ARW's C&G+RNA Manufacturing Must-Reads (I LOVE YOU, PIZZA 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.

February 9^th was not just an important day because I had lots of great ATMP-centric resources to share, but it also happened to be National Pizza Day. As we approach Valentine’s Day and my adoration for pizza truly knows no bounds, each section of this manufacturing must-reads features a “Valentine” to our beloved, Pizza, and (sort of) to the therapies we work with every day. Enjoy the cheese.

[“ARW on RNA:” mRNA MEETS HARRY POTTER!]
Let me take you back to my place.

• Seeing as 93% of Americans bring pizza home for dinner once a month, it’s clear that the majority share my love of pizza.
• But I’m pretty confident in declaring that the first episode of "ARW on RNA" is the first and only piece of content in existence in which Harry Potter and mRNA reside in harmonious unity.

[GMP PRINCIPLES / ATMP QUALITY]
You’re so much hotter than your twin, DiGiorno.

• Frozen pizza is not an acceptable suitor — especially considering < 30 % of the cheese on a frozen pizza is real. Don’t cheat on takeout pizza with frozen pizza. Just don’t.
• Yes, we always want to be cost-conscious. But we also want the FDA and our patients to see our therapies — and all the materials and processes underpinning them — as a product of the highest quality.
• Hence why I went through the FDA’s Cell & Gene Therapy CMC townhall transcripts with a fine-toothed comb and isolated several best practices from their recommendations in my latest article, “GMP Principles: The True Star of Our Cell & Gene FDA Interactions.”
• In the previous article, I touched briefly on plasmid quality, primarily as it relates to viral vector gene therapies. But the popularity of BioPhorum’s recent article “Release Specifications for Plasmid Master Cell Banks, Plasmid DNA” across Life Science Connect’s publications demonstrates the industry’s immense appetite for greater clarity around this critical starting material.

[mRNA STABILITY]
You’re hot then you’re cold but I’ll never say no.

• There are a lot of ways to consume a pizza (i.e., hot or cold, with a fork and knife or the real way — with your hands.)
• Not surprisingly, approaches for approving mRNA stability are just as multifaceted. I liked this cleverly titled review: “The Storage & In-Use Stability of mRNA Vaccines & Therapeutics: Not A Cold Case.” Unlike most reviews that focus primarily on drug substance/drug product optimization for improved protein expression, the authors instead walk us through current or emerging strategies for improving stability on the drug substance and drug product (mRNA-LNP) levels.
  • However, this article is truly a smorgasbord of information, with sections dedicated to such critical topics as “stage-appropriate” analytical characterization, product packaging, and regulatory guidance/emerging acceptance criteria — and so much more!

[FDA GUIDANCE / UPDATES]
I knead you.

• Waiting for regulatory guidance/clarity is just as much an exercise in patience as waiting for pizza dough to rise.
• I’ve already spread the good word about the highly anticipated comparability guidance, which is still on the FDA’s list of forthcoming 2023 Cell & Gene Therapy-related guidances.
  • But it’s also good to see regulators paying attention to the use of human- & animal-derived materials in CGTs — which was another big focus during the Town Halls — as well as how to assess donor eligibility and test allogeneic cells that have been expanded for use in therapies.
• If the comparability guidance is the delightful sheen of grease you’d never dare dab off your piece of pizza, be sure to tune into my Cell & Gene colleague Erin Harris’ panel discussion “Scaling Cell Therapies: Establishing Comparability in Manufacturing” next Monday, February 13.
• Speaking of guidance, don’t be afraid to show/give your clinical teammates a little bit of love. Maybe even send them a pizza to enjoy while watching the FDA's latest Town Hall on (rare disease-focused) gene therapy clinical development.
• You know the saying: it’s better to have loved admired a regulator and “lost” them than to have never loved appreciated their insights at all. Or something like that. All this to say: One of the FDA’s leading CGT figureheads, Wilson Bryan, will be retiring in March.

[BUILD-BUY-HYBRID MANUFACTURING]
I’d never hide your beauty in a box.

• If there’s one thing we can say about the ATMP manufacturing world, it’s that we really don’t like to be boxed into one single manufacturing strategy.
• Though the build vs. buy debate has settled down as of late, I liked Louis Garguilo’s editorial on the in vivo CAR-T company Umoja Biopharma who are currently “working on themselves right now,” but one day hopes to share their life/therapies/dreams with a CDMO partner.
• A few months ago, I published a series of three articles digging into the different perspectives and needs (on both the innovator & CDMO side) informing the ATMP space’s unique “couplings.”
  • Part 1 explores the hybrid manufacturing model from the innovator’s perspective;
  • Part 2 digs into the business model considerations facing CDMOs; and,
  • Part 3 examines what risk-sharing means/looks like in our outsourcing/tech partnerships today.

[CMC TEAM MANAGEMENT]
I “chews” you.

• Asking whether pineapple belongs on a pizza is one topic that will quickly help you determine who your real friends are. (It belongs, btw.)
• Unfortunately the do’s-and-don’ts of pizza toppings were not one of the topics discussed in this (still fabulous) podcast, Best Practices When Building High Performing CMC Teams.
  • Should an hour be too much commitment, I’d point you to my favorite portions of the discussion:
    • 17:30-36:40 — How to communicate what matters to Tech Ops with your C-Suite and your board, and what that looks like/entails
    • 43:30-49:03 — Good habits to embrace & bad ones to avoid as a Tech Ops leader

[mRNA MARKET OVERVIEW]
In the limpid pools of your pepperonis, I see a new shimmering world.

• The mRNA world is far from new and shiny, all things considered. But there have been some resources released lately showcasing just how much the space — for both vaccines AND therapeutics — has grown.
• Exhibit A: This free-to-download (semi-complete) slide deck Beacon Intelligence put together for the recent mRNA-based Therapeutics Summit EU. The available slides showcase the current size of the industry, predominant indications/modalities, delivery vehicles, and a few other factors to background check if you’re not entirely sure what to think about the “new girl/guy” next door. (Free registration required to download.)
• Likewise, this Pharmaceutics journal article on the development and preclinical/clinical applications of protein-replacement mRNA therapies is as well-rounded as a perfectly symmetrical pepperoni.