ARW's CGT+RNA Manufacturing Must-Reads (OUTLANDISH ‘HOLIDAY' 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.

Though I normally pick just one theme for these newsletters, July 27th — the date this newsletter was sent — offered too many fantastic choices to simply pick just one. Thanks to my paralyzing indecisiveness, each section of must-reads is organized according to the most ludicrous holidays one could ever dream of “celebrating.” Pour yourself a scotch and/or get yourself some chicken fingers (because it’s national scotch AND national chicken finger day) and check out some of the latest happenings in the ATMP manufacturing space. And… in case you were wondering, no — I didn’t make any of these up.

Oh, #%^$. It’s Bagpipe Appreciation Day.
[mRNA IMMUNOGENICITY]

• I’ll leave it up to you whether the expletive is expressing your unbridled enthusiasm or your absolute disgust for bagpipes.
• Just as bagpipes are an acquired taste (to say the least) so, too, are our therapies when it comes to our immune systems. A few weeks ago, I shared an article series comparing fly fishing to the R&D work being done to identify the right immunogenicity profiles for our mRNA vaccines and therapeutics.
• I’m excited to share that the accompanying ARW on RNA video, "Fly Fishing Meets mRNA," is officially live, and I daresay it is way better than a chorus of bagpipes (even should you choose to listen to my narration...).

Freeze! It’s Air Conditioner Appreciation Week.
[SUSTAINABILITY]

• I do at least think about the penguins on their melting ice cubes each time I turn my AC down a few degrees. 😬
• This article from Dark Horse Consulting entitled “Cell & Gene Therapy Has Come of Age” is just as refreshing as an air conditioner on a hot day — but Anthony Davies’ emphasis on our industry’s need for “grown up CMC” speaks to several non-environmental (but equally important) measures of industry sustainability we still have yet to achieve.
• Though we tend to think of sustainability predominantly in terms of our environmental impact, the recent AGC CDMO Summit gave me a few other ideas on how we can meaningfully define what sustainability means in our CGT technical operations. Check out one of my latest editorials, “From The Lion King to Cell & Gene: ‘The Circle of Life’ for Sustainable CGT Products & Businesses.”
• If you’re still worried about the poor aforementioned penguins (which, you should be BTW), this article defining CDMO environmental sustainability efforts and “the complicated question of outsourcing costs” provides a sweeping look at how CDMOs are approaching flexibility and sustainability in manufacturing today.

Stop drooling and grab a spoon — it’s National Crème Brulée Day!
[REGULATORY]

• I can think of no more appropriate “dessert” than some of the latest news out of the FDA.
• You’ve probably already licked the bowl clean by now, but on the off chance you missed the dessert cart, the FDA released its long awaited and highly anticipated CGT Comparability guidance last week.
  • If you’re craving just a small taste of something sweet, Cell & Gene published a quick(er) summary of some of the FDA’s recommendations for reporting changes, performing a risk assessment, and evaluating your analytical approach.
• At a recent RAPS/USP workshop, the FDA shared updates and perspectives on (the currently lagging) industry uptake of advanced manufacturing approaches — including but not limited to continuous manufacturing, precision analytics, and AI/ML. This article in RAPS focused predominantly on the progress toward & myths stymying industry progress toward continuous manufacturing — but, if you’re curious, the article also outlines the other projects that have garnered funding.
  • Speaking of continuous manufacturing: thanks to a grant from the FDA, researchers from MIT, Penn State University, and Rensselaer Polytechnic Institute will be working on a pilot continuous mRNA manufacturing platform. ReciBioPharm will be responsible for implementing said-platform in a pilot-scale manufacturing facility.

It's Walk on Stilts Day — because, really, what could go wrong?
[MANUFACTURING/SCALE-UP]

• Luckily, for those of us with a crippling fear of heights or terrible balance on our human-sized legs, these articles provide a nice “birds-eye” view of AAV and mRNA manufacturing and scale-up processes, and both can be read from the comfort (and stability) of your desk chair.
  • In particular, Challenges in Scaling-Up AAV-Based Gene Therapy Manufacturing looks at how successfully we’re carrying QBD principles over from the world of well-characterized mAbs into the “fuzzy” world of gene therapy characterization.
  • Likewise, BioPhorum is back at it with one of their valuable papers providing an overview of the end-to-end mRNA drug substance and drug product manufacturing processes and scale-up considerations [free registration required to download].

Barbie-In-A-Blender-Day — coming soon to a Jamba Juice near you.
[mRNA QUALITY]

• Oh yes, this is an actual day (thanks to a piece of art). But it’s also a day dedicated to freedom of expression — and, like our hearts, our mRNA needs to be pure to express itself freely and properly.
• If you’re looking to follow someone who has mastered the art of LinkedIn “expression,” be sure to follow Pedro Morais, whose recent post provides several great resources on mRNA IVT impurities, as well as two new publications outlining approaches for reducing double-stranded RNA formation.
• Though it’s roughly a year old, this article from the artists at Moderna on sterile filtration of mRNA-LNPs is worth adding into “the mix.” [Institutional login/purchase required to access full-text.]

Bored people, rejoice! It’s Take Your Houseplant and Your Pants for a Walk Day.
[AI/ML]

• Yes, we can apparently make celebrations out of anything.
• Now, you’re probably wondering what these “celebrations” have to do with AI/ML — and if you guessed “absolutely nothing,” you’d be right! BUT there were two articles penned recently walking us (and our plants and our pants) through:
  • Several clear-cut definitions to “de-buzz” the language used to describe AI in manufacturing, as well as strategies to chip away at the barriers holding our use of AI in manufacturing at bay. [Here’s a Realistic Look for AI in Biomanufacturing]
  • A breakdown of the current regulatory frameworks for AI/ML implementation, accompanied by three steps for building a future implementation and validation framework.

Get thee to the tin can phone! It’s Cross Atlantic Communication Day.
[DATA INTEGRITY]

• Yeah, ok, we don’t use tin can phones anymore — but let’s not kid ourselves here; we still rely on some archaic practices in the pharma realm.
• In particular, as one author writes, our current narrative-heavy & document-centric methods for capturing all of our CMC and manufacturing data are doing us a disservice as we try to transition into the world of digital CMC and FAIR data management. [Lost CMC Data In An ALCOA+ World]

Don’t you dare make that cell therapy — It’s National Intern Day. Make them do it.
[“BASIC” EDUCATION]

• To be fair, I feel like we’re all still “interns” learning the ropes in the ATMP space.
• Though we do know our fair share, for those of you who want to brush up on your knowledge or help your spouse/friends understand the words you’re saying when you curse about all your work problems, I offer two handy resources to use or share:
  • A crash “course” on the dizzying number of AAV serotypes and their applications in gene therapy.
  • An MIT course (for purchase or audit) on making a cell therapy—the principles and practice of manufacturing.