By Anna Rose Welch, Director, Cell & Gene Collaborative
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Since I last sat down with Ken Chrobak, VP of CMC for Wugen, to discuss the manufacturing and outsourcing challenges and opportunities facing the St. Louis-based biotech, the company has celebrated several big milestones. These milestones include securing funding to advance the company’s lead program — a memory NK allogeneic cell therapy targeting AML and solid tumors — and partnering with Alpha Biopharma to manufacture and develop these allogeneic therapies for the Asian market. In addition to its memory NK platform, the company has secured an FDA IND and presented preclinical data for its allogeneic CAR-T therapy in T-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma. (Wugen first licensed this CAR-T technology from Washington University in St. Louis in 2018.)
But behind every celebratory press release and the funding fireworks show is a flurry of never-ending work happening behind the scenes. Like many other young CGT companies, Wugen is rapidly growing in terms of headcount, clinical development, and global reach. Though these are universal challenges across the entire pharma industry (and, of course, outside of pharma), the CGT sector certainly “packs its own punch.” After all, much of this growth is happening alongside all the arduous work that comes with championing new modalities and bespoke manufacturing platforms and working within the lines of clarifying regulatory paradigms.
In the cell therapy space, there is a metaphorical battle shaping up between the two types of therapies: autologous vs. allogeneic. As one of the articles from my Top 5 manufacturing trends and themes of 2021 argued, however, such stark “one-or-the-other” thinking ignores the fact that lessons can be learned from and applied across these (albeit quite different) manufacturing models. This is where Chrobak and I started our conversation — in what ways the autologous space has informed Wugen’s pursuit of allogeneic therapies, and how Chrobak and his team have implemented these learnings into the work they’re doing today.
Applying Lessons Learned In Autologous Manufacturing To Allogeneic Platforms
As Chrobak explained, donor selection is one area companies can benefit from prior experience in the autologous realm. Given the up-close-and-personal work done with each individual donor’s (quite variable) cells for autologous therapies, you can learn a lot about the ideal — and, just as important, the less ideal — donor phenotypes for a cell therapy. Not only is securing the appropriate donors essential for the clinical profile, quality, and durability of an allogeneic treatment, but it also ensures a company can make and supply enough batches of the therapy for clinical trials and, eventually, commercial use.
The early days of CAR-T autologous manufacturing also provided allogeneic companies fantastic case studies on what can happen when outsourcing overly manual and scaled-out manufacturing. Because an autologous therapy is only earmarked for an individual patient, it would be financially impractical to manufacture each patient’s therapy in its own manufacturing suite at a CDMO. In turn, contract manufacturers would typically manufacture multiple products for different clients in the same suite at the same time. Such an environment, if not carefully managed, increases the odds of cross contamination or confusion on the floor. Companies outsourcing their autologous therapy development needed (and still need) to pay careful attention to the layout of manufacturing facilities and the movement of their materials and the CDMO’s staff throughout the workstations within the space.
This scrutiny of partners’ manufacturing suites was one aspect of autologous therapy development that Chrobak and his team have adopted and adapted when outsourcing their allogeneic therapy development.
“Since Wugen is a small company and we don’t have our own manufacturing facility, part of our manufacturing due diligence is to make sure our outsourcing partners’ facility layouts are appropriately segmented and staff movement is stringently regulated so that there’s no chance of a contamination or mix-up.”
Thanks to the (slow but sure) roll-out of automated cell processing equipment (e.g., Miltenyi Biotec’s CliniMACS Prodigy®), operations with manufacturing sites are becoming more streamlined and manageable as we enter the age of allogeneic cell therapy development. As Chrobak explained, each manufacturing suite can be equipped with several cell processing devices, and staff are subject to strict gowning and task management protocols (i.e., they are generally permitted to only support one manufacturing lot at a time).
As Cell Therapy Evolves, The Outsourcing Landscape Must Too
Despite the streamlining opportunities integrated cell processing technologies can offer innovators and CDMOs, such technologies still leave more to be desired from allogeneic manufacturers — particularly as it relates to scale. While current technologies can produce several hundred milliliters worth of a product to treat an individual patient, such levels of production are ill-equipped to treat a thousand-plus patients annually. In turn, companies have had to get creative in the cell expansion phase to ensure they achieve larger scales. (Have I mentioned lately that cell culture has never been sexier?)
While “getting creative” could mean writing your cells a sonnet (check that one off the list) or playing them Chopin in a candle-lit room, a common strategy today is for manufacturers to rely on a patchwork of different vendor technologies to achieve their cell culture goals. Cell isolation could be performed using the Prodigy, for example, while the scale-up might be best accomplished in a larger rocking bioreactor followed by purification using another technology.
“You might leverage technology from the antibody world and cell therapy world and piece together a system of unit operations that, after performing some welding between units, will be completely closed,” Chrobak said.
As he acknowledged, going the “Frankenstein” route (as I termed it) isn’t necessarily the most ideal or convenient approach; after all, it requires greater optimization to ensure each piece of equipment works together and is compliant. But he reminds us that, “Most companies out there, including Wugen, know that speed is a top priority. We don’t have the luxury of sitting and waiting for several years for a single company to pull all the technological pieces together.”
That said, Chrobak is optimistic that, with time and greater collaboration between vendors, anything is possible. He pointed to the antibody world as a great example of how vendors can and have collaborated to promote greater interoperability between their technologies. When optical sensor technologies became the hot new invention in the late 2000s, sensor technology vendors made a concerted effort to team up with single-use bioreactor vendors to ensure their products could be seamlessly integrated. In some cases, they were sold together as a package deal.
“I suspect there will be more partnerships like this springing up in the future,” he offered.
In particular, Chrobak sees greater unification between vendor technologies as a critical component in the industry’s journey away from paper and toward electronic batch records. After all, the more interoperability between the systems, the more feasible it would be to create a single platform capable of managing multiple systems.
“It’s a lot harder to move away from paper to electronic batch records when you’re juggling four different systems that may or may not connect to each other,” he concluded. “Once you get more mature technology — ideally one system that can control and streamline multiple pieces of equipment — it becomes much easier to move beyond our reliance on paper batch records.”
In part 2 of our conversation, Chrobak and I dig into the challenges Wugen has faced pivoting from the more familiar world of T cells into the realm of NK cells.