Are We Actually Living In An mRNA Regulatory "Desert?"
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
Over the past few weeks, I’ve spent what seems like an inordinate amount of time focusing on regulatory matters spurring discussion in the mRNA space today. And this article will be no exception.
I recently attended a panel discussion during an RNA-LNP virtual summit hosted by Cytiva. In my previous article, I shared several insights from a regulatory-centric panel about how our shift to smaller scales/smaller patient populations may impact our infrastructure and manufacturing capability needs in the long-term. However, we can’t talk about manufacturing advancements — both infrastructure-wise or technological — without at least acknowledging that such innovations go hand in hand with regulatory guidance, oversight, and/or approval.
As we already know, the mRNA field — thanks to its nascence — is in desperate need of modality-specific (and LNP-specific) guidance. Likewise, as the panel went on to discuss, the existence of the FDA’s Advanced Manufacturing Technologies designation and CBER’s Advanced Technologies Team (CATT), are both great indicators of the agency’s interest in partnering with the industry to arrive at compliant implementation strategies for advanced manufacturing and testing technologies across all modalities. However, when it comes to defining, let along achieving, maturity in these regulatory arenas, poet Robert Frost said it best: We have “miles to go before we sleep.”
Fortunately for us, the panel shared a few important reminders for us all as we continue to navigate mRNA in a variety of different therapeutic applications and, perhaps, as we explore the implementation of advanced manufacturing technologies in our mRNA-LNP manufacturing processes. In the second of this three-part article series, I walk through one big takeaway I had from this panel’s conversation about the current state of mRNA regulatory affairs. Part 3 provides a closer look at some of the considerations and challenges we’ll likely face as we strive to achieve three long-term development and manufacturing milestones in the RNA therapeutics space. Stay tuned!
We Are Not Lost In A Regulatory “Desert” — Even Though It Feels Like It
We may not have any mRNA-specific regulatory guidances (yet), but as the panelists reminded us, we’re not necessarily wandering through a barren desert starving for information. There have been a handful of documents that have become our “bread and butter” today. For one, our “legacy” guidance came in the form of the WHO Technical Report, “Evaluation of the quality, safety, and efficacy of mRNA vaccines for the prevention of infectious diseases.” (The scope also includes saRNA.) We’ve also seen an often-cited guideline from US Pharmacopeia (now in its 3rd edition) singling out mRNA-LNP CQAs and the methods with which we can better understand them. Across the pond, the European Pharmacopeia has been equally busy, releasing three general mRNA-focused texts (currently drafts) — one on plasmid preparation for mRNA drug substance and two centered around mRNA vaccines. (For a more extensive albeit not up-to-date list of relevant regulatory guidance, please refer to this previous Advancing RNA article from 2022.)
Each of these texts/guidelines serves an important purpose: To place the industry on a path toward shared foundational development principles. As difficult as it is to be working without more targeted mRNA-centric regulatory guidance today, it bears a reminder that good (a.k.a. well-reasoned and appropriate) regulatory guidance for mRNA products can only come with greater regulatory exposure to a diverse array of mRNA/RNA modalities in multiple therapeutic contexts (i.e., not just prophylactic vaccines). In other words, there is an important purpose behind our waiting game for guidance.
Like every panel in the ATMP and mRNA space, the speakers emphasized the importance of early and frequent communication with the agencies to garner modality- and product-specific answers to our questions. These conversations are exceptionally important seeing as the aforementioned pharmacopeial guidelines are not gospel and remain what I like to call “living” documents.
Though we may be without mRNA-specific resources today, I appreciated one speaker’s salient reminder that the resources we do have today — those that are more broadly ATMP-centric and compliance-related — are equally important and directional for our mRNA-LNP products. As we already know, mRNA-LNPs are sterile products, and as one of the speakers pointed out, sterility is a globally understood and regulatorily harmonized concept. Existing ICH guidance — including ICH Q13 on continuous manufacturing and ICH Q1A(R2) on stability testing — as well as ongoing revisions from the Pharmacopeias — for example, forthcoming revisions to USP <665> on extractables & leachables for single use systems — are only a handful of the guidances the panelists called out as being important resources for us moving forward.
“Our guidances and guidelines really do represent a certain level of maturity,” one speaker added. “So don’t undervalue the intelligence from those concept papers, listening groups, and the strategic focus areas coming out of the regulatory agencies. All of these resources give us early visibility into what might be forthcoming guidance in the near future.”
However, the regulatory agencies won’t be — and frankly shouldn’t be — our only outlet for discussion, education, and conversation on regulatory CMC and compliance matters. Organizations, like PDA and (to some extent) BioPhorum, play a critical role in interpreting guidances, penning industry resources/guidelines/position papers, and/or hosting joint meetings with regulatory agencies and the industry. In particular, BioPhorum hosted an RNA-centric ATMP workshop earlier this year that I had the great pleasure of attending and from which I shared several “Hot Takes” on scale-up, nonviral delivery, critical process parameters, and personalized medicine production. This event was hosted literally a week after USP held its two-day virtual forum on the state of analytical methodologies in mRNA development.
“As we continue to grow this industry in emerging and developing markets, it’s going to be really important that we all just continue to share as much information as we can,” one speaker concluded.
Continue on to part 3 here: A "Flight Plan" for Achieving These 3 mRNA Development Milestones