An article for ColdChainInfo.com by package design expert Scott Dyvig
Cold Chain Design for Frozen Products
In my last article entitled “Design Considerations for Dry Ice Shippers”, I reviewed the complexities of creating dry ice packaging systems for temperature-sensitive products. But more and more pharmaceutical companies are losing favor with dry ice as a refrigerant. Before we dive into the basics of designing thermal packaging using frozen gel packs, let’s review some of the reasons why there is a movement to avoid dry ice.
Dry Ice Issue #1: Hazardous Material
The International Air Transport Authority (IATA) and Department of Transportation (DOT) consider dry ice a hazardous material when shipping, and for good reason. There are three very real and dangerous consequences if dry ice is not treated correctly. First, dry ice poses an explosion hazard by creating a larger volume of gas relative to its solid form. If this sublimation occurs in a sealed container, the changing pressures could create an explosion. Second, dry ice is a suffocation hazard. Because gaseous carbon dioxide displaces air, improper ventilation could create an oxygen-deficient atmosphere when packing or unpacking the container. Finally, dry ice is a contact hazard and can cause damage to human skin when unpacking the container.
Certainly, the pharmaceutical and biotech industries have been dealing with the regulations related to shipping product on dry ice for years, but this classification can add costs, delays and even carry a risk of injury to their customers.
Dry Ice Issue #2: Effect on Products
The sublimation of dry ice creates a CO2-rich atmosphere within the insulated shipping container. While most products are hermetically sealed with barrier packaging and unaffected by this issue, there are instances where a high level of carbon dioxide could affect the drug or medical device. The primary packaging for products that are shipping under dry ice conditions should be evaluated to ensure it would prevent carbon dioxide from contacting the drug or device.
Dry Ice Issue #3: Effect on Primary Packaging
Last and possibly most important, pharmaceutical companies shipping vials are finding that dry ice’s extreme cold can contract the vial’s rubber stopper and lose the integrity of the vial contents as well as over-pressurize the vial due to gas ingress. In a recent memo to vaccine administrators, the Minnesota Vaccines for Children program announced that Merck’s VARIVAX, Zostavax and ProQuad MMR vaccines would no longer be arriving packed in dry ice as of June 2011 because “The manufacturer found that severe cold from dry ice (i.e., colder than 58°F) may cause the vial stopper to contract thus threatening sterility of the vaccine.” (June 8, 2011 Broadcast Fax) Note their typo of “58°F” instead of “-58°F”. The official temperature range for VARIVAX according to Merck is -50°C (-58°F) to -15°C. They do not mention issues with the stopper, only stating that “Use of dry ice may subject VARIVAX to temperatures colder than –58°F (–50°C).” Articles from as far back as 2008 have noted that in a 483 issued to Merck, the FDA included concerns about shipping on dry ice due to ingress of gas and over-pressurization. These drugs are examples of the trend by pharmaceutical and biotech companies to change the way temperature-sensitive products are shipped. Products that were previously shipped on dry ice with an acceptable temperature range of <0°C are now shipped with frozen gel packs in a configuration designed to keep them below 0°C, but warmer than -50°C.
Cold Chain Engineering for Frozen Products
There are three steps which are key to the design of a successful cold chain packing configuration for frozen products. First, one must identify the best refrigerant and insulated container based on the product load. Second, configure the product load and refrigerant to optimize the efficiency of the phase change materials. Finally, test the configuration against the summer ambient profile at a thermal test lab to document the temperature results.
Step One: Identifying Suitable Cold Chain Materials
Water-based refrigerants, the “bread and butter” refrigerant for passive cold chain packaging systems, are not a viable solution to hold product below 0°C, as most have a phase change point within a few degrees of this criteria. Natural temperature variances within the container may cause products to rise above 0°C during warmer portions of distribution.
To hold product temperatures below 0°C, a different class of refrigerants should be used. There are a variety of choices available from cold chain packaging manufacturers that can be used as the refrigerant for frozen products. ThermoSafe Brands sells a variation of their U-TekTM line that phase changes at -23°C. TCP Reliable’s Cryopak offers a refrigerant with a phase change point at -20°C called 20 BelowTM. Cold Chain Technologies sells KoolitTM Gel Packs in the 500-ST line that phase change at -23°C. In addition, some manufacturers also sell phase change materials (PCMs) with a melting point near -50°C.There are several manufacturers of PCMs, for a complete list see ColdChainInfo.com's Refrigerants Directory.
The product temperature criteria will dictate what phase change material is used for the final configuration, but the overall theory is to precondition the refrigerant below its phase point and maximize the efficiency of the configuration to reduce weight and size. For example, if the product temperature must remain below -10°C, the configuration should use PCMs that phase near -20°C and are preconditioned at -30°C (+/- 5°C).
