasing the column length and improving separation efficiency of compounds with similar partition coefficients by raising the theoretical plate number (N). Alternatively, injection can be placed between the rotors, enabling a truly continuous (uninterrupted) sample injection, that results in a continuous separation process and high production output.

Continuous CPC involves a sequence of steps where injection remains continuous. In addition, with four built-in pumps, Continuous CPC allows continuous switching of both CPC modes in a continuous manner, namely ascending and descending (Fig. 4.) modes. The flow direction and the roles of the upper and lower phases switch multiple times, with each phase acting as the mobile phase at different points, optimizing separation efficiency without interruption by switching between ascending and descending modes. This design enables the process to be extended into a repetitive cycle, ensuring continuous operation and sustained production.

At the end of the continuous approach process, less-retained and highly-retained components are collected at opposite ends of the column. The key to this approach is inverting the elution mode before any collected product becomes impure, so it maintains the maximal purity, while it minimizes sample loss, and increases the productivity.

The emergence of MDM-CPC has introduced a user-friendly alternative to industrial chromatographic
separations. MDM-CPC allows for the efficient separation of molecules with very different
characteristics and also with highly similar partition coefficients from complex matrices, such as raw plant extracts. The primary goal is to reduce purification time, increase
production volume, and reduce the cost of the operation.

With these advantages, CPC, especially in its dual-mode and multiple dual-mode configurations, is proving to be a powerful alternative to traditional batch extraction and chromatography, offering higher efficiency, productivity, and scalability for various industries, including pharmaceuticals, biomanufacturing, and natural product extraction.

This setup can be classified alongside simulated moving bed (SMB) technology, in which a binary mixture is continuously separated into two fractions at very high throughput. In the literature, various terms may be encountered for this configuration—such as Sequential CPC (sCPC), True Moving Bed (TMB), trapping MDM, or “intermittent” CCC—yet the same underlying system is being described.