Inside All-ScaleFlow: Continuous End-to-End RNA-LNP Manufacturing

Messenger RNA technology is moving beyond pandemic-scale vaccines to encompass a broader range of therapeutics. Moderna's recent Phase 3 success for an individualized neoantigen therapy exemplifies this shift, alongside the establishment of COVID-19 as the extreme high-volume end. This clinical progress is spurring both emerging and established developers to expand RNA medicine development, either through contract development organizations (CDMOs) or by establishing their own production facilities.

To enhance both development and production efficiency, CDMOs and drug makers require rapid changeovers and flexibility across sequences and production scales. All-ScaleFlow, a solution developed by Dillico, aims to address these needs by integrating RNA synthesis, purification, buffer exchange, and lipid nanoparticle (LNP) formation.

This integration enables a seamless, continuous manufacturing process that does not necessitate larger batch vessels. The patent-pending semi-continuous intravenous transcription (IVT) core RNA synthesis process initiates with fixed IVT unit volumes injected into the patented Dillico spiral-shaped semi-continuous reactor. The reactor operates within a temperature-controlled environment, where each unitary volume progresses through a series of loops before exiting for potential enzymatic treatment and quenching.

This design maintains consistent batch reaction conditions without the need for progressively larger vessels. The All-ScaleFlow platform further integrates multi-column chromatography and multi-stage solid-phase titration filtration filtration (SPTFF) for RNA purification, concentration, and buffer exchange. Surge tanks buffer the eluate from the cyclic chromatography, maintaining a controlled flow into the continuous purification SPTFF and LNP mixing stages.

After LNP encapsulation, a second multi-stage SPTFF step removes ethanol and finalizes the buffer exchange prior to in-line dilution or excipient addition and sterile filtration. By coordinating flow rates and interfaces, the system facilitates continuous production from IVT crude to formulated mRNA-LNP while minimizing intermediate stops.

The system also includes an automated clean-in-place and sterilization-in-place (CIP/SIP) station to mitigate supply chain risks and promote long-term sustainability. This station utilizes common cleanroom utilities to clean and sanitize the stainless-steel process path, potentially saving up to 450 kg of single-use plastic (~200k$) for a large-scale batch IVT production.

The Process Simulator, a key component of All-ScaleFlow, employs mechanistic process models derived from empirical knowledge bases generated through experiments with standard, off-the-shelf process components. Given a product and process requirement, the Process Simulator calculates the global constraints required to operate the continuous process as a coordinated system and identifies robust conditions that satisfy quality attributes and throughput targets.

This capability reduces the number of physical experiments needed during process development and supports right-first-time execution, thereby avoiding costly trial-and-error with production materials and analytical testing. The Process Simulator also streamlines technology transfer by guiding users through a structured, step-by-step workflow, thereby lowering the entry barrier for teams unfamiliar with continuous processing.

Additionally, the system contextualizes real process data, making them suitable for data-lake applications.