Meeting the cell and gene therapy scale-up challenge

Improving patient access is a UN goal but for companies transitioning from trials to full-scale production, IP is essential, explains Katherine Collins of Mewburn Ellis.

One of the pivotal challenges in the development and commercialisation of cell and gene therapies (CGT) lies in scaling up production. This challenge is particularly pronounced as companies transition from clinical trials to full-scale commercialisation—a major step in the lifecycle of any innovation of this kind.

It could also be a significant factor in achieving good health and wellbeing for all.

The inability to scale up the manufacturing process to produce the required amounts for clinical trials and commercial therapy can lead to the failure of a product.

As part of the approval process, regulatory bodies require thorough documentation of the production processes, making it difficult to alter manufacturing processes later in the commercialisation process.

Draft FDA guidance titled "Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products" addresses this issue by stating: “We recommend that any extensive manufacturing changes be introduced prior to initiating clinical studies that are intended to provide evidence of safety and effectiveness in support of a Biologics License Application (BLA).”

Scale-up concerns grow

As concerns around manufacturing and scale-up have increased, investors commonly look at whether companies have well-thought-out plans for scaling up. In a survey of factors that were most likely to influence their decision-making process for investing in a cell and gene therapy company, manufacturing and scale-up were chosen as a top-three factor by 37% of respondents in 2018.

However, by 2021, this number had increased to 48% of respondents. Similarly, the number of respondents ranking manufacturing and scale-up challenges in the top three greatest barriers in the decision to invest in a CGT product opportunity increased from 45% to 63%.

These aspects mean that the "rush to the clinic" approach that was commonly taken with small molecule drugs does not work well for cell and gene therapies. Instead, aspects of scale-up and manufacturing ought to be considered early in the development process.

The realisation that manufacturing was a significant hurdle to getting to market and for successful commercialisation of a product has shifted the focus of many cell and gene therapy companies.

However, for the cell and gene therapy industry, scaling up is not only a hurdle but also an opportunity for innovation. Intellectual property plays a vital role in protecting and commercialising such innovations.

Automation changes the game

For cell and gene therapy companies, any improvement or advantage in their production process can be a valuable asset, potentially eligible for patent protection. Many companies in the field are focusing on platforms dedicated to enabling efficient scale-up. For such companies, having a strong IP portfolio can allow them to attract the investment required to increase capacity and market reach, providing their scale-up solutions to a wider audience.

Automation is emerging as an important component in the scaling up of cell therapies. Companies such as Mytos, Miltenyi BioTec, and Cellular Origins have produced automated, closed cell processing platforms. These platforms promise not only larger and more efficient batches of cells but also enhanced reproducibility. This minimisation of variability is a crucial aspect in meeting regulatory standards and ensuring consistency in therapeutic outcomes.

There is also a push to move to a full and comprehensive digitised approach to data collection. Previous manual and/or paper-based recording can be a bottleneck to batch release of a product. Furthermore, capturing the full data during processing and manufacture of the cells allows for a more thorough understanding of the underlying causes of process deviation and differences in batch outcomes. By integrating digitised data collection early on in development, processes can be improved and optimised more quickly.

AI-based optimisation can also play a role in scale-up. For example, Form Bio uses AI-based optimisation to design vectors for the expression of CARs and T-cell receptors in therapeutic cells. The AI model predicts secondary and tertiary structures in the vector that could lead the replication machinery to fall off and optimizes the sequence to prevent this.

Manufacturing aspect

The improvement and streamlining of manufacturing play a huge role in patient access. Labour costs represent a significant portion of the overall expense in cell therapy production. It is estimated that labour costs make up around 50% of the cost of a cell therapy product.

Therefore, manufacturing issues are not only a barrier to the development of a product, but once approved, they may also be a barrier to patient access. With the high costs of manufacturing being a major factor in the high per-patient costs of such therapies, the products become inaccessible to many.

Reducing the manufacturing costs would therefore contribute to the commercial viability of a therapy and facilitate wider patient access. With the withdrawal of several cell and gene therapy products from certain regional markets due to commercial reasons, thinking ahead and investing in the manufacturing process to make it as financially viable as possible is crucial.

As well as technological advances in manufacturing per se, a move towards partnerships and the sharing of manufacturing resources can also help provide solutions to these issues.

The investment in the processes and facilities required for manufacturing cell and gene therapy products is a barrier for many small and even mid-sized companies in this space. Outsourcing the manufacturing to contract development manufacturing companies (CDMOs) or partnering with a larger company are two routes to overcome this issue. As well as providing the physical manufacturing resources, CDMOs and larger, more experienced companies can bring their expertise to a given product’s development to increase the chances of success.

Portfolio approach: More efficiency, different risks

Some companies and investors in the field are seeking to resolve these issues by taking a portfolio-based approach. They may secure common manufacturing approaches, technologies, and/or infrastructure that allow for consistency and predictability in operations across the portfolio companies' various assets. This approach allows companies to spend less money on infrastructure and focus their resources on the actual development of a product.

As with any approach that involves the sharing of technologies and resources, having strong IP in place around a party’s assets is important. Companies with strong IP portfolios are also more attractive to investors and potential partners as it demonstrates the company’s ability to protect its innovations and maintain a competitive advantage in the market.

In conclusion, the scaling-up challenge is a critical point in the development of cell and gene therapies. Companies that invest time in planning a route forward have a much greater chance of success.

Companies are currently developing and investing in scalable technologies and automation, as well as looking to data-driven approaches to address current hurdles. As the cell and gene therapy field progresses, these advancements pave the way for more therapies to successfully move from development, to clinical trials, and on to commercialisation.

Therefore, with advances in manufacturing of cell and gene therapy products ultimately leading to wider patient access, these technologies could play a key role in the UN’s third Sustainable Development Goal, which is to ensure healthy lives and promote well-being for all at all ages.

Katherine Collins is an associate, patent attorney (life sciences) at Mewburn Ellis.