Considerations for a first-class cold chain: an interview with Emily Hopewell
In this interview, Emily Hopewell (Indiana University) discusses the importance of considering the end-user in developing a cryopreservation protocol to support adoptive therapies.
This interview is part of the RegMedNet In Focus on cryopreservation. Discover expert opinion and top tips for cryopreservation in the feature now.
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Please introduce yourself and your organization?
I am the Director of Cell and Gene Therapy Manufacturing and an Assistant Professor of Clinical Medical and Molecular Genetics at Indiana University (IN, USA). We provide process development services and both cell and viral vector manufacturing services for both internal and external investigators for early phase clinical trials.
How have cryopreservation techniques and applications evolved since you have been working in the field?
I joined the field of cellular therapy in 2003 as a technologist at the Moffitt Cancer Center (FL, USA). Most of our focus was on cryopreservation of mobilized apheresis products for transplant. We had a few experimental trials using modified cell lines or cells isolated from patient tumors. At that point, all products were cryopreserved using an ‘in-house’ preparation of 10% DMSO with serum and saline in a controlled rate freezer. The biggest change in my career has been the variety of cellular products that need to be cryopreserved with the explosion of cell and gene therapy. Along with this, commercial cryopreservation reagents specific for various cell types are now available, helping to standardize the cryopreservation formulations.
Why is effective cryopreservation a challenge?
Effective cryopreservation is a challenge because we are trying to suspend a living cell with the intent to reanimate it exactly as it was. There are so many factors at play during the process and all of them contribute to its success or failure.
Cryopreservation should be optimized to preserve the function of your cells of interest. If you have a heterogenous population of cells, that adds another layer of complexity to the process. Additionally, your cells need to be as healthy as possible. If you have to keep the cells in culture longer than normal to reach your desired dose prior to cryopreservation, you need to consider the molecular changes that are occurring in the cells and if those changes may be detrimental to the overall function or health of the cells.
Another challenge to overcome is thermal cycling. Monitoring your storage freezers is not enough; you also need to consider every time the cryopreserved cells are transferred from one piece of equipment to another, from the time you remove the cells from your controlled rate freezer or passive freezing device to place them in liquid nitrogen storage all the way to removing for thawing, and every transfer in between. Each of those points is an opportunity for thermal cycling.
How should therapy manufacturers consider the end user when developing their cold chain and cryopreservation process?
This is a key point that can get overlooked and cause major consequences. Thawing techniques are just as critical as cryopreservation techniques. It is important to understand the end-user and what capabilities they have on site, including how much experience the end-user has thawing living products. It doesn’t matter how well validated your thaw process is if the end-user cannot perform the process.
It is also important to understand the tolerance of the cells during thawing. Certain cell types are more susceptible to variations in thawing than others. All of these aspects need to be considered and defined to help ensure the end-user understands and complies with the process. Without this, the next ground-breaking therapy may never happen.
How do hospital/healthcare needs (of a cryopreservation process) differ to those of a commercial cell therapy manufacturer?
The key difference in most cases is the phase of manufacturing. Manufacturing in a hospital or academic setting involves manufacturing a variety of different product types for relatively short periods of time, often a few years, in early phase trials. There is a focus on tuning the process based on the cell type or development of novel methods to meet the investigator’s needs. There has to be a well-defined process in place to develop, test and optimize the cryopreservation method for each new clinical trial or product.
In a commercial cell therapy manufacturing setting, the focus is on trying to lock down and standardize an existing cryopreservation process to move a product towards licensing.
What role does a regulator play in the final cold chain?
The ultimate goal for everyone involved is to provide a safe and functional product to the patients, regardless of product phase. It is important for the regulator to assess the final cold chain just as the manufacturing process is assessed and based on the phase of the product. The final cold chain must have adequate controls and documentation to ensure the product has not been compromised.
What can end users do to ensure quality and viability of the final cryopreserved product?
It is important for the end-users to have some background knowledge of cryopreservation. The key is to have open communication between the manufacturer and the end-user to ensure that the product is handled properly, that temperature excursions and thermal cycling are minimized, and that thawing and post-thaw manipulation is standardized as much as possible.
How can cryopreservation/cold chains evolve to meet future requirements?
A major hurdle to widespread use of adoptive cell therapies is dissemination of the final product. Manufacturers still rely on academic hospitals and research centers to treat patients because these centers have the required storage capacity and experience thawing cellular products. This reliance creates a bottleneck in the product chain and limits the number of patients who can be treated. This also biases the patients who can be treated to those within a certain radius of the facility, depriving many who live in rural areas or developing countries. Most small hospitals do not have liquid nitrogen storage capacity or transplant teams. Those are two challenges that can be addressed through adaptation of both cryopreservation and cold chain.
Cryopreservation needs to be optimized with the end-user in mind. The ultimate goal is to provide the end user with a simple standard method of thawing that has clear guidance on exactly how to thaw the product or allows use of an automated thawing device that is cheap enough to be widely distributed and easily verified. The cold chain needs to mature to allow reliable ‘just-in-time’ delivery of products regardless of the location. If these two challenges can be overcome, we will be able to bring life-saving treatments to so many more patients.
How can people contact you for more information?
You can email me at emlhope[at]iu.edu
This feature was produced in association with Brooks Life Sciences.