By Anna Rose Welch, Director, Cell & Gene Collaborative
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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
Step 5: Add your cheese. Then add more. If you think you have too much, it’s probably still not enough
Step 6: Don’t be afraid to get fancy with your ingredients/toppings
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.