From concept to clinic – partnering to scale up cell and gene therapies

Cell and gene therapies (CGTs) have expanded treatment options across oncology and rare diseases in recent years, bringing targeted approaches that were previously out of reach into clinical practice.1 The landscape continues to evolve, with advances in gene editing and cell engineering driving rapid growth in the number of therapies in routine clinical use, and attention is now shifting from scientific feasibility to the practicalities of commercial manufacturing. This transition from research and development to clinical manufacturing remains a critical challenge to the success of new therapies.

Manufacturing of CGTs is complicated by the fact that they are highly personalised, often using primary cells derived from the patient themselves. Each individual therapy requires multiple complex manipulation steps, which can introduce significant variability during development and manufacturing. Processes established at the research stage often require modification or replacement during scale-up, creating an additional development burden and potentially delaying regulatory approval and market release. Ideally, technologies used for cell engineering during development should maintain performance, consistency and reproducibility as processes expand beyond small-scale operations.

However, achieving this level of consistency is not always straightforward, as primary cells can vary considerably according to donor source, disease state, activation status and broader biological context. Electroporation is one example of an enabling technology used during both R&D and large-scale production of CGTs. Electroporation allows the effective, non-viral delivery of genetic material into cells, and its performance across development stages can significantly influence process efficiency and overall manufacturability. Understanding the wider process – including upstream and downstream steps and the biological state of the cells – is invaluable for informing electroporation parameters and defining protocols that are suited to the specific cell and process conditions, helping to maintain reproducibility between batches and during scale-up.

Like that of any therapeutic, the development of CGTs spans multiple stages, from early research and proof-of-concept studies, through process development, to scale-up and clinical manufacturing. Each stage introduces new technical and operational requirements, as well as biological challenges, and the transition between stages is often associated with significant process change. In early research, workflows are typically optimised for flexibility and speed, with small-scale systems used to screen numerous constructs, delivery methods and cellular responses. As programmes progress, these processes must be adapted to meet the requirements of larger-scale manufacturing, including increased volumes, tighter process control, the cost and availability of good manufacturing practice reagents, and stricter quality standards. This transition is rarely linear, as any changes in equipment, materials or process parameters can introduce variability that requires additional optimisation and validation.2,3 Reoptimising the production process at each scaling stage can extend development timelines and increase the risk of process failure. Variability introduced during scale-up may affect cell viability, transfection efficiency or product consistency, all of which are critical quality attributes in CGT manufacturing.

In addition, process changes can have regulatory implications, particularly as programmes move into clinical and commercial phases, with guidelines such as ICH Q5E requiring manufacturers to demonstrate that production changes do not affect product quality, safety or efficacy.4 As a result, there is increasing focus on strategies that minimise process changes across the development pathway. Approaches that enable continuity between R&D and manufacturing can help to reduce the associated burden and make scaling up more predictable and efficient. Unfortunately, this continuity is not achievable for every technology or process, as cells can respond differently to changes in culture format, density, handling or the microenvironment.5 Platform strategies therefore need to account for biological variability as well as engineering requirements to ensure reliable and robust manufacturing.

However, the performance of electroporation is influenced by multiple factors, including electrical parameters, cell type, buffer composition and process conditions. Careful optimisation is vital to achieve the desired balance between delivery efficiency and cell viability, yet these parameters can be sensitive to scale and may not directly translate from small batch processing to large-scale production. In small batch processing, cells may move directly and quickly into electroporation under relatively static conditions. At larger scales, cells often need to pass through longer fluid paths, and may be processed in sequential batches, increasing time in buffer, exposure to shear stress and oxygen, and heat accumulation, which increases the potential for clumping or dead cell build-up. These factors can affect cell health and process efficiency, making it challenging to maintain consistent performance when transitioning from research to manufacturing environments.6,7

Scalable electroporation technologies aim to address this challenge by enabling similar process conditions to be applied across different stages of development. Parameters developed on systems designed for early-stage screening can be transferred directly to instruments used in process development and manufacturing, allowing entire protocols to be transferred with minimal modification and reducing the need for repeated optimisation. This transferability depends on careful development of instruments and consumables, with extensive characterisation of the amount of electrical energy delivered and heat generated across formats. This helps developers to ensure that established protocols maintain alignment across platforms, which is particularly important in CGT manufacturing, where small changes in process conditions can have a significant impact on product quality.

