ARW's Cell & Gene + RNA Manufacturing Must-Reads (Mac & Cheese 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.

When I sent this newsletter on July 14, it was National Macaroni & Cheese Day. Because I celebrate anything and everything that has to do with cheese, I put together a step-by-step guide to making yourself and/or your family dinner tonight, along with a few tips to keep your ATMP manufacturing on track, too. As you will likely note, the words “Grab the box of KRAFT” do NOT appear anywhere in these instructions. Lyophilization has its place, but it is most certainly not for cheese. And if you’re lactose intolerant, don’t worry, this newsletter is 100% dairy-free. Enjoy!

Step 1: Pick your favorite recipe & acquire the necessary ingredients

• You may be thinking you don’t need a recipe for “just” a pot of noodles and cheese. But such over-simplification has no place in the culinary world — let alone in your regulatory interactions. As this post on LinkedIn from an FDA CMC reviewer hints, asking the agency broad, vague questions will get you broad, vague answers.
• Luckily, if you are new to FDA meetings protocol or would like a good refresher, the FDA is dishing out some best practices on its *new* webpage: “Interactions with OTAT.” There are resources/tips specific to each type of meeting, including INTERACT, pre-IND, Type A, B, C, and pre-BLA (among other) meetings.

Step 2: Figure out just how many pounds of pasta you’re going to need

• Oh, scale-up. It’s as important a concept in the kitchen as it is in the manufacturing facility. However, sometimes, you may only be cooking for one or two which has its own scale/incentive issues. Hence why the FDA’s Peter Marks has been touting the importance of the Bespoke Gene Therapy Consortium which aims to establish an “operational playbook” (templates) for more efficient development, manufacturing, and regulatory submission/review of AAV gene therapies for 5 to 6 of these rare diseases.
• Of course, before we streamline vector testing/development/delivery, we need to understand AAV biology better. The BGTC has released several RFPs outlining AAV gene expression and vector production-related research objectives. These RFPs will be discussed in a free webinar TODAY, 7/14, that will, luckily, be recorded and shared via the BGTC website later this month.

Step 3: Bring your water to a boil and take care to not overcook (or undercook) your pasta

• There is truly no better analogy for what an FDA guidance should be than the cooking guide for a noodle. You want your pasta to be “toothsome” but not too crunchy or reduced to slimy mush. This is basically what you all said to the FDA in your comments on the CAR-T Cell Therapy Products draft guidance.
• Ok, I exaggerate. If you want to forge through the extensive commentary yourself, here are some spoonful-sized summaries of where the guidance may be half-baked. The first 7 pages of ARM’s comments are also a clarifying, worthwhile read.

Step 4: Make your roux/ béchamel

• The base of any good béchamel-based mac & cheese is a roux — that magical combination of butter and flour that transforms milk into a thick béchamel. Likewise, Industry 4.0 promises great transformation for pharma. I loved this breakdown of the opportunities and challenges of pursuing Industry/Pharma 4.0 and how to chip away at improving your technical infrastructure if you’re a smaller, resource-strapped company.
• Over the past few months, there have been a couple of initiatives worth noting to advance the industry’s experience with digital manufacturing technologies. This includes McKinsey’s newest CGT-specific Digital Capabilities Center in NJ and the Robotic Manufacturing Consortium , which is focused specifically on industrializing cell therapies.

Step 5: Add your cheese. Then add more. If you think you have too much, it’s probably still not enough

• For all my Schitt’s Creek fans out there, “Just fold in the cheese… I don’t know how to be any clearer!” (This is hands-down one of my favorite scenes from the show.)
• Just as David Rose didn’t know how to begin “folding broken cheese,” your analytical team is facing pressing questions about measuring a CGT’s potency. Luckily, the APEC-USP Training Center of Excellence hosted a bioassay training program sharing potency assay best practices and case studies. Here is a write-up of the key takeaways from the session, or you can view the session for free by registering/signing into the USP Access Point.
• Though my advice for adding an “infinite” amount of cheese is the exact opposite of what we strive for in making any product, there cannot be noodles in our casserole that aren’t completely full of cheese. We can (sort of) say the same thing about our AAV.
• Dark Horse Consulting recently published a Q&A discussing their recently proposed draft guidance on AAV full-empty capsid ratios. But why limit our palates to just full-empty? As the authors explain, there are a few other just-as-important AAV impurities and CQA-centric questions that could use more attention/resources.

Step 6: Don’t be afraid to get fancy with your ingredients/toppings

• Butternut squash, buffalo chicken, truffles, lobster… synthetic plasmids? There are a lot of ways to dress up mac & cheese, and based on the latest news in the mRNA space between Pfizer & synthetic DNA company Touchlight, the ATMP industry is hungry for alternative critical raw material options.
• In fact, back in a 2022 CGT manufacturing outlook article, one Renovacor executive specifically pointed to synthetic DNA as an area that could have great influence on reducing CGT/mRNA therapeutics’ COGS — but only if more options become available.

Step 7: Devour your delicacy — you deserve it!

• But take care that you don’t burn your mouth. This is just one of the many short-term (albeit benign) risks of a steady diet of mac & cheese. To understand the complexity of evaluating risk vs. benefit, check out part one of a three-part series on bluebird bio’s adcom in which I discuss how the committee members approached the risk vs. benefit ratio for bluebird’s two gene therapies and what this may mean for your own ATMP after commercialization.
• For another real-life look at risk vs. benefit, this Atlantic article on the how, why, and huh?! of one gene therapy patient’s changing hair color is an intriguing read.

Step 8: Outsource the dishes & clean-up to your kids or partner. It’s good for them.

• Really though, who doesn’t love some good outsourcing trends/stats for dessert?