ARW's C&G (+RNA!) Manufacturing Must-Reads (Dracula 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 June 2 for all you practical people who, like Carlin, abhor the question, “Where is it?
As we recently celebrated the anniversary of the publication of Bram Stoker’s legendary novel, Dracula (May 26), I invite you to suspend all disbelief and read five recently discovered chapters that were cut from the original draft of Dracula. These chapters, like the novel, are in the form of journal entries and letters. They were written by a young scientist, Dr. Cillian M. Carmichael (aka C.M.C)., who embarks upon what he believes to be a visit to a new CDMO and finds himself trapped at Count Dracula’s castle with no hope of escape. Who knew they were talking about advanced therapies back in 1897?
CHAPTER I: C.M.C.’s JOURNAL [TIME AS COGS]
31 May. — Though the Count be gracious — and thankfully, has not again grabbed for my throat whilst I shave — I cannot shake that I am a prisoner in this castle. During our latest conversation, I took the opportunity to focus his thoughts on the passage of time at the castle — namely, when I may depart. However, to my even greater puzzlement, he launched into a much stranger conversation on the importance of time in cell and gene therapy manufacturing.
“I pray you, my good young friend, that you take greater care in qualifying your starting and ancillary materials,” he said. “Only in taking this time upfront will you achieve the deep philosophy behind CMC.” (“Time Well-Spent: Embracing Opportunity Costs In Gene Therapy Manufacturing” featuring Kee-Hong Kim, CTO, Tenaya Therapeutics.)
What could I do but bow acceptance at such a well-articulated best practice? It is easy to be overpowered by fear in such a quick-paced industry, especially when we don’t know which differentiating factors will dictate a product’s market dominance. (“Gene Therapy Competitive Dynamics: Winner Takes All?” by C. Zacharko, et. al.)
Once my feelings of being a rat tapped in a cage passed, it became clear: Even more promising advancement can come to those companies, like mine, that take the necessary time — especially as time brings with it great technological and market advancements. (“What’s The Rush? Fast Followers Mine Cell & Gene Gold,” by ARW).
Now, if there was but a door to the outside world!
CHAPTER II: C.M.C.’s JOURNAL [INDUSTRY UPDATES]
Midnight. — I have once more seen the Count leave the castle, scaling the walls in a lizard-like fashion. I saw my chance to learn the secrets of this castle. After trying every locked door, I happened upon one that gave away. The room contained nothing but a roughly hewn table upon which lay a crudely written document. I will transcribe it here as best my memory serves me in the case I should escape and live to share such wisdom with my team.
CHAPTER III: C.M.C.’s JOURNAL [SUPPLY CHAIN]
Dawn, 1 June. — It would appear I am not the only scientist who, driven mad by capacity constraints, mistook Count Dracula’s castle as an eligible CDMO. In my explorations of the castle’s hallways and library, I have found the remnant belongings of those who came before me:
- One process map documenting the movement of a product through the complex supply and stakeholder ecosystem for CGTs
- [Insert desired #] of single use bags, missing since 2020
- One scroll containing the most comprehensive analysis of the current and predicted future of the single-use bottleneck known to mankind
- One box containing copies of FDA’s, EMA’s, and ICH’s unharmonized guidelines on plasmid quality in viral vector manufacture (pages unbound and shuffled)
- One accompanying cheat-sheet unpacking the regulatory & supply chain implications for plasmids as critical starting materials in the manufacture of viral vector gene therapies. (Free registration required)
CHAPTER IV: C.M.C.’s JOURNAL [REGULATORY]
Unknown. — I have surely crossed the threshold of madness. I spend what may be my final waking hours reciting regulatory policy. That these guidelines are my only source of comfort is just another sign of my unending despair. To spell out their insights here be my only lethal weapon against the net of doom ensnaring me — Lord, help me, and those to whom I am dear!
- Oh, that I should live to see a a CGT-specific comparability guidance — the FDA hints it may be so soon!
- Speaking of timely guidances, the FDA released its draft guidance, “Risk-Benefit Considerations for Product Quality Assessments,” for NDA- and BLA-seeking products.
- A glimmer of hope for us all: The FDA plans to increase its CGT “group communications” (i.e., guidances, workshops, and webinars) to make up for staffing shortages/individual communication shortfalls.
CHAPTER V: LETTER TO C.M.C.’s TEAM [CGT/RNA DELIVERY]
Team —
If you are reading this, it is a miracle; I bribed a gardener to sneak out this letter.
This “vendor meeting” has gone horrifyingly awry.
What I believed was a visit to discuss formulation and delivery was but a sinister ploy to further the Count’s own ambitions of demonic blood lust. I am incapable of escape except to venture from my room to the library.
It is ironic I should be enclosing several purloined articles on next-generation delivery methods in this letter which itself may never be delivered. But I dare not stop and think or I may go mad.
- STAT +: “From Burst Bubble to Medical Marvel: How Lipid Nanoparticles Became The Future of Gene Therapy” (subscription required)
- Nature Reviews Drug Discovery: “Engineering Precision Nanoparticles For Drug Delivery” [in cancer medicines, immunotherapy, and in vivo gene editing] (published Dec. 2020)
- Science: “Better Lipids To Power Next Generation of mRNA Vaccines”
I pray this letter is safe in your hands. These may be the last words I ever write — at least, as a man. Good-bye, all!
Editors Note: Dr. C.M.C. was never seen again. Despite the madness that engulfed his mind during his misguided stay at Count Dracula’s castle, his legacy are these notes that — upon discovery — enabled his team and others like him to progress the CGT industry away from the darkness and into the light.