The RNA Therapeutics Supply Chain: A Platform of Relationships
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
It sounds like the start of a bad joke: An editor and a supply chain expert walk up to a tower of whoopie pies at an mRNA conference.
But in the real world, this is how I happened to meet Greg Troiano, head of cGMP strategic supply and operations for Sanofi’s mRNA Center of Excellence. In fact, I owe him endless thanks for not allowing my interruption of his dessert “sourcing” to dissuade him from sitting down with me to share his experiences navigating the burgeoning mRNA supply chain.
There were a few reasons I was particularly excited to pick Troiano’s brain. Over the past few years, I’ve heard members of the RNA space attest to the increasing availability and quality of mRNA raw materials, suppliers, and CDMOs post-pandemic. In fact, though there has been an increase in biotech demand, the supply of RNA-specific raw materials has finally caught up and, in some cases, has surpassed the post-COVID explosion of demand. However, conversations digging into RNA-specific sourcing considerations have been few and far between. In turn, I’ve been increasingly curious about where we’re seeing the greatest growth in material availability and supplier capability, particularly as we forge through this age of intense process development for both linear and next-generation RNA constructs. I was also excited to learn where opportunities remain for innovator companies and suppliers to better collaborate and improve the overall quality of the products we’re striving to bring to the clinic and market.
Enter Troiano. Together, we delved into the nuances, challenges, and opportunities for growth that currently exist within the mRNA drug substance and drug product (i.e., mRNA-LNP) raw material sourcing worlds. Though our daily work is to identify the relationship(s) between our raw materials, our products, and our processes, I loved Troiano’s beautiful reminder of how critical the supplier relationship is to the work we do as individual companies, as well.
“We often celebrate the fact that the mRNA development process is quicker than that of cell-based products,” Troiano explained. “But in reality, building an mRNA/RNA platform takes a lot of time, and that process is built around relationships. Your platform is not just your molecule; it’s literally a platform of relationships.”
mRNA Isn’t Easy — And Neither Is Navigating Its (Still Growing) Supply Chain
Though this article will be focused specifically on material sourcing challenges and opportunities, I’ll admit it’s difficult to draw a neat box around the term “supply chain.” As Troiano nicely spelled out, supply chain is a sweeping term that not only encompasses starting and raw materials and excipients, but which also incorporates the distribution and analytical testing of drug substance samples throughout development; the formulation of the drug substance into the drug product; device design; fill-finish and packaging; and the product’s journey to the patient.
We also can’t forget that our suppliers also have their own suppliers — a fact that is incredibly important to acknowledge in the RNA space given the complexity of some of our products. For example, as I recently shared in an article, one in vivo gene editing RNA product can equate to four module threes in a single BLA filing, thanks to the sheer number of drug substances with which we may be working — a complexity which Troiano confirmed and expounded upon.
“What’s unique about mRNA is that your starting materials [i.e., plasmids & nucleotides], raw materials [i.e., enzymes], and excipients [e.g., custom lipids for an LNP] can have the complexity of, or in some cases even be classified as, drug substances themselves,” Troiano explained. “Not to mention each of these starting and raw materials comprise other raw materials, some of which may even be custom-made. So, the RNA supply chain is an intricate network, to say the least.”
The fact that the (coding) RNA space is far from homogenous in terms of modality and therapeutic intent is another variable making our supply chain-centric conversations far from linear. For example, though many in the industry, including Troiano, are heartened by the growth we’ve observed in the RNA and LNP supply chain post-pandemic, many of these improvements are predominantly benefiting companies working on first-generation — or linear — mRNA vaccine products. However, many of us are hard at work on next-generation RNA products. Our next-gen RNA pipelines not only comprise self-amplifying and circular RNA, but also novel LNPs and other delivery vehicles to overcome our LNP products’ innate attraction to the liver. Such innovations will no doubt necessitate that companies continue to balance sourcing a mix of off-the-shelf, custom, and next-gen materials (e.g., alternative capping reagents) in the near term.
Fortunately, Troiano doesn’t expect our ongoing innovation will get the best of us or our suppliers in the long term. We’re not necessarily starting from a blank page.
“Though we can’t magically make any version of these next-gen RNA products and have billions of doses today, suppliers will be able to leverage much of what’s been done so far,” Troiano explained. “A lot of the next-generation enzymes and reagents are still small scale, but once we have more clinical data, it won’t take long to see more rapid growth.”
But availability and scale are not the only forms of growth for which we need to advocate in the supply chain. As existing and new suppliers across the globe start to cater to the mRNA/RNA therapeutics market, it’s only natural our supply chain network might become akin to a complicated game of Cat’s Cradle. (Strings everywhere!) And, in most cases, it is a sponsor’s responsibility to unify all these strands into an easily managed network.
Troiano does envision a future in which some of these material management burdens may be eased, thanks to the fact that many of our products may share certain raw materials. In such cases, sponsors will be about to order and stockpile larger quantities of, for example, certain enzymes and lipids, upfront. In fact, given the likelihood we’ll one day be able to develop and commercialize multiple products under the same “platform”, as well as implement continuous manufacturing for certain RNA products, Troiano anticipates sourcing larger quantities of materials upfront will become standard practice. Barring any raw material bottlenecks, the mRNA platform is ideal to permit continuous progression from sequence design, plasmid development, mRNA transcription, and even fill finish in the long-term. Please note, however: as large-scale production of LNP products typically requires explosion-proof facilities with ethanol handling capabilities, it’s still rare to find fill-finish facilities offering these capabilities today.
