ARW's ATMP Manufacturing Must-Reads (ST. PATRICK'S DAY 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 roundup article.

Seeing as St. Patrick’s Day weekend is (basically) upon us, it should come as no surprise that I’ve chosen to pair your latest batch of must-reads with lines from some traditional Irish drinking songs. Because what is St. Patrick’s Day, really, without green beer/whiskey and articles on CGT contamination control? Please read (and celebrate) responsibly.

A barrel of malt, a bushel of hops, you stir it around with a stick, the kind of lubrication to make your engine tick. ~Charlie Mopps (Beer, Beer, Beer)
[mRNA SUPPLY CHAIN]

• Sounds GMP to me.
• Over the past few weeks, I’ve written a handful of pieces delving into the state of the mRNA supply chain, starting with this fantastic conversation with Sanofi’s Greg Troiano. Here, he shares his perspectives on where the mRNA supply chain has grown, where it could continue to grow, and his go-to tips and tricks for working with mRNA supplier partners.
• Though Irish drinking songs have their own “poetic charm,” nothing can compare to the true Bard, Shakespeare, who, as it turns out, had a lot to say about RNA GMP principles. In my latest Shakespeare-inspired article, “To Thine Own [mRNA Product] Be True:” Shakespeare’s Guide To RNA GMP Principles, I highlight best practices offered during a panel discussion last fall entitled “To GMP or Not To GMP” on how we are/can navigate GMP principles for mRNA therapeutics.

Seven old ladies locked in the lavatory. They were there from Sunday to Saturday, nobody knew they were there. ~Seven Old Ladies
[PLASMIDS]

• If there’s anything that is as “unsung” as these apparently incredibly forgettable seven (7!) old ladies, it would be our plasmids.
• Fortunately, there have been a few articles/authors published recently that have made our “shrinking violet” plasmids impossible to ignore — starting with this informative discussion unpacking USP’s recent general chapter on plasmid DNA for CGT/RNA therapeutics, focusing in particular on current differences between non-GMP and GMP-compliant plasmids.
• Though synthetic plasmids were not in scope of the USP chapter, there has been a lot of growth in the supplier space to bring synthetic plasmids to greater maturity. This Pharma’s Almanac article shares some of the benefits of and current approaches to synthetic plasmid production, as well as some of the suppliers that refuse to be locked away and forgotten in a lavatory.
  • In fact, synthetic plasmid DNA is just one of the many potential approaches outlined in this article on reducing nucleic acid contamination in AAV.

...I spent all my money on whiskey and beer, but now I've returned with gold in great store, and I never will play the wild rover no more. ~Wild Rover
[INDUSTRY FUNDING]

• Need funding? ^^^ I think I found you an investor.
• Our friend “The Wild Rover” might not be the only one looking for somewhere more substantial to put his money than just booze; according to a recent survey from GlobalData ($$$ to access), 44% of those surveyed are optimistic biotech venture capital funding will return to pre-pandemic levels in 2024. For a quick but free write-up of some of the data included in GlobalData’s recent survey, check out this article in Pharmaceutical Technology.

There's a leprechaun regulator in my room. He swats me with a broom ~ The Leprechaun
[REGULATORY]

