The Real Cost of Flexibility: Q&A With Sebastian Arana

In a conversation with Pharmaceutical Executive, Sebastian Arana, head of process solutions, MilliporeSigma discussed the operational tradeoffs facilities face as they move toward multi-modality production and the persistent cost and scale-up challenges shaping cell and gene therapy, mRNA, and ADC manufacturing.

Arana explained that the real cost of flexibility isn't equipment, it's integrating different manufacturing philosophies and processes into one operating model, noting that platform approaches and campus-style facilities with shared utilities are helping sites hedge against shifting volumes across modalities. Turning to cell and gene therapy, he compared the field's current state to where monoclonal antibodies stood 20 to 30 years ago, pointing to simpler processes, better yields, shorter production times, and reduced product loss as the levers that will eventually bring costs down, with the biggest opportunity lying in shifting from manual, case-by-case processes to scalable, reproducible manufacturing.

On mRNA, Arana reflected on the boom-and-bust cycle following Covid, saying the key lesson wasn't to build less capacity but to avoid building single-use infrastructure, pushing companies toward designs that offer optionality across assets, modalities, and locations, often through retrofitting existing facilities rather than building greenfield sites. Finally, addressing antibody-drug conjugates, Arana identified containment and segregation as an underestimated structural bottleneck stemming from the intersection of biology and chemistry, positioning purpose-built, single-use equipment as a key solution MilliporeSigma is investing in to support customers scaling ADC production.

A transcript of Arana's conversation with Pharmaceutical Executive can be found below.

Pharmaceutical Executive: What does a facility actually have to sacrifice in terms of optimization when it commits to multi-modality production, and is the flexibility worth the tradeoff?
Sebastian Arana: A new modality often requires a completely new way of working on the site. So, the equipment can be ready before the workforce even is. A new modality per-say is something completely different case by case, right? So, for most of organizations, the near-term opportunity to work on this is to have a platform approach. A platform flexibility with different type of biologics. We're talking about mAbs and different biologics subclasses, so even though, not full interoperability is doable, that will help the site to be ready.

A few other things we have seen, a campus style type model, such as modular trains can be can be utilized with a common share of utilities and or other assets that can be shared within the site. It's something companies are increasingly doing to offer that multi-modality approach.

The real trade-off is not really on the equipment side, it’s more so a tradeoff for companies to be able to integrate all the different manufacturing approaches, philosophies, and processes in one flexible operating model that this requires. Yes, flexibility is usually worth it and multi-modality is a hedge our customers have access to that supports how volumes can evolve within different molecules and within different assets in the market.

PE: The cost-per-dose problem in cell and gene therapy remains one of the most stubborn barriers to commercial viability. From a process solutions standpoint, where is the most meaningful cost reduction still available?
Arana: We strongly believe cell and gene therapy today is roughly where mAbs was, call it 20, 25, even 30 years ago, right? I'm not saying this in a negative way or criticizing cell and gene, it’s just a reminder that it takes a lot of time and process optimization to really get to the right unit cost.

I think the cost comes out of fundamentally four places. Number one, simpler processes. Number two, better yields, so that means all the technology advancements that needs to happen over time. Number three, shorter production time, which comes with better production approaches as customers and companies learn how to run their assets better. Finally, number four, less product loss. A combination of these four is what will help the industry over time achieve a lower cost and bring this technology to patients.

But still, I would say the single largest opportunity is moving from highly manual, highly customized processes that we see today in cell and gene to manufacturing that is scalable and reproducible. Again, we are like mAbs was 30 years ago with everything. It's very manual, very case-by-case, and it's not scalable enough, so that's part of the improvement that should happen in the next coming years.

PE: mRNA manufacturing scaled explosively during Covid and then the industry had to figure out what to do with all that capacity. How has that boom-and-bust cycle shaped how your customers are now designing flexible infrastructure?
Arana: We saw a big a big boom during Covid years for obvious reasons. So I think the fundamental lesson learned here from that cycle is not to build less, it was don't build anything you can only use one time. We now are seeing customers and companies designing for optionality now and making sure they have flexibility in case volume comes in a different asset, a different modality, or in a different location. That mindset is completely new and definitely an outcome out of Covid.

For example, retrofitting an existing facility is often faster and more economically viable than building something completely greenfield. So, we see a lot of companies just retrofitting or adjusting their site to one, be faster with the new modality they need to manufacture and secondly achieve their goals. Speed used to mean compressing timelines and to produce a molecule, you need to go faster and Gantt charts get stressed and get tighter. It also means reducing the number of process reinventions or process improvement that typically a molecule will see in the life cycle. So that's also what we're seeing as well, right? It's one-in-a-life type of type of environment that I'm sure after the next pandemic, we'll see other lessons learned.

PE: ADCs are having a commercial moment, but the manufacturing complexity hasn't gotten easier. Where are the process bottlenecks that are actually limiting how fast the ADC pipeline can move from clinical to commercial scale?
Arana: ADCs are booming and we will continue to see them do so. ADCs sit in the intersection between biology and chemistry and part of the challenge is that most facilities are built for one or the other, so that results in what is called a structural bottleneck. We see containment and segregation are the biggest constraint that typically people or our customers underestimates, so in other words, supply chain is now a scale-up constraint, not a downstream concern anymore.

I would say to be purpose-built and to use single-use equipment is one of the cleaner more straight answers to address this. That's why we, at MilliporeSigma, are heavily invested in building and helping our customers with our single-use platform to help them as they scale up their ADCs platform and capabilities.