Building flexibility into GMP CAR T cell therapy manufacturePublished: November 18, 2019
Christin Tischner currently works at Miltenyi Biotec as a Clinical Supply Chain Manager. This interview was conducted when Christin was working in her previous role as Tech Transfer Project Manager for CAR-T Cell Manufacturing at Cellex. She is a Molecular Biologist by training and obtained a PhD in Genetics from the University of Cologne.DOI: 10.18609/cgti.2019.144
Citation: Cell & Gene Therapy Insights 2019; 5(10), 1385–1390.
What are your current responsibilities and activities at Cellex?
CT: I’m leading the project of design and set up our new GMP facility. We are operating a smaller Cell Factory in Cologne already, but due to the increasing demand we needed to increase our manufacturing capacities. My main responsibilities relate to facility design and process implementation.
It’s an interesting period to be designing and establishing a new cell and gene therapy manufacturing capability. ‘Flexibility’ seems to be the watchword, given the rapid development of both enabling and therapeutic technologies in the space – how are you seeking to build this key element in to your facility?
CT: There are different perspectives from which to look at it. First of all, it is good to have a flexible plan or a modular design that you can adjust and expand easily. Right now that is very important because both our own internal CAR T cell therapy program and also the projects we are running together with sponsors as a contract manufacturing organization are in the early stages.
When we think about future commercialization we obviously will need to increase our capacities. We took that into consideration from the very beginning. The modular design enables a ramp up when it’s needed.
The other aspect, which makes flexibility a requirement for us as a CMO, is that we have to adjust our processes in accordance to sponsors technologies and requirements we need to implement.
We have taken a modular rather than an open space approach, because for us as a CMO, it’s not really realistic to follow this ‘ballroom’ concept: when you have to orchestrate several customers, confidentiality becomes an issue. Therefore, it is essential for us to offer dedicated units. Especially, since we are not working completely paperless just yet, separation also helps to ensure chain of identity.
Can you tell us more about the process you are following in transitioning Cellex’s proprietary CAR T cell platform into the GMP setting? What are/were some of the key issues and considerations, and how have you sought to address them?
CT: The company originally started as an apheresis collection center for hematopoietic stem cells with profound experience in cell therapy, so it was always in our mind that if we were to start with the CART cell approach, we would really want to prioritize bringing it into a GMP manufacturing setting.
From the beginning, it was our goal to conduct most manufacturing steps in Class D cleanrooms and avoid the need to work in higher cleanroom classes as much as possible, for cost reasons apart from anything else. So consequently, we really wanted to work in a closed, automated system.
That meant we made the fundamental decision to use the Prodigy platform early on and then, during the R&D process, we used MiniMACS separation columns and also the CliniMACS – so not automated, but with the same principle of cell sorting. That made it easier for us to go step-by-step as we progressed in our research and started scaling-up the process.
We stayed basically with the same core technique and that’s why the transition for us was pretty straightforward. And although we’re only at the tech transfer stage from R&D to GMP manufacturing for our first clinical trials, which should start at the end of 2019, we haven’t observed any difficulties as yet.
What learnings and experience have you been able to leverage from other branches of the Cellex business – the HSC collection division, for example?
CT: I’m quite new in the cell and gene therapy field, but I think there has been a great deal of focus on the manufacturing process – which technologies and devices to use, where you can cut costs, etc. – and now people are starting to look in earnest at what is upstream and downstream of the process.
So upstream, of course, is the collection of the starting material and since we have extensive experience with apheresis, we know how different the starting material can be. You have that issue with healthy donors, but even more so with patients. However, we have great staff working in our collection site who are expert with the settings of the apheresis machines and who can really fine tune the collection process to obtain high quality starting material.
This is something to consider: some clinical sites conduct apheresis protocols very frequently, but many others don’t. This means the staff are not always particularly experienced. In addition, clinics might perform apheresis collection for various CAR-T cell trials for different pharmaceutical companies and therefore the collection procedure might differ. So we decided to offer a kind of service whereby we train the staff at other collection sites with which we work, as well as our own staff, because we have this really good hands-on experience in-house. We realized the importance of this quite early on – that it was key to focus on this element in parallel with our manufacturing improvement.
