The following article originally appeared in BioInsights on April 22, 2023.
Charlotte Barker, Editor, BioInsights, speaks to William Swaney, President of Manufacturing, Expression Therapeutics, John (Yoshi) Shyu, Director, Global Scientific Applications, Corning Life Sciences, and Nikhil Tyagi, Director of Cell Therapy Process Development, Center for Breakthrough Medicines.
Watch the webinar or read the full interview below.
Q: What are the biggest challenges that the cell and gene therapy industry faces in getting products to market quickly?
WS: Cell and gene therapy companies, regardless of their development stage, all have the same goal of reaching the market. To get to market, you need to manufacture the product and complete initial early-phase clinical studies. Considerations will be different for the company based on its development stage. Drivers often include the disease indication, whether it is single or multiple treatments, and the platform chosen. The dosage and route of administration will also come into that discussion. In addition, it is worth noting the regulatory considerations as well as the intended markets you want to serve. Regardless of company size, everybody wants to build manufacturing facilities that are flexible, modular, and sustainable.
A big challenge currently facing early-stage startups is that over the last few years, venture capital funding and mergers and acquisitions have slowed down considerably. Many firms are cash-starved and are unable to capitalize on their ideas and move into the clinic. One of the big paradigms for early-stage companies is whether they outsource to a CDMO. If you are fortunate enough to be an early clinical-stage company with in-house manufacturing, talent acquisition, and retention will be key to getting products translated and into the market quickly. Supply chain management is also going to come into that, as well as regulatory compliance.
For commercial-stage companies, the lack of harmonization across some of the major global markets impedes moving things into the market. For example, requirements are different in Europe and the USA.
NT: As all cell and gene therapies are new, we do not have much data available on safety and efficacy. Over time, more data will become available and once we have an increased understanding of safety and efficacy, we should be able to bring more therapies to the market.
JYS: After seeing how the market has exploded in the last several years for cell and gene therapy, a common question is how do we get things faster? How do we get the product in an amount that is more relevant to the indications that scientists are studying? Having the right infrastructure, the right platforms, and the right support structure to generate enough material to be able to complete a program are all key considerations.One common challenge in the market is that despite our great ideas, we need to further understand what is needed from a workflow perspective to be able to accomplish our goals
Q: In addition to reducing time to market, how can we make cell and gene therapies more accessible?
NT: Cell and gene therapies are a promising field, and we have seen early results in diseases including cancer. The only problem is that these therapies are very expensive. Current cell therapies range from $300–500K per dose, and gene therapies are over $1 million per treatment. This is inaccessible to most patients.
If we can reduce the cost, then we can bring those therapies to the wider population. The main problem is how to do so. In my opinion, we must develop more cost-effective and affordable manufacturing processes. Can we reduce the length of the manufacturing process? Can we bring automation to these processes?
Allogeneic cell products could significantly reduce cost compared to autologous therapies and we would be less likely to experience supply and demand issues if bulk manufacture became possible.
Another consideration is the reimbursement landscape. Currently, our insurance policies do not cover these expensive cell therapies. We need to create more therapies with affordable manufacturing processes and work with governments to make these accessible to every patient.
WS: When these products come into the early phase of development, there are often still open manipulations or unclosed steps. This leads to requirements for working in the appropriate environment, for example in an ISO Class 7 room with ISO Class 5 biosafety cabinets in the USA, or with Grade A operations occurring in a Grade C room in the EU. If you can close those processes, you may be able to decrease the amount of clean room required, which would have a significant impact on the cost of manufacturing.
NT: Most cell and gene therapies are being developed in academic institutions and startups. Those companies and institutions have narrow pipelines, only working on one or two products. They are making their own manufacturing facilities, which is adding to costs. If we can bring those manufacturing processes to CDMOs or large pharmaceutical companies that already have manufacturing facilities, we can reduce the risk of investing in a single-product pipeline and enable the production of more doses in a shorter timeframe.
Q: What are the key factors you would advise looking for when selecting a manufacturing platform?
JYS: One of the most important questions is: what is the life cycle of your process? If your product needs to be produced for the next year or two, does your platform allow you to produce two, three, or even five times the amounts you need right now? If so, your process will cover your life cycle for the next couple of years. If not, you may need to look at more nimble platform alternatives to increase size. The platform you are selecting needs to meet your current needs in addition to your future needs for the next several years, or the entirety of the process life cycle.
NT: As mentioned earlier, most of the manufacturing platforms for cell and gene therapies are currently open and manual. We need to develop more simple, affordable manufacturing platforms, and investigate both unit automation and end-to-end automation. Current cell therapies are very complex. If we can develop a more automated process − closed, and GMP compliant − we can reduce the length of the process and cut the cost of manufacturing. The first requirement is to develop an easy-to-use, affordable, robust, and reliable manufacturing platform.
For all cell therapies, we are dependent on source material from the patient, which shows large patient-to-patient variability. This underscores how important it is to develop a robust and reliable manufacturing platform to reduce manufacturing failure.
WS: We need to move towards flexibility, scalability, and simplicity in closing and automating processes. We also need the flexibility to do small-dose manufacturing, as there is still a huge unmet medical need for ultra-rare diseases, as well as produce larger product doses. The platform needs to drive both large and small requirements.
Q: What are your thoughts on transitioning between platforms as you scale up and advance through the preclinical and clinical pipeline? And what are solutions providers like Corning doing to optimize that compatibility?
NT: It is important to choose wisely when selecting a platform. Most of these therapies are being developed in startups and academic institutions that do not have a vision for Phase 3 and commercial manufacturing. Transitioning from preclinical to clinical becomes challenging, particularly in the case of cell therapies, which are not the same as small molecules or monoclonal antibodies. A small change, such as a change in the growth factor in the media, can result in a different product.
