By Anna Rose Welch, Editorial & Community Director, Advancing RNA
A few weeks ago, I published an article recapping my biggest takeaways from the PDA ATMP conference. Throughout the many technical discussions of the two-day event, I was predominantly struck by how often the conversation circled back to the importance of humility and self-improvement in our CMC. That we can even draw parallels between continued personal growth and iterative innovations in our product and platform development is one of my favorite things about CMC.
Since publishing that article, I’ve continued to read and hear more about the importance of “growing up” in CMC. Perhaps the best example of this was a blog post by Dark Horse Consulting’s CEO Anthony Davies, in which he shared some good news with us: As the CGT industry crosses the line of 21 FDA approvals, we are officially a “grown-up” field. In fact, if all FDA reviews on the docket go according to plan this year (9), we’re only one product approval shy of achieving Scott Gottlieb’s previously mind-blowing projections of 10 CGT approvals per year. But I also appreciated Davies’ strong reminder at the end of the article that a “grown-up field” demands “grown-up CMC” (i.e., process, analytics, and COGS).
As I wrote in a previous article, the ATMP space is currently in the midst of an intriguing identity crisis (of sorts) about what it truly means to “grow up.” On the one hand, we can argue growing up means clearly understanding how our products fit into the compliance frameworks we’ve long relied upon for more established modalities. But as it stands today, our advanced therapies — particularly on the autologous side of things — don’t always linearly fit into these frameworks. In turn, this raises some bigger question about who or what (i.e., our industry, regulators, the regulatory frameworks) will be responsible for changing — and to what degree.
We also can’t talk about change in the CGT space without touching on the world of process (including analytical) and manufacturing changes. Comparability has been one of this industry’s biggest, most fearsome monsters under the bed. (If you listen closely, you can hear it snarling under there with the tentacled potency assay monster.) Such anxiety — though warranted — demonstrates that changing our manufacturing process is as much a mental hurdle to overcome as it is a physical change to our process (but hopefully not to our product). And it’s hard not to see why. As one speaker at the PDA event explained, “As a BLA reviewer, I’ve seen many problems caused by the introduction of a new manufacturing process or method that provided marginal improvement, but which derailed the whole process. It’s a very hard choice to make, but it’s advisable that companies not make changes until you are ready to face the consequences.”
I’ll be the first to admit that such advice suggests any change requires more mental, emotional, and technical maturity than maybe even the most ambitious among us would (ever) like to embody.
But more and more regularly, our current dialogue around comparability suggests that we’re entering a new era — one in which we are being pushed to be more open to and accepting of change for our CMC to “grow up.” On the one hand, we now have a draft comparability guidance, which has been a long-awaited and important milestone for the space. We also just saw an accelerated FDA approval of a gene therapy product that underwent a major manufacturing change late enough in development to warrant a clinical comparability study. (Stay tuned for more on this juicy case study in a future article.)
But I daresay this is still just the beginning. If “grown-up” CMC with manageable COGS and broader patient access is the goal, we will inevitably be called to pursue manufacturing efficiencies in the forms of better (or simply new to us) raw materials, technologies, and partnerships. Unfortunately, these efficiencies and/or the resources to explore them thoroughly won’t always be there when we most need them — i.e., in the earlier stages of development.
We can all agree that changes are not to be made lightly, especially as we continue to identify the proper balance of risk and benefit in our quest for quality and efficacious products and manufacturing efficiency. But part of evolving as manufacturing experts and helping our CMC “grow up” is to acknowledge that our paths forward throughout any stage of development will inevitably include changes — be they minimal or plan-derailing — and to plan accordingly.
In fact, I appreciated hearing an FDA representative at the PDA conference offer a piece of advice that beautifully demonstrated the importance of this growth mindset. Though their advice specifically refers to analytical development, I think the sentiment carries over nicely into any functional area of development.
“Your initial methods aren’t going to be the same, whether you change them completely or you automate them,” one FDA speaker shared. “You may not know what those changes are going to be from the get-go, but it is beneficial to know that you’re going to make a change and build retains into your process.”
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