Of course, it’s not just about the starting material collection and the bioprocessing – the delivery of the finished product to the clinical point of care and administration to the patient are also crucial. I think it is equally important to train clinical staff in these aspects.
Another strong point of focus from the start for us was the supply chain, particularly relating to scheduling and transport of leukapheresis and the final drug product. For normal stem cell donation, you have to make sure the apheresis product arrives at the clinical point of care within the 72 hours shelf life. To facilitate a smooth and on time transport, Cellex always had a scheduling and logistic team in house. To avoid any transportation related problems and to guarantee chain of identity we use on-board couriers. Talking about CAR-Ts as a personalized therapy with even shorter shelf life, these precautions become even more important.
How and where specifically will utilizing the Prodigy system impact the ongoing manufacturing model and strategy that Cellex pursues? What’s the direct impact on the design of your new facility, for example?
CT: As I mentioned previously, it definitely influences the cleanroom design – the completely closed and automated system will ensure we can have all of our manufacturing space only in Class D.
The open steps required for the medium preparation are performed in isolators, which are Class A devices positioned in Class C suites. All the other process steps like cell separation, transduction, cultivation, formulation – it’s all Class D, which makes it much easier to work with. In addition, the environmental monitoring is less intensive and running expenses and maintenance costs are reduced. These aspects really influenced our choice of set-up. For us, it was very clear from the beginning that we wanted to try to put the Prodigy in the Class D cleanroom, and the local authorities approved it, which was great!
How important is a holistic approach to the entire manufacturing and supply chain in this particular technology space? How do you seek to apply this philosophy to Cellex’s work in the cellular immuno-oncology field?
CT: For advanced therapies like the CAR-Ts a holistic approach which unites all stakeholders including collection center, courier, manufacturing site, trial manager and sponsor is essential particularly when you think about scaling up for commercialization. Software solutions have been designed to efficiently schedule apheresis and manufacturing slots and the shipment from the clinical to the manufacturing site and vice versa and simultaneously control COC/COI. Those platforms allow traceability throughout the product life cycle and notification about deviation when they occur. However, implementation can still be affected by the IT infrastructure at the different sites.
I could envision that the application of those software solutions might be challenging especially for hospitals involved in several CAR-T trails when all sponsors use different approaches.
However, in preparation for higher patient numbers reduction of paper based work is crucial, not only to reduce the work load but also to support traceability.
What is the endgame for Cellex in terms of commercial scale CAR T cell immunotherapy manufacturing? What will that look like, ultimately?
CT: We believe it is most realistic, at least for the moment, to have centralized CAR T cell manufacturing. Our GMP facility in Cologne is centrally located within Europe enabling us to supply clinical sites without difficulties. However, since manufacturing capacity must be further increased to meet commercial need this could be divided to several sites spread out around Europe to reduce transportation time.
We feel it is probably too difficult to do bedside manufacturing. From our experience, Prodigy is easy to work with – the set-up is pretty straight forward – but it’s still a sophisticated machine, and we want to have well-trained and experienced staff in our cleanrooms not least for troubleshooting. I am not sure whether or not individual clinical sites have high enough patient numbers to reach that routine or cover the costs related with setting up a GMP unit for ATMP manufacturing.
In the end, I think shortening the process is an interesting and important goal to work for. Reducing the transportation time and therefore even avoid the need for cryopreservation could be a step in the right direction.
Authorship & Conflict of Interest
Contributions: All named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Disclosure and potential conflicts of interest: The author declares that they have no conflicts of interest.
Funding declaration:The author received no financial support for the research, authorship and/or publication of this article.
Article & copyright information
Copyright: Published by Cell and Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.
Attribution: Copyright © 2019 Christin Tischner. Published by Cell and Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0.
Publication date: October 23 2019.
Clinical Supply Chain Manager,
At the time of interview:
Tech Transfer Project Manager for CAR-T Cell Manufacturing,