As referenced in a previous blog post, understanding the proper method of safely cryopreserving your material is essential, but of equal importance is determining the optimum maintenance temperature. There are many factors that need to be considered when selecting an effective maintenance temperature. Those factors include volume, handling processes, storage and handling equipment and the impact of multiple short duration exposures. In this two part blog series, we’ll discuss four areas that need to be understood to determine the optimum maintenance temperature for advanced therapy material.
Volume, Packaging, and Storage
Volume is perhaps the least complex but most often overlooked variable in temperature selection. At its most basic, the lower the product volume, the faster it will thaw and cross the glass transition point. Therefore the smaller the volume, the lower the storage temperature required to ensure product integrity. There are other factors such as the type of vessel in which the product will be stored that needs to be considered in conjunction with the volume. A tear drop vial, for example, will offer more thermal protection than a standard cryovial. Additionally, if the drug is administered in multiple volumes, the actual temperature selected will need to be modified by the volume of each dose. Volume is an important factor but only one of many.
The consideration that goes hand in hand with volume is packaging and storage configuration. The lower the volume, the greater the impact of packaging and storage decisions. These topics will be discussed in a future blog but it is important to keep in mind that sound packaging and storage choices can have significant impact on the ability to maintain proper temperature of product, particularly in low volume situations.
Handling Processes and Validation
The static temperature of the material impacts the handling time. It is important to note that the impact on handling time created by lowering the static temperature is not a linear function. In a prior post, my colleague Alex Esmon demonstrated that as static temperature is lowered, the working time to the breach of the glass transition point increases exponentially. However, this does not mean that setting the temperature as low as possible is the best course of action because each time the temperature is lowered the cost to store and ship increase.
There are several points throughout the supply chain in which drug product could be exposed to non-controlled temperature conditions, if diligent handling processes are not in place. Consider these potential movements:
- Control rate freezer to storage box
- Storage box to freezer rack
- Freezer rack to freezer
- Freezer to packaging and labeling processing
- Back to freezer rack
- Freezer rack to freezer
- Freezer to distribution pick/pack
- Pick/pack to distribution rack
- Distribution rack to dry shipper
- Dry shipper to thaw process
- Thaw process to bedside
How does one minimize exposure to a potential temperature excursion? The answer lies in evaluating and understanding the time each step takes and the environment in which the process takes place (ambient, -140°C CryoCart, in a -80°C freezer, etc.). Time-out-of-temperature profiles need to be established during the product development process. They must then be tested against each process step to ensure they can be performed within the time-out-of-temperature limitations. The time allowed for each step should include the time to complete the actual process plus a reasonable margin for error. Fisher BioServices has extensive experience in developing time-out-of-temperature profiles for a wide range of advanced therapy material for one simple reason. Only through understanding each process thoroughly can the optimum storage temperature be determined. The more steps you have in a given process, the greater the potential for time-out-of-temperature excursions. The time-out-of-temperature and the extremes in temperature differential will indicate the need for a lower static temperature.
Stay tuned for the second blog post, which will focus on the final two factors that impact optimum maintenance temperature for advanced therapy material. In the meantime, check out my eBook Commercially Successful Cell Therapies: Navigating the Ultra Cold Chain Distribution Minefield. It reviews several variables that must be address to ensure you don't inadvertently limit your product's scalability and commercial viability, incur unnecessary costs and complications downstream, or fail to meet FDA criteria for documentation of cold chain requirements.