ARW's ATMP Manufacturing Must-Reads (OPERA 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. Once a month, 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.

Not only is it almost Valentine’s Day, but February 8 is Opera Day. And, as it turns out, there are some incredibly romantic opera quotes out there that not only capture the “romance” of this season but which I strongly believe will leave you feeling the love for the important work you do day in and day out. Or not. Probably not — but it’s the thought that counts, right? Please also note, this roundup pairs nicely with chocolate.

I speak of love awake, I speak of love in my dreams, to the water, the shadows, the mountains, to the flowers, the grass, the fountains. ~ The Marriage of Figaro
[PHACILITATE ATW 2024 EVENT RECAP]

• Omg shut up.
• Though I’m certainly one to talk — I went long in my recent article recapping 4 pieces of wisdom I walked away with from Phacilitate’s recent Advanced Therapies Week. Not to mention, the article is titled “From ‘Barbieland’ to ATW 2024: Evolving from the ‘Stereotypical’ Advanced Therapies,” which helps keep this month’s “hot pink” vibes going strong.

Put on the costume and the face in white powder. The people pay and laugh when they please ~ Pagliacci
[SUPPLY CHAIN PANEL DISCUSSION]

• Well, we won’t be face-painting, and thanks to a sponsorship from Thermo Fisher, you won’t have to pay to laugh with us. But my forthcoming Advancing RNA panel discussion on the mRNA (in-bound) supply chain with Sanofi’s Greg Troiano and Life Edit’s April Sena will be a fantastic and educational spectacle, nonetheless.
• Register here to join us on Feb. 21 at 11 AM ET to discuss the health of the current mRNA-LNP supply chain and how these experts are selecting vendors, navigating GMP principles, and working to reduce cost of goods for mRNA vaccines and therapeutics.

Son io. Eh si. Il problema si son io ~ Anti-Hero
[EDUCATION]

• Yeah, you didn’t realize translating Taylor Swift lyrics into Italian would be so damn operatic, did you?
  • You’re welcome.
• Ok, T. Swizzle may not exactly be “opera,” but her song “Anti-Hero” rewritten to become “Antigen Hero” by the geniuses at the National Center for Therapeutics Manufacturing is beyond worthy of ticket sales for the way it entertains and educates.
• Making mRNA more relatable to the general public — as the video above does (to an extent) — will be essential to the sector’s long-term commercial growth, especially because, as I argue in one of my latest columns, mRNA’s ability to be used as a vaccine and a therapeutic poses some intriguing regulatory and public relations challenges.

Have you come down from heaven, or am I in heaven with you ~ Il Trovatore
[REGULATORY]

• I don’t know where the ^%$& you think you are, but this is an FDA Townhall. So…
• Speaking of which, the FDA does have a few events coming up, starting with:
  • A webinar co-hosted by the Standards Coordinating Body on the recently finalized Consensus Standards Recognition Program. You can register here to attend on Feb. 21 from 11 AM-1 PM ET.
  • On March 7 from 1-2 PM ET, the FDA will be returning to the stage, this time as the soloist in a webinar on its recently finalized guidance on CAR-T development.

Farewell past, happy dreams of days gone by. The roses in my cheeks already are faded ~ La Traviata
[FUTURE CGT TECHNOLOGIES]

• Well, before you go slamming the casket lid closed, these new therapeutic “scorchers” should make you feel like you have at least one foot outside of the grave.
• ARM and Catalyst Health recently released a new report, "Preparing for the Future: Emerging Technologies Shaping the CGT Landscape." This report highlights a really nice “cast” of ATMP characters, all of which are expected to add some drama to the regulatory paradigm and chase Wagner’s Valkyries away. (Think: In Vivo CAR-Ts, non-viral delivery, and RNA therapeutics, to name just a few!)

None shall sleep! None shall sleep! ~ Turandot
[CELL THERAPY ADVANCES]

• %$#@&!
• Based on the latest outpouring of good news/resources in the cell therapy realms, I’m not sure there’s been much sleep happening in that particularly motivated sector of the ATMP space.
• For one, my colleague Tyler Menichiello details the biggest regulatory, legal, and clinical strategy and scale-up challenges and triumphs behind-the-scenes of India’s historic approval of its first domestically produced CAR-T cell therapy — ImmunoACT’s NexCAR19.
• Meanwhile on this side of the pond, Kite has set a new record in cell therapy turn-around-time, now releasing the product to patients in 14 days (down from 16 days).
• In December, ISCT and FDA co-hosted a cell therapy liaison meeting to discuss IPSC starting materials, QC testing for point of care manufacturing, and rare disease therapy commercialization hurdles — to name just a few. In addition to cataloguing the links to the presentation slide decks, there is also a helpful high-level summary from each presentation here.
  • The summaries from presentations #2 and #3 are particularly worth a gander.
• ISPE just published a new ATMP guide discussing (GMP) manufacturing facilities development and design specifically for allogeneic cell therapies — albeit with cross-over to other ATMP modalities, as well.

