"Mirror, Mirror…": Reflections On Reducing mRNA Production COGS

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

If there’s one thing I’ve learned about myself so far this year, it’s that I can fit a Disney reference into almost any conversation about mRNA — whether it be about selecting an outsourcing partner or managing our COGS.

To quote Snow White: “Mirror, mirror, on the wall, what is the most cost-effective mRNA production process of them all?”

Here at Advancing RNA, there is no Evil Queen behind the scenes (*ahem*…), and I certainly don’t (claim to) have a real magic mirror hanging in my office. But I’d like to believe that the editorial we publish here “reflecting” the current state of the industry and the thoughts of our peers certainly functions as a magic mirror from time to time. In fact, we could even go so far as to say that streaming any Advancing RNA Live panel discussion — in which we only see the faces/torsos of the speakers shining out from our bright computer screens — could be akin to looking into a wisdom-espousing mirror. (Just go with it, please…) 

We covered a lot of ground in my latest panel discussion on mRNA analytical and manufacturing technology innovations, and I encourage you to check out the full video or the shorter snippets catalogued on Advancing RNA. However, we certainly can’t talk about technological innovations in the RNA field without also weighing these innovations’ impacts on COGS.

Here, I outline three overarching words of wisdom I gleaned from Life Edit Therapeutics’ April Sena; Tune Therapeutics’ Tyler Goodwin; and University of Sheffield’s Adi Nair on how the mRNA/RNA industry can better control production costs — particularly as it relates to raw material sourcing and usage.  

1. “Spare no expense” on your upstream process.

“Spare no expense” may seem like strange advice in an article about controlling/lowering overall COGS. But you likely already know where this is going, especially since this often-shared best practice is hardly unique to the mRNA sector. Fortunately for us, this panel homed in on what this phrase can mean today for RNA makers specifically.

Though IVT is arguably much simpler and more efficient than cell culture, our current lack of real-time monitoring makes it more difficult to fully understand — and better manage — the kinetics of our IVT reactions. As both Adi Nair and Tyler Goodwin explained during the panel, many of us are currently striving to understand the kinetics of our IVT reactions — in particular, our sequenced product-to-substrate ratios — by analyzing samples taken at different time points throughout the IVT process. Though this may be “as good as we can get right now,” Goodwin admitted, this approach doesn’t always give us conclusive answers around which materials we may need to add — and when — to ensure a successful reaction. As both speakers emphasized, the more we understand the kinetics of our IVT reactions, the better equipped we are to control our reactions and reduce process-related impurities.  

Likewise, as Nair went on to explain, there remains a lot of opportunity to reduce costly material waste during our processes.

“For a normal IVT reaction, proprietary capping reagents are required in a high concentration, but that reagent is not completely utilized,” Nair explained. “The capping reagent is the most expensive material, but at the same time, so much of it goes to waste after the process is completed. Can we somehow reuse this capping reagent? That’s an approach we’re taking here at University of Sheffield to figure out how we can recycle unincorporated capping reagent for subsequent reactions.”

Sena and Goodwin also acknowledged that improvements on the raw material side can reduce the amount of capping reagent needed, as well as reduce dsRNA formation — Aldevron’s Codex HiCap polymerase being a good example.

“Utilization of novel enzymes may come with higher costs,” Goodwin offered, “But if these enzymes can drive efficiencies upstream and reduce impurities, this can have a much more profound effect on the downstream process and allow for the downstream to be much more efficient and improve yields. Investing in novel enzymes has enabled us to limit the number of different chromatography steps necessary to get a clean product.”  

(BTW, speaking of RNA drug substance purification, be sure to check out Nair and his colleague Zoltan Kis’ work here on continuous RNA purification — an approach which offers improved resin utilization, among many other improvements.)

2. We need both competition & consolidation to bring down COGS

These two terms may seem at odds with one another. But when it comes to the supply chain, we do actually need both to achieve more cost-effective development.

At the start of a new industry, it’s not unusual to be limited in terms of how many partners and/or raw material suppliers with which we can work. In the earlier pandemic days of mRNA development, for example, it wasn’t unusual to hear the industry bemoan the lack of competitors for capping reagents. However, as our industry has continued to grow, Sena has noted — and continues to celebrate — the increasing number of raw material options hitting the market.   

“CleanCap is great, but there’s more beyond CleanCap now; everybody is making cap analogues,” Sena said. “It’s great to see that healthy competition.”

It’s not just important to have multiple options available, it’s also important that we streamline access to materials. We are starting to see instances in which CDMOs and suppliers are teaming up to offer clients direct access to raw materials — with the recent Aldevron-TriLink supply agreement for CleanCap being a great example. However, as Sena argued, our field needs more supply agreement collaborations like this.  

“It would be great to be able to go to a CDMO and get everything you need for the mRNA production from that CDMO,” Sena added. “The current piecemeal approach is not cost-effective, and it’s a headache. So, making sure the necessary materials can be sourced by the mRNA manufacturer is key.”  

3. A larger industry & targeting more populous indications isn’t just great for patients…

There’s also that fun little phrase we use in this industry called “economies of scale.”

We have Goodwin to thank for this closing quote in which he nicely articulates why literally everyone wins by bringing mRNA therapeutics into the clinic and onto the market for larger indications.

“We can’t forget about economies of scale,” he concluded. “There’s a lot of interest from raw material suppliers to make raw materials cheaper. So, I think as we start to need more materials — particularly to support larger scale batches — prices will hopefully go down, as well.”