As demand for DNA and RNA therapeutics continues to accelerate, manufacturers are under increasing pressure to improve efficiency, reduce risk, and scale production without expanding facility footprints. One emerging solution is the integration of traditionally separate downstream steps into a single automated platform.

Asahi Kasei Bioprocess, has addressed this need with the THESYS^® platform, a suite of oligonucleotide manufacturing technologies designed to streamline workflows from synthesis through downstream processing.

In a recent podcast, Sagar Bhatt, Senior Project Engineer at Asahi Kasei Bioprocess America, discussed the development of an integrated system within the THESYS C&D/TFF system combines cleavage, deprotection (C&D), and tangential flow filtration (TFF), and why this shift represents a meaningful evolution in oligonucleotide manufacturing.

Rethinking a Fragmented Workflow

Historically, oligonucleotide production has relied on a series of disconnected unit operations. Cleavage, deprotection, ultrafiltration, and diafiltration are often performed across multiple systems, sometimes even in different rooms.

“Cleavage and deprotection are often carried out using fairly basic setups… and in many cases, they still involve a lot of manual handling,” Sagar explained. “They also typically require additional equipment, like separate tanks, which adds complexity to the process.”

This fragmented approach introduces several challenges. Material transfers between systems increase processing time and create opportunities for product loss. In addition, deprotection reactions, particularly for RNA, require careful thermal control due to heat generated during acid addition.

“If the rate of the acid addition and resulting temperature rise are not controlled carefully, it can negatively impact the product… and damage product quality.”

Facility constraints add another layer of complexity. Because oligonucleotide processing often involves flammable solvents, operations must occur in hazardous environments. However, traditional filtration systems are not typically designed for these conditions, forcing manufacturers to physically move material between areas.

Recognizing these inefficiencies, Sagar and his team saw an opportunity to simplify.

“By integrating these operations into a single physical equipment and related automation, we could potentially streamline the workflow, reduce handling steps, and significantly improve overall manufacturing efficiency.”

From Concept to THESYS^® Integration

The idea of combining reaction-based and membrane-based processes might seem complex, but Bhatt emphasized that the separation of these steps is largely historical, not technical.

“Cleavage and deprotection are reaction steps… whereas TFF is a membrane separation process,” he said. “Though there are different mechanisms involved, they can operate on the same product stream and can share the same fluid handling architecture if designed properly.”

Within the THESYS^® platform, this integration is enabled through automation and system design that bring multiple unit operations into a single, cohesive workflow.

Advances such as closed-loop temperature control, precise dosing, and real-time pressure monitoring allow both reaction and filtration steps to be managed within one system boundary.

Equally important was designing the platform for hazardous environments from the outset.

“That eliminated the need for intermediate product transfers, which made this integration approach much more practical.”

Engineering for Efficiency and Scale

One of the most significant engineering challenges was balancing performance with practicality.

“Designing the combined system to keep the footprint to a minimum while also taking operability and maintainability into consideration was one of the biggest challenges,” Sagar said.

The team also focused on minimizing holdup volume, maximizing product recovery, and ensuring cleanability for GMP operations—all within a compact system design aligned with THESYS^®’s broader focus on efficient, scalable manufacturing systems.

The result is a platform that delivers efficiency gains primarily by eliminating transfers.

“In traditional setups, the material moves between different systems and sometimes even between different rooms,” he explained. “Each transfer adds time, manual handling, and potential product loss.”

By consolidating operations into a single THESYS-based system, manufacturers can complete processes sequentially without interruption, reducing both time and risk.

Improvements in Safety and Process Control

Beyond efficiency, integration significantly enhances safety and control.

“Operators no longer need to move material between systems in solvent handling environments,” Sagar said. “Keeping everything inside one enclosed physical system significantly reduces exposure risk and handling errors.”

From a control standpoint, a unified automation framework governs all stages of the process.

“The same system carefully controls dosing and temperature during the reaction phase and also controls pressure and flow during filtration,” he noted. “The unified control improves reproducibility and helps contain the process within validated operating conditions.”

Footprint and Operational Savings

The benefits extend to facility design as well.

“Instead of installing separate systems with their own vessels, pumps, and control panels, manufacturers operate one integrated system,” Sagar said. “This can free up valuable clean room space and reduce infrastructure requirements.”

Fewer systems also mean fewer cleaning cycles, fewer validations, and less maintenance, resulting in meaningful operational savings over time.

Designing for Flexibility: A “Built for You” Approach

A defining characteristic of the THESYS^® platform is its flexibility. The system is designed to align with each customer’s process rather than enforce a rigid standard.

“The system is designed to adapt to each customer’s manufacturing process rather than forcing the customers to adapt their processes to the equipment,” Sagar explained.

For example, the system can accommodate different filtration control strategies.

“Some customers perform filtration using transmembrane pressure… while others use permeate flow. The system has the capability to operate on both.”

Customer feedback also shaped physical design elements, including vessel sizing, filter configurations, and facility integration.

“These kinds of small but critical considerations help the system fit naturally into the customer’s manufacturing environment without major disruptions.”

Validation, Compliance, and Integration

Integration also simplifies GMP validation.

“When you combine multiple operations into a single system, you reduce the number of vessels, process flow paths, and connection points,” Bhatt said. “That means fewer product contact surfaces to clean and validate.”

The system uses hygienic design principles and recipe-driven automated cleaning cycles, with electronic batch records supporting compliance.

Importantly, the THESYS^®-based system integrates easily into existing manufacturing lines.

“The upstream synthesis process does not change,” Sagar noted. “After synthesis, the product simply enters this integrated platform.”

Because the system is designed for hazardous environments, it can be installed directly where cleavage and deprotection already occur, eliminating the need for downstream relocation.

Industry Recognition and Future Impact

The system’s impact has already been recognized with an Interphex Innovation Award, which Sagar described as “a strong validation from the industry.”

“The award recognized that integrating these steps… addresses real challenges that manufacturers face, like complex workflows and inefficient equipment setups.”

Looking ahead, he sees integration—central to platforms like THESYS^®—becoming a core design principle in oligonucleotide manufacturing.

“As demand for DNA and RNA therapeutics continues to grow, manufacturers will need equipment that supports higher throughput, consistent product quality, and faster batch turnaround.”

Integrated, modular platforms will play a key role in meeting these demands.

“Over time, we are likely to see more compact automated systems performing multiple process steps… helping facilities scale production more efficiently and accelerate the development of new therapies.”

A Shift Toward Smarter Manufacturing

The integration of cleavage, deprotection, and TFF within platforms like THESYS^® represents more than just a technical advancement, it signals a broader shift toward streamlined, automated, and modular biomanufacturing.

By reducing complexity, improving safety, and enabling scalability, integrated systems are poised to redefine how oligonucleotides are produced, bringing the industry closer to faster, more efficient delivery of next-generation therapeutics.

To learn more, please see Optimize Your Oligo Manufacturing