Digital: Cell Therapy Processing

As more and more cell therapies move from experimental treatments to commercial realities, manufacturing remains the primary bottleneck to patient access

A new technology that combines the power of microfluidics with advanced automation is emerging as a solution to tackle supply issues, thereby unlocking the true potential of cell therapy. Such all-in-one and yet modular manufacturing and analytical platform address cost, scalability and process complexity simultaneously, therefore reshaping how living drugs like CAR-Tcells are developed and delivered. The next frontier is no longer biology: it is industrialisation.

An increasing number of patients are being treated every year by ex vivo gene-modified cell therapies. Since the first commercial approvals in 2017, ex vivo CAR-T population has grown from ~100 to ~10,000 new patients by year nowadays, with access continuing to expand by ~20 to 30% yearly. While in vivo approaches hold tremendous promise, patients cannot afford to wait for that future to arrive. Science works, manufacturing does not. Cures have been built, but delivering them at scale is difficult. Unless we fundamentally rethink how these therapies are manufactured, they will remain extraordinary treatments available only to a limited number of patients. What the industry needs now is a new generation of manufacturing technologies. By making cell therapy production better, faster, cheaper and closer to patients, tool providers can help transform these therapies from remarkable cures for a few into a standard of care for many.

Over the past decade, cell therapies have demonstrated transformative clinical potential across oncology, autoimmune diseases and rare disorders. However, despite strong clinical efficacy, their broader adoption remains constrained by manufacturing challenges. Autologous processes are associated with complex, labour-intensive and difficult to scale, while infrastructure requirements limit deployment to a small number of specialised centres.

Current manufacturing paradigms rely on fragmented workflows resulting in long vein-to-vein times, high cost of goods (COGs) and variability in product quality. As the pipeline expands and indications shift toward earlier lines of treatment and larger patient populations, the need for a step-change in manufacturing approaches has become critical.

Traditional cell therapy manufacturing involves discrete unit operations: cell selection; activation; gene modification; expansion and formulation. Each step typically requires dedicated equipment and manual transfer of materials, increasing contamination risk and operational burden. The next generation of manufacturing platforms aims to integrate these steps into closed, automated systems. By consolidating workflows, these platforms reduce operator dependency and streamline process execution. Integration also enables tighter control over critical process parameters, improving reproducibility and product consistency. This shift mirrors earlier transformations in the field with the manufacturing of monoclonal antibodies, where integrated bioprocessing replaced multi-step, manual operations. However, in the context of living cell products, the challenge is significantly greater due to biological variability and sensitivity to environmental conditions.

One of the most promising technological enablers of this transformation is microfluidics. By miniaturising and precisely controlling the cellular microenvironment, microfluidic systems offer several advantages over conventional culture platforms:

• Enhanced mass transfer: thin culture chambers and high surface-area-to-volume ratios improve oxygen and nutrient exchange. Some might even call it ‘biometric’

• Reduced reagent consumption: the smaller volumes enabled by microfluidic confinement allow for more efficient utilisation of high-value reagents, such as cytokines and viral vectors, bringing cell manufacturing closer to the scale and efficiency of natural biological systems

• Precise control of conditions: flow dynamics, shear stress, exposure times can be finely tuned, overall gentler conditions to cells, meaning better cell quality in the end

• High throughput architecture: parallelisation of microchambers provides linear scaling while preserving process conditions and process development flexibility. Microfluidics miniaturise manufacturing into compact units, enabling the industry to scale production capacity rather than facility footprint. and manufacturing organisations (CDMOs), academic medical centres and eventually regional hospitals. This shift has several advantages:

Unlike traditional scale-up strategies, which often require re-optimisation at each scale, microfluidic systems enable scale-out approaches. This preserves process fidelity while increasing throughput.

• Reduced vein-to-vein time

• Improved patient access

• Lower logistical complexity

• Greater flexibility in scheduling treatments

• Fresh input and output with better quality profiles.

Manufacturing cost in cell therapy is typically driven by three major factors: labour, reagents and infrastructure. Emerging integrated platforms address these simultaneously:

Automation reduces manual handling steps, decreasing operator time and minimising human error. Closed systems also reduce the need for high-grade cleanroom environments, further lowering operational complexity. The integration of image-based cytometry for real-time monitoring will further enhance the value of microfluidic manufacturing. In the long term, these capabilities could extend beyond in-process controls to allow the automation of aspects of release testing directly into the workflow.

Microfluidic environments, combined with onboard analytics, enable reagent consumption to remain proportional to the target cell dose. They also eliminate the need to fill process volumes that do not actively interact with cells. This is particularly important for expensive inputs such as viral vectors, cytokines and specialty media, where excess reagent use can significantly increase manufacturing costs and overall COGs.

Compact, bench-size systems with high throughput capabilities greatly reduce facility footprint and capital expenditure. This also opens the possibility of more distributed or even decentralised manufacturing models, including deployment in hospital settings.

