Cell and Gene Therapy Logistics: Meeting the Supply Chain Challenge

Disruptions in cell and gene therapy logistics drive manufacturing innovation, but significant bottlenecks continue to hobble supply chains

The global supply chain system is, in some ways, self-optimizing. The incentives are clear: create maximum profit. Goods and services are produced and sold as inexpensively as possible, in quantities demanded by the market. This straightforward observation should not come as a surprise to most. Consumers have quickly become accustomed to robust yet flexible supply chains, which can not only deliver goods rapidly but can also predict where goods are most needed. There is a reason Amazon can deliver most goods within 2 days, often on the same day. This form of just-in-time ordering, assuming goods will be on-hand for shipment at a moment’s notice is something employed not only in the consumer markets and Amazon but also in the pharmaceutical manufacturing sector. But there are limitations: a fast supply chain is a fragile one. Keeping unused capacity and emergency material on hand is a cost, and one that has not always been carried.

Clinical manufacturing for complex modalities, like the cell and gene therapies produced by contract development manufacturing organizations (CDMOs) like Charles River Laboratories, are no exception.

“The entire field always worked on a just-in-time ordering scheme,” explains Dr. Matt Hewitt, Executive Director of Scientific Services Cell and Gene Therapy at Charles River Labs. “[Extra stock] takes up a lot of room and we don't want to pay for warehousing space.” Just-in-time ordering for manufacturing was a problem waiting to happen and left the cell and gene therapy field — and the entire global supply chain — vulnerable to disruption. Inevitably, these disruptions arrived in the early months of 2020, with the COVID pandemic upending cell and gene therapy logistics and their supply chain.

Top Cell and Gene Therapy Logistics Issues

Transportation Delays

For Katherine Turner, Senior Director of Clinical Operations at Charles River’s Memphis location, which specializes in cell therapy manufacturing, the impact was significant. “Since the COVID pandemic started,” says Turner, “transportation is all over the place. There are no guarantees, no way to know if your product's going to get there tomorrow, if it's going to end up at the airport, if it's going to end up at somebody else's airport… there's no way of knowing.” For some cell and gene therapy products, even the smallest of disruptions can be back breaking. “Once the material leaves the patient's body, it [might] have to be back in within 48 hours, which is crazy,” says Turner.

Overlap with COVID Vaccine Manufacturers

Transportation woes were not the only impact to cell and gene therapy logistics during COVID. “RNA vaccines and their manufacturing processes use many of the same things as cell and gene therapies,” says Hewitt. For regular production, the supply of plasmid and by extension viral vector consumables was “pretty much immediately cut off,” as various governments employed National Defense Act (NDA) or similar local laws to compel suppliers to supply COVID vaccine manufacturers first. “Even things like bags and clinical connectors we use in cell therapy, the vast majority of supply was consumed by [COVID] vaccines… there really was no area in cell and gene that was untouched,” says Hewitt.

Cell And Gene Therapy Restrictions

While an enormous effort has focused on shoring up supply and logistics issues caused or exposed by COVID in the cell and gene supply chain, there are more basic issues in cell and gene therapy production — significantly more restrictions than the average industry. The biggest is that, unlike traditional manufacturing, the ability to move facilities or to create a new production plant for an existing product is not easy. “Unlike plastics and metal, cells are like little humans on their own… the cells that acted and did what they did at your [production facility] may not do the same thing [elsewhere],” says Turner. While these problems can be overcome with additional development work and comparability studies, even switching to a scaled-up production line might require months of extra time for testing and FDA approval, an expense and risk not many companies are willing to take, especially if they are close to commercial approval.

Competition for Critical Supplies

There are other limitations as well for cell and gene therapy logistics. Key pieces of equipment for manufacturing facilities like emergency backup generators, electrical switch gear, computer chips, and even glass are proving difficult to source. Generators are especially important, because losing power can jeopardize the entire line. “Generators right now can have a 14 to 18-month lead time. So, if we're building an expansion… it's going to be at least 18 months probably before it's done if we have to wait for a new generator,” says Hewitt.

The breadth and specificity of cell therapy development makes adjusting and sourcing an arduous process. “There’s upwards of eight or 10 different cell and gene therapy logistics actions needing to happen in concert in order for [a cell and gene therapy] product to be manufactured successfully and on time,” explains Hewitt. Limitations can arise in multiple places. “In many of our processes, serum is used in media to stimulate cell growth. [Serum] can be very expensive because there are a very limited number of clinical-grade vendors in the world.” As demand increases, so does the pressure on the cell therapy supply chain, which soon increases the expense and lead time. Innovative alternatives become extremely valuable. Fortunately, this pressure has led to the development of said alternatives, lessening the cell therapy supply chain’s reliance on blood products. “Now we're seeing medias come out with serum supplements or replacements… and we're starting to see a lot of medias coming to market which don't require serum at all,” says Hewitt.

Industry Growth Puts Pressure on Cell and Gene Supply Chain

While innovations can alleviate these cell and gene therapy logistics issues, limited supplies are a major problem facing the industry, one that shows no sign of stopping. “Companies are [already] starting to get wary of sourcing critical raw materials from potential competitors… if market pressure comes to bear on starting materials, those potential competitors will prioritize their own programs over shipping out,” says Hewitt. There are still relatively few commercial cell and gene therapies, but this is expected to change as programs in late-phase development go commercial. These cell and gene supply chains will be further tested if and when a cell therapy is commercially approved for treating large solid tumors. Even modest projections estimate the future demand to be multiple orders of magnitude greater than the present, a time when companies are already struggling to meet demand. “We're going to see pressure on the cell and gene supply chain for critical raw materials as additional therapies are approved because we're all competing for the same consumables,” says Hewitt. Capacity expansion is the obvious solution, and suppliers are expanding, but it’s likely there will be continued disruptions in the short-term, potentially raising prices.

Looking to the Future

The number and variety of manufacturing innovations to address assist cell and gene supply chain are well beyond the scope of this piece, everything from increased automation and decentralized manufacturing to finding ways to make more therapies allogeneic. Hewitt’s attention is to the future, and with inevitable scaling issues. “[With almost] 2 million new cases of cancer per year in the US, if we assume even a 20% market penetration for cell therapy, you're looking for at least 350,000 doses per year just in the US… we need to learn as much as possible from the Amazons.” Ultimately, the only constant is change. “I don't know that we'll ever go back to the pre-COVID way of doing things. I think this has opened the eyes for a lot of people,” says Turner.