Closed System Cell Therapy Manufacturing – Moving from the lab to clinical and commercial production

Show Notes:

I began the discussion by asking about the key considerations for taking a cell therapy from the academic setting to a clinical and eventually a commercial process. Phil described how important it is to understand the biology of the product and that it is key to identify as early as possible the scale of treatment, how many therapeutic doses, and the adoption rate. Then companies should begin to envision their process. Process development will need to ensure that the product is scalable to meet the required doses, understand the number of cells per dose, and to close and connect the processes. All this needs to be done while also considering regulatory requirements.

Next, I asked what are the biggest challenges to achieving this and Phil described how just a few years ago, there was not a wealth of products or technologies available specifically for cell therapy manufacturing. This lack of designated products required a piecemeal cobbling together of materials and equipment – for instance, many times products came from protein therapeutics production. These off the shelf products, not designed for the purpose of producing cells as final products, were not able to be connected in a streamlined process or one that was amenable for cGMP.

I then asked Aaron why a closed system is so important in the cell therapy space. Aaron first defined a closed process as a process where the biological material is never exposed to the open environment. By removing the exposure to the open environment, you can reduce the risk of contamination. Closed systems also enable increased automation, which can reduce timelines and cost. It can also permit better facility use in that you take better advantage of the technology footprint, can have multiple patient samples in the same room, and lower clean room requirements all of these factors can improve cost and facility utilization.

I followed up with Aaron about the hurdles to achieving a completely closed system. He said that coming into the space with no equipment or kits specifically designed for cell therapy and/or using newly designed equipment can make it difficult to have an integrated and closed system. Also, living cells are more complex and therefore more challenging to manufacture than small molecule or protein based therapeutics. These considerations have made it more difficult to rapidly move to a closed approach. Aaron also mentioned that having a completely closed system could limit your flexibility and productivity. For example, if you are using a single closed technology system that is used for the entire process, you could lose overall productivity because you could not introduce a new patient sample until the entire workflow is completed.

Then I asked Aaron what advice he had for companies that are making this transition and what kind of support is available to them. He suggested that companies should understand the product they are trying to develop and what product requirements will be, if approved. It is best to start with an end vision. For example, how many doses are required for such an indication then start working backwards to see what is required from the process. There is a misconception about the process needing to be completely closed during early clinical development and trialing, instead regulators want to see a phased process and see that improvements are being made throughout clinical scaling up. Groups developing therapies in this field are brilliant but often have more expertise on the biology or clinical side of things. However, there are experts in cell therapy manufacturing that can provide scale-up and manufacturing expertise that can guide companies through the process, helping with speed, productivity, cost savings and flexibility. For example, GE Healthcare and CCRM collaborate to offer tailored process development services to companies in this space. GE Healthcare also just launched a Fast Trak training course as part of the broader Enterprise Solutions offering to educate cell therapy companies about cell therapy manufacturing.

Next, I asked Liz about her process development work at the Centre for Advanced Therapeutic Cell Technologies (CATCT) in Toronto, which was created with support of GE Healthcare and the Federal Economic Development Agency for Southern Ontario. I asked her what details of a client’s current process is she most interested in. Liz explained that there are two main types of information needed. First are details about their current process, what’s working well for them now and what areas are challenging and need improvement. Secondly, they also want to understand the company’s near-term needs and long-term needs. For example, solutions to enable the manufacturing of early clinical trial material requires a short timeline, but long-term goals for manufacturing might be different.

I followed up by asking Liz if she could walk us through what a working relationship between a client and her and the team is like and if there are any common challenges that most companies experience. She said close interaction and communication with the company they are working with is key. It is important to recognize complementary skills and to make sure that any suggested process changes don’t affect the biology. It is also very important to understand priorities to ensure that clinical timelines are met and that process development work is done in advance of those timelines. They also need to be sure they understand and align with the way the company is handling cells and carrying out analytics. For example, cell counting with different equipment can create quite different results, if they know that there are going to be differences in equipment upfront then they can take that into account and ensure comparable outputs.

Then I asked Liz what her favorite process development “tools” were. She said that new tools including hardware and reagents are coming into play quite quickly. They like to use Design of Experiment (DoE) approaches to examine how multiple factors impact the cell culture and how they might interact with each other. They do this by using scaled down bioreactors and automated liquid handling tools. It allows them to take a broad look at parameters and impact to choose the design space that is most appropriate and then explore it at larger scale.

To close, I asked Phil where he thought the cell therapy industry is today and where it needs to go to fully realize its promise. Phil said that the industry is fairly far along on therapeutic evolution and design of therapies. One big change he has seen over the past several years and believes will become more prominent, is for therapies to have a component of genetic modification or manipulation. This will drive rethinking the manufacturing process, how many cells are required, are their other cell types that could be more effective, etc. The challenge to manufacturing and commercialization is two-fold. First, we have to think about the broader supply chain elements and how we bring all the pieces together or incorporate the manufacturing center into the broader clinical delivery path. The second is that it takes several years to invent and develop new technologies that might be helpful today, but the therapies are constantly evolving too. Thus, as a technology supplier, you must make assumptions about where the industry is going.

Last, I asked the panel members if they had anything else to add for readers. Aaron said that this is an extremely exciting time and in the last year there have been real advances in transitioning therapies from clinical to commercial stages. These advances mean new technologies and a manufacturing focused paradigm is important. There are groups out there like GE Healthcare and CCRM to help companies developing these therapies and it is never too soon to start thinking about the commercial process.

I then followed up with a question about when companies should start looking for outside help. Liz reiterated that it is never too soon. She said groups are starting to think about process implications early on and her clients are coming in pre-clinical, Phase I, and Phase II because they need process development work to meet near term goals and further commercialization.

Thank you to our panel for this podcast, it was a very informative discussion on cell therapy manufacturing and interesting insight into helping companies move from the lab to clinical and commercial manufacturing.

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