Decentralized manufacturing of advanced therapies seems to be an emerging trend. GEN spoke to Nick Medcalf, deputy challenge director, medicines manufacturing at Innovate UK, about the benefits and challenges facing the industry.

What are the main challenges to decentralized manufacturing within the industry?

Medcalf: Because you’re moving away from the economics of scale to closer to the clinic, the batches are smaller and some of the traditional paradigms for quality assurance, such as proof of sterility, are harder to arrange. Thus, you need to have a manufacturing system that includes quality assurance within the system itself.

Automation is often presented as a way to remove the single largest source of infective risk, i.e. the human operator. For example, the self-sterilizing reusable units being developed at the University of Osaka under Professor Masahiro Kino-oka allow small-scale production with a high degree of confidence in the aseptic management of the environment.

Another challenge is defining a product that has variable characteristics. The main reason for decentralizing is to allow customization to a patient, which means you need to have a hierarchy of levels of specification. For example, with bioprinting, which also produces a customized product, you need to define bulk properties, but you also need to set constraints around how it’s anchored or implanted into the patient.

What trends are you seeing around decentralized manufacturing?

Medcalf: With decentralized manufacturing for [advanced therapies], it’s all about higher value and smaller batches, so the key to success is often to coordinate production with clinical practice. That requires getting the geography right, which means a supply chain with a chain of custody to go with it.

Nick Medcalf [Innovate UK]
Coordinating with clinical administration blurs the boundaries between producer and customer. Instead of a transactional arrangement, all parties must take custody of the product, which explains why Innovate UK has been investing in the Advanced Therapy Treatment Center Network since 2018.

There’s also been a definite trend for about 20 years of moving from big pharmaceutical or medical technology companies integrating their own pipeline towards open innovation models, driven by an academic base or small startups. Given that the sector wants to reduce development times, we can create manufacturing platforms similar in size to benchtop apparatus, which can be scaled out rather than scaled up.

This has become especially desirable since the global financial downturn in 2008. Investors, generally, don’t now want to install large-scale new equipment. If the product doesn’t work, and there’s been a lot of scale up, they’re not going to recover that investment in equipment. Whereas, if you’re scaling out, you can scale your equipment with production volumes and market growth.

Of course, if you scale out, there’s now a technical question about ensuring reproducibility site-to-site and between operator crews. To solve that, I think there’s a middle ground between human operators and full automation. You can deploy intermediate technology tools, such as a pedal-operated dispenser, for example, to normalize processes that usually depend on operator skill. Encouraging the development of this technology is why I set up a competition on mechanizing and improving advanced therapy production, a few years ago.