Ultimately, we cannot overstate the importance of co-location/centralization of the supply-chain for RNA products. Not only will this pave the way to continuous manufacturing in the long term, but, even more importantly, it will improve the overall efficiency of our drug product manufacturing in the near term. After all, “Each time you ship your drug substance or product to another site, you need analytical testing to demonstrate the quality has not changed and that there have been no mix-ups,” Troiano said. “These quality reviews add to the overall timeline of your development.”
Material Availability & Supplier Capability: Separate, But Equally Important “-ilities”
A few months ago, I penned a series of articles on outsourcing best practices for viral vector-based cell and gene therapies — the first article of which revealed an industry that no longer had “capacity” at the top of its CDMO wish-list. Rather, the progression into mid-later stage clinical trials necessitates partners that know their way around analytical testing, comparability exercises, and commercial manufacturing expertise.
It was refreshing to hear that this capacity vs. capability discussion is already being had in the still young RNA space. Of course, as we are still predominantly a pre-clinical/Phase 1 industry, capacity will still be top of mind. For example, as Troiano pointed out, we’ve already seen several firms venture into the lipid manufacturing space to make better use of small molecule API capacity in this age of biologics. We are also seeing the same expansion happening to bolster plasmid and enzyme production.
But it’s important we acknowledge that expansion of the supplier world for RNA players does not automatically equate to capability. At the end of the day, capability and quality of offerings is what will bring our products to market — not just capacity and material availability.
As Troiano went on to explain, though the lipids composing our LNPs are small molecules, they still require unique handling and often chromatography needs. The same can be said for plasmids for RNA production. Though plasmids play a leading role in development programs across the ATMP space, circular plasmids must be linearized to produce mRNA — a step which requires a restriction enzyme and a specific purification process. Seeing as plasmid is the critical starting material for our mRNA, I need not underline how important it is to get our plasmids right from the beginning. But a partners’ capability becomes even more important as we explore personalized RNA vaccines and cell therapies, both of which demand quick turnaround time and leave no room for manufacturing failure.
Perhaps one of the most exciting — but equally challenging — aspects of our industry is that the performance of our product relies on so much more than just our RNA drug substance. “mRNA is a complex formulation; our product, processes, and formulation all define the performance and mechanism of action,” Troiano explained. “You can sequence a plasmid for the same antigen so many different ways and get the same amino acid sequence but different performance in terms of mRNA translatability, stability, and durability.”
“Good [Definition] Practice:” Defining “Phase Appropriate” For RNA Products
Our ongoing efforts to understand the role our raw materials play in our molecules’ quality and clinical performance ultimately require innovators to “up their supply game” in several ways.
Given the novelty of the RNA market and the diversity of experience and capability across the supplier market, RNA supply chain executives may find it necessary to advocate for a larger and more specialized supply chain team than is customary for legacy biologic products to carry out the necessary vendor and material risk assessments.
“In developing a traditional biologic, you might treat a process aid or a raw material that is not in your final formulation as low risk and do a paper qualification as opposed to a formal audit,” Troiano explained. Given the novelty of the RNA and LNP spaces, he emphasized performing thorough (and ideally in-person) vendor qualifications, especially as more suppliers and material alternatives — often embodying varying ranges of quality — enter the market.
Though he admitted his list of “must-ask” questions for prospective vendors spanned 10-plus pages, he urged fellow RNA companies to, first and foremost, scrutinize a prospective partner’s knowledge of the product/material that they produce. While there’s been an increase in GMP materials, it also bears repeating that we should not take a material’s “GMP” status at face value. It’s been reiterated at many conferences and by the FDA that GMP is not a grade, nor is it a guarantee of a raw material’s quality so much as it is a symbol of good documentation practices (and basic marketing). As Troiano reaffirmed, GMP is no guarantee that the vendor understands what they are producing or that the production process for that material produces a consistent supply.
“A supplier may have had the facility controls in place, but do they have the product understanding and knowledge?” he asked. “A material can be made in accordance with GMP, but that material might not be fit for purpose. Have you as the sponsor done critical material attribute studies to determine that you’re specifying your raw materials properly? Do you know what it means for your product if a specific material is above or below a specific quality threshold?”
Though a quality by design approach places just as much emphasis on critical material attributes as it does critical process parameters, we rarely have adequate resources to do material characterization as thoroughly as we’d like — especially given the intensity with which we must analytically scrutinize our process development efforts today. In turn, the ATMP industry has been exploring (or rather, grappling) with the concept of phase-appropriate development — a term which will mean something completely different to everyone you ask. (Hence our “grappling.”)
Seeing as the supply chain for RNA therapeutics was quite limited when our first wave of products entered the clinic, our industry has grown to the point we can start refining our definition of what “good enough to enter the clinic” means by 2024 standards.
To be clear, there will still be many unknowns at the time we enter the clinic. As Troiano reassured, “thoughtful risk-taking” at this stage is preferable to accruing an exhaustive (and expensive!) base of knowledge around every possible variable — especially given the high risks of clinical failure.
“Everyone would love to have more information, but there is a business risk of taking too much time before you get into the clinic,” he explained. In turn, he encourages development and quality teams to arrive at and clearly document internal standards around what phase-appropriate means in terms of Phase 1 and Phase 3 expectations.
“I’m not a big fan of the phrase ‘It’s a race to the market” because the applications for mRNA are so broad,” Troiano explained. “This is not a zero-sum game; there will be room for everyone. But seeing as mRNA is a big modality in the infectious disease space — in which many indications change seasonally — there will be limited and more competitive markets for specific products. So, you must get comfortable with entering the clinic and developing knowledge in parallel.”