Cell and gene therapy has moved from the fringes of experimental medicine to the front line of biotechnology’s most consequential advances in the space of a single decade. What used to be theoretical ideas explored in academic papers have become approved clinical reality: CAR-T cell therapies for haematological cancers; Gene replacement therapies for inherited disorders, which previously had no solutions; and an ongoing pipeline of products for diseases across oncology, rare disease, and ever more common chronic conditions.

There have been significant developments in science. The CGT manufacturing platform has been lacking in progress. Manufacturing of cell and gene therapies (CGT) is a manufacturing process with unique challenges that has no historical equivalent in pharmaceutical manufacturing. The products are living or genetically modified biological materials, have limited shelf lives, are very sensitive to handling conditions, and are produced with extremely complex production processes. Patients requiring them often can’t afford to wait for a supply chain. 

That’s where that development is going.

All the manual processing was automated

The first generation of CGT manufacturers was based on manual processes that were highly skilled, requiring complex steps of cell handling, viral vector production, and quality Sterility testing for ATMPs to be carried out by hand in cleanroom facilities, and protocols were based on research lab, not manufacturing design or practice. This was sufficient for small-scale manufacture for clinical trials. It can be totally unfeasible for commercial use to produce therapies for thousands or tens of thousands of patients.

One of the most important structural changes in CGT manufacturing is shifting from manual to automated closed-system processing, which is being propelled by the scale-out problem — producing more doses without having to proportionately increase the number of highly trained operators, and the cleanroom area they need.

Automated cell culture Advanced Therapy Products systems that monitor and regulate growth conditions in real-time; automated fill-finish systems that eliminate the manual steps most susceptible to contamination and variability; and automated systems that can make vector production and cell manipulation steps consistent across large production volumes are all progressing quickly. The pharmaceutical equipment manufacturers and biotechnology tools companies investing in this space are ultimately tackling an actual commercial bottleneck, and what’s being seen in each new generation of manufacturing equipment being released is improvement.

Decentralised and Point-of-Care Manufacturing

Autologous CGT — where therapies are produced using the patient’s own cells — poses a challenge that cannot be solved in a nice way with a centralised manufacturing model. These cells need to be taken from the patient, then moved to a manufacturing facility, undergo a lengthy multi-week production process, and finally be returned to the patient in a clinically viable form. All of those links add up in terms of risk, delay, and cost.

In recent years, decentralised manufacturing, in this context, the production of CGT products as close to the point of care, preferably within hospital systems and not in centralised commercial facilities, has also become a viable alternative to the hub-and-spoke model that has been followed by the first generation of commercial CGT. For certain indications, this is already known to be feasible, as proven by academic medical centres that have manufacturing facilities for CGT. The challenge now is to reduce the technology of manufacture to a scale that could be economically viable at a wider range of sites.

A viral vector manufacturer progresses

One of the major production bottlenecks in the CGT sector has been the viral vectors, which act as the delivery vehicle for genetic material to enter cells in the context of gene therapy and in many manufacturing processes for cell therapy. Current manufacturing platforms are unable to reliably and commercially manufacture AAVs, such as lentiviral vectors, in sufficient quantities.

Several technological developments are tackling this head-on. In new facility designs, suspension cell culture systems for producing AAV are replacing legacy cell culture approaches that traditionally have been based on adherent cells, which are more difficult to scale up to commercial production volumes. The purification of viral vectors is also progressing, with improved chromatography and filtration techniques yielding improved purification and yield compared to older technologies.

The emerging vector serotypes, as well as modified capsids with novel tissue targeting and immunogenicity, have opened new therapeutic windows and generated new challenges for the production process, which need to be overcome by the platform technology.

The ability to control the process using PAT and Real-Time Quality

The idea behind quality by design – building quality into the manufacturing process, not testing it at the end – has been a part of the regulatory framework for pharmaceutical manufacturing for some time now. This not only reflects regulatory philosophy, but it is also a fundamental principle in CGT, where product quality is synonymous with product identity and biological activity. It is required by the manufacturing process.

The use of PAT — the real-time measurement, monitoring, and incorporation of the same into manufacturing processes for continuous assurance of product quality is developing at an accelerated pace in the context of CGT manufacture. Real-time monitoring of cell viability, density, metabolites profile, and vector titre using in-line sensors enables the ipsc manufacturing process to be manipulated in real time, instead of testing at the end of the process to determine if the batch is acceptable or not.

The transition from batch and test to monitor and adjust in manufacturing has a tremendous impact on yield and regulatory compliance. The batches that are heading towards failure can be identified and addressed before it reaches an unrecoverable state. Process variations are identified and addressed on-the-fly instead of after the fact. The data produced offers regulators a greater degree of understanding and assurance of the process than can be achieved using end-point-tested methods.

Conclusion

Cell and gene therapy is not simply a “tech problem” for the manufacturing sector. It is the middle block where the science becomes patient-friendly treatments, affordable in healthcare systems, and clinically relevant time frames.

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