Pure Goddess, whose silver covers these ancient sacred plants, we turn to your lovely face unclouded and without veil. ~ Norma
[ANALYTICS]

• “New assay, who ‘dis?”
• Since our assays aren’t exactly prone to flattery, allow me to offer instead this stack of resources I’ve found that can hopefully help us out instead:
  • Broad CGTs:
    • On February 22 from 8:30 AM-5:00 PM, USP will be hosting a forum on innovative analytical approaches for cell and gene therapies, which will include a deeper dive into the use of NGS-based techniques. Register here.
    • No doubt, you caught word that the FDA recently issued a draft guidance for CGT Potency Assurance. Thanks to Cell & Gene expert contributor Tim Sandle for breaking down his biggest takeaways from the guidance.
    • PDA published a feature on the promise of advanced nucleic acid testing (NAT) methods in navigating CGTs’ unique viral contamination risks.
  • AAV
    • This review outlines why AAV remains a “talented” but “difficult soprano” to work with analytically and where opportunities lie to improve analytical testing in GMP settings moving forward.
    • This publication by several Patheon and NIBR experts showcases a GMP-compliant LC-MS workflow for AAV characterization.
  • Nucleic Acids:
    • As a friendly reminder, USP will also be hosting an mRNA Open Forum on February 28 & 29. The agenda will cover a wide range of analytical challenges and coding RNA modalities/therapeutic approaches. You can register here.
    • Thanks to a general lack of reference standards, mRNA quantification (both in LNPs and as a stand-alone DS) might feel as hard as trying to shatter a glass with your own voice. Luckily, these folks have put together an article outlining the pros (and yes, some cons) of a mass-spec-based approach for quantifying encapsulated mRNA.
    • Got dsRNA? This article by several folks from Brown University presents an (optimized) S1 nuclease-assisted microfluidic approach for dsRNA detection as an alternative to the current industry standard dot-blot method.

Ah, come back again as you were then, then when I gave you my heart, ah come back to me! ~ Norma
[COMPARABILITY]

• FDA to industry: Excessive whining about what your therapy once was will be insufficient to demonstrate analytical comparability.
• The byline for this article alone — “The Comparability Tales: A Phase Appropriate Roadmap for CGT Drug Product Development” — is full of CGT star power. But it also provides a nice, brief “plot summary” from a recent ASGCT CMC symposium and workshop.
• For those of you working with AAV specifically, ISPE published a guide on AAV comparability and lifecycle management in accordance with FDA, Volume 4, EMA, and ICH Q5E regulations.

Love is a rebellious bird that nobody can tame, and you call him quite in vain if it suits him not to come ~ Carmen
[LNP DELIVERY]

• We probably don’t want to refer to LNPs as “rebellious birds,” per se, but be honest; that sounds so much sexier than our go-to term of endearment: “little fat blobs.”
  • It does. Don’t lie.
• A couple of LNP-related overviews on how we can “tame” our LNPs in the long-term, caught my eyes in recent weeks, including:
  • Lipid Nanoparticles: From Liposomes to mRNA Vaccine Delivery, a Landscape of Research Diversity and Advancement.
  • Chemistry & Art of Developing LNPs for Biologics Delivery: Focus on Development & Scale-Up
  • Lipid-Based Nanoparticles for Drug/Gene Delivery: An Overview of the Production Techniques and Difficulties Encountered in their Industrial Development

Hell’s vengeance boils in my heart; death and despair blaze about me. ~ The Magic Flute
[CRYO CONSIDERATIONS]

• Ok, first of all, chill.
• To help you out with that, a few really cool folks at BMS penned this Outsourced Pharma article presenting common FAQs about cryo-shipping for CAR-T therapies. They also break down the main cast of characters (i.e., cryo-shippers & logistics providers) and how best we can qualify and validate potential partners.
• For those of you who really just can’t stop your heart from boiling, I see you (I really do) and offer a slightly less frigid article by a team of Roche experts investigating mRNA-LNP shelf-life stability under nonfrozen conditions. [Institutional access required.]