There is a great deal of demand from people who have already developed their process using standard, open, and flatware culture systems, but when moving from preclinical to Phase 1 or 2 need to improve their process. Service providers like Corning are helping us here.
Taking the example of an open stem cell therapy process, there is a scale-up limit on growing cells in T flasks or HYPERStack® cell culture vessels. Scale-out is limited due to the labor-intensive processes required. Platforms like flatbed bioreactors, fixed bed bioreactors, and stirred tank bioreactors are possible options, though comparability needs to be considered. If the process is developed in a 2D platform, it is challenging to move from 2D to 3D, as it will change the biological properties of your product.
I am currently working with Corning on the Ascent® FBR System which is a highly compatible platform. We can easily scale up the process, and close and automate steps. Companies like Corning and other service providers are working towards this, and as CDMO service providers, we are quickly adapting those technologies.
JYS: Transitioning between platforms at any stage of the manufacturing process is a pain point. If you are transitioning between platforms directly, the optimization time tends to be short, at a maximum of 2 months. When transitioning, you must ensure you have the correct support structure both from the supplier and the technical personnel to allow you to transition collaboratively. Technical assistance becomes a critical component for anyone transitioning between platforms.
WS: There are many learnings to be had at the early stage of preclinical development. We are on board with the concept of maintaining platform fidelity throughout the clinical development program. If possible, you should avoid switching platforms or producer cells, because that will affect some of the key quality attributes of your products. For example, if you went from using an adherent cell line to make lentivirus to a suspension cell line, this changes the downstream purification platform and may require expensive bridging studies to show comparability.
We are also working on the Ascent fixed bed bioreactor for that same reason. The data provides us with the ability to stay with our adherent cell lines, our plasmids, and our existing process. It is good to hear that other people are seeing the same benefits that we are seeing.
Q: In what specific areas have you seen the greatest impacts of global supply chain shortages and price increases? What is your advice to others on how to address this ongoing issue?
WS: Early in the pandemic, there were huge supply chain issues with the acquisition of PPE and plastic labware. There was an inability to acquire multi-tray stacks and culture media because everything was dedicated to vaccine development. That situation has improved tremendously, but we are still seeing issues with plastic bags and product containers. Recently in the USA, we have seen a challenge in getting medical-grade CO2 delivered to manufacturing facilities.
We have addressed those challenges by working with our primary, secondary, and tertiary sponsors to provide uninterrupted acquisition of raw materials. We have also assessed having a larger standing inventory. When we first resumed activities in our manufacturing facility, we were seeing lead times approaching 40–50 weeks for a customized product, even for simple things such as longer tubing or different connectors. We had to evaluate whether customized products were worth it, especially if there was an equivalent product we could get off the shelf.
It is also paramount to have good relationships with your suppliers. You need to be able to pick up the phone and talk to someone about your needs and have a supplier who recognizes those needs and strives to fulfill them. That is critical to being successful today.
JYS: Coming out of the pandemic, many manufacturers, including Corning, have learned how critical it is to have a secure supply chain. When a specific therapy or program advances to the next stage or shows promise, you may suddenly require a lot of material. If using a platform with a long lead time, that can become a challenge. My advice to anyone working in cell and gene therapy is to let your suppliers know ahead of time when you anticipate ramping up production so everyone can prepare and secure inventory. Do not be shy about informing your suppliers that there a potential for a surge so that we can assist in securing that inventory.
Q: What advances in terms of platform, process, or partnerships have you been most excited about in recent years, and what’s on your wish list for the future?
NT: Cancer is the leading cause of death worldwide. We have seen a lot of advances recently, particularly in the case of immunotherapy, with a few curative drugs on the market. We have checkpoint inhibitors like PD-1 and CTLA-4, and recent CAR T cell therapies approved by the FDA, which are all very effective. I am amazed by the progress in the cancer field.
On the gene therapy side, we have a couple of technologies, including CRISPR/Cas9, that have increased precision. Novel technologies are making a great impact on patients’ lives.
In future, I would like to see more precise and selective gene editing tools. For cell therapies, I would like to see strategies to reduce the manufacturing cycle. Currently, the cell therapy manufacturing cycle ranges from 9 days to 4 months. A few companies are working on reducing manufacturing time, and a goal in the space is to bring this time down to 1–3 days.
In addition, we need to automate processes, either the unit operations or the whole process end-to-end. I would like to see end-to-end automation in manufacturing processes to increase the manufacturing success rate and manufacture more drugs in a shorter time. In this area, a few companies are working on making a GMP-in-a-box approach.
WS: Over the last couple of years in cell and gene therapy, we have seen movement into licensed products. This has been a seminal moment for the field. The success that we are seeing in the CAR T cell therapy arena has been amazing.
One thing that would be beneficial would be a movement away from autologous T cells towards off-the-shelf allogeneic products that accomplish the same goal. That would eliminate some individual product manufacturing. We would also like to see broader personalized medicine, where a patient’s novel epitopes expressed on their cancer can be reverse-engineered to make a CAR T cell or a product. To achieve this, we need to make small-dose products in a robust and fast manner.
JYS: One recent advance I have seen is platforms becoming smarter. Corning is creating platforms with smart sensors that can provide a feedback loop and let researchers know if something is trending differently from expectations. Having these types of tools that you can add to platforms gives a greater sense of security that your process is advancing correctly and that you will be able to achieve your desired output in a more controlled manner. On my wish list is the ability to fully remove the scientist from the production room and allow remote control of what is happening.