ARW's C&G Manufacturing Must-Reads

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 October 28th, for all you practical people who, like Carlin, abhor the question, “Where is it?”

The Illiad & The Cell Therapy Facility: A Choose Your Own Adventure Story 

• Behold our anxious (but beloved) hero who is setting out to build a cell therapy facility! Here, in adventure one (of five), our protagonist finds themselves fortuitously in the company of Scott Bertch (Tenaya Therapeutics) and Alexis Melendez (Kite Pharma) who share their tips on where to begin such a massive endeavor.

“Nobody Puts CMC In A Corner”  

• For those of you disappointed by the lack of CMC focus during the FDA AAV toxicity advisory committee meeting in September, maybe you’ll agree with this roundtable discussion that future C&G AdComs should be evenly split between clinical and CMC experts — or that there should be an altogether separate CMC-specific AdCom.  
• What your full-empty capsid ratio means clinically and what — if anything — should be done about it were two unanswered questions from the FDA’s AdCom meeting. In a recent blog post, I offer my take on how the industry and regulators could start answering these bigger quality questions. Hint: Sharing is caring.

Twinsies?!

• The biosimilar nerd in me went wild over the final FDA guidance, “Interpreting “Sameness” Of Gene Therapy Products Under The Orphan Drug [ODD] Regulations.” This brief guidance (which is just confusing enough to be a tongue twister) isn’t CMC-centric, but it’s still fun to wrap your brain around.  
  • Spark Notes: If gene therapy A and gene therapy B are targeting the same indication and apply for ODD, the FDA will (generally speaking) consider them “different therapies” and grant them each ODD if 1.) they express different transgenes, and/or 2.) they have a different vector (gammaretrovirus vs. AAV) and/or 3.) they have a different serotype (i.e., AAV2 vs. AAV5) or tropism (gammaretrovirus vs. lentivirus). Beyond that, it gets complicated.  
  • Promotors, enhancers, or the cell-type transduced could be differentiating factors when two therapies have highly similar transgenes and/or vectors.   
  • BONUS TONGUE TWISTER: “Virologist Victor ventured to validate a vat of viral vectors; how many viral vectors did virologist Victor venture to validate?”

Decentralized Manufacturing Will Not Be Built In A Day* 

*Unlike Rome; Rome was definitely built faster 

• Back in August, the MHRA became the first regulatory agency to propose a new regulatory framework for point-of-care manufacturing (POC) for ex-vivo cell and gene therapies. The public consultation period concluded in September, but the MHRA's proposals are all nicely outlined here.   
• This must-read BioInsights article summarizes key takeaways from a June workshop discussing POC manufacturing and the MHRA’s proposal. The authors raise four areas of concern: quality control, equipment & standardization, qualified personnel, and hospitals.   
• It will be essential that other regulators align around such a concept and release their own (hopefully highly similar) guidances in the future, says this blog post from Pinsent Masons.  
• As far back as 2018, the FDA’s Peter Marks and Scott Gottlieb combined their brain power on this NEJM article which hints at the concept of POC manufacturing for stem cell/other regenerative medicines (Figure 1).

A Not-So-Brief History Of Viral Vector Platforms 

• This Nature article (Feb. 2021) provides a solid overview of adenovirus, AAV, and LVV production platforms, clinical trials, and the current and future challenges facing each vector in the gene therapy world.

Talking In Circles About Continuous Manufacturing  

• In recent weeks, H.R. 4369, a.k.a. the National Centers of Excellence in Continuous Pharmaceutical Manufacturing Act of 2021 was passed from the House to the Senate. This bill would allow the FDA to designate academic institutions as centers for excellence in CM and provide grants to fund their research into CM technologies. 
• For those of you saying, “Well that’s great, AR, but we’ve got bigger, more accessible fish to fry than Continuous Manufacturing,” I hear you and offer you this (2019) pharmaphorum article elaborating on how CM could benefit gene therapy manufacturing efficiency & COGs.

“Ancillary Materials” 

• As for the “random s$%^ that will change your life this week,” I have found for you: fugitive zebras; bees learning math; “Sprinklegate;” and a too-good-to-be-true study on James Bond’s exposure to infectious agents. You know you want to read that last one.