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The early success seen on the market for approved cell and gene therapies poses both technical and manufacturing challenges for pipeline candidates on the road to commercialization.
The early promise offered by cell therapies and gene therapies that have thus far been approved by regulatory authorities is tempered by the challenges associated with developing, manufacturing, and delivering these types of therapeutics to patients. The complexities of producing these therapies are testing established practices—from starting materials, to process development, to current good manufacturing practice (CGMP) compliance, to supply chain security and reliability.
In a recent webcast, “Editors’ Series: Overcoming Commercialization Challenges for Cell Therapies and Gene Therapies,” held by Pharmaceutical Technology in conjunction with INTERPHEX on July 28, 2020 (1), industry experts discussed the challenges of bringing new cell and gene therapy products to market. Thomas VanCott, global head of product development at Catalent Cell & Gene Therapy; Alan Moore, chief strategy officer, The Discovery Labs; and Christopher Murphy, vice-president and general manager, Viral Vector Services, Thermo Fisher Scientific shared their insights on the major issues facing the cell and gene therapy sector.
Cell therapies, which are still “young” in the biopharmaceutical marketplace, in particular face many technical challenges moving from the clinical stage to commercial stage. Manufacturing a cell therapy is complex and involves multiple sequential steps, for example, from preparing the sample, to washing, to selecting the right phenotypes, to activation, to the transduction step, to expansion, to harvest, to formulating the product, noted VanCott in the webcast.
“In the clinical steps, these are often done in open steps with a high amount of labor and a high risk for contamination. When we think about scaling this to commercial, one of the things we really need to be thinking about is how to simplify and automate the process, and to go from open systems to more closed systems,” he said. VanCott pointed out that moving toward more automated closed systems can reduce labor cost and reducing the probability for contamination.
“We also need to look at the analytics. As complex as the manufacturing processes can be, so are the assays. To be able to optimize and validate assays, especially some of these potency assays and the phenotyping assays, is a challenge for this field,” VanCott added.
Other technical challenges for cell therapies, particularly autologous cell therapy, is dealing with the inherent variability of the starting material and the fact that there is often very little starting material to work with, Moore chimed in. “Often, there are very little materials available to conduct the studies needed to establish robust processes. In some cases, you can’t use normal human donor cells in lieu of the disease-state cell, so autologous products are certainly challenging,” Moore observed.
Moore noted that there are ways to attempt alleviating these challenges, such as the inherent variability issue, to some extent by, for example, providing kits, establishing processes at the sites where the raw material (cells) are collected, and also by ensuring that the vein-to-vein logistics are established. Furthermore, it is important to coordinate these logistics with the manufacturing schedule. Maintaining chain of custody, maintaining chain of identity, and also being able to come up with an effective manufacturing and distribution network are ways to alleviate stresses on the system, he said.
A big question for the cell and gene therapy market is, will existing or planned capacity for viral vectors meet the needs of the market moving forward?
Looking at the current success of cell therapies and gene therapies on the market today and taking into consideration that a large number of candidates are in development for future potential entrance into the market, there is currently insufficient capacity to meet anticipated demand, said Murphy.
One reason for the shortfall, Murphy pointed out, is that the facilities that were used for more common proteins and monoclonal antibodies (mAbs) are not well suited to do viral vectors manufacturing because of the need for specific requirements, such as a biosafety level 2 requirement, airflow considerations, and certain unique elements in the manufacture of viral vectors that are not needed with mAb manufacture. Another reason is that, for the volumes needed, yield is low, meaning that a significant amount of capacity is required just to make enough to meet the patient population. “I think capacity is growing, and certainly there is much investment, but if you look at the trajectory of the market that could be $17 billion by the end of this decade, there is going to be a need for more capacity,” Murphy asserted.
“The analysis I’m seeing of the market is that capacity is not going to be enough in the therapeutic indications that are growing, particularly as gene therapy moves to treating more commodity-type indications and indications that are not rare diseases with small populations. If we’re going to be seeing that, then we really need to drive up capacity as well,” Murphy said.
Moore agreed with Murphy’s assessment. “I’ve seen estimates right now where we’re looking at a capacity shortfall of five times what is needed, and in five years the market is going to be 50 times underserved. Now that assumes success of the cell and gene therapy field, but we’re beginning to see early success with indications that require massive doses of vector. I think we’re going to continue to need to build out capacity and continue to focus on improving yield per square foot,” Moore stated.
