In this interview, Andreas Bosio (Miltenyi Biotec GmbH) discusses the challenges of producing clinical-grade cells and the advantages of using the CliniMACS Prodigy® Adherent Cell Culture System for cell manufacturing.
Please introduce yourself and your institution.
My name is Andreas Bosio, I am a senior manager in the research and development department at Miltenyi Biotec GmbH (Bergisch Gladbach, Germany), a leading biotech company. In the last 30 years, we have gained extensive experiences in cell manufacturing, FDA approval processes, phase I clinical trials, and CAR-T cell production.
There are a number of clinical trials for age-related macular degeneration (AMD) and Parkinson’s disease (PD) based on human embryonic stem cells or induced pluripotent stem cells worldwide.
What are the advantages of cell-based therapies as a treatment for these diseases?
Both diseases are idiopathic, which means for most patients the exact cause for the disease is not known. Subsequently, there is no clear prophylaxis. What we do know, is that at least one particular cell type is affected, such as retinal pigmented epithelial cells in AMD or dopaminergic neurons in PD. At the time of diagnosis, a substantial number of these cells are already lost. From a mechanistical point of view, functional replacement of these cells seems to be an obvious way to go. Cell replacement may still not cure the disease, but it may significantly improve the patient’s quality of life.
What have been the challenges in producing clinical-grade cells required for the trials?
Protocols used so far for the differentiation of pluripotent stem cells have been developed without paying too much attention on the complexity of handling steps, reagents, and consumables. However, under good manufacturing practice (GMP), protocols need to be highly reproducible, which can only be achieved if they are not too complex.
Many hurdles have to be overcome to develop protocols, which allow the generation of functional cells. In addition, producing clinical-grade cells poses the demand of streamlining all steps in a way that a technology transfer of the protocol to a GMP facility is doable. Furthermore, the transfer of all reagents to an appropriate quality also sometimes necessitates changes of the protocol to achieve the same efficiency. Finally, quality controls need to be defined and incorporated into the process to assess residual pluripotent stem cells as well as identity and purity of the target cells.
Costs and scalability are often discussed as challenging factors for producing clinical-grade cellular products. What is your view on this?
Yes, this is a critical issue. From my point of view, a cell therapy will only be commercially viable if you can produce the cells to a price and at a scale that all patients can be served without running the healthcare system into financial challenges. Although from a patient’s perspective a curative therapy does not have a price, from a community’s perspective, the cost of some treatments can be too expensive for the healthcare providers.
Scaling up is not trivial; if the initial production set up is not scalable on its own, a lot of changes must be implemented to reach the goal, including changing instruments, culture wares, and sometimes even culture modes.
How do you see the role of automation in large-scale cell manufacturing?
Automation of manufacturing should help to make a process reproducible, it should reduce the costs, and allow for up and out scaling. Advanced therapy medicinal products (ATMPs) are heavily defined by the manufacturing processes, which substantially increases the need for automation. Ideally, an automated system allows for the production of low cell numbers as needed for phase I clinical trials in a cost-effective way, but could be scaled up by parallelizing the automated production in a ballroom concept.
Have you already implemented automation in your cell manufacturing workflow? If so, how did you achieve that?
Yes, we have, thanks to the work of Sebastian Knoebel’s team (Miltenyi Biotec GmbH). We were lucky to have already a fully implemented manufacturing instrument in the company, the CliniMACS Prodigy, which has been used for the preparation of hundreds of cell doses, mainly hematopoietic stem cells and T cells. Still, we had to adapt the system from its original setup for suspension cells to a setup optimal to process large numbers of adherent cells.
We succeeded and established a new CliniMACS Prodigy—based system, the Adherent Cell Culture System for manufacturing of adherent cell types. Now, we have all features implemented in this system so that we can use it for the expansion of mesenchymal stem cells, pluripotent stem cells, and differentiation of pluripotent stem cells towards dopaminergic neurons. The system enables routine production of small phase I batches up to mass production of thousands of doses in a ballroom approach. Moreover, the system is flexible enough to be used for experimental optimization of early-stage manufacturing protocols, for example, for new cell types.
Can you reveal more details of your system? Do you think it is what is needed for the stem cell therapy field?
This cell manufacturing system consists of the CliniMACS Prodigy Instrument itself, a dedicated tubing set, and the software (in this case the Adherent Cell Culture Process). The instrument includes a combined centrifugation and cultivation (CentriCult) unit, a magnetic separation unit, and a peristaltic pump. The dedicated tubing set connects all compartments and offers a sterile closed environment. All necessary steps for cell manufacturing are modularized in the CliniMACS Prodigy Adherent Cell Culture System. These steps can be the coating of culture ware, inoculation of cells, maintenance-, expansion-, or differentiation-culture, media changes, and harvesting including concentration and washing of cells. It also has a density gradient module to isolate cells, such as mesenchymal stem cells, from primary cell materials.
Flexible combinations of different modules allow customizable manufacturing of various adherent stem cell and other cell types. The culture capacity for adherent cells can be enlarged by using external culture vessels, which can be connected to the tubing set. Furthermore, the cell production process is GMP-compliant and meets documentation requirements.
What are the next steps in stem cell research? Do you think that we are ready for stem cell therapies?
We are only at the beginning, but yes, I think we are ready for stem cell therapies. We have learned a lot from cell therapies using hematopoietic stem cells, and more recently CAR-T cells, and are now ready to transfer this knowledge to pluripotent stem cell—based therapies.
The most important current learnings are on the safety of pluripotent stem cell—derived cells. A number of patients have already been treated in the last several years across the globe. To my knowledge, no serious adverse effects have been documented. Trials to show functionality are on the way or about to start.
We will face progress and setbacks, and we will learn which individual cell type or which cell type combination is more effective in the treatment of certain diseases. This will help us to further optimize these cell therapies. Therefore, a clear understanding of the identity of applied cells, along with the capability of sorting pure and viable cells, is very important. Another challenge we are facing is to understand how to pre-condition patients to optimize cell engraftment and to reduce rejection rate.
Currently, we are using allogenic cells, but we are also considering using other cell resources, such as engineered universal cells, haploidentical, or even autologous cells. The latter depends on the ease, cost, and reproducibility of reprogramming. There is still room for improvement.