ARW's CGT+RNA Manufacturing Must-Reads (Epitaph 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.

Though there were a lot of great holidays to choose from for this newsletter’s creative theme, I just couldn’t tear myself away from the truly bizarre “Plan Your Epitaph Day.” As you ponder the legacy for which you’d hope to be celebrated in the far future, I’ve grouped each of your manufacturing must-reads under several 100% real epitaphs that also — believe it or not — nicely describe the themes and challenges we’re facing in the ATMP manufacturing space today. May you read in peace.

[MANUFACTURING COGS]
“COGS: Spent, But Never Forgotten”

• Ok, I made this one up. But if we want patients to benefit from all our hard work, we must take this “epitaph” to heart and never forget the importance of achieving greater cost efficiencies.
• It’s hard to get too deep in the weeds on COGS given the intricacies of our individual products. But this certainly didn’t stop Dark Horse Consulting’s Katy Spink from drilling into the topic a bit more deeply with me in a recent conversation. In one of my latest columns, I share a few of Spink’s “words of wisdom” on how to evaluate your COGS levers throughout development.

[QUALITY]
“Grace, dignity, and elegance personified.”

• If we cannot use these words (originally describing Joe DiMaggio) to also characterize the state of our supply chain & raw materials, what are we doing with our lives?
• The long-gone but still celebrated Italian violin makers of the early sixteenth century had a thing or two to teach us about going to great lengths to obtain high quality raw materials. Check out my newest “ARW on RNA” video, in which I explore the ways in which violin making is akin to the process development work we’re doing to arrive at the highest quality mRNA drug substance(s).
• Though it’s been tenuous at times, we are luckily getting more resources dedicated to helping us better understand and evaluate the quality of our raw materials. Most recently, the International Pharmaceutical Regulators Program (IPRP) released a reflection paper comprising general recommendations on how to evaluate raw material quality (i.e., grade) and define a material’s quality attributes. The paper also identifies where we may run into challenges with commonly used CGT raw materials.
  • ICYMI, this reflection paper is a good companion piece to some of the FDA’s GMP-oriented recommendations I captured following the 2022 cell and gene therapy town halls.
• Don’t forget the other still-existent and relevant raw material- and GMP principle-centric documents that can help us out:
  • EMA: Q&A on principles of GMP for the manufacturing of starting materials of biological origin used to transfer genetic materials for the manufacturing of ATMPs (2021)
  • BioPhorum: Raw Material Risk Assessments (2019)

[REGULATORY]
“Goddamn you all: I told you so.”

• Please note, H.G. Well’s words here are (probably) not the best way to justify our efforts to our FDA CMC reviewers.
• This statement will also (most likely) not come up during the FDA’s next Gene Therapy CMC Townhall, which will be taking place on April 25, 2023 from 11:30 AM-1 PM ET.
• As of last Saturday, the FDA’s CMC Development and Readiness Program (CFRP) is open for applicants. For those of you craving additional FDA interaction, be sure to review the scope of this pilot to see if your program is eligible.
• In general, efficiency has been top-of-mind for the FDA as of late. As Peter Marks explained in one of his slides at the Gene Therapy for Rare Disorders conference last month, accelerated approvals for gene therapy, concurrent submission and product review with regulatory authorities, and the Operation Warp Speed for Rare Diseases communication pilot are three of CBER’s main focuses these days.
  • Speaking of concurrent submission/product review: if you’re hoping to work with both EMA and FDA but don’t quite know how to make the EMA-FDA Parallel Scientific Advice (PSA) program work for you, check out this fantastic publication explaining the “why” and “how” of the PSA, as well as several best practices for sponsors applying for the program.

[mRNA REGULATORY]
“[Moderna] did it the hard way.”

• Ok, yes, I took a few creative liberties here with Bette Davis’ epitaph... but if Bette had heard Moderna’s presentation on the work it took to document, submit, and amend the regulatory documentation for its mRNA vaccine, I daresay she’d be cool with my amendment.
• Of course, we won’t all have to do it the same way Moderna did. In fact, as I argue in my first of three takeaways from Moderna’s regulatory CMC-centric presentation, it’s probably a blessing that one of our challenges ahead will be bracing for more realistic post-pandemic regulatory interactions.

[ANALYTICAL DEVELOPMENT]
“To see a world in a grain of sand/ and a heaven in a wildflower/hold infinity in the palm of your hand/and eternity in an hour.”

• If you were thinking this is just a wordy poem by William Blake and not an epitaph, well then, congrats on passing English Literature 101 in college.
• Blake may not have been writing about the time, effort, and importance of developing a matrixed potency assay to “see a world and a heaven in [your therapeutic],” but luckily the Alliance for Regenerative Medicines/ASGCT have done this for us in their brand new white paper sharing the industry’s biggest potency assay-related concerns/challenges/opportunities discussed during a working session last fall.
  • If potency assays are causing you significant grief and you’d like to continue dwelling on the strife, I see you and refer you to my previously-shared write-ups on this same ARM/ASGCT workshop — albeit it, with infinitely more melodramatic titles/article images:
    • CGT Potency Assays: When Will We Wake Up From The Nightmare?
    • Overcoming CGT Potency Assay Woes: Four Best Practices
• In other heavenly analytical news, the British Pharmacopeia Working Party for ATMPs has released a draft guidance for T Cell & NK Cell Characterization assays. Be sure to submit any feedback you may have for MHRA/BP by May.

[PROCESS INTENSIFICATION]
“Let ‘er rip!”

• In addition to letting regulatory and cost-related efficiencies “rip” (Preach, Leslie Nielsen), here are a handful of journal articles I’ve found lately showcasing the technological/process-related improvements being explored today:
  • “Toward Autonomous Production of mRNA Therapeutics in the Light of Advanced Process Control and Traditional Control Strategies for Chromatography” (https://bit.ly/426A1eL)
  • “Process Improvement of AAV Production” [to support large-scale preclinical animal studies in labs] (https://bit.ly/3G5qbjB) [Jan. 2022]
  • “Machine Learning & Metabolic Modeling-Assisted Implementation of a Novel Process Analytical Technology in CGT Manufacturing” (i.e., LVV production) (https://go.nature.com/3JlzKwO)
  • “Process Intensification for LVV Manufacturing Using Tangential Flow Depth Filtration” (https://bit.ly/3G4vSyv)