ARW's C&G+RNA Manufacturing Must-Reads (Pinocchio Edition!)

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

Day-in and day-out, I write, read, listen to, and watch as much content as I can about CGT and RNA therapy manufacturing, in particular, and/or other ATMP industry-related topics that you should at least be aware of in the manufacturing facility. Every two weeks, I compile the articles and industry updates I think are most worthy of your time into an unconventional newsletter format (below) and send them out via email.

On this day in 1940, Disney launched its film, Pinocchio. In honor of “Pinocchio Day,” which is celebrated on February 23, this edition of your manufacturing must-reads is organized according to several “truths” or “lies” about ATMP development. While uttering some of these statements out loud could make your nose grow longer, please note, all the articles shared here are as true/accurate as they come.

[FDA TOWN HALL TAKEAWAYS]
“Goldilocks & The Three Bears” is actually a story about the CGT space.

• Well... no. But after listening to the FDA’s Cell & Gene Town Halls, I firmly believe we are currently living in our own version of “Goldilocks and the 3 Bears” when it comes to our CMC initiatives.
• My latest article analyzes how our quest for “just right” is reflected in the questions we posed to the FDA during each Town Hall about comparability and CGMP principles.

[TOOLS & TECH]
“There’s totally a tool for that.”

• While I tend to be skeptical of such unbridled confidence, there could be some truth to this statement, depending on your process dev/mfrg goals.
• This article, “Emerging Technologies & Companies in CGT Manufacturing,” is longer than Pinocchio’s nose after telling multiple lies — but it’s well worth the endeavor. Not only does it list the start-up technology companies working to develop/improve analytical and manufacturing equipment for (immune) cell therapy and gene therapy (AAV/LNP), but it also reviews innovations related to plasmid DNA, viral vector analytics, chromatography, LNP manufacturing, transfection, cell separation/selection, and... — the list keeps going.
• If you’re craving a bit more of a “compare and contrast” approach, this article in bioengineering highlights the benefits and existing challenges of current cell culture bags, G flasks, bioreactors (rocking/stirred/etc.), and semi/fully automatic closed bioreactor systems.
• For more on bioreactors, this article reviews the automated and semi-automated bioreactor platform options available specifically for producing clinical grade CAR engineered cells. The original review is not open access, but you can find the full-text embedded in this LinkedIn post from Ben McLeod.
  • FYI, Ben is a great person to follow on LinkedIn if you want to keep up to date on the scientific/manufacturing-related research/publication world.

[REGULATORY PATHWAY]
“FDA launches CMC knitting group to bolster informal industry/agency communication.”

• I desperately wish this were true; I bet Peter Marks knits a killer afghan.
• Though a knitting group isn’t in our future (yet), the FDA is working on making a few of our other wishes come true.
  • The Office of Therapeutic Products will be hosting an upcoming workshop on Advanced Manufacturing & Analytical Technologies for Regenerative Medicine Therapies on March 14 from 9-5 PM ET.
  • CBER is getting ready to launch an Operation Warp Speed for rare diseases pilot program. The goal is to enable real-time communication during clinical development for therapies (ATMP or otherwise) treating rare diseases with no alternative therapies.
• If you’re passionate about coming up with new ways to use scientific and clinical advancements to streamline regulatory policy, Friends of Cancer Research will be hosting a virtual meeting on March 8 to explore how we may be able to/should be doing so in the future. You can register for “The Next Generation of Cellular Therapies: Opportunities to Accelerate Development” here.
• Though we hope to make development and regulatory approval more efficient — and the accelerated pathway exists for us to do just that — the FDA’s Wilson Bryan shares a few pretty important reminders and concerns about using the accelerated approval pathway more regularly for CGTs in this recent Bloomberg Law article.

[mRNA IVT]
“Sharing Is Caring.”

• That’s 100% true — unless we’re talking about germs or any story that starts with the phrase, “I really shouldn’t be telling you this, but...”
• When it comes to the IVT process, however, we could all stand to share a bit more. That’s why Frontiers in Molecular Biosciences have put forth a call for abstracts on a wide host of topics around better understanding the IVT reaction/process and the resulting mRNA yield/quality. Topics up for grabs include emerging analytical tools, polymerase designs, enzymatic capping advances, and purification challenges — to name just a few.

[QUALITY]
“The Process Is The Product.”

• Alright, I’ll admit this statement is kind of tricky. A lot of people say this — but quite a few also argue it’s not true, given our immature understanding of our ATMP products’ structure and function.
• Luckily, in the mRNA space, we’re seeing a few efforts to better characterize our products.
  • Though USP’s Analytical Procedures for mRNA Vaccine Quality draft guidelines (for mRNA drug substance) left folks wanting more, the Standards Coordinating Body website reveals that ISO is working on a preliminary work item, “Guide for methods for the measurements of mRNA-LNPs.” (From here, you can click the “New To The Portal” tab to see a tiny bit more detail.)
  • FYI, this is Part 3 of a series of preliminary work items on gene delivery systems. Part 1 is focused specifically on vocabulary and Part 2 is on methods for qualification of viral vectors.
• mRNA isn’t the only modality that wants to become a “real” boy highly characterized molecule; AAV is also on a similar path to greater “self-actualization.”
  • To stay up to date on the biggest challenges in (analytically) interrogating your AAV, be sure to register for ARM’s and USP’s AAV Analytical Characterization Workshop on March 8-9. It can be live-streamed or attended in-person.

[GENE DELIVERY]
“This Must-Reads newsletter always delivers the goods — and the humor never falls flat!”

• If these statements are not true, well then... my inbox is here for your honesty/grievances.
• While I wouldn’t go so far as to say that your dislike of my newsletter humor is “an infectious insult,” this publication by our friends at Pfizer used these exact (and amazing) words to describe the impact of transient transfection on HEK 293 cells.
• While we most commonly rely on viral vectors or electroporation to engineer CAR-T cell therapies, this article explores some of the work being done using polymer- and lipid-based approaches for T-cell engineering.

[SOPS HUMOR]
Writing SOPs is as easy as making a PB&J.

• Repeat after me: writing is agony (she says, revising this sentence for the 76th time in an hour).
• But if you don’t believe me, check out this highly entertaining video of kids trying to teach their dad how to make a PB&J sandwich. It not only proves that giving clear instructions is hard, but it shows there are just as many complex ways of “developing” a PB&J sandwich as there are a CGT — and the inefficiency of some methods thanks to vague "SOPs" can be positively virtuosic.