A comprehensive manufacturing and development plan helps guide the process, but significant hurdles to commercialization still exist.
Creating a solid manufacturing and development plan is critical to successfully shepherding a promising cell therapy from discovery to market, but there are still significant roadblocks and technical challenges that are preventing a large number of cell therapies from being commercialized. This was the conclusion of a panel presentation titled “Targeting the End Game: Keys to Reaching Commercial Viability by Establishing the Right GMP Processes for Cell Therapy Clinical Trials from Processing to Delivery to the Patient” at BIO 2104 in San Diego, Tuesday.
Session moderator, Brian Hanrahan, program manager at Invetech, laid out the structure and requirements of a sound plan for guiding a cell therapy from IND to commercialization. Requirements such as process integrity, product quality, scalability and regulatory issues, which have very low importance at the IND stage, are of high or critical importance as the cell therapy moves through trials. Likewise, flexibility and operational efficiency, which are highly important in early stages, decline in importance the closer a therapy is to commercialization. Understanding this is important to developing a holistic and forward-looking approach to scale up.
“Because of these changes, a company developing cell therapy products has to stop, to look up and look at this vision, a bit earlier on than getting into Phase III and at the last moment saying they are going make some changes,” said Hanrahan. “In the early stage you had the ability to change the process and that’s what you intended to do, but as it evolves and begins moving into commercial it becomes much harder to change.”
Developing a Solid Plan
Even though scientists have been working on the production of cell therapies for the better part of 30 years, the track record of bringing them to market is not good. The sobering fact remains that not many cell therapies make it into commercial production and even fewer have become commercially viable. According to Robert Preti, president and CSO of PTC, a contract developer and manufacturer of cell therapy products, there has been progress over that time. However, he said it is still important to step back to try to understand why so many potential therapeutics reach the cusp of coming to market only to ultimately fail.
“If we are going to complete this journey from bench to bedside, we can’t be thinking strictly about what happens today,” Preti said. “We’ve got to be thinking about the ultimate deliverability of the product.”
A significant consideration for bringing a potential therapy to market can often be out of the hands of the company that made the discovery and may not even take into account whether it is effective. As companies consider how they will scale production, they need to consider both what the anticipated cost of the product will be and, further, whether healthcare payers will reimburse for the product.
Michael May, CEO of the Center for Commercialization of Regenerative Medicine (CCRM) agreed cost and the potential for reimbursement for a cell therapy can significantly affect development plans. “You can kill technology ideas or cell therapies early on if, in fact, you can answer the question that it won’t be paid for,” May noted. “That can be determined by the cost of goods, how much headroom there is for technology improvement over the standard of care, or what the burdens on healthcare systems or insurance companies are.”
GMP Roadblocks for Cell Therapies
There are a number of unit operation roadblocks when it comes to establishing good manufacturing practices from early trials through to commercial production. These include working cell banking; expansion; cell washing and concentration; and fill and finish. Consensus among the panelists was that cell washing and concentration challenges were predominant, if only because of its wide applicability among many different processes.
“(Cell wash and concentration) has front end applicability for patient-specific material. Typically nothing comes in as a homogenous cell population, but we like to deal with that in step one of the manufacturing process,” said Preti. “You have to build a wide enough funnel that takes in some heterogeneity, but it would be nice to have something that separates cells out and concentrates them properly.” It is also a significant issue prior to fill and finish, he added.
There are also significant hurdles in expansion, primarily related to the inability to accurately characterize cells. Unfortunately, those looking to learn from the successful scale up of monoclonal antibodies might be looking in the wrong place, said Anthony Davies, president of Dark Horse Consulting. “Everyone looks back at the monoclonal field for lessons learned and history,” Davies said. “The thing is, if you compare one monoclonal antibody to another, they are much more similar to each than if you compare one cell therapy to another.”
Taking cell banking as an example, he noted that common practice for monoclonal antibody production would be to make half a dozen working cell banks or even master cell banks. Via characterization, the best bank can be identified based on which produce the most potent product or have the best yields and then selected for production. “Doing that for cell therapies is really difficult because most cell therapy programs don’t have a good surrogate assay for how good your cell banks are,” Davies concluded. “So that is an analytical deficiency.”
The Characterization Conundrum
These “characterization gaps,” Preti noted, have provided the developers of cell therapies with a bit more leeway from regulatory agencies as biotech companies have presented a package of functional assays combined with flow cytometry snapshots bundled together as a characterization package. But the danger is if the manufacturing process is changed, it can change the product but not the characterization profile. So while it may breeze through regulatory review, he said, “we could create a product that doesn’t work, or isn’t as effective.”
May agreed. “I think characterization is the main issue that is challenging the industry. We don’t really know well enough what these cells do and how they do it, which causes all kinds of issues.”
One of these issues is a popular sentiment within the industry that “process is the product,” meaning that the method of producing the cells is the product more than the cells themselves.
“It is justifiable to say that the process is the product, because we don’t characterize the product well enough. But this is a bad thing and will evolve over time,” said May. “The product needs to be the cells and well-characterized cells with certain properties.”
As Preti sees it, the notion that the process is the product “is one of the issues that is preventing us from getting products from the bench to the bed. The emphasis needs to be on our ability to characterize a product and to think about where that analytic development and characterization falls in a proper development scheme. There is no doubt that processes will change over time. All processes in Phase I will change by the time they go to commercial production; they will not survive.”
Chris Anderson (firstname.lastname@example.org) is the former chief editor of Drug Discovery News, which he helped launch in 2005.