ARW's CGT+RNA Manufacturing Must-Reads (BAD PICKUP LINES 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.

Occasionally, I have readers who will go above and beyond and suggest potential themes for future newsletters. This week, you can “thank” a fellow reader for recommending “bad pick-up lines” as the creative theme. Regardless of your relationship status, please let these “charmers” be a reminder to love the one you’re with and/or yourself. Or, if you’re allergic to affection of any kind (#preach), let these must-read articles be your excuse to keep avoiding all human contact. Here’s to keeping ATMPs sexier than these pick-up lines.

You are hotter than the bottom of my laptop.
[COMPARABILITY]

• Though we may all secretly hope someone will say this to us, when it comes to our ATMPs, please note: a significantly “hotter” (i.e., a much higher quality post-change product) may not actually be “comparable"... according to page 2 of the FDA’s comparability guidance.
  • Can I get a “yay” for… mediocrity?
• For those of us who are dedicated to improving our therapies’ quality and/or scalability via process changes, we were recently privy to an incredible case study on comparability via the Sarepta gene therapy adcom meeting. Here, in part two of this two-part article, I outline the basics behind the change and why Sarepta ultimately had to perform a clinical comparability study.
• For those who want a nice refresher on the FDA’s comparability guidance itself, I’d refer you to this BDO blog post that walks us through some of their high-level takeaways and best practices.

Want to go half on a baby?
[OUTSOURCING]

• I’m good, thanks — but, given some of the innovative risk-sharing/contracting practices happening in the CGT outsourcing world, I daresay you could find a CDMO who’d dig this question.
• If you’re looking to get a better (i.e., more quantitative) picture of gene therapy CDMOs, Industry Standard Research recently released its 2023 Gene Therapy CDMO Benchmarking study. Though it costs as much to read as having an actual baby, I hate to break it to you — the best things in life just aren’t free.
• Speaking of innovative outsourcing models, kudos to my colleague Louis Garguilo of Outsourced Pharma for providing a look into the rise of the “cleanroom on demand” or “bridge facility” outsourcing model. Though it’s a few months old, it’s a worthwhile refresher on how leading companies like Moderna have employed hybrid outsourcing strategies.

Do you believe in love at first sight, or should I walk by again?
[FACILITY SITE SELECTON]

• For what it’s worth, you should always make someone walk by again, and again — the bigger the crowd watching, the better.
• In fact, some might argue there is no such thing as love at first “site,” for a variety of different reasons. Check out this blog post that provides a number of important CGT facility site-selection tips, including (but not limited to) how to establish your manufacturing baseline needs and site assessment checklist.

Did it hurt when you fell from the vending machine? Because you look like a snack.
[mRNA CHARACTERIZATION]

• I’ve always dreamt of finding someone who looks at me the way I look at a sprinkle donut.
• Speaking of ogling, there’s a lot of exploration being done to better understand mRNA’s “assets.” For a wide-ranging exploration of the pros and cons of the different methods being used to characterize mRNA today, check out this review article from Mass Spectrometry Reviews.
• But if you want to get even more up-close and personal, check out mRNA’s [poly A] tail:
  • Journal of Pharmaceutical and Biomedical Analysis: A Single-Nucleotide Resolution Capillary Gel Electrophoresis Workflow for Poly(A) Tail Characterization in the Development of mRNA Therapeutics and Vaccines
  • Analytical Chemistry: Liquid Chromatography Methods for Analysis of mRNA Poly(A) Tail Length and Heterogeneity

If you were a booger, I’d pick you.
[STANDARDS]

• It’s always good to have high standards.
• As we all will readily admit, there are a variety of areas in which our industry needs to become more standardized. For those of us on the autologous cell therapy side, this was a great article outlining several different organizations’ current efforts to standardize apheresis site qualification/site auditing and product labeling.
• A few months ago, USP quietly released the second edition of its Analytical Procedures for mRNA Vaccine Quality guidelines. It’s worth noting that USP heeded the industry’s calls for greater insights into mRNA-LNP drug product — not just mRNA drug substance — in the second edition guidelines. This BioProcess Online article predominantly breaks down what we currently know about mRNA DS and DP CQAs, as well as the revised lists of methods to explore for mRNA characterization and release.

You dropped something... my jaw.
[INSPECTIONS/COMPLIANCE]

• Hopefully the first time you heard this phrase it wasn’t coming from an FDA or EMA inspector during a tour of your facility.
• But in the case that it was… perhaps you’d like to attend a webinar on “Inspection Readiness, Management, and Response: Best Practices and Strategies for Successful Regulatory Inspections.”
• At the end of August, Annex 1 went into effect. A few weeks ago, PDA sent out a survey to learn more about the industry’s anticipated response to and/or potential barriers to implementation/maintaining compliance. The results of this survey can be found here.
• This roundtable article in American Pharmaceutical Review continues to dig into the ripples caused by Annex 1, homing in on the current state of microbiology operations and contamination control. I particularly appreciated the experts’ insights on how ATMP development is/should be impacting companies’ microbiology operations and the rising importance of implementing rapid microbial methods and/or PAT/automated release testing to maintain compliance.

Well, here I am. What are your other two wishes?
[RNA DELIVERY]

• It’s kind of fun to imagine a world in which our therapies say exactly this when they arrive at the organs/cells of their (our) dreams.
• Over the past few weeks/months, I have amassed a stash of RNA therapy delivery-related articles. As the genie of this newsletter, I’ll be generous and grant you a whopping five articles instead of a measly three:
  • “Emerging Circular RNA Field Split On What To Deliver & How To Deliver It” (subscription required to read)
  • Targeted Delivery of Oligonucleotides Using Multivalent Protein-Carbohydrate Interactions (Jan. 2023)
  • Review article: Targeting Cancer with mRNA-LNPs: Key Considerations & Future Prospects the full text of which can be found via this LinkedIn post.
• Engineered Lentivirus-derived Nanoparticles (LVNPs) for Delivery of CRISPR/Cas RNP Complexes Supporting Base Editing, Prime Editing, and in vivo Gene Modification
• Hydrogels for RNA Delivery

If you were a flower, you’d be a damnnnnn-delion
[PODCAST RECS]

• I love me some good word play.
• If you enjoy listening to people saying words to you instead of singing them — also known as a podcast — here are a few recommendations, starting with my colleagues’:
  • Erin Harris’ Cell & Gene: The Podcast — the latest guest of which was none other than the FDA’s Peter Marks, who walks us through the current regulatory landscape for base and prime editing.
  • Matt Pillar’s Business of Biotech Podcast. He most recently featured the CCO Dan Kirby of cell therapy company Orca Bio. If you’re preparing to move into pivotal trials and thinking about commercialization, this one is worth a listen.
• Quality folks, be sure to check out the lineup at the newly launched, “Let’s Talk Quality: The Podcast,” hosted by Hemish Ilangaratne. Episode one on scaling quality functions featuring Sangamo’s Chief Quality Officer and Episode 2 on adapting, overcoming, and improvising as a quality leader with the VP of Mustang Bio caught my eyes in particular.
• The Drug Solutions Podcast hosted by the Association for mRNA Medicines’ founder Chris Spivy recently featured the CIO of Maravai LifeSciences and the CEO of Acuitas Therapeutics discussing the past, present, and future of mRNA.