Your C&G Manufacturing Must-Reads (Philly Cheesesteak 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 C&G therapy manufacturing, in particular, and/or other C&G 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. But inboxes can be shifty places. (Cue George Carlin on “Losing Things.”)

So, here’s a “permanent” copy of my C&G Manufacturing Must-Reads newsletter that was delivered on March 24, for all you practical people who, like Carlin, abhor the question, “Where is it?”

As March 24^th just happened to be National Cheesesteak Day, this is the “Philly Cheesesteak edition” of your manufacturing must-reads, in honor of our many friends in “Cellicon Valley”/Philadelphia. As I’m based in the lowly western half of PA (a.k.a. Pennsyltucky) and pledge my loyalty to Pittsburgh’s Primanti Bros sandwiches, I turned to some real Philadelphians to get the lowdown on all the cheesesteak gossip — of which, by the way, there is an absurd amount.

The Art Of “Franchising” Your CGT Manufacturing Paradigm

• It's sacrilege to take the “Philly” out of “cheesesteak” and replace it with any other city. But for CGTs to be successful, we must be able to reproducibly manufacture a CGT across the globe. Your fellow Cell & Gene Collaborative “Cellebrity,” Ken Chrobak, VP of CMC for allogeneic cell therapy firm Wugen, filled me in on all the hard work he and his team are doing to establish a global commercial manufacturing infrastructure.

Swiss Cheese Is NOT An Option: Be The “Whiz” Of Your Supply Chain

• For another perspective on scaling-up, this great write-up touches on a variety of stem cell manufacturing topics — most notably how companies can prepare to transition into Phase 3 and confront the “killer costs” associated with increasing raw material quantities and QC. Those two factors are just as terrifying as the Cheez Whiz label.
• Flashback to when I talked with the Ludek Sojka, CTO of SOTIO, about who should be at the [lunch] table when discussing and forecasting your raw material needs, and how these discussions pave the way for more cost-effective supply-chain management.
• This article by two USP experts and an expert from South Korea's NIFDS is a goldmine of information. In addition to summarizing ongoing efforts to align around raw material standards, the article also dives into tips on analytical comparability and emerging raw material QC methods that came to light during an Oct. 2021 ATMP workshop.
• The Video Journal of Regenerative Medicine has been posting a smorgasbord of brief video clips from interviews carried out during Phacilitate's Advanced Therapies Week. This quick, two-minute clip outlines what firms will need to do to implement a patient-centric supply chain, especially as definitions of raw materials continue evolving/clarifying.

“Wit or Witout [Onions]?” The Essential & Nonessential Ingredients Of A CDMO Partner

• Following Life Science Connect's 11th annual CMO Leadership Awards, Industry Standard Research dug into which performance metrics matter most to those selecting CDMOs today — and how those preferences have shifted over the past 5 years. Capacity, quality, and cost have all been bumped up in the priorities line, but what are they cutting in front of?

“Fresh, Never Frozen” Is Just For Ribeye — Let's Freeze-Dry The AAV

• Some folks at Biogen have published an intriguing paper in the Journal of Pharmaceutical Sciences outlining the lyophilization process of AAV8. Just like any great cheesesteak sandwich requires a well-marbled piece of meat, your AAV requires the perfect ratio of temperature and moisture to emerge from lyophilization as its best, most stable self. [Subscription required]

“Finely Sliced Or Shredded?” FDA Adds More Meat To The Gene Editing Discussion

• In a sudden burst of CGT-centric productivity, the FDA released two draft guidances last week. Because reading guidances is hard, I'm still digesting the one on CAR-T. So, firstly, here are a few key takeaways to note on the Human Gene Therapy Products Incorporating Human Genome Editing draft guidance.
  • Some analysts have declared this guidance to be as benign and unspectacular as "Geno's Steaks" and "Pat's King of Steaks" may be to actual Philadelphians. But it's still just as iconic.
  • The gene editing (GE) menu spans nuclease-dependent (i.e., CRISPR-Cas, TALENs, zinc fingers, meganucleases) and nuclease-independent technologies (i.e., base editing or synthetic triplex-forming peptide nucleic acids).
  • Most public discussion on the guidance so far homes in on the clinical portion of this guidance. To play it safe, FDA recommends that sponsors stagger trial enrollment and observe trial participants for 15 years. (None of this is new information to those in gene editing, btw.)
  • Risk vs. benefit of a GE therapy remains a key consideration for the FDA. This ratio will vary across indications.
  • On the CMC side, there's some juicy discussion of what the FDA would consider a drug substance vs. the drug product (p. 5). Delivery seems to play a large role here.
  • Got RNA/DNA/proteins being delivered in-vivo by nanoparticles? The GE components are a drug substance. Got the GE components delivered in vivo by viral vectors or plasmids? The GE components are the DP. Got “certain” nanoparticles delivered in vivo? These NPs may be considered a delivery device (p. 7).
  • No surprise here, but the quality of the reagents used when manufacturing the GE component are heavily stressed and must be thoroughly documented and/or referenced. FDA is open to a phase-appropriate approach, emphasizing GMP for later stage clinical development.
  • The guidance breaks down the intricacies of testing ex-vivo and in-vivo GE DPs (pp. 7-9), focusing specifically on nanoparticle development for in vivo delivery (e.g., formulation, the CG component's incorporation efficiency), and stability and potency for both in- and ex-vivo candidates.
  • Allogeneic cell therapies that have some element of ex-vivo genetic editing may warrant more “extensive analysis” of donors, purity, on/off-target GE events, etc., (p. 8-9).