By Anna Rose Welch, Director, Cell & Gene Collaborative
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The phrase “time and money” will inherently be uttered in any discussion on manufacturing — regardless of whether you’re creating a drug or building an airplane. But when thinking about the high cost of goods (COGS) in drug development, we’re more likely to think about the costs of all the tangible drug development resources — namely, the equipment and technology, media/reagents, single-use supplies, and (finely itemized) outsourced services.
In the CGT space, we’re certainly becoming more acquainted with the “time” costs associated with CGT development, thanks to CMC problems and/or outsourcing capacity and supply chain shortages. However, I’d still argue that “time” is not one of the goods that naturally comes to mind upon hearing the phrase COGS.
Perhaps the closest we’ve gotten to incorporating “time” into the overall costs of drug development is the oft-quoted 2016 Tufts study, which pegged the average R&D costs for a new drug/biologic to be upwards of $2.9 billion. Besides this eyebrow-raising figure, the author’s decision to lump the costs of abandoned/failed candidates into the overall cost of an approved product was quite notable. We don’t often acknowledge the impact that outright failures or “going the extra mile” in certain aspects of development (deep characterization upfront, for example) can have on the overall COGS for a new therapy. But every failed experiment, every assay that doesn’t become part of a product’s release, and every candidate that ultimately gets shelved comes with a cost — both in dollars and cents and in time/opportunity.
Spending the time and money upfront on manufacturing is not yet “muscle memory” for the pharma industry which has historically prioritized clinical milestones. In fact, for many investors and executive leaders, it’s been a learning curve to understand and accept that establishing the necessary manufacturing infrastructure first thing is a necessary opportunity cost. Accomplishing innovative, standardized, and/or next-generation manufacturing strategies (i.e., novel capsid designs or stable cell lines) will require a smorgasbord of “time and money”— both of which could alternatively be lavished on the development of another product candidate. But in most cases, you’d be hard-pressed to find a CMC team that isn’t willing to spend the time and money on going the extra mile, especially given the analytical and comparability challenges wreaking havoc on CGT companies’ timelines.
In my previous article with Kee-Hong Kim, CTO of Tenaya Therapeutics, we focused on the economic pressures facing CGT companies in establishing a scalable and reproducible manufacturing process on the path to an IND. But our conversation also touched meaningfully on the importance of time — that intangible COGS — in the drug development paradigm.
It goes without saying that “taking time” to get a solid process in place is a best practice. But what I particularly appreciated about my conversation with Kim was how his own experiences and perspectives helped define what exactly “time well spent” means in the CGT development process.
To Reach The CMC Finish Line, Don’t Bolt From The Starting Line
For Kim, the step in the AAV gene therapy development process most deserving of time is in the qualification of the critical starting material — namely the cell lines and the critical ancillary materials like plasmids for transfection or recombinant baculovirus or adenovirus for infection.
“You cannot expect your AAV to be reproducible if you have questionable or shaky starting and ancillary materials,” Kim explained. “If there is a mistake in the transfection process — for example, the therapeutic gene is not packaged properly into the capsid — you don’t want to move forward; that will only end up costing several million more dollars.”
To develop a reproducible product, companies need to have all the resources we typically calculate into overall COGS — for example, the high-quality starting cell lines, plasmids, and the most discerning assays and sequencing technology. (As we discussed in our previous article, Kim can celebrate a job well done if the final drug product’s therapeutic gene sequence and the potency match those that were isolated in the research phase.)
However, in addition to having the best technology, Kim specifically called out the importance of giving teams the time to do this essential analytical work. Though CMC in the CGT realm is already an accelerated process, the time spent on qualifying the starting and the ancillary materials is a critical step on the way towards achieving what Kim calls the “deep philosophy” behind CMC.
We use a lot of words to describe the ideal manufacturing process: well-controlled, reliable, and consistent, to name just a few. However, for Kim, the goal of every manufacturing team should not just be to come up with a reliable process, but a robust process.
Much like time and money, the term “robust” suffers from a lack of concrete definition or, perhaps, too many varying definitions. After all, as history is replete with press releases boasting “robust” manufacturing processes, we can also argue that the term is used too frequently to describe what should only be considered “robust-like” processes. That’s why, to Kim, the difference between a “robust-like” or “reliable” process and a truly “robust” process boils down to the long-term control a company has over its materials and chemistry.
“In my mind, robust means you can reproduce your product over time,” he explained. “You can make your product in January and again in August and your process produces highly similar material. But to do that, you must have very strong mastery over the “Control” portion of CMC.”
Kim went on to list a handful of questions manufacturing teams must be prepared to answer (and clearly document), not only as an in-house exercise but also to garner the FDA’s trust and approval.
“How do you release your starting material?” Kim offered. “What are your release criteria — and how do you control that release? What are your in-process assessment and in-process quality control procedures? And, more importantly, how do you prove your product and your formulation has the stability to guarantee a long shelf-life?”
The Tangible Benefits Of Hiring Manufacturing Talent Early
It’s a regularly professed best-practice that CGT companies should have manufacturing expertise represented on the executive committee and/or on the board from day one. There is no such thing as “too early” when it comes to establishing a manufacturing infrastructure for a burgeoning CGT company.
Kim himself was approached and hired four years ago when Tenaya was still in the midst of its early research — an appointment that even took Kim himself slightly by surprise.
“I was hired super early,” Kim laughed. “I remember asking our CEO, Faraz Ali, why he wanted to hire me at such an early-stage company. I warned him that, once I start, I’m going to need to spend a great deal of money and asked if he and the company were ready for that.”
Obviously, we know how this story turned out: the job was offered, and Kim accepted — a decision he attributed to CEO Ali’s sound reasoning. As Ali had expressed (and many other executives will reaffirm), too many CGT biotechs have learned the hard way that establishing a manufacturing infrastructure should be just as foundational as the company’s scientific mission. It’s often after entering Phase 1 trials that a company quickly realizes the therapy can’t be reproduced at the same quality and will be facing expensive and time-consuming process changes and comparability exercises.
Though Kim was originally taken off-guard by Ali’s proactive manufacturing mindset, he agrees that this approach was necessary, not only for the growth of the company but also for the patients that Tenaya will treat with its future therapies.
“I came in early, which meant I had a lot more time,” Kim emphasized. “I had the time to hire the right people; I had the time to identify the largest risks about which the FDA will ask questions. This is all knowledge I’ve collected from 17 years of previous, painful failures. But it was from these failures that I’ve learned the most valuable lessons on how to implement and maintain a robust CMC framework that will ensure Tenaya’s future gene therapies reach patients.”