Blog | July 1, 2022

ARW's Cell & Gene Manufacturing Must-Reads (Asteroid Day Edition!)

Anna Rose Welch Headshot

By Anna Rose Welch, Director, Cell & Gene Collaborative
Subscribe to my blog ARW on CGT here!


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.

When this newsletter was originally sent on June 30th, the world was celebrating “Asteroid Day.” I know that sounds like an extremely odd thing to “celebrate.” However, before you run to the nearest bunker, you should know that Asteroid Day is actually a real, UN-sanctioned global awareness campaign that is an “annual brain dump of everything related to asteroids” (i.e., asteroid science, research, tracking, characterization, and defense).

Naturally, I couldn’t think of a better way to celebrate “Asteroid Day” than by turning your C&G + RNA manufacturing must-reads into a similar “awareness” campaign to keep your own development efforts up-to-date and “asteroid-safe.” Below, you’ll find several very over-the-top “development doomsday” scenarios and the corresponding “life-line” articles that should be included in your (bunker?) libraries. Enjoy — and stay safe out there.

Doomsday Scenario #1: “I woke up this morning in a manufacturing facility and I don’t remember who I am or how to science.”

  • Step 1: Don’t panic. We’ve all been there.
  • Step 2: Check out my conversation with Mark Gergen, CEO of Poseida Therapeutics, who reminds us that it’s important to embrace our inner Renaissance man/woman/human and see things through multiple lenses — especially in the manufacturing world. It’s only in stepping farther back from a scientific and engineering problem and approaching it as a generalist that we’ll best be able to mature the CGT manufacturing paradigm. In the article above, he shares his thoughts on which manufacturing advancements/decisions can benefit the most from this generalist approach.

Doomsday Scenario #2: Our favorite vendor just introduced us to their “facility pet,” Peggy, the python. Peggy loves bioreactors.

  • If that’s not an advertisement for single-use, I don’t know what is.
  • Honestly though, you’re not the only one who has a snake charmer on speed dial. Figures out of the FDA suggest the agency has been having a hard time following up with manufacturing facilities after they’ve been inspected. Out of the 70 % of follow-up letters sent in 2021, the agency has only completed regulatory actions for 48 % of them. That’s down from 78% of classification letters sent and 63% of regulatory actions completed in 2020.
  • As a source in this article points out, biotechs should make sure they have well-stocked and dual-source supply-chains because such a lag in FDA oversight could impact their partnerships and the supply of certain critical raw materials/supplies in the future.

Doomsday Scenario #3: Our newest hire just held a vial of our drug product up to the light and said, “It looks clear to me.”

  • That certainly takes “voluntary consensus standards” to a whole new, disturbing level.
  • Sure, your new hire’s laser-strength eyesight may be the least arduous method for characterizing your product…but the FDA recently outlined its plans to recognize certain standards in its “ Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies” draft guidance.
  • In this guidance, the FDA shares how it will evaluate and recognize voluntary consensus standards and how ATMP companies can document standards in their regulatory documentation. Following the industry comment period and publication of the final guidance, CBER will publish a list of “recognized standards” to help guide ATMP companies’ choice of standards for a (potentially) more streamlined and predictable review process.

Doomsday Scenario #4: Tom Cruise will be starring in our FDA AdCom Meeting to determine the risks vs benefits of our therapy. He cited his performance in “Risky Business” as preparing him for this “role of a lifetime.”

  • So much for him not wanting to “spend the rest of [his] life in analysis.”
  • We can at least celebrate that the FDA put together a draft guidance on “ Benefit-Risk Considerations for Product Quality Assessments,” AND that we also have some smart, helpful brains giving us the “spark notes” version of this guidance and its potential impact. While you do all the hard CMC work upfront so your FDA product quality-related assessments — and, eventually, your future advisory committee meetings — are low stakes, let’s just keep Tom Cruise locked away in detention.

Doomsday Scenario #5: I think we’ve done it! We proudly present the first syringe that a patient can use to self-administer their gene therapies directly to ANY organ of their choosing.

  • NOPE.
  • While I applaud your desire to embrace patient centricity, it’s always good to be reminded that one size/tool does not fit all — especially when we’re talking about delivering an advanced therapy. This article is a great overview of the advances being made and benefits of several different delivery systems, including lipid nanoparticles, microneedles, cellular delivery, and cell squeezing.
  • Of course, let’s not forget about the vectors. A few months ago, McKinsey published a white paper digging into the three major challenges impacting scale-up of viral vectors for larger indications — namely production system selection, downstream processing optimization, and CMC standardization. But before you get weary of all these challenges and go back to your aforementioned six to 20 inch-long needle option, the folks at McKinsey also have five strategic considerations to help your company plan to meet the needs of larger patient populations.

Doomsday Scenario #6: LNPs have been declared the “Official Delivery Vehicle” of the mRNA space. #LNPs4EVA

  • At least that hashtag makes for a catchy bumper sticker.
  • But for those of you wondering why such a statement is equivalent to a “doomsday” scenario, I think this article provides a really interesting “hot take” on why the success with mRNA vaccines using LNP delivery may have actually stymied long-term mRNA therapeutics development.
  • This article is about more than just delivery though — there are some provocative tidbits about how the supportive manufacturing infrastructure and its related costs and the mRNA industry’s pipeline development/market competition could evolve (perhaps for the worse) in the long-term if our development and commercial strategies don’t evolve accordingly.

Doomsday Scenario #7: … Someone left an anonymous love poem in my BSC comparing my freckles to nanoparticles that went straight to their heart...

  • I’m sorry, I just couldn’t help myself. *Cough*
  • Anywho ... I never thought I’d call an article on nanoparticle characterization “riveting,” but considering I’ll be having a small group discussion with USP on mRNA analytical characterization next week, there were some snippets here that served as worthwhile primers on the tools being used today to characterize the nanoparticle portion of a nanovaccine’s (NV) formulation.
  • This article primarily proposes characterization strategies for NVs as opposed to therapeutics, the latter of which will, of course, have their own analytical nuances and (quite different) immunogenicity assessments. But if analytics and/or delivery excite you, then you and your freckles will love reading this.

Doomsday Scenario #8: Only the wealthiest countries have access to advanced therapies.