ARW's CGT+RNA Manufacturing Must-Reads (Oscar The Grouch 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.
May 30, when this newsletter was sent, was Oscar the Grouch Day. So below, I’ve taken the liberty of grouping your must-reads under an “inspirational” quote from everyone’s favorite curmudgeonly Sesame Street character. In addition to learning something new, I hope you’ll also fully embrace Oscar’s passion for being as grouchy as possible — and that you’ll share that spirit with everyone you love most.
“Just because you’re trash doesn’t mean you can’t do great things. It is called ‘Garbage Can,’ not ‘Garbage Cannot.’”
[mRNA REGULATORY]
- Inspirational t-shirts emblazoned with the second half of this quote were sadly NOT part of regulators’ and Moderna’s mRNA success story. But as Moderna’s Director of Regulatory CMC, Chris Kelly, explained in a presentation last fall, “[Garbage] Cannot” was not part of his team’s vocabulary.
- In the final installment of this four-part article series, I outline the current regulatory landscape for mRNA-LNPs.
- ICYMI: Parts 1-3 are also linked at the bottom of this article for easy reference.
"Rainy days are my favorite. I like to watch everyone who forgot their umbrellas at home.”
[GLOBAL ATMP REGULATIONS]
- Getting stuck in the rain sucks — especially when that “rain” is actually the “wrath” of the regulatory agencies raining down upon you and your regulatory filings.
- Just as you should never leave home without an umbrella, be sure to take advantage of all available opportunities to hear from regulators — including the FDA’s next Cell Therapy CMC Town Hall next Thursday, June 8 from 11:30 AM to 1:00 PM ET.
- In addition to town halls, there have been a few important steps taken to (sort of) simplify your development program. In particular, I’d call your attention to two big efforts to harmonize across regulatory agencies and streamline regulatory reviews, including:
- The FDA’s recent adoption (and EMA’s anticipated future adoption) of ICH guidance S12 on nonclinical biodistribution for gene therapies.
- The MHRA just announced that it will be implementing an “international recognition route” for medicines approval. Medicines approved by FDA, TGA, Health Canada, PMDA, HAS (Singapore), and Swissmedic will be eligible for streamlined MHRA assessment and earlier patient access in the UK.
- There are very few details around what the FDA intends to do to reform what Robert Califf calls the currently “messy” advisory committee approach. However, Califf recently emphasized that regulatory progress in Alzheimer’s, obesity, and diabetes indications dictates the need for future adcom reform to keep things from turning into a raging dumpster fire.
- I may have added the dumpster fire bit.
“Knock three times on my trash can lid and then I’ll know it’s you.”
[AAV ANALYTICS]
- If only we had the same simple code for “ID-ing” our AAV vector.
- In 2021, USP and NIST and NIIMBL announced a round-robin study to identify the best methods for — and the interlaboratory differences that arise — in measuring full-empty capsids.
- Since then, things have been a bit quiet on the standards front — or at least they were until two weeks ago, when MHRA and Cell & Gene Catapult shared an update from their collaborative reference material pilot study. The AAV2 reference material was produced via the Catapult (in coordination with the MHRA) and underwent a pilot study in several UK labs. You probably won’t be surprised to learn that, once again, interlaboratory measurement differences and a lack of standards remain a common industry foe.
- Just as our buddy Oscar can go long on the beauty of a full garbage can, the FDA and companies alike have been waxing poetic about the beauty of demonstrating a full capsid. Look no farther than this article evaluating the performance of SEC-MALS in measuring full-empty capsids and product instability.
“Ding-dong! You’re wrong!”
[mRNA IMMUNOGENICITY]
- ^^The phrase we never want the immune system to say to our advanced therapies.
- Thanks to my ongoing video series, ARW on RNA, I have recently emerged from a deep dive into the worlds of fly-fishing and mRNA vaccine and therapeutics immunogenicity. As I argue in part 1 of this two-part article, there are some (gorgeous) parallels between a fly-fisherman’s and the mRNA industry’s efforts to ensure our mRNA vaccines and therapies approach the innate/adaptive immune systems appropriately.
- ICYMI (or are bored at work): my recent videos have compared the process of developing mRNA therapeutics to practicing magic in Harry Potter, playing The Game of Risk, violin making, and carving the sculpture of David.
“I have here some newspaper 13 months old. I wrapped fish inside it; it’s smelly and cold. But I wouldn’t trade it for a big pot o’ gold.”
[SUPPLY CHAIN]
- My greatest hope is that you feel the same amount of delirious joy over your own supply chain as Oscar does his.
- But if all you feel is disgust (at his and yours), be sure to check out these two articles digging into the nuances of ATMP supply chain management.
“Who said you could get in my trash can facility?!”
[IN-HOUSE VS. OUTSOURCING]
- ^^Words we’ll (hopefully) never hear from our CDMO partners in relation to their facilities — or trash cans, for that matter.
- In fact, based on this article unpacking the results of a recent outsourcing research report, a (albeit slight) reduction in demand for CDMOs in the upcoming years could only amplify CDMOs’ calls/desires for partners.
- Though the article above proffers several reasons for a slight downturn in outsourcing practices, the maturity of internal capabilities could be one such reason for less reliance on external partners. I particularly appreciated this Q&A with an Adaptimmune executive that went much deeper on some of the cell therapy-specific reasons behind internalizing manufacturing. The article also delves into how the company is planning for future internal capacity — and external partnership — expansions.
“So, close your eyes and dream of all the wonderful trash mRNA therapies yet to come.”
[mRNA RESEARCH]
- Believe it or not, sometimes, even Oscar the Grouch can be an optimist when it comes to next-gen therapies.
- In recent months, there have been a handful of reviews penned showcasing the possibilities (and complications) of using mRNA in prophylactic/therapeutic vaccines and protein replacement therapeutics, and self-replicating mRNA as a cancer immunotherapy.
- While immunogenicity, ex-hepatic delivery, stability, and durability of response are topics getting us all riled up today, we unfortunately can’t dream our way out of our current endosomal escape problems also limiting our RNA therapies’ delivery/efficacy.
- As this article explains, we still have a lot to figure out about 1.) The mechanisms by which our RNA therapeutics end up where they need to be (a cell’s cytoplasm) and 2.) the strategies we can employ to help our RNA therapies bypass an endosome’s covetous lipid bilayer barrier without increasing a therapy’s cytotoxicity.
- Please note, formatting for this article is wonky — you must “zoom in” to read.
“Frowning makes me happy. Can’t you tell?”
[YOUR DAILY CRISPR JOKE]
- Turn that frown upside down with this tweet combining two of my absolute favorite things in this world: ATMPs and cats.
- I know. You’re welcome.