Scalability & Decentralised Manufacture Vs Comparability and Potency Assays: Pain Points and Opportunities

This Event Report assesses scalability and comparability of crucial assays within the theme of automating release for autologous products.

What are crucial assays being used in manufacturing, and what are the worst pain points? Can we scale assays used in the field, and will there ever be comparability?

Bringing together diverse senior specialists in cell therapy, manufacturing, gene therapy, machinery, and cryogenics, today’s working group split into two groups to tackle two areas of issue and opportunity in the industry.

Group One: Scalability and Decentralised Manufacture

We can improve scalability in infrastructure. A crucial point for this is in-line testing for sterility; we have unified standards for common material, but it’s more difficult for autologous products. Although decentralised manufacturing would be ideal, it’s too much of a leap to achieve soon. Instead, we believe a more pragmatic approach would be to focus on how we can manufacture several products in one suite; helping the industry by providing risk reduction guidelines here is feasible.

Group Two: Comparability and Potency Assays

How can we standardise and achieve comparability? Do we need it?

Standardising cell lines can help us get there, but we’d end up with artificial lines and readouts, which would need balancing. Every cell is different; even counting for different cell types isn’t straightforward. Using monoclonal antibodies as a comparison, we can forecast a similar maturation process for this area.

Potency assays are crucial. As the industry matures, we’ll see standards narrow over time. Ultimately, we expect consolidation to 3-5 key assays, which moves us towards comparability. Our suggestion is for an international group to work on standardization towards this end.

Group One Discussion

“Robust traceability and sterility on incoming material mean a better outgoing product; if it’s good going in, it’s going to be better going out.”

Scalability: How do we scale up processes from just one manufacturing line? Trial numbers are an issue, with numbers small and scalability limited. Once the solid tumour space gains data, we’ll have issues making therapies fast enough in the autologous space.

Fully closed systems: Our discussion brought a conclusion that a fully closed system is key to success. This will help reduce and mitigate risk from multiple runs, patients and samples – or whatever a given process is defined around. It allows us to avoid changing air systems and means multiple patients can be treated closer together. Closing down all elements of manufacturing and ensuring traceability, however, will prove challenging.

In-line monitoring issues are key and would be very useful for achieving closed systems. Closing processes can lessen the need for in-line testing. Starting material is key, and tumour samples that need T-cell extraction and manipulation are a challenge.

Sterility: We’re limited in our use of tumour-infiltrating lymphocytes (TILs) and in manufacturing. We must be able to agree on what is acceptable to bring into an environment as we monitor sterility. Incoming material sterility is a challenge. We can close systems and manufacturing, but dirty products determine everything thereafter.

Robust traceability and sterility on incoming material mean a better outgoing product; if it’s good going in, it’s going to be better going out.

Sterility concerns for TILs remain high. We’re opening a person in a non-sterile situation. Can we improve the control systems we have in place?

Decentralised manufacturing & risk reduction: Moving production to the point of care has merit. The more we remove human involvement and minimise contact points, the better the product. Logistics issues happen regularly and can be a death sentence for patients.

With decentralised manufacturing a pipe dream for now, we believe multi-use facilities could provide practical and effective improvements. To achieve this, we need to aid the industry by providing a base template for risk reduction principles as an output for our group.

Group Two Discussion

“Maturation is ongoing even in established industries. Looking ahead 5-10 years, we expect continuous evolution.”

Potency assays: What can we do to address potency? Assays are specific, making achieving a universal assay unlikely. Comparability is difficult, and it’s more likely we’ll see several core assays emerge or be implemented.

This remains a sticking point and is realistically too difficult to pursue a universal standard in the foreseeable future. Cell engineering is increasingly complicated, even if a baseline is obtained from a vendor. Companies also tend to manipulate purchased cells, making comparability even harder. We expect the FDA to begin at a broad scale before narrowing restrictions down; we’ve seen this in other areas like blood.

Patient material & standardised cell lines: Do we want patient material as the target or a standardized cell line? Is the goal comparability among methods or capturing the true mechanism of action? These are diametrically opposed principles.

The further we go towards standardisation; the more artificial effects we may see in our assays. Genetic manipulation of cell lines is going to vary from company to company; trying to force a standard cell line isn’t feasible. We agree that standardising is important if we’re unable to capture the true mechanism of action.

At a high level, similarities exist. Providing a list of qualified instruments or measurement guidelines is a practical step the group can work towards.

Clinical trials and generic cell therapy: Are we going to see head-to-head clinical trials versus generic cell therapy? What are we comparing to? Do we expect new cell counting tech to be comparable to manual? Do we need comparability or can it be done case-by-case? The stage of the industry matters; we have little to compare things to right now. Pragmatically, we must ensure that any new counting method is compared to and improved from any previous method used; any less and we risk the health of patients.

Trials are here to tell us how well products work in Phase III. There’s a reason we don’t jump from an in-vitro assay to an approved product: we don’t know if a product will work the same way in a mouse as it does a patient. Models and targets vary and greater comparability in phase 1 could help.

Vectors: We all know of issues around packaging, encapsulation, to name but two. We’re challenged by multiple processes and a limited definition of standards.  An international group that can develop and share these would be ideal.

Maturation is ongoing even in established industries. Looking ahead 5–10 years, we expect continuous evolution; early approval will bring about standardisation faster and there will be a mix in this group of products.

This session was moderated by:

This session was hosted in partnership with Miltenyi Biotec on Tuesday 14th September.

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