ARW'S CGT + RNA Manufacturing Must-Reads (SPAM EMAIL 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.

Though I suppose every week feels like “National Email Week,” we were smack-dab in the middle of the official National Email Week when this newsletter was sent around. So, to celebrate that fact, I organized your manufacturing must-reads according to several (no doubt) familiar email “subject lines.” Who knew spam emails could be so closely related to ATMP manufacturing challenges?

ATTN: Unusual account activity detected!!!
[mRNA IMMUNOGENICITY]

• This is essentially the go-to “subject line” for any of the immune system’s emails.
• In my last newsletter, I shared part one of a two-part article series outlining the similarities between fly-fishing and the R&D we’re doing in the mRNA space to navigate the complexities of the immune system. Here, in part 2, I delve more deeply into the function of the immune system and the process- and design-related considerations we’re making for our mRNA vaccines and therapeutics.

3 hawt stepps 2 attract ur souwlmate
[PARTNERSHIP/COLLABORATION]

• ATMPs are sexy, don’t get me wrong. But if you’re trying to snare a development partner and/or improve your existing partner relationships, these “3 hawt stepps” are (probably) not going to be your go-to best practices.
• Lucky for you, I sat down with executives from two partner companies — cell therapy biotech Inceptor Bio and technology platform company Ori Biotech — to discuss the ways in which the autologous/ex vivo manufacturing paradigm is shaking up technology partnerships. Here in part 1, we start by providing a more concrete definition around what risk- (or value-) sharing looks like today in ATMP partnerships.
• If there’s one area where any partnership is bound to be tested, it’s during the tech transfer process. Thanks go out to the folks at Dark Horse Consulting who have just published a white paper walking us through the most important steps/considerations to make as you assess your partner’s capabilities.

RE: Why don’t u like me?
[REGULATORY]

• Don’t you laugh — we’ve all sent this email (or text) at some time or another. People suck sometimes.
• Lucky for us, the FDA is taking one for the team and isn’t afraid to “DTR.” In recent weeks, the agency published a brief update/clarification to the definition of “face-to-face” meetings. We can now officially consider an in-person or a zoom call with video a “face-to-face” meeting (albeit only for specific meetings).

2 boxes GR8 stuff for $5
[ANCILLARY MATERIALS]

• I suppose that’s one way we can describe our latest raw materials shipment…
• How we/the regulatory agencies and pharmacopeias define raw materials, ancillary materials, and starting materials is, unfortunately, riddled with as many inconsistencies as the spelling in spam emails. That’s why I was a big fan of this brief article from Voisin Consulting Life Sciences which puts USP and European Pharmacopeia/EMA material definitions all in one place. (There’s a part 2 on starting materials forthcoming!)
  • Speaking of pesky definition differences, I wanted to reshare this article on the active ingredient vs. excipient debate raging in the mRNA space today. A fascinating topic to watch in the years ahead.
• In the past few weeks, there’s seemingly been a rush to build greater plasmid DNA capability across the CGT/RNA industry — which makes the good folks at Fairfield Market Research veritable fortune tellers for penning their recent article, “Plasmid DNA Manufacturing to See Impressive Growth In Years Ahead.”
  • If plasmid quality is also of concern, be sure to tune into this upcoming USP webinar, " Quality considerations for plasmid DNA as a starting material for CGTs," on June 21 @ 11 AM ET.
• Because we’re still waiting for an email with the subject line, “Got endonuclease release criteria?” BioPhorum has released a white paper advocating for a harmonized testing and release framework for endonucleases (and, hopefully, a future with more targeted/endonuclease-specific compendial standards).
  • Please note: Materials used in mRNA product manufacturing (i.e., RNase, DNAse) & sequence-specific endonucleases (e.g., CRISPR CAS-9 and restriction enzymes) are excluded from the scope of this whitepaper.

MAILER DAEMON: Undelivered mail returned to sender
[NONVIRAL DELIVERY]

• This may not be spam — but it is a terrible LNP (ex-hepatic) delivery joke.
• Over the past few weeks/months, I’ve been collecting a wide array of materials on everyone’s favorite nonviral delivery vehicle. Whether it be formulation-, cryopreservation-, or R&D/process development-oriented, there’s something here for everyone.
  • Cell Discovery: Lyophilized mRNA-lipid nanoparticle vaccines with long-term stability and high antigenicity against SARS-CoV-2 [January 2023]
  • Biomaterials Science: Successful batch & continuous lyophilization of mRNA LNP formulations depend on cryoprotectants and ionizable lipids [March 2023]
  • Molecular Therapy Nucleic Acids: The impact of nucleoside base modification in mRNA vaccine is influenced by the chemistry of its LNP delivery system [May 2023]
  • OpenNano: Lab-scale siRNA & mRNA LNP manufacturing by various microfluidic mixing techniques – an evaluation of particle properties and efficiency [July 2023]

Pills for Potency. Fast Delivery!
[POTENCY ASSAYS]

• Sorry, sender: Wrong potency.
• But speaking of fast delivery… there’s still 14 hours to sign up for Alliance for Regenerative Medicine’s upcoming webinar on potency assay development challenges. The webinar will take place tomorrow, Friday, June 16 at 1 PM ET.

Dear Beneficiary
[REIMBURSEMENT]

• To be fair, we all hope that insurers and government pricing watchdogs will tell us that our therapies are the worthy “beneficiaries” of $1,567,352.38 (or some other well-chosen number).
• But we also know that solving our CMC problems isn’t the only challenge to getting our therapies to patients; we (and our patients) also need someone to pay for them. This article in Molecular Therapy Methods & Clinical Development provides a fantastic overview of current access and Medicaid coverage challenges for approved CGTs, as well as solutions for CMS/Congress to enact to alleviate coverage burdens for Medicaid patients.

Kitten picsssssss
[PET GENE THERAPY]

• Why yes, I have gotten this email before — and yes, I did request it.
• Researchers recently published a study in Nature revealing that an AAV gene therapy has kept female cats kitten-free for two years.
  • If you’d prefer the “science-lite” version of the study data (which also boasts a picture of kittens), check out the Science article here.