ARW's C&G Manufacturing Must-Reads (GIANT RODENT! 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 April 7 for all you practical people who, like Carlin, abhor the question, “Where is it?”

Though April 7 offered a lot to celebrate, including National Burrito Day, National Beer Day, and No Housework Day, it was also International Beaver Day. After googling why we’d ever celebrate such a thing, I couldn’t help but be charmed by the eloquence of the holiday’s overall mission: To “celebrate and raise awareness of the plight of the rodent.”

So, this is your “GIANT RODENT!”- themed newsletter on the many plights of CGT manufacturing (with some unbelievable facts about beavers thrown in for good measure).

Why It Doesn’t Pay To Be An “Eager Beaver” In CMC

• I love to ask CGT CMC experts what advice they’d give themselves if they could “swim back upstream” to the start of their CGT manufacturing journey. I daresay we can liken this advice on incremental innovation from Wugen’s VP of CMC Ken Chrobak to the methodical process of chipping away at a tree using only your teeth [a.k.a. crudely closed, partially automated equipment] and constructing your house [therapy] one stick [priority] at a time.

CGT Industry Building Bigger Dams Amidst Changing Ecosystem: Slap-Happy Or Pragmatic?

• There’s been a lot of chatter about a potential slow-down in biotech venture capital funding. Forbes has a great article outlining how firms seeking Series A and Series B funding are experiencing a slight slow-down or pullback, but common opinion (in this article at least) is that the beavers aren’t & shouldn’t be slapping their tails to warn of danger just yet. 
• That said, CGT companies have been more regularly announcing layoffs to keep the funding pool deep enough to sustain longer-term development. Recent examples include Bluebird Bio, Orchard Therapeutics, Taysha, BridgeBio, and Passage Bio.
• This funding pullback could potentially signal we’re reaching a key inflection point in which investors and, in turn, the many companies entering the CGT market today are more closely scrutinizing what success should/could look like for a young CGT biotech.
• “Splash-back” to this lively and somewhat spicy conversation with Bob Hariri, CEO of allogeneic cell therapy company Celularity, who broached the topic of industry consolidation with me last year in our article, “Is the CGT industry too diluted to sustainably scale manufacturing?”

Manufacturing Failures: The 220 Lb. Ice Age Beaver In The Room

• Though we can be thankful beavers are no longer bear-sized (insert teeth gritting emoji here), there’s still a lot of room for CGT players to grow more analytically savvy to reduce out of spec product releases/manufacturing failure rates. Look no farther than this gem of a competitive analysis piece which revealed the impressively large (18 percent) manufacturing failure rate of this recently approved cell therapy. Then, for more context, compare that product’s 18 percent to its competitor’s failure rate of 1.5 percent. [Free subscription required]

Beavers’ Orange Teeth Pale In Comparison To This CGT Research

• Sure, a beaver may have third eyelids that act as goggles and nose and ear valves that shut to keep out water. But in the CGT industry, researchers have also been evolving the laborious autologous CAR-T development paradigm using an implantable subcutaneous scaffold to engineer and deliver CAR-T therapies in vivo — all in a single day. Take that evolution. [Subscription required — unless you just want to read this thorough and free article outlining the research.]
• Shut off the Iron Maiden and Judas Priest and cue Handel’s “Water Music.” Your HEK293T cells will (sort of) thank you.

If FDA Can Approve A Beaver’s “Vanilla Goo,” Surely Your CAR-T Product Is Next

• I can’t wait to read the industry’s comments on the FDA’s newly released draft guidance, “Considerations for the Development of CAR-T Products.” So much attention has been lavished on the gene editing guidance that it’s almost as though this guidance didn’t happen. So, here are just a few broad CMC observations/best practices I chiseled out from this massive guidance.
  • Pay no attention to the giant CAR-T in the title; for the folks working with CAR-NKs and/or TCR-modified T-cells, this guidance and the recommendations within are still broadly applicable to you.
  • Though CMC moves in this industry, FDA seems cognizant that a lot of information will be unknown at the time of IND. This means that CMC information may be submitted and that GMP manufacturing may be tackled in a “stage/phase-appropriate” manner (p. 6). However, I’d bet a kit (baby beaver) that “stage appropriate” will mean something different to everyone.
  • Go nuts with characterization early on to really fine-tune your release criteria (p. 6); after all, one of Cell & Gene Collab’s New Years Resolutions touched on why this is important, as well as why companies shouldn’t be afraid of what the FDA may ask you to do with this early characterization info.
  • FDA expects you to have a very clear picture of what is packaged in your viral vectors, and this guidance continues to emphasize that clearly. In my words, FDA advises folks to not get too carried away with unnecessary or unjustified “bells and whistles” (e.g., “unnecessary” transgenes, or unsupported inclusion of suicide genes, t-cell persistence elements, etc.) (p. 4).
  • The analytical discussion continues on page 11, reminding us of the (easier said than done) importance of having adequate samples with which a company can compare changes in assay methodology and/or for comparability. In general, FDA is a big proponent of splitting donor leukapheresis into two portions to enable side by side testing of old and new processes (p. 18).
  • That said, they also drop in this intriguing little nugget about the potential of using healthy donor CAR-T cells for conducting comparability for autologous CAR-T products — in some instances (p. 18).
  • Oh, comparability (p. 16). There are three specific instances FDA outlines as being major changes warranting more “robust” comparability studies: switching to a new facility, moving from adherent to suspension for vector production, and changing the concentration/type of growth factors in cell culture media.
  • The guidance’s focus on multi-site manufacturing and multi-site analytical testing is particularly notable, especially given the MHRA’s guidance on POC manufacturing last year.
  • The FDA emphasizes multi-site manufacturing would best be supported by using the same SOPs, training, equipment, and ancillary materials (if possible) AND by defining CQA acceptance criteria to ensure analytical comparability of products manufactured across multiple sites.
  • Page 27 outlines the clinical protocols to follow in the case of manufacturing failures, which further exemplifies just why it’s so important for manufacturing and clinical teams to be in sync.