In addition to technology selection, technical expertise plays an important role in the development and scaling of CGT processes. The complexity of these therapies means that optimisation is often iterative, requiring detailed understanding of both the biological system and the engineering parameters involved. Working with an experienced commercial partner with significant expertise and process knowledge across diverse CGT workflows can help to guide efficient process development. Historical data sets and established protocols provide a more reliable starting point for optimisation, often reducing the number of experimental iterations required considerably. This is particularly relevant in electroporation, where parameter selection can influence both delivery efficiency and cell viability, which, in turn, impact therapeutic efficacy.

Ongoing technical support is also a key consideration. Training, troubleshooting and process guidance can help to ensure that technologies are implemented consistently across different stages and sites. This also gives researchers access to field-based expertise developed across a broad range of workflows, from widely used approaches to more specialised applications. As programmes progress, this support may extend to considerations such as process transfer, scale-up strategy and regulatory requirements. In this context, collaboration between technology providers and therapy developers can help to keep continuity across the development pathway. Rather than a transactional relationship, this approach emphasises shared understanding of process requirements and long-term alignment between collaborators to reduce risk, improve reproducibility and smooth the progression from concept to clinic.

The number of CGTs progressing towards commercialisation continues to grow, and the demands on manufacturing processes – and regulatory requirements – are increasing accordingly. Scalability, reproducibility and process robustness are becoming central considerations, alongside the need to reduce timelines and manage development costs. Modular, flexible platforms that maintain consistency across upstream and downstream process parameters – from early research through to manufacturing – can help to reduce variability and limit the need for repeated optimisation, contributing to more predictable development pathways.

At the same time, broader operational factors – such as supply chain reliability, access to critical materials and the availability of skilled personnel – can all influence the success of CGT manufacturing. Standardisation of processes and structured knowledge transfer will be essential to ensure consistent implementation across sites and stages of development. As manufacturing networks expand, the ability to maintain alignment between research, process development and clinical production environments will become increasingly important.

The ability to apply consistent electroporation conditions across different stages of development is particularly valuable in supporting reproducibility and process continuity. Scalable electroporation platforms that maintain alignment across these stages can help to reduce development complexity and improve overall process robustness. More broadly, successful CGT development will depend on the integration of appropriate technologies with technical expertise, and collaboration between developers and technology providers to navigate the shift from early discovery to commercial manufacturing. As the field continues to rapidly evolve, approaches that account for both scalability and process reliability in cell engineering will be critical to advancing the next generation of therapies.

Rama Shivakumar is senior manager, technical applications at MaxCyte, where she has spent more than 25 years supporting the advancement of cell engineering technologies. She serves as a scientific subject matter expert across cell and gene therapy applications, including gene editing, CAR-T, NK and T-cell engineering, viral vector production and protein production. Rama collaborates across R&D, product development, field applications, and scientific communications to help translate complex science into practical solutions for researchers and customers worldwide. She holds a master's degree in Molecular Biology from Indiana University School of Medicine, IN, US.

Nitin Kulkarni has been a senior field application scientist at MaxCyte for last five years. Nitin has worked on all the stages of cell and gene therapy, ranging from optimising experiments in academic settings, process development for clinical application, all the way to assisting commercial manufacturing for cell therapies. For over 12 years, he has helped advance customer applications and technologies with his expertise in cell culture, molecular biology, immunology, bioprocessing and microfluidic cell isolation technologies. Before joining MaxCyte, Nitin did his postdoctoral research in autoimmune diseases and in cancer at Beth Israel Deaconess Medical Center (BIDMC) in Boston, MA, US, followed by his roles in Scientific and Product Support for Corning Life Sciences and MicroMedicine.

From concept to clinic – partnering to scale up cell and gene therapies

Commercial development and scaling challenges

Role of electroporation and scalable platforms

Partnership and technical expertise

Future considerations

Closing perspectives