ARW's C&G + RNA Manufacturing Must-Reads (New Year's Resolutions 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.

In keeping with the theme of a new year — and because today, January 12, is “Stick To Your New Year’s Resolutions Day” — I offer you these must-reads, along with a handful of resolutions for you, in the case you need some inspiration. Only a few them are mine, personally... but I'll let you guess which ones those might be.  

[FDA/COMPARABILITY]
Resolution #1: I will not compare myself to others.

• ...But, uh, first, how are you approaching comparability?
• It’s almost impossible to provide actionable “comparability” practices because such advice will be extremely product/situation specific. But this was still a big topic of discussion during the FDA’s Cell & Gene Therapy CMC Townhalls. Here, I share the FDA comparability recommendations that jumped out at me most during these two separate events.

[INDUSTRY FUNDING]
Resolution #2: I will make more money in 2023.

• (She says confidently, albeit while reluctantly crossing “rob bank” off her list of earning strategies.)
• At least when it comes to ATMP deal making/funding, things have felt a bit touch and go for the past few months — and likely will for the foreseeable future. But this article in Biopharma Dealmakers takes a look back at the still impressive slew of ATMP financing, M&A, and strategic alliance deals made in 2022, arriving at some conclusions about which factors may draw the most deal-making attention moving forward.

[HIRING]
Resolution #3: I will make new friends at work.

• Addendum: This will not mean streaming every season of Friends while at work.
• I really enjoyed this CMC-specific 2022 recap and 2023 outlook. Though this is a well-rounded article covering technology and funding predictions, the author also homes in on which technical skill sets will be most important to have in your/your manufacturing partners’ ranks in 2023.
• This feature — Assessing Workforce Needs for the Emerging CAR-T Cell Therapy Industry — was published in Feb. 2022 but I’m still going to share it because it’s arguably even more relevant today as firms continue progressing farther into the clinic. In surveying cell therapy manufacturing-specific job postings (all of which were from companies with commercialized products), the authors provide young CGT companies with a better sense of where/how much they may need to grow their talent pools to meet future commercial demand.

[FDA/REGULATORY COMMUNICATION]
Resolution #4: I will be touch with my friends and favorite coworkers more regularly.

• Or maybe just watch/listen to them be amazing from afar because human contact still = nope.
• Honestly, my coworkers amaze me daily. In a recent Life Science Leader magazine article, my colleague Ben Comer has published an exclusive interview with the FDA’s Peter Marks, within which Marks shares more details around the FDA’s goals for its forthcoming CGT pilot program. (Free subscription required.)
  • Please note, for the 10 companies selected for the pilot, the FDA would be looking to respond to inquiries within days. Now THAT is a resolution.
• The conversation about communication with and from the FDA continues in my other colleague Erin Harris’ “Cell & Gene: The Podcast” interview with Marks. Though the entire interview fills me with joy, you can always skip directly to what I thought were the most interesting tidbits: from 9:00-12:00 minutes and 16:15-22:00 mins (particularly 18:00-19:00).

[INDUSTRY TRANSPARENCY]
Resolution #5: I will be more generous with my CGT manufacturing knowledge.

• If legal will let me.
• All IP-related jokes aside, I’ve been keeping tabs on the FNIH’s Bespoke Gene Therapy Consortium — and it’s starting to put the pieces in place to align around a “uniform AAV manufacturing process.” In recent news, FNIH has released a request for information to gather information from potential manufacturing partners, as well as more information about eligibility and next steps following the application process/review.
• Mark your calendars for Jan. 24 & 25: The FDA & ASGCT will be hosting a live event on Immune Responses To AAV Vectors. Tune in to hear some of the current thinking and regulatory guidance on this critical topic.
• “Practice more intellectual generosity” was one of four best practices I gleaned from an ASGCT/ARM potency assay working session. In addition to discussing the many scientific and analytical challenges of demonstrating the potency of our ATMPs, this session revealed a few best practices to make our analytical efforts a much less daunting challenge.

[CAPACITY OUTLOOK]
Resolution #6: I will embrace hopefulness and optimism about the state of the world.

• That’s a lovely resolution. I’ll be sure to wave at you from the corner with all my fellow pessimists.
• Though it took place in late October, this Outsourced Pharma Live discussion "What’s Driving The Cell & Gene Therapy Outsourcing Capacity Cycle?” is still a highly relevant and optimistic discussion on the state of capacity in the outsourcing market today. (And it’s segmented into a dozen smaller installments for more selective listening.)
• But the outsourcing sector can’t stop growing yet; as my 2023 mRNA/RNA Outlook article explains, establishing the necessary supportive manufacturing infrastructure was one of several important “to dos” for the mRNA/RNA industry in 2023 (and beyond).

[PRODUCT QUALITY]
Resolution #7: I will be pure of heart.

• Or at least I’ll make sure my products are more pure.
• Over the past few months, I’ve amassed a collection of quality-related materials, including:
  • The British Pharmacopeia’s consultation document on the characterization of the particle population in AAV products. Comments are open until January 31!
  • Keeping on the AAV train, you can also check out Assessing Production Variability In Empty & Filled AAV by Single Molecule Mass Analyses, which evaluates the use of mass photometry (MP) and charge detection mass spectrometry (CDMS) in characterizing AAV8 and AAV2.
    • This is an oldie-but goodie Cell & Gene Collaborative article reminding and/or alerting you to this ongoing USP/NIST/NIIMBL effort to figure out the best analytical approaches for measuring empty-full capsid ratios.
  • If one of your resolutions is to better understand the integrity/composition of your mRNA-LNPs in the new year, this review explores the use of anion exchange and ion-pair reversed phase (IP-RP) liquid chromatography, as well as oligo mapping, 5’ endcap testing, and lipid compositional assays.
  • If “get my mRNA to express more protein!” is also one of your goals for this year, I’d like to reshare this piece from our comrades at Ultragenyx, who highlight the IVT improvements they made which resulted in a reduction of dsRNA and, in turn, a simplified purification process and “more efficient” protein expression.
  • We also have our good friends at Moderna to thank for this article sharing how they developed an engineered (or “mutant”) T7 RNA polymerase. They argue that modifying T7 RNAP is an important strategy for reducing dsRNA production and for streamlining mRNA manufacturing.