This blog contains information originally published as part of the Business of Biotech podcast

Pillar, M. (Host). (2021, June 7). RNA-Engineered Cell Therapy With Cartesian's Dr. Murat Kalayoglu [Audio podcast episode]. The Business of Biotech. BioProcess Online.

Early clinical trials will make or break a developing drug or therapy. To maximize your chances of success from the start of a project, a focus on Good Manufacturing Practice (GMP) standards for phase 1, first-in-human trials, is important. It’s even more important for cell therapy development, where even the smallest errors can spell big trouble.

Dr. Murat Kalayoglu, Co-Founder and CEO of Cartesian Therapeutics, has witnessed the ways in which regulatory and GMP standards have evolved over the years — first as CEO of Topokine Therapeutics, acquired by Allergan in 2016, and now at Cartesian, a fully integrated, clinical-stage biopharmaceutical company developing novel cell and gene immunotherapies.

Dr. Kalayoglu recently sat down with The Business of Biotech podcast to talk about how we in the cell therapy space should approach our phase 1 clinical trials, from raw material management to interpreting guidance and early-stage manufacturing.

Guidance, Not Instruction

The FDA’s guidance documents regarding Phase I clinical trials are “appropriately broad,” Dr. Kalayoglu says. For Cartesian and other clinical-stage companies, it offers some flexibility in achieving trial goals. “I think the companies that do well take the guidance to heart, but tailor it to meet the demands of their team and organization with respect to the indication they’re working on and the products they’re developing.”

While the guidance surrounding small molecules and biologics has become well-established over the years, cell therapies don’t have the same lengthy regulatory history. There’s also an overarching effort in pharmaceutical trials to close as many steps of the process as possible, Kalayoglu says, but that isn’t always practical in cell therapy. “Ultimately you’ve got to use your own judgement in terms of what product you’re trying to develop for what purpose, take the guidance and everything else you know about keeping a product safe and sterile, and apply it in the context of exactly what you're trying to do, as opposed to what someone else is trying to do.”

Ideally, a company’s interactions with a regulatory authority will be less transactional and more relationship-driven. The cell and gene division of the FDA is one of the most engaged segments of the agency when it comes to communicating with companies, in Kalayoglu’s experience – he recommends reaching out early and often, especially for nascent players. “You need that sort of back-and-forth engagement, especially at the early stages.”

Phase 1 GMP: Key Elements

The jury’s still out on whether cell therapy manufacturing can achieve the same process-level consistency used to produce traditional biologics. Part of that uncertainty comes down to variability: in allogeneic therapies, for example, manufacturers are generating individual lots from a master cell bank, retrieving new, unique tissue with each new lot. “If you're going to grab some new tissue and create a new master cell bank, you're grabbing new patient tissue with unique, and really uncharacterized properties, in terms of cell expansion and cell function,” Dr. Kalayoglu says.

Manufacturing tens of thousands of proteins within a given cell and predicting their behavior and interactions by placing them in completely artificial environments is asking a lot when compared to manufacturing a single purified protein, Dr. Kalayoglu says. “The critical parameters have to do with the inherent functionality and expansion potential of the cell. Everything else you can try to control, but there are some inherent properties that we just don't know about.”

There are ways to minimize variability through GMP practices, Dr. Kalayoglu says — things like very specific standard operating procedures, detailed batch records, and other fundamental practices, including talent acquisition. “Unless you actually have that experience as a manufacturing organization, in terms of both volume [and] the team that you built in order to think through the implications of each step, you're just not going to learn from each of these steps. the way that you otherwise would,” he said. “You'd be missing a huge opportunity to reduce the variability and create the very best product possible.”

Learning by Doing

Dr. Kalayoglu told BioProcess Online that Cartesian made the decision to invest in its in-house manufacturing capabilities back in 2018, and has since built cross-functional teams to support its end-to-end development. “We started off on this path with a CRO who was very motivated and did a fine job, but we realized we weren’t going to be able to learn as much as possible for each and every engineering and production run until we brought everything in-house.” That move has taught Cartesian a lot.

One key thing the company has learned during this process is the importance of closely evaluating its raw material management. While it’s important to source from manufacturers experienced in producing GMP-grade materials, it’s also important to critically evaluate the potential risks involved when those raw materials interact with cells. “You also want to do things in a phase-appropriate way, so that you’re not unduly burdening your manufacturing process.”

The pandemic has taught Cartesian and many other companies the importance of supply chain planning for lead times when sourcing raw materials. “We try to plan ahead and keep up with our expectations and try to bring materials in-house so that we don't get caught off-guard,” Dr. Kalayoglu says.

One other potential mistake developers make is in assuming the data produced at smaller scales will translate to larger ones. “I see people getting caught off guard there, because cells just don't necessarily behave the way that you would expect them to.”

To learn more about early-stage GMP standards and what Cartesian is doing to innovate in the cell therapy space, listen to The Business of Biotech.

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