Moore explained that, to some extent, these fields of medicine were ignored for more than a decade because there was considerable doubt as to what the long-term future was for gene therapy, and certainly for cell therapy there was limited investment. “Now that folks are focused on making product that are going to serve a very large industry, I think we’ll see progress,” he affirmed.
VanCott concurred that capacity is not sufficient, but that the industry is seeing some movement towards building up needed capacity. “I think my colleagues stated it very well, but we (Catalent) have spent, and others have spent, much time looking at this market, and it is pretty remarkable. If you take a snapshot of all products, say, in preclinical development and add some success rates that we’re seeing so far in the market, and you use average doses for systemic vs. localized products, you get to see some staggering volume rates,” VanCott observed.
“If you then look at the supply that’s out there and take into account the new growth, there is much investment in additional capacity. Furthermore, if you take into account the potential for better efficiency, higher yield—which do happen, and is happening continually—it will still come out to be that demand will outstrip the supply,” VanCott continued. “So, I think a couple of things can happen. I think we will see more capacity, and I think we will see a drive by many companies out there to continue to invest in processes that can enhance and increase the yields that we’re getting. Certainly, it’s a challenge for all of us that are in the field, and we’re going to strive to scale up capacity to meet the demand.”
Cell and gene therapy drug developers facing manufacturing challenges while bringing a product candidate to market may benefit from looking at the well-established world of mAb manufacturing. The key to the growth of commercial manufacturing for mAbs lies in the heavy investments made in engineering technologies, said Murphy. The cell and gene therapy fields are, today, still heavily focused on the R&D stages in the development of manufacturing processes, but not so much focused on investing in the engineering element for scaling up and improving yields, he adds. In comparison, focus on engineering investments have been a big focus by industry for the commercial manufacture of mAbs.
“I think there’s something to be said about that kind of investment and that expertise used to drive up yields, instead of, what I call, more classical, empirical approaches where we’re trying different ratios of plasmids and transient processes, and so on, for instance,” Murphy said. There is something to be learned from the investment focus of mAb production. Murphy observed that companies are starting to invest in the process engineering side of cell and gene therapy manufacture, which is a positive development.
In return, the mAb manufacturing industry can learn from the cell and gene therapy innovators, which are improving analytics. One example is the advancement of analytics that can support the testing and release of viral vector molecules for gene therapy. In addition, there are some innovative rapid testing techniques being developed in the cell therapy field that are advancing sterility assurance. “In addition, because we are dealing with a very single-use-technology-heavy industry, I think there will be things we’ll learn in making vectors and scaling up these technologies that can be applicable to mAbs and recombinant protein manufacturers,” Murphy stated.
Meanwhile, Murphy believes that some testing methods and analytical techniques from mAb manufacture can be leveraged to benefit cell therapy manufacture. “There may even be some facility design and features from mAbs that we can leverage,” he added.
For gene therapy manufacturing, a focus on engineering and the idea of using formal mixing studies to ensure an understanding of the dynamics present in a transfection event—both of which have been used in the mAb industry for years—can be highly applicable to the scale up of gene therapies, Murphy also observed. “The good news is, we’re already using scalable technologies to make vectors, and we’re moving away from ultracentrifugation. By doing these things, I think we’ve already leveraged some of the mAb bioprocessing technologies in the cell and gene therapy fields.”
In addition to challenge of capacity constraints, cell and gene therapy commercial manufacturing faces an issue of starting materials supply. In going from clinical to commercial phases, will supply of starting materials be enough for scale up or scale out?
VanCott emphasized that, when discussing viral vector production for gene therapy, it must be taken into consideration that supply and demand for the starting materials for these vectors is similar to that seen in other products. Plasmid DNA, one such starting material, is essential to both cell therapy and gene therapy manufacture, for example. Analysis has shown that the demand for DNA technologies, such as plasmid DNA, is increasing rapidly and is exceeding current available supply, VanCott observed.
