Over the years I have encountered a number of clients with cell-based therapies in late stage clinical trials who were storing their material at the investigative site until it was administered to a patient. This type of storage arrangement is complex and requires a good deal of investigation and preparation on the part of the sponsor or CRO in order to insure success.
Remember that the investigative site is the last link in your chain of custody, and the chain is only as strong as its weakest link (discussed in my Cell Therapy Webinar). If the investigative site does not follow the same standards as those followed in the manufacturing and distribution processes, the integrity of the cell therapy can be lost.
I would like to explore the circumstances that necessitate clinical site storage for cell-based therapies, the equipment and processes you will need to put in place, and some alternatives worth considering.
When You Have to Keep Cell-Based Therapies at the Clinical Site
The three most common situations I have encountered are the following:
- Allogeneic (not patient-specific) drug products for treating acute or traumatic conditions. These include stroke, acute cardiac events, spinal injuries or brain trauma, in which treatment must be administered within a very short window. The short time frame is complicated by the fact that these cases cannot be predicted and treatment cannot be scheduled in advance.
- Autologous (made from a patient’s own cells) or allogeneic cell therapy products that require multiple doses over a relatively short period of time (usually five to 10 days).
- Products (autologous or allogeneic) where the strength or the volume to be delivered varies based on conditions that present at or about the time of administration.
Possible Alternatives to On-Site Storage
In the case of the first situation above—allogeneic products that are administered to treat acute or traumatic events—the most common alternative explored is just-in-time shipment. This can appear realistic, albeit expensive, on paper. However, it is far more complicated in practice, because of the narrow window of opportunity.
For instance, the patient must often be brought to the hospital, be diagnosed and evaluated by a participating physician, and then agree to participate in the trial. This process can consume significant portions of the critical time window. Just-in-time also requires that the point of distribution run on a 24/7 basis, respond immediately to a call for treatment, and have multiple courier services available for delivery. There is also the challenge of getting high value cryogenically preserved material into a hospital or medical center at off hours or on weekends.
The most commonly employed alternative for situations 2 and 3 above is the use of the dry shipper as a short term storage vessel. A good dry shipper can hold temperature for 10 to 15 days and in theory should be able to serve a as a short term storage solution. There are, however, some challenges to consider in actual practice.
Remember that a dry shipper’s temperature hold time (or static hold) is based on the unit remaining sealed. Opening the shipper multiple times to remove doses will reduce the static hold considerably and render the temperature monitoring log virtually useless. This disruption in temperature monitoring can jeopardize the chain of custody for the final doses.
The greatest area of concern, however, is the orientation of the shipper during transit. As discussed in a previous blog, "10 Things You Should Know About Dry Shipping Before Shipping High Value Biologics", the orientation of the shipper has a profound impact on the overall hold time. A dry shipper positioned on its side can lose as much as 60 percent of its hold time; if it is inverted, it can lose as much as 80 percent. Because there is no reliable way to track orientation while in transit, the actual remaining hold time of a dry shipper used for temporary storage at a clinical site is an unknown.
Making the Most of Storage at the Clinical Site
Given the challenges of the alternatives, on-site storage is often determined to be the safest and most reliable option. However, there are a number of variables you need to consider. First and foremost is who supplies and maintains the cryogenic storage equipment—the site, the sponsor or the distribution partner? If you are using the equipment already in place at the site, be sure to ask these questions:
- Will a unit be dedicated to your project or shared?
- Who will have access, how is access controlled, and how is it documented?
- How much space is available and will be dedicated to your project?
- Has the equipment been validated? When?
- Has the internal temperature gradation of the storage device been defined (the temperature inside a LN2 tank can range from -130°C at the top to -195°C at the bottom)?
- How is the temperature monitored? How is it documented? Will you have access to that data?
- In case of equipment failure, who is responsible? Who is notified? When are you notified?
- What happens if equipment fails? Is a ready and waiting back-up unit on-site?
- Are there validated standard operating procedures (SOP's) in place for receiving and transferring product from a dry shipper into the site storage tank, and for removing a dose from the tank while protecting the remaining doses? If not, you will have to provide one.
There is another option for relying on clinical sites to correctly store your product: a partner that is well versed in the storage, cold chain transport, and handling of cell-based therapies. Click here to read Part II of this blog post. If you are interested in related information, please read our blog on "10 Things You Should Know About Dry Shippers Before Shipping High Value Biologics" and download the Dry Shipping InfoPoster below.