The Ins And Outs Of In-House Manufacturing: Building A Cell & Gene Production Facility

By Life Science Connect Editorial Staff

Deciding whether to bring manufacturing in-house or outsource it to a partner can be a daunting decision, particularly as market forces continue to put pressure on small biotechs. Yet through employing flexible and sustainable design strategies and best practices, combined with contingency planning based on current market conditions and exit strategies, companies can make building their own facilities a reality.

In a recent Cell & Gene Live, chief editor and host Erin Harris spoke with experts from two such companies, who shared their experiences with standing up state-of-the-art manufacturing facilities in a competitive and shifting market. Speakers for the event included:

• Will Junker, head of vector manufacturing quality, Kite Pharma
• Mitch Lower, senior vice president of technical operations, Kriya Therapeutics

In 2021, Kriya completed renovations on a 51,000 square foot facility in Research Triangle Park, North Carolina, focused on cGMP production for its pipeline of gene therapies. Kite Pharma, which has commercialized both Yescarta and Tecartus, has likewise established cell therapy manufacturing sites in California, Maryland, and Europe.  

Choosing to build a manufacturing facility as a small or mid-size biopharmaceutical company hinges on a highly individualized evaluation of an organization’s resources and needs. For many, the benefits of pursuing an in-house facility – complete control over production, coupled with long-term cost savings – make it an attractive option. Overcoming the challenges that accompany this pursuit requires a thorough understanding of the demands of cGMP production, compliance, and regulatory considerations, among other variables. But as access to CDMO capacity becomes harder to come by for many of the niche advanced therapies entering the development pipeline, the build vs. buy decision has become more crucial than ever.

The Why Behind Build in Build vs. Buy

For Kite Pharma, the degree of control made possible by bringing manufacturing in-house was one of the primary drivers of its decision to build. In particular, the issue of intellectual property was a key consideration for Kite: “Making versus buying, or in this case, building versus contracting, has a lot of internal advantages associated with protection of intellectual property, but also with understanding and managing your overhead, having a faster time to market for cell therapy,” Junker said. Kite’s therapies are autologous, making this control all the more valuable, as Kite can manufacture a patient dose unimpeded by competing interests from other companies. “Every lot of product we make is for a single patient, and especially in the oncology space where a lot of our products are [targeted], time is of the essence.”

The types of therapeutics Kite manufactures require a comparatively small facility footprint; moreover, these autologous products require the flexibility to scale out horizontally, as their manufacturing occurs at the bench scale. “The more of these suites, the more benches we have available, the higher our capacity at a facility,” Junker said. “Having that flexibility in-house is a huge driver of success.” For Kriya, this control and flexibility is equally important – formed three years ago with a goal of advancing gene therapies to larger populations and more common therapeutic areas, it has prioritized scaling up while lowering cost of goods. “We knew we had multiple products in multiple therapeutic areas and a relatively large pipeline growing,” Lower explained. “We did a lot of early evaluation to determine that in addition to control and potentially cost reduction, there's some real benefits in areas that come back with that word ‘control.’”

Lower cited building intangibles in addition to physical space – things like knowledge retention, internal capabilities, and interoperability between business units. “As you develop your workflows in your work streams, you'll develop a critical path to clinical trial that really starts all the way back in your vector design and your plasma design and it will look different than an external development and supply profile,” he said. “So with that you also learn where you can take risks, where you can maybe cut a corner or two and hopefully that allows you to reach those milestones more quickly in support of a clinical an IND and a clinical trial start flexibility.” This ability to pivot may be critical, and can be inhibited by the need to negotiate development slots with a CDMO, he added.

Achieving Speed to Clinic with The Right Build Strategy

Choosing to build or to buy starts with charting a path from preclinical to clinical to commercial, all while establishing an understanding of supply chains, demand, facilitating patient access, and resources. “Are you depending on venture capital or are you an established company branching into a new space? When I look at our experience [at Kite], it was really important to be able to support a market the moment we got approval from the FDA,” Junker said. “With an autologous process, you can’t really build inventory ahead of time, but what we needed was availability of slots to manufacture existing and standing contracts with authorized treatment centers that we have established or the hospitals that we work with that are really processing our product to the patient, as well as have the capacity ready to go to have approval together with your BLA to immediately manufacture.”

Although a cell therapy production facility like those employed by Kite are less complex to build than a cell recombinant plant, Junker said, it still requires a close evaluation of suite configurations, air handling, materials handling, and other considerations that are both cGMP requirements and workflow optimizations. “It takes a while to qualify and validate all those systems,” he explained. “The sweet spot is that you have a successful Type A meeting, meaning you go out of your clinical trials into a point where the FDA is happy with your data and you show efficacy, you show safety, and from that moment on you better be starting to build, because otherwise you drag your clinical phases out longer and you're not going to achieve approval right off the bat with your BLA, because that's what the FDA is also looking for.”

In Kriya’s case, the company reached a point of both technical achievement and fundraising success that triggered a decision point – how could it leverage its Series A funding as effectively as possible? According to Lower, this meant monitoring across business units, from pilot plant scale up to vector and plasmid core operations to GLP and GMP supply, in order to determine the scope and timing of an eventual facility. “We were trying to go very fast,” Lower said. “We didn't have a process yet, so it was designing a building without a process to design it to. So moving those kind of ideas against what was available in the market and how long we could stay with, say, a third-party supplier.”

As for timing, Lower said Kriya based its decision to build on having advanced a few of its programs far enough to develop a process, in conjunction with R&D and its development team, that “created a strike zone” for the development team to fit it into its manufacturing platform. “There's a lot of risk with that approach and so tempering optimism is really important to make sure the timing doesn't mismatch, you don't deliver something late or something too early where you have excessive overhead costs dragging down the organization, particularly as an early startup with limited funding.”

Conclusion

The highly manual nature of most cell and gene therapy production necessitates a great deal of expertise, both for a modality itself and the equipment and protocols employed to produce it. These small-scale, in-suite processes require operators that possess significant expertise, which can drive costs and result in scarcity, depending on where a facility is located. Supply chain accessibility is another factor that can be highly influenced by location; other considerations, such as whether a facility is a new build or renovation, a greenfield or brownfield development, can also impact this assessment. “We were really focused on deploying our capital efficiently as a small startup with limited funds. We wanted to make sure we were building fit for purpose and not overbuilding or being too optimistic,” Lower said. “Start with really making sure you develop two-way communication with your executive team and your board of directors and your investors and an open dialogue on risk and constantly seeking continued alignment. Once all those are in place then and you can identify your location, then kind of get into the nitty gritty of finding a site that meets that fit for purpose design and your timelines.”