The Sponsor of a clinical trial had purchased comparator product from a distributor where storage guidelines were published as -20°C. Unfortunately the distributor had no access to the detailed temperature stability data that would have been established during the clinical trial process. So when the time came to address blinding the comparator product the Sponsor, wanting to ensure product efficacy, insisted on a zero time out of environment packaging process. How does that work if the product is stored at -20°C?
Packaging clinical trial product at ambient temperatures (15°C – 25°C) is routine. If the product is refrigerated (2°C – 8°C) there is usually some tolerance that allows it to be packed in a timed ambient environment without compromising efficacy. However, when the product is frozen at -20°C or in even colder environments (e.g. -40°C or -80°C) there are special considerations which must be addressed.
- Label Material: Adhesives behave differently based on the temperature they are applied at, the temperature they are stored at (and for how long), and the material they are applied to. Standard labels adhere at temperatures up to -28°C so, in this situation, applying them to product within a -20°C environment is not an issue. There are specialized cryogenic labels designed to withstand storage at ultra-cold temperatures. It’s important to note that, when working with ultra-cold product, it’s typically necessary to temper the product and the label to a different temperature. Additionally it’s essential that condensation from the primary container be thoroughly removed before completing the labeling process.
- Packing over Dry Ice: A common approach to packaging at low temperatures is to use specialized tables / carts with dry ice baths, or by placing dry ice on a table covered with a layer of plastic. The labeling and secondary packaging process takes place adjacent to the dry ice to maintain its temperature. Usually these processes require timed test runs to refine and perfect the process. Timers are placed at each workstation to ensure the job takes place within guidelines e.g. no more than 8 minutes. Our tests have shown that labeling over dry ice, while not providing the same controls as the frozen storage units, certainly provide better protection than packaging at ambient temperatures. The disadvantage is that validation is challenging and there is limited control.
- Packaging in Environment: While it’s highly unlikely that humans could package in an ultra-cold environment, packaging in a -20°C environment is a viable option. In this scenario the packaging suite could be built within or connected to the walk-in freezer so the product never moves out of environment. Because of the cold environment, it requires increased staffing levels so that teams can rotate in and out of the environment according to established operating procedures. The advantage to this approach is that validation and control is clearly established. This is how we solved the above comparator blinding challenge.
There are additional considerations that must be addressed when packaging cold product. Most facilities have a centralized storage area with walk-in refrigerators and freezers, as well as banks of upright freezers set at different temperatures e.g. -40°C, -60°C, -80°C. The packaging rooms are located elsewhere within the facility. Special precautions are required to provide adequate protection for the product as it moves from the storage unit to the production room. Whether that’s a dry ice bin, a specialized container, or even a portable freezer with temporary battery power, each approach will protect product and extends the packaging window.
With today’s advanced therapies, maintaining temperature is becoming more critical than ever. Most of these products are biologics and vaccines in syringes, vials and auto-injectors. In some cases we are receiving product where the tolerance doesn’t allow more than a minute out of environment. As a result we are increasingly receiving requests for zero time out of environment packaging. Our solution is simple. Bundle up, stay warm, and keep the product cold.
There are numerous considerations when designing your packaging solution, including unique challenges associate with biologics and cold chain. Learn more.
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