By targeting all three cost drivers concurrently, these technologies offer a pathway towards making cell therapies economically viable viable in larger indications and eventually in less life-threatening indications.

Centralised manufacturing models introduce logistical challenges, including cryopreservation, transport delays and complex chain-of-identity requirements. These factors contribute to long turnaround times and increased risk of product failure. Decentralised manufacturing has emerged as a compelling alternative where the therapies are produced closer to the patient. Integrated, compact platforms are key enablers of this new model. By simplifying workflows and reducing infrastructure requirements, they make it feasible to deploy manufacturing capabilities in distributed contract development

However, decentralisation also introduces challenges related to standardisation, apheresis collection and data management, which must be addressed through robust digital infrastructure.

As manufacturing systems become more connected and integrated, the importance of digitalisation increases. Modern platforms incorporate sensors, imaging technologies and software systems that enable real-time monitoring of cell growth, viability and phenotype. Key benefits include:

• Process characterisation: continuous acquisition of process and bio data enables deeper characterisation of critical quality attributes throughout manufacturing, rather than relying solely on end-point measurements

• Deviation management and root-cause analysis: real-time monitoring provides greater visibility into process variability, facilitating earlier detection of deviations and more efficient investigation of out-of-specification or out-of-trend events

• Process optimisation: data-rich manufacturing environments support accelerated process development, tech transfer, and comparability assessments across donors, sites and systems

• Digital batch records and scalability: automated data capture reduces manual documentation burden and supports the management of thousands of individualised manufacturing batches, a critical requirement for the large-scale deployment of personalised cell therapies

• Regulatory readiness: end-to-end digital traceability strengthens Good Manufacturing Practice compliance, creates a foundation for advanced control strategies and evolves regulatory expectations for the future of cell therapy.

Advanced real-time analytics, including image-based assessment and machine learning, are beginning to replace traditional, labour-intensive assays. This transition is critical for scaling and streamlining manufacturing while maintaining quality.

While large-scale commercial manufacturing is a long-term objective, there is an immediate need to support process development (PD) and early clinical stages. Flexible, modular systems are particularly valuable in this context. PD is essential in cell therapy and is in effect part of lead optimisation: target product profile aspects like purity and potency largely depend

on manufacturing conditions. PD requires the ability to screen a large design space of critical process parameters, eg multiplicity of infection (ie, average number of viral particles added per target cell during gene transfer), culture media concentrations, or activation parameters, among many others. Currently accessible platforms offer very limited capabilities for process optimisation, resulting in products going into the clinic often somewhat unpolished. Microfluidic platforms with independently addressable bioprocessors enable massive parallelisation of experiments with minimal resource consumption, creating a big opportunity for derisking assets before first in human. Beyond fundamental improvement of product profile, high throughput PD also supports emerging trends towards:

• Shorter manufacturing timelines

• Lower therapeutic dose levels

• More complex constructs (eg, multi-gene edits).

By enabling rapid iteration and higher sophistication, these next-generation systems align with the increasing pace of innovation in cell therapy.

• Validation and regulatory acceptance

• Integration with existing workflows

• Training and user familiarity

• Demonstration of consistent clinical outcomes.

Early engagement with stakeholders (drug developers, clinicians, CDMOs and regulatory bodies) is essential to address these barriers. External user-testing programmes and collaborative studies play a critical role in generating the data needed to build confidence.

The evolution of cell therapy manufacturing is entering a new phase. The convergence of microfluidics, automation and digitalisation is enabling a transition from artisanal processes to trustworthy industrialised production. Key trends likely to shape the future include:

• Standardisation of automated manufacturing platforms

• Increased use of real-time analytics boosted with artificial intelligence

• Growing of decentralised manufacturing models

• Continued reduction in cost per dose.

Although current automation efforts are largely focused on CAR-Tand TCR-T modalities, the field is rapidly expanding to include other cell types such as TIL, MAIT, γδ-T, Treg, NK, iPSC, HSC as well as macrophages. New platforms are being designed with this diversity in mind. Customisability is achieved through:

• Configurable workflows

• Adaptable culture conditions

• Compatibility with different gene delivery methods.

While viral transduction remains largely dominant in the current clinical pipeline, non-viral gene delivery approaches, such as electroporation and lipid nanoparticles, are gaining traction. Manufacturing systems must be able to accommodate these evolving strategies without requiring significant redesign.

Despite their potential, new biotools face several challenges to widespread adoption:

As these technologies mature, they could unlock the large-scale adoption of cell therapies, shifting them from niche to widely available treatment options.

Thomas Denèfle is director of Product Management and Early Access at Astraveus, leading strategic product development fueled by market insights and driving early adoption initiatives. Thomas focuses on aligning product design with customer needs to ensure strong product-market fit. His scope spans market analysis, portfolio strategy, user adoption, external marketing and communication, as well as business development for technology collaborations to enhance features set. He works closely with CDMOs, biopharma, biotech, hospitals, and academia to define use cases, and support go-to-market strategy while securing early partners for incremental external user-testing.