• Anybody else picturing Peter Marks wearing the Lucky Charms hat and holding a broom?
  • You are now.
• I was particularly “struck” by a couple of great regulatory articles and opportunities to note, starting with:
  • This DIA Global Forum article which poses the question — and provides an answer — as to whether all (non-infectious disease vaccine) mRNA products should be categorized as gene therapies by regulators. A true must-read for those of you interested in/concerned about the direction in which mRNA regulations are or should be moving in the future.
  • For CAR-T & AAV gene therapy developers:
    • Cell & Gene has published two articles by Dark Horse consultants, both of which leave no “steps unswept” in their lengthy but worthwhile/detailed examinations of:
      • The changes/clarifications we saw (and did NOT see) made to the FDA’s final CAR-T guidance, and;
      • What’s new and which questions remain unanswered in the FDA’s finalized gene editing guidance.
    • On Friday, March 15, the FDA will be hosting an Adcom to review the risk vs. benefit of moving J&J and Legend’s Carvykti and BMS’ Abecma into earlier lines of therapy. While there’s a lot of discussion about clinical trial design and its impact on overall survival, I was struck by this (intriguing) indication that Carvykti’s manufacturing may also get some attention:
      • “J&J and Legend also hope to expand Carvykti’s manufacturing qualification measurements so that fewer products will be deemed out of specification. In the last nine months, Carvykti’s out-of-spec rate is in the “teens range,” Huang said, referring to the partners’ rate of production failures.”
    • Following an ASGCT FDA Liaison meeting, ASGCT has published a well-rounded breakdown summarizing takeaways from presentations on AAV safety, on- and off-target editing, and some of the most recent FDA initiatives. Links to presentation slides are also available.
    • The Bespoke Gene Therapy Consortium recently published the first of many more iterative versions of its “Regulatory Playbook,” which unites currently disparate regulatory guidance and regulatory best practices to help educate and guide readers through various aspects of the AAV gene therapy regulatory submission process.
  • Across the pond, the EMA has recently unveiled a few updates that may cause you to miss your mouth whilst knocking back a shot of Jameson, including:
    • The 2024 Work Plan for the Committee for Advanced Therapies (CAT); and
    • A Q&A on the “EMA pilot offering enhanced support to academic and non-profit developers of ATMPs.”

There’s pubs and there’s clubs and there’s lassies there, too… the beer is all free, and there’s bottles of rum growing on every tree ~Fiddler’s Green
[“PLATFORMING”]

• You say “Paradise,” I say “Platform”... ize.
• The “party animals” at BioPhorum have gone above and beyond buying everyone a round by putting together a white paper of best practices on how best to platform process development and characterization knowledge (internally & externally) across similar AAV and cell therapy products.
• Though we often talk about “platforming” in terms of our products/internal manufacturing platforms, I liked this article calling attention to the pressing need for an established and harmonized global “regulatory platform,” if you will, for mRNA therapeutics.
• In fact, the newly launched Alliance for mRNA Medicines will be hosting an in-person global summit on how we can harmonize the regulatory pathway for mRNA vaccines & therapeutics in D.C. on April 4, 2024. Registration for non-AMM members is $250.

Will you kindly tell me who owns that horse outside the door where my old horse should be? ~Seven Drunken Nights
[COMPARABILITY]

• Maybe — and hear me out — it’s the same old horse, it just looks “newer,” post-Guinness?
• One of Advancing RNA’s favorite contributors, Elaine Peters of Genentech, fearlessly tackles one of the ATMP space’s favorite topics of discussion — comparability — in her latest editorial, dedicating a few (but not all) sections to the challenges of comparability for mRNA therapies.
• You may have caught word that Kite reduced its manufacturing turn-around-time for Yescarta from 16 to 14 days. (Hello, comparability!) My colleague Erin Harris gets the inside scoop on the “new horse” in the cell therapy race from Kite’s Global Head of Tech Ops via a recent episode of Cell & Gene: The Podcast.

...a bucket of whiskey flew at him; it missed, and…the liquor scattered over Tim; Now the spirits new life gave the corpse, my joy! ~Finnegan’s Wake
[CONTAMINATION CONTROL]

• I can appreciate that you feel dead inside — but please keep your “emotional support whiskey” out of the clean room.
• If (non-whiskey-related) contamination control of your ATMP is top of mind — which, it should be — I offer the first of this three-part article by several ValSource consultants on how to best leverage the aseptic risk evaluation model (AREM) to safely navigate the unique challenges of ATMP aseptic processing.

And the wind blew cold and lonely across that Widow’s moor, and she never, ever turned away a traveler from the door. ~The Widow & The Devil
[OUTSOURCING]

• Unlike this song’s insatiable widow, you most likely caught wind of one outsourcing firm’s decision to take some of its fill-finish facilities off the market.
  • Oh, Catalent, you saucy minx.
• My colleague Louis Garguilo of Outsourced Pharma penned a three-part series discussing the ramifications of Novo Holding’s acquisition of Catalent on the broader biopharma space. [Part 1] [Part 2] [Part 3]
• For a few perspectives on the impact this could have on the ATMP space, in particular, I’d refer you to this BioProcess International article: Novo Catalent Deal Primed To Shake-Up CGT Outsourcing Space.