The quality and consistency of starting material can have an enormous impact on downstream manufacturing processes in cell therapy. Recently, Hitachi Chemical partnered with HemaCare to write an article for BioInsights detailing the importance of starting material quality, what impacts starting material stability, and strategies for improving starting material stability and shelf-life.
Here is a brief list of highlights from the joint article:
How Time to Delivery Impacts Source Material Stability
As noted in the BioInsights article, “The challenge we are now experiencing is the requirement for that starting material to be both available in sufficient quantity and of the highest quality to ensure consistency downstream.” If the starting material for a cell therapy product is of insufficient quality and stability, then the downstream manufacturing processes, such as cell cultivation and modification, will be adversely impacted.
Since this is of such high importance, what are the major factors that impact source material stability and quality?
Aside from errors in the collection process, the time those materials take to reach their destination can have a huge impact. The longer starting materials spend in transit from the collection site to the modification site—and then from the modification site to the point of care—the worse their stability and quality will be. Essentially, the cells “will begin to die” soon after collection. The moment collection is completed, the proverbial clock is ticking to get the starting materials to the modification site.
One of the common issues in the cell collection process is the risk of delays in transportation. Even in a well-optimized transportation network, risks are always present, such as mistimed deliveries, traffic jams near distribution centers and delivery destinations, or errors in package handling procedures. The article notes that this can impact “the cost of goods and also the shelf-life limits of both your materials and the final product.” This is often because significant delays may cause the starting material to degrade to the point where its ability to meet critical quality attributes post-modification is no longer guaranteed—necessitating replacement.
Cryopreservation and Starting Material Stability
The use of low-temperature preservation techniques in order to slow cell death is becoming increasingly common in cell therapy manufacturing supply chains. As noted in the article, “Data has demonstrated that hypothermic storage can improve the stability and extend shelf-life of starting materials like bone marrow and peripheral blood stem cells.” Repeated research shows that hypothermic storage techniques can reduce the rate of cell death during transit. These techniques can greatly improve the stability of starting material for cell therapy products and the distances such material can be transported.
However, as noted in the article, “While hypothermic conditions offer improved stability of starting materials, significant loss in both cell viability and function can still occur over the initial 24–48 hours post collection.” Cold storage may impact the ability of the cells to multiply post-modification in the cell culture phase of manufacturing. This, in turn, limits the size of the dose that can be produced as well as its potency (therapeutic cells that do not multiply may not be as effective for treating patients with oncology indications).
This fact highlights the necessity of conducting thorough testing with preservation techniques to discover how they impact long-term stability and viability for starting materials and final products. Not every cell therapy product will be able to use the same preservation techniques to extend their starting material stability.
The Potential for Onsite Modification
As the cell therapy industry continues to move toward globalization, the distances between collection sites and processing sites (and the processing sites and patients) is likely to increase. If cryopreservation cannot be universally applied, other methods for improving starting material stability will be required.
One method of improving starting material stability suggested in the article was the virtual elimination of transit times via onsite processing of therapeutic cells. However, this tactic does have its downfalls. Although, “rapid manufacturing, such as bedside operations” would be beneficial, “this seems to be a future vision that is some way off commercial use.” As of right now, it would be impractical to install all of the necessary equipment for cell modification at every treatment site, while also providing each healthcare provider with the requisite training for meeting QTPPs for each cell therapy product.
A close second option would be to leverage the use of contract development manufacturing organizations (CDMOs) that have appropriate cleanroom facilities in different regions to shorten the distance starting materials have to travel. Although this will require a successful technology transfer to the CDMO, it is much more efficient than trying to do the same for every healthcare facility that provides care for patients undergoing cell therapy treatment.
Interested in reading the full article? You can read it on the BioInsights blog now. If you have any questions about optimizing your starting material collection process and supply chains, please contact our team.
