From The Editor | July 17, 2024

A "Hot Take" On mRNA Critical Process Parameters

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

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As a young girl who dreamt of becoming an archaeologist akin to Tomb Raider’s Lara Croft, I could never have dreamt I’d one day have any semblance of a “take” — let alone a “hot take”— on Critical Process Parameters (CPPs). The term “hot take” may even seem a bit dramatic in the context of manufacturing, which shouldn’t be dramatic at all if it’s being done right.

But as my previous “hot take” articles following a recent BioPhorum RNA-focused ATMP member event have (hopefully) demonstrated, there remain many paths not yet traveled in the mRNA space, and even the ones we have more regularly traversed are not yet clearly mapped. Bushwacking up a trailless mountain — as many of us may feel we’re doing today with the development of our mRNA therapeutics — is bound to be accompanied by its fair share of drama.

I see this “drama” taking shape in a couple of different ways. On the one hand, the choices we make today about which processes do matter most for our different types of encoding RNA products are literally charting the course for what our platforms will become. These choices already have had and will continue to have a dramatic impact on the industry, regulators, and patients globally. But on the other hand, the diverse therapeutic goals we have for a singular drug substance (mRNA) can make alignment around such things as CPPs a difficult and potentially dramatic exercise.

These dynamics became increasingly apparent to me as I listened to a presentation unpacking the results of a BioPhorum benchmarking survey on CPPs for plasmid linearization, mRNA drug substance, and mRNA drug product production. For one, these insights revealed that we seem to be reasonably aligned around which process parameters are most critical to the quality of mRNA/LNP drug product and what aspects of our processes may negatively impact DP Critical Quality Attributes (CQAs). At the same time, these survey results also demonstrated that we are not nearly as aligned around which parameters most significantly inform our drug substance quality — a factor that is perhaps exacerbated by the variability in our therapeutic goals for our drug substances (e.g., gene editing, protein replacement, vaccination, etc.). Such therapeutic variability only adds to the complexity of understanding what is critical to measure and monitor for DS.  

Now, alignment or lack of alignment on DS/DP aside, these results reveal a very important but frustrating truth:

Hot Take #5: Until We Have More Clinical Data, Our Processes Will Remain Frustratingly Enigmatic

And please note, when I say more clinical data, I mean clinical data demonstrating how all our different encoding RNA modalities work in a variety of prophylactic and therapeutic indications. Until we have more of this data, alignment around CPPs — at least as an entire industry with many diverse therapeutic goals — will be no mean feat. After all, our product’s quality is a lot more than just assays and quality ranges for each CQA; it’s also supported by our products’ clinical performance.

As I listened to the conversations sparked by this benchmarking survey, I was reminded of a takeaway I had from an advanced therapies conference a few years ago. During a panel discussion, one speaker made a bold argument: The process is not the product. As I explained further in this previous article — and as I’m starting to hear reiterated in the mRNA space — relying on the principles of QbD as many of us are wont to do is not exactly easy in the broader ATMP/mRNA space today. After all, QbD was created with well-characterized biologics in mind.

We’ve made great strides in the mRNA/RNA analytical/quality space today — the recently released 3rd edition of the USP guidelines on analytical quality for mRNA vaccines being a great example. But for our next-gen products — be it a linear mRNA protein replacement product or a circular RNA-based gene editing product — we’re missing that critical clinical data giving us insight into how our products’ structures/CQAs truly impact their clinical functions. Though we’re not living in a data-less world, as we all know well, each product is unique, and our clinical experiences outside of the vaccine realm (and let’s be honest, even in the vaccine realm) are still quite “patchy.”

This “patchiness” — and the aura of mystery it lends to our products’ functions/processes overall — was nicely reflected in our discussions on DS CPPs during the BioPhorum event and it was also noted that there were a number of parameters identified that could be monitored (hence a very long list of potential Critical Process Parameters), which translated to a lot of diversity in DS processes overall.

When it came to DPs, on the other hand, I liked one attendee’s summary of why a majority of benchmark survey respondents were aligned in considering the parameters identified as critical: “As drug product people, maybe we just think everything is always critical.” (This was exceptionally true in mixing and dilution, FYI.)

On the surface, this greater alignment over DP CPPs may seem like a positive. After all, we ultimately want greater alignment as an industry and with regulators in the long term. But such consistency also arguably reflects our intense discomfort at the thought of underestimating any parameter.

I’ll always be the first to argue that it’s best not to underestimate how critical something might be, particularly during these early days in the industry. In fact, my goal for this entire series of “Hot Takes” was to urge us all to be more aware of where our knowledge and conversations remain limited in the mRNA space today. But it would seem, at least based on the results of this survey, that I’ve been preaching to the choir. The general inconsistency reflected in DS CPPs and our alignment in DP CPPs both ultimately support the same conclusion: We are greatly aligned around just how much we don’t know today.      

Missed the previous “hot takes”? Catch up here!

Please stay tuned as well for a future BioPhorum paper on the range of CPPs for mRNA-LNP DS/DP!