CGT Manufacturing Resolution #3: Embrace — Don't Fear— Deep Characterization Of Your Products

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

In early December, I invited Katy Spink, COO and managing partner of Dark Horse Consulting, to sit down with me for a discussion on her expectations and predictions for CGT manufacturing paradigms in the new year. But because cross-industry collaboration, face-to-face communication, and transparency are critical in this burgeoning industry (and, let’s be honest, can be a lot of fun), Katy and I were also joined by a small group of CGT manufacturing experts from different companies across the industry.

Our conversation ultimately outlined five best practices — or, more fittingly, New Year’s Resolutions — that companies should embrace in 2022 that will (incrementally) help us define and achieve manufacturing maturity in the future.

In the third of this five-part article, Spink dives into resolution #3, recommending that companies be analytically ambitious from the very beginning.

If there was one event in 2021 that really drove home the importance of CGT analytical development, it was the resignation of a CEO following continued challenges with a CGT potency assay. The FDA’s advisory committee meeting on AAV toxicity in September was another great indication that when it comes to analytical characterization, companies are regularly finding themselves up a creek without the most sea-worthy assays.

Being a sucker for analogies, I enjoyed Spink’s use of the “blind men and the elephant” analogy to explain where we as an industry currently are in understanding our CGT products analytically.

“One man feels the tail and thinks it’s a worm, while another guy feels the leg and thinks that it’s a tree,” she joked. “I feel like that’s what we do a lot of the time with our cell and gene therapy products; we identify a couple of surface markers, perform some G banding and think we understand our product. But because sponsors don’t want to use more powerful tools such as next-generation sequencing and single-cell RNA sequencing as release assays, they too frequently shy away from using them to deeply characterize their products. As a result, they end up ‘feeling around in the dark’ when it comes to characterizing their products.”

The best advice Spink can offer firms looking to mitigate future risks with their products on an analytical and a clinical level is to invest in deep characterization early in development. These characterizations should not be viewed as specifications or release assays but rather as an exercise to get to know the product better. The more deeply a company knows its product, the better it can make decisions about which attributes are the most important as development progresses.

To some, this exercise may seem somewhat daunting, in part due to the slowly clarifying CGT regulatory paradigm. Companies may be concerned that presenting such a breadth of analytical information to the FDA will lock them into validating and setting specifications around a large portion of these product characteristics. We’re all familiar with the sentiment, “The reward for good work is more work.”

But Spink reassures companies that, in her experience, such concerns are unfounded; in fact, if anything, the deep characterization work — even when carried out on a research basis — will only strengthen your overall “regulatory argument,” Spink explained. “Our experience has been that the FDA is pragmatic in terms of what it asks of companies and is appreciative when companies demonstrate they’ve established greater product understanding from the get-go.”

Coming up with a list of New Year’s Resolutions is hard work. So, click here to figure out the fourth resolution to add to your CGT manufacturing list.

Further Reading:

• For more on where the analytical paradigm has given the CGT industry trouble, be sure to check out Spink’s fantastic article, “2020:The year the FDA ate our field for lunch (and why),” as well as this discussion between Spink and her Dark Horse colleague, Don Fink, on the clarifying regulatory guidelines.
• Dr. Scott Gottlieb shares his perspectives on the importance of advancements in analytical characterization for the CGT regulatory paradigm and the broader industry in this Cell & Gene Collaborative article.