PCMs, gel packs, gel bottles or any refrigerant, should be preconditioned at least 10°C below the phase point to ensure the refrigerant is completely within its solid phase and is not a mixture of liquid and solid. Allowing the refrigerant to phase between solid and liquid for the duration of the shipment will optimize the use of the gel weight and will be important in the final configuration. If gel packs are frozen in corrugate shippers, it can take over a week to fully freeze. Increasing the freezer’s air flow, storing the gel packs on open racks, or setting the temperature to more than 10°C below the phase change point can help reduce the time to freeze.
The choice of insulated container material is dependent on the required performance duration of the thermal shipping system. Most overnight and some two-day shippers can be designed in expanded polystyrene (EPS) containers. However, some two-day durations and most three-day durations require a polyurethane (PUR) container with better R-value to hold product loads below freezing. Durations beyond three days can be configured in PUR containers but to reach an efficient container size and PCM ratio, you should consider package designs using Vacuum Insulated Panels (VIP).
Step Two: Identify an Optimal Configuration
In most designs involving frozen configurations, it is not critical to completely surround the product payload with gel packs, as it may be in 2-8°C designs. For frozen configurations, it is generally adequate to only place frozen refrigerant below and above the product payload. Below is an example of a typical cold chain configuration for a product load with a <0°C or <-10°C temperature range.
Frozen Configuration Side View
It is important to include more gel packs above the product load because the cold dense air created by the frozen refrigerant will continue to fall through the duration of the thermal test and keep the product load cool. The frozen gel packs at the bottom of the configuration are usually the last to phase at the end of the thermal test as they are kept at a lower temperature (thus slowing the phase change process) by the cold dense air from the upper gel packs.
Frozen refrigerant such as gel blankets (thin mat of individual pockets of gel ice that remain flexible when frozen) will phase change faster than thicker gel bricks and should be avoided if the goal is to leverage the weight of the refrigerant to obtain the longest performance possible. Generally the refrigerant should be at least 24 oz each, ideally 36 oz or 48 oz. The larger mass and thicker dimensions of the refrigerant will slow the phase change process by reducing the relative surface area for external temperatures to contact the refrigerant.
Air flow within the packing configuration is also important to ensure that cold air from the top frozen gels can circulate to the product load below. If any corrugate pads are used, they should be cut an inch shorter than the length and width of the box to allow adequate air flow. Molding in air channels into the internal cavity of EPS containers is also a great help to optimize the efficiency of all of the frozen gel packs within the design.
Step Three: Test and Document the Successful Solution
To qualify a cold chain shipping configuration to be used throughout the year, it must be properly tested against both summer and winter ambient profiles. However, with product temperature criteria that is open-ended on the cold side, such as <0°C or <-10°C, it is not necessary to include winter ambient profile thermal testing as long as the same configuration is packed throughout the year and the configuration is successful against the summer ambient profile. In addition, if there is a cold temperature limit, such as -50°C used for Merck’s VARIVAX, and the criteria is colder than any temperatures that can be experienced by the package during transport (typically set at -30°C), then winter ambient profile testing is also not necessary to defend the qualification of the packaging solution.
The placement of the thermocouple probes to measure temperatures within the product should focus on the top corners of the product mass. This area will almost always be the location of the warmest product temperatures at the end of the thermal test, thus it is critical to include a thermocouple as close to the top corner of the product load as possible.
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As pharmaceutical and biotech companies are moving away from dry ice for shipping certain temperature-sensitive products, the industry has responded with refrigerants that can phase change near -20°C or -50°C to replace dry ice in the cold chain configuration. Although less efficient, PCMs have fewer hazards than dry ice. These PCMs are not classified as hazardous materials by IATA or the DOT, do not pose significant safety risks to packaging line workers or customers unpacking the container, and do not pose risk to the products being shipped.
Choosing the optimal container material (whether EPS, PUR or VIP) and determining the ideal amount of refrigerant is critical in developing a successful packing configuration. When testing a cold chain design for frozen product, it is important to focus on the top corners of the product load and ensure product temperatures are measured in this area. With attention to the thermodynamics within the container, a packing configuration can be designed to maximize the phase change from solid to liquid for the PCMs to hold the product load within the required temperature range for the full duration of the thermal testing.
Author
Scott Dyvig has designed more cold chain shipping systems than he can remember. During his tenure as a Lab Manager for ISC Labs, he worked with many of the world’s largest pharmaceutical and biotech companies to develop custom packaging that was innovative, efficient and reliable. He now works as a freelance cold chain packaging designer and can be reached at scott.dyvig@gmail.com.