When looking for a new fill-finish solution for its gene therapy manufacturing operations, CDMO FUJIFILM Diosynth Biotechnologies turned to isolator technology offered by Vanrx Pharmasystems. We speak with Thomas Page, Vice President, Engineering and Asset Development, to learn why.
It’s been a major focus for us for several years; in fact, our College Station (Texas) site is a center of excellence for gene therapy. We have two facilities in Texas, with a total of around 200,000 square feet dedicated to advanced therapy manufacture, and we plan to deploy another $120 million into these products in the next few years. One of our goals was to create a vertically integrated CDMO for gene therapies, so we’ve had to ensure we have incredibly strong process development, and expertise in early and late phase manufacturing. The last piece of the puzzle has been to integrate the drug product offering as well because it’s really critical for some of these products to avoid additional freeze-thaw cycles.
A lot of senior people have had careers based on recombinant protein manufacturing and this can leave them with blind spots – because they have good solutions and want to apply that to other product types, but it’s not always appropriate. One of the challenges of operating in the advanced medicine field is that it’s incredibly diverse in the number of ways people want to manufacture these products, scale-up, and present the final drug product, so there are big differences in formulations, batch sizes, and operations like fill-finish. This means that for us as a CDMO, flexibility is crucial.
These therapies also require the very highest levels of quality. Some of them use live viruses and you need containment for contamination control, as well as for protecting the operator. Isolator technology is crucial for this. We use advanced mobile clean rooms, which you can think of as a piece of equipment – like an isolator that you can walk into. Product changeover is also crucial to consider. Early on, we opted for single-use, completely disposable fluid paths, and to make our rooms completely VHP-able.
We put together a venture team of senior people with various different areas of expertise, including quality, operations, commercial, engineering, and technical specialties. The team outlined what technologies and solutions we’d need to serve the market and decided that they would only consider isolator-based filling systems. We also wanted to be able to fill syringes, vials, and cartridges. The team opened discussions with a few different companies and then did a really deep failure mode and effects analysis (FMEA) dive to understand the ins and outs, the hazard pathways and the risk controls with different approaches within the industry. We scored each vendor and Vanrx scored twice as high as the next closest competitor, so the choice of who we should work with was very clear. We chose to use the company’s SA25 Aseptic Filling Workcell.
We have found that we are a good match in terms of how we like to work and our ultimate goal: to improve patient outcomes and patient access.
We have used the system for numerous fills for different live viral agents. We chose the system based on minimizing risk to the patient, as well as minimizing product loss. We have been working through several different iterations of components for a client to screen different approaches to filling – taking advantage of the fact that the unit does not have a hazard pathway that involves contact surfaces. All of the components are held by the nest; for example, there is no stopper bowl. This allows us to take earlier developmental material and fill it into an array of components, performing screening efficiently and giving the client the best primary container possible. The elimination of gloves has also been a bonus.
I think this type of technology is very beneficial for manufacturers and regulators alike. Simple designs that eliminate whole hazard pathways are easier to regulate, easier to understand – and reduce risks to the patient by many orders of magnitude.
Assess the blind spots that you might be carrying, if you are not experienced in this space. Step back and look at your risks from first principles and design your risk controls. Also, choose partners that align with your philosophy of quality and risk control.
What’s the story behind Vanrx?
Before starting up Vanrx, my co-founder and I were involved in developing biologics and creating manufacturing solutions. It was clear that manufacturing processes were becoming more complicated, and that batch sizes were getting smaller – new technologies were needed! We started Vanrx about 12 years ago to design automated fill-finish technologies that met the need for faster changeover and implementation rates, while greatly reducing all associated risks from a process and sterility standpoint. Essentially, our technology is about putting liquid into small containers. That sounds very simple, but if you can’t get it into that container perfectly, and with every variable you could possibly imagine, then you have nothing.
How do manufacturing processes vary for cell and gene therapies compared with traditional biologics?
There are many different methodologies, formulations, and processes, but, as Thomas explained, one of the biggest challenges is the diversity of approaches for gene therapies. Each product is different from the last. In terms of equipment, traditional biologics manufacturing makes medium to high volumes of products that are all the same. Changeover periods, involving sterilization, preparation, and cleaning, might happen once or twice a week for a given product. But for cell and gene therapies, you may have a different batch of products every hour, each for a different patient – the difference in total changeover time is dramatic.
To adapt, we have utilized the flexibility of our machines. They are much more software-based than traditional systems, with a lot more interoperability. But a lot of work goes into making the system so simple to use. We have more people working in controls and software than we do in the actual machine building.
What advantages does your technology have over other systems that are available?
The largest competition in this space is manual filling – a person in an isolator suit filling containers by hand. It’s well accepted, but it is slow and cumbersome, with much greater risk in terms of sterility. And frankly, it’s just not scalable. A regulator once told me that it breaks their heart to see brand-new therapies with so much science built into them being piped by hand into a vial!
How do you work with FUJIFILM Diosynth?
We work with FUJIFILM Diosynth as a partner. Working together continuously allows skills on both sides to be applied in new ways, and we have constant feedback to start working on long-term challenges. At the moment, we are completing a second system for the company that uses our new high-accuracy peristaltic pump technology – offering around six times better accuracy than traditional pumps, which is essential for the new process they are implementing.
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