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

By Anna Rose Welch, Director, Cell & Gene Collaborative
Subscribe to my blog ARW on CGT here!

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.

It was recently National Christmas Lights Day. As such, it only made sense to accompany the must-reads below with several best outdoor “lighting” practices to ensure your yard decorations — along with your professional deliverables — are less like Chevy Chase in Christmas Vacation and more like this family from New York with their Guinness World Record-winning 686,811-light display. (Santa) Hats off to the overachievers that had the patience to count those lights.

First, get inspired by previous masters of exterior illumination
[CGT OUTLOOK]

• Look no farther than this “bright light”: I still (and will always) owe former FDA Commissioner Scott Gottlieb a debt of gratitude for allowing me to ambush his COVID tour last year and for patiently answering my questions about the future of CGT CMC for this Dec. 2021 Cell & Gene Collaborative article.

Map out your grand vision: Know which type(s) of light(s) will create the desired visual effect & atmosphere
[RNA MODALITIES]

• String, Rope, Icicle, Fairy, Multi-Color... the list goes on — and in the RNA therapeutics space, we’re faced with similar questions about which modality will give us the most optimal therapeutic effect.
• For an all-encompassing review on all-things mRNA — whether it be purity, cargo optimization, dosing, delivery/delivery vehicles, and/or future applications — I’d direct your attention to this piece published in Nature Biotechnology: “Unlocking The Promise of mRNA Therapeutics.”
  • Stability, formulation, and delivery (LNP or otherwise) are big pain points stymying mRNA’s clinical potential. This GEN article shares broad learnings and recent developments in all these areas and more from Moderna, Arcturus, TechImmune, & CEPI. In particular, Moderna’s (brief) update on stability-threatening lipid-mRNA adducts is worth a closer look.
  • When it comes to structure as function, mRNA’s cap and tail are must-haves for mRNA expression. This academic study explores how this method of optimizing the sequence of the poly-A tail resulted in increased protein production and duration of expression in cell lines and mice.
• Self-amplifying RNA is most often discussed in the context of the vaccine space; that’s why this article illuminating research into & opportunities for saRNA as a protein replacement therapy in different indications caught my attention.
• There’s also a lot of excitement on the more commercially established non-coding RNA modalities. This was a great interview with the CEO of a Korean & U.S.-spanning RNAi company covering scientific advancements and business strategy in the RNAi space.

Invest in more efficient lighting technology
[MANUFACTURING EFFICIENCY]

• When it comes to viral vector manufacturing, AAV is that neighbor whose LED-laden yard brings all the oglers. But the LVV space next door is working just as hard to put on a good, cost-effective show. Feast your eyes on this article by several researchers at National Research Council Canada outlining the pros and cons of current/upcoming LVV process innovations that will improve manufacturing/cost efficiency.

Don’t bite off more than you can chew
[FDA INSPECTIONS/GMP VIOLATIONS]

• While I celebrate your efforts to recreate your molecule — and map out its biological cascade — in twinkle lights on the roof of the manufacturing facility, that won’t distract the FDA from your biggest GMP shortcomings.
• As RAPS reports here, the FDA’s onsite inspections are becoming a more frequent occurrence post-COVID lockdowns. In turn, of the 62 FDA warning letters issued in 2022, 42 were issued following an onsite inspection.
  • For a breakdown of the 10 most frequently cited GMP deficiencies, ECA Academy took one for the neighborhood here.

Double (& triple) test that your lights and outlets work
[ANALYTICS]

• While you’re at it, do this for your therapy, too.
• Thankfully, the folks from Dark Horse Consulting present us with a dazzling foray into analytical strategies for testing identity, purity, and potency for autologous and allogeneic cell therapies, as well as genome integrity testing for viral vector-modified and gene-edited cell therapies. (Free registration required)

Have someone hold the ladder as you climb it. Or, you know, just call a professional like the rest of us
[OUTSOURCING]

• My parents called their ladder “the widow maker” for a good reason.
• Forecasting the future outsourcing needs of the ATMP industry seems just as perilous as venturing up a rickety ladder. In the second part of a three-part series on the ATMP outsourcing paradigm, I highlight some of the business and manufacturing considerations/challenges CDMOs are facing as they strive to meet innovators’ not-yet-standardized manufacturing needs.
• A great counterpart to my article above is this one — “ATMP Report Identifies Outsourcing Realities” — in which my colleague strings together various data points from ASGCT’s Q1 2022 report to clarify the current/future outsourcing landscape.

Thank your [insert family member here] for teaching you “everything” you know about exterior illumination
[REGULATORY GUIDANCE]

• Like your “hands-on” father-in-law who got tied up in the lights on/off the roof last year, the FDA is putting on a few upcoming educational spectaculars you really won’t want to miss.
  • On December 7 from 12 PM - 1:30 PM ET, the FDA will be hosting a Cell Therapy CMC Town Hall. Register here!
    • You can (re)watch the FDA’s gene therapy town hall here.
  • On December 16 from 8 AM - 4 PM ET, the FDA will also be hosting a public workshop on Assessing Genetic Heterogeneity in the Context of Genome Editing Off-Targets in Gene Therapy Products.
• The former biosimilar nerd in me celebrates this new EMA reflection paper on criteria to be considered for the evaluation of new active substance status of biological substances. In fact, just like all the coolest Christmas decorations in a big box store, ATMPs get their own section of this document (starting page 7/14).
  • Though it’s slightly different contextually, I’d argue that this reflection paper is thematically akin to FDA’s final Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations (Sept. 2021). Might I recommend a comparability study of the two documents?