Dr. Alex Van Hagen, Life Sciences Sector specialist, Watson-Marlow Fluid Technology Solutions; James Drinkwater, head of GMP Compliance, Franz Ziel GmbH and Dr. John Milne, director of Training and Education, National Institute for Bioprocessing Research and Training (NIBRT), discuss the advantages of single-use technologies in CGT manufacturing platforms.
Harriet Wills (WMFTS UK)
Key insights:
- CGT commercialisation is on a firm and fast trajectory, yet many challenges remain in the manufacturing stages.
- Hand in hand with single-use technologies, ATMP platform technologies are delivering efficient manufacturing solutions through flexibility and digitalisation.
- Single-use technology gives the option to remove every pathway associated with a batch and replace it with a new pre-validated system.
Cell and gene therapies (CGTs) present huge promise in the fight against a range of previously untreatable diseases. However, investment in this sector is not taken lightly. Typically, developers must invest billions of dollars in therapies that might take ten years to reach the market as they battle the odds against high failure rates.
Many more advanced therapy medicinal products (ATMPs), such as CGTs, are now entering the commercialisation stage. Finally, they are set to bring a return on investment and deliver their promises to the patients who need them. As developers embark on this next phase, new pressures emerge. Organisations must meet ever more stringent compliance standards and ensure the very highest quality and safety levels, while consistently driving down costs through efficiency.
CGT commercialisation is on a firm and fast trajectory, yet many challenges remain in the manufacturing stages. ATMP platform technologies are providing solutions for some of the most demanding manufacturing challenges the industry has ever had to face. Hand in hand with single-use technologies, platform technologies are delivering efficient manufacturing solutions through flexibility, modularisation, intensification, automation and digitalisation.
Recouping development costs
Harriet Wills (WMFTS UK)
The average cost to develop a new therapy stands at $1.3 billion. When a CGT gets to the commercialisation stage, there is enormous pressure to recoup this cost. Manufacturing efficiencies are critical here to provide the cost savings that deliver payback without transferring unnecessary cost burdens to payers or patients.
For highly targeted CGTs, reducing manufacturing costs is challenging. Very small batches require single-use fermenters; in the case of autologous treatments like CAR-T cell therapy, this might be one fermenter per patient and a complete upstream single-use fluid pathway. This costly but robust approach is necessary because every wasted millilitre could lose thousands of dollars.
The advantages of single-use
Ensuring safety
Contamination is a huge risk in the production of CGTs, and the very highest standard of aseptic processing is needed to mitigate this. CGTs are often injected straight into extremely vulnerable patients, and sterility must be ensured.
The latest revision of the GMP Annex 1, the European Union's requirements for the manufacture of sterile medicinal products, addresses these issues in a standardised, mandated way. It requires manufacturers to increase contamination control measures, barrier technology and automation to reduce risk to patients and operators. Requirements, such as pre-use post sterilisation filter integrity testing (PUPSIT) that use sterile filter testing within single-use fluid paths, will increase the focus on ensuring each element of the manufacturing process accommodates the nuances of CGT manufacturing.
ATMP manufacturing platforms, utilising single-use components and drawing on the latest technology and industry experience, are ideally placed to fulfil these goals.
Tried, tested and pre-validated technology
It is already known how to safely transfer cells in the biologics sector, using peristaltic pumps with fast, non-shearing processes, and we already use reliable bioreactors and suspension-based culture systems in biologics manufacturing. Where tried and tested equipment is fit for purpose, it can easily be incorporated into new CGT workflows.
Single-use technology is an obvious choice, giving the option to remove every pathway associated with a batch and replace it with a new pre-validated system. Without clean-in-place (CIP) or sterilise-in-place (SIP) requirements, single-use systems can guarantee sterility and meet small-batch and bespoke needs.
Single-use pathways often come pre-validated for regulatory compliance and this is extended into some automated, modular equipment too. Pre-validated, standardised systems bypass bespoke validation and design processes, provide a key part of a robust contamination control strategy and can lead to faster regulatory signoff. These are all important aspects of an efficient manufacturing process that is designed to get CGTs to commercialisation faster.
Flexibility
CGTs are a broad and diverse range of therapeutics, so manufacturing platforms need to reflect this. There is strength in standardisation from modular equipment and single-use pathways, but this shouldn’t come at the expense of flexibility, which is the only way to ensure the most efficient and effective production.
Platforms need to accommodate different batch sizes, from clinical production to small batch processes. They also need to be suitable for scale-up to meet increasing market demands. Ideally, this scaling potential needs to be incorporated in the research and development (R&D) stages. By using systems in R&D that have manufacturing-scale counterparts, small batch production can be easily and predictably upsized for larger allogeneic production.
Flexibility also needs to extend to the future. Given the fast-paced environment CMOs and CDMOs find themselves in, manufacturing systems need to offer the ability to be adapted for future requirements. More static equipment with stainless steel components is very hard to adapt without relative difficulty. Single-use technologies provide the solution; as long as the processing equipment can facilitate the required action, any component can be included within an assembly.
Modularity
Modular systems that are pre-validated, enclosed and automated address many of the pain points of regulatory compliance, safety, waste reduction and changeover between products. Far from restricting flexibility, these systems are often fully configurable. ATMP filling platforms, for example, can now be configured to process a range of different products, with or without containment.
Bringing life-changing therapies to market with single-use
CGT manufacturing requires an evolution of existing methods, rather than a revolution. The advantages of single-use components are well established and their incorporation into CGT manufacturing platforms is already transforming the industry.