A Roadmap to Level 3.1 Process Intensification for mAb Downstream Purification

Industrial Background Of Process Intensification for Downstream Bioprocessing

For years, process intensification in bioprocessing has promised efficiency, cost savings, and scalability—but the industry's progress has been gradual and fragmented. While upstream continuous processes have seen notable advances, the downstream side—for example in monoclonal antibody (mAb) purification—has struggled to keep pace. The only success may be the multi-column loading continuous chromatography (4C) within still a single processing step. Connected batches or integrated processes combining two or more processing steps have been generally considered as very challenging because of the flow/pressure incompatibility between some steps ie. Chromatography and filtration. The lack of a software platform at benchtop for orchestrating the operations from one step to another is another major challenge.

The industrial categorization of process intensification falls into five categories:

L0: No intensification

L1: Intensification within a single step

L2: Two steps connected through holding vessel and there is coordinated operation from one step to another

L3: Semi-continuous connected processing steps with orchestrated operation from one to another with no or small intermediate holding vessel

L3.1: Complete steady-state flow-in/flow-out continuous process with no control logics between the process steps

Current success with process intensification has been very limited with most being at level 1 and struggling at level 2. The long-standing goal of achieving a fully continuous, end-to-end downstream process with steady-state input and output has remained just out of reach. Until now.

Enabling Level 3.1 Process Intensification for mAb Downstream Purification

A newly developed benchtop platform called M++ from Lisure Technology is changing the game. It enables a concrete, realistic path to Level 3.1 (L3.1) process intensification: a system where all unit operations flow continuously, and most reach or approximate steady-state. At its core is the M++ benchtop system purposely designed with powerful liquid handling capability and innovative process configurations.

Level 3.1 process intensification represents the highest level of process connectivity, integration, and automation within a bioprocess, characterized by a fully connected, closed-loop, continuous flow-through system. In Level 3.1, every process step—regardless of whether it is steady-state or periodical—is designed for constant flow operation. This is the key departure from Level 3, where discontinuities and hold steps are still common.

The Roadmap to Level 3.1 Process Intensification

The level 3.1 roadmap is enabled by M++’s powerful liquid handling capability, connected batches through innovative process configurations, and integrators made of M++ external modules. A double stream delivering M++ unit with an integrator forms the basic architecture needed for continuous end-to-end processing of the level 3.1 intensified process.

Here are the critical developments that came together on M++ to eventually unlock Level 3.1 process intensification, innovations at both platform and process level:

• Innovative Process Configurations

The roadmap includes new process configurations that enable non-fluctuating flow for normal flow filtration and tangential flow filtration. These are not batch-mode mimicries—they are continuous by design.

• Platform Capability

M++ delivers double streams flow—a fundamental requirement for parallel or hybrid continuous processing. This design allows multiple processing steps to receive and process feeds simultaneously.

• Sub-Module Assembly

Processing components are in form of assemblies made of M++ sub-modules. They work with the main module of M++ to perform integrated processing and connected batch steps.

• Integrator

Integrators are a special kind of M++ assembly. It synchronizes multiple process steps, buffers inconsistencies, and serves as the connective tissue between upstream and downstream modules.

How Level 3.1 Process Intensification Works on M++

The power of this roadmap lies in its real-world practicality. M++ isn't a future concept or a theoretical model—it’s a working benchtop POC system, designed for immediate testing, iteration, and scale-out. Each assembly is designed for plug-and-play functionality, allowing biomanufacturers to build toward L3.1 process intensification in stages without having to overhaul their infrastructure.

The roadmap enables true steady-state flow-in/out, which means production is more efficient and product quality is more consistent. Scaling-up becomes a matter of copying M++ system/flow paths/process recipes rather than rebuilding systems. In fact a complete L3.1 mAb downstream purification process can be demonstrated on benchtop scale with 4 M++ units.

With M++’s one-stop tech transfer capability, such L3.1 process can be immediately scaled up for clinical manufacturing and continue on to commercial manufacturing.

The Impacts on Biopharmaceutical Industry

Achieving Level 3.1 process intensification marks a tipping point for mAb downstream processing. It brings the vision of fully continuous biomanufacturing within reach, not just in pilot labs but in real production environments.

Cost savings from reduced buffer volumes, lower downtime, smaller equipment footprints, and continuous processing are only part of the story. The real win is process agility—the ability to adapt, quickly proof-of-concept (POC), scale-up, and respond to demand without the rigid constraints of traditional batches.

The roadmap delivered through M++ is a leap, not a step. It presents a practical path for biopharmaceutical companies who are ready to transition from lengthy and costly R&D project to immediate benchtop-scale proof of concept (POC) in their drug development pipeline.

With M++ platform and this roadmap to Level 3.1, the basic building blocks for L3.1 are here. L3.1 Process Intensification for downstream bioprocessing is no longer just a vision. It's a system we all can build.