“Looking at the timelines of much of the viral vector manufacturing on the market, one of the biggest delays in product[manufacture] is based on the inadequate source of supply of plasmids,” VanCott said. “It is true that more companies, including Catalent, are investing in bringing this capacity (raw material/plasmid capacity) online for all, but also to integrate internally for in-house vector manufacturing processes. I think this will alleviate the constraint to some degree, but this shortfall is something that has to be considered.”
“One of the things we don’t really know as yet is the impact of COVID-19 on normal healthy donors [for cell therapy manufacturing],” Moore said, bringing up the pressure posed by the current pandemic. “There are a number of companies that have entered the field which recognize the need for curated and tested donor material. Even regional blood centers are seeing that they can play a role as a supplier.”
Moore considers that regional blood centers can potentially provide some benefit in terms of reducing cost. For one thing, blood centers have long-established supply chains. For another, they have established, robust methods for transmitting materials to clinical sites. Furthermore, they enjoy the low cost associated with a significantly high volume of consumables and materials, Moore elucidated.
“I think, from an autologous standpoint, there should be adequate materials to support both autologous and allogeneic manufacturing,” Moore said.
“I think what we’re going to see is a standardization of processes, which will make the supply chains a little less complex,” added Murphy. “Whether that’s going to be in transfection or one or two minor processes, I think the standardization of processes will help enormously, in addition to yield improvement.”
A particularly unique challenge faced by cell therapies, specifically autologous cell therapy, is meeting a strict turnaround time while maintaining GMP compliance. This is one of the greatest challenges that autologous cell therapy manufacturing poses, confirmed Moore.
An important practice in autologous cell therapy manufacture should be to evaluate the combined logistics for the vein-to-vein loop alongside the manufacturing. Moore emphasized that it is crucial to establish a link between the logistics (i.e., the logistics provider) and the manufacturing (i.e., the contract development and manufacturing organization [CDMO]). “Establishing that link will allow for control over the vein-to-vein,” Moore said.
Another important area is establishing processes, policies, and quality control (QC) paradigms that support parallel patient processing and manufacturing. This can often be difficult for personnel to embrace, Moore cautioned, because people are often coming from a field where it was a one product–one factory scenario. Multi-patient processing is possible, however, and there are products that have been licensed with that paradigm. It is possible to use placards and temporary segregation in the manufacturing facility for multi-patient processing, which is based on risk assessments and ensuring that the facility has the correct design for it, Moore stated.
“This is important, not just for the efficiency of getting the product back to the patient and for compliance, but also for driving down the costs of manufacture, which is prevalent in the minds of the ones developing these cell therapy products,” Moore said.
Moore also added the idea that holistic scheduling is another important consideration in the overall logistics of cell therapy manufacturing. “It is important to make sure that the logistics team and the QC team are doing environmental monitoring. It is also important that the analysts who are performing the in-process testing and the quality assurance (QA) staff who are going to be reviewing the product are all appropriately scheduled. More often than not, there are changes in the schedule of receipt of the patient material, and in many cases—in oncology, for example—these patients are in a bad way. They have failed multiple rounds of frontline therapies, so it is important to have the ability in the clinical site to have established coordination among the entire manufacturing team,” Moore explained.
The ability to review batch records in real time (i.e., establishing modular batch records) also comes into play. With modular batch records, a team can do reviews such that, when the end of the process is reached and the product is being prepared for release, only a small amount of time need be spent with QA review. “The team would really only be addressing exceptions in the batch record and communicating with the client and the clinical representatives about the transport of the material back to the site,” said Moore.
“So, it is challenging, but there are established methods and approaches that can allow for good CGMP compliance while speeding the product along,” Moore concluded.
In the Editors’ Series webcast, Moore, VanCott, and Murphy provided further discussion on the challenges, industry trends, and strategies on the road to commercialization for cell and gene therapies. Figure 1 highlights insights gained from the webcast from participants who shared their individual challenges on their own path to cell and/or gene therapy commercialization.
1. Pharmaceutical Technology, ““Editors’ Series: Overcoming Commercialization Challenges for Cell Therapies and Gene Therapies,” Webcast, July 28, 2020.
Supplement: Outsourcing Resources 2020
When referring to this article, please cite it as F. Mirasol, " Commercialization Poses Challenges for Cell and Gene Therapies," Outsourcing Resources 2020 Supplement to Pharmaceutical Technology (August 2020).