Overcoming manufacturing and financial challenges of personalized cell therapies

Person-specific cell therapy could potentially offer a cure as opposed to ongoing treatment, but it is also a disruptive technology that doesn't currently fit into traditional therapeutic manufacturing processes.

There's already a lot happening on a small scale; a huge amount of research on every possible therapeutic angle is being conducted across the globe, but as yet there are few routine therapies. The big question is where do we go next?

There's not much happening on the process development side and there isn't a lot of manufacturing capacity. This is a particular issue for personalised therapies because one batch is one process for one patient, which means that the research scale is the same as the production scale; however, manufacturing processes are not the same as research processes. Although the equipment still looks like research equipment, the regulatory environment applies to full scale manufacturing. There is also the issue of clinical trials; trials as we know them are expensive. It's difficult to get funding for them and there is also the question of whether the traditional trial structure is suitable for personalised cell therapies.

There are also additional hurdles:

• approvals are complex

• large scale manufacturing doesn't exist

• there's nothing in place for purchasing these therapies into national health services

• cell therapies are "living" and don't have a long shelf life

• the therapy also includes both donation and delivery.

Personalised medicines do not fit into the supply chain currently in place so at the moment there's a lot of research with nowhere to go. However, if personalised treatments were to come to fruition then what we would see is a decrease in caring for patients with long-term chronic conditions and an increase in smaller, local diagnostic and treatment centres.

Manufacturing solutions

At the moment, manufacturing equipment technology for cell therapies is very expensive: the disposables are very expensive, the reagents are very expensive and the equipment is expensive, but this partly reflects the clever technology that has gone into their development.

For example, when developing T-cell therapies, the initial purification can be done completely manually using a centrifuge to separate the white blood cells from everything else; however, another option is to use a Cobe 2991 cell processor (Gambro, Sweden), which can handle larger volumes. Unfortunately, this system is expensive and, as with many other equipment involved in this space, requires a lot of aseptic operations to put it together. It is also not a closed system.

Moving into the cell selection stage of T-cell development, one of the most widely used systems is the CliniMACS (Miltenyi, Germany) system, which relies on magnetic separations. Although this is a closed system when it's running, putting it together at the beginning requires an aseptic environment. A newer system, which is generating a lot of interest, is the BD Influx (BD Biosciences; CA, USA), which is the first system based on fluorescence-activated cell sorting.

For cell expansion, there is everything from 24-well plates through to WAVE bags and cell expansion bags with multiple areas that can be expanded into. Recently, there has been quite a lot of interest in the WAVE system, which is widely used in biopharmaceutical processes to culture cells.

The ideal facility

The standard facility for cell therapy manufacturing is currently a grade A/B environment where only one therapy can be worked on per room. The next generation of facilities, however, would include grade D rooms with isolators for aseptic manipulation. This would enable a much higher throughput. Ultimately, it would be beneficial to use facilities that are fully automated where thousands of therapies can be run simultaneously. eXmoor pharma is currently working on these next generation facilities and processes with a number of clients.

In summary, cell therapy manufacture currently involves manual processes, a lot of aseptic connections, grade A/B rooms, a small number of vendors selling highly specialised equipment, and high costs for reagents and consumables. Much of the work is also currently being conducted by researchers.

Ideally, we would like to get to closed robust systems, grade D rooms that can accommodate many therapies, a large number of vendors with validated manufacturing equipment, readily available GMP reagents and GMP operators.

Achieving this is a bioprocessing challenge, but it is not impossible.

Financial viability

How can industry make a return on cell therapy investments? One aspect is to look at where the costs are and how we can reduce them.

For a small A/B type facility conducting first-in-man studies with only a few staff, the facility and staff cost per therapy is a significant amount because of the low utilisation rates. If you take the same processes, but increase the throughput, use more staff and run the equipment 24/7, you immediately reduce the facility and staff cost per therapy. The costs associated with reagents and raw materials, however, will remain, and further cost savings need to be achieved (Figure 1).

Figure 1: This chart shows how manufacturing costs can be driven down as processes move from low utilisation (research scale) through manual to automated and how the raw material proportion becomes ever more significant. Although each process is confidential, this chart is illustrative and compiled from a number of different facilities.

Another important consideration is protecting intellectual property and ensuring that someone in the chain gets the recovery. At the moment, we're seeing the development of a lot of clever technology owned by various suppliers, but no means of protecting the IP in the therapy itself.

What could be beneficial is collaboration between equipment providers, cell therapy manufacturers and specialised healthcare providers, which would ensure investment recovery along the complete supply chain and facilitate delivery to the patients. For example, the UK's National Health Service (NHS) system currently spends £100 billion per year, but the agency has been told to cut £15 billion between 2011 and 2014. If it was to invest in helping cell therapy manufacturers get started, however, it could ultimately reduce costs and result in smaller, more local facilities and better treatments.

Traditionally, pharma has found cash cows to fund the development of their next product, but this resource isn't really available for experimental cell therapies. We have to think differently if this industry is to be successful — it's no good relying on the same old supply chain and hoping it can be tweaked a bit to make it work.

Dr Angela Osborne eXmoor pharma concepts Ltd