The Cold Chain: What You Don't Know

By Gail Dutton, contributing editor

Pharmaceutical supply chain experts are among the best at managing the cold chain, but new innovative packaging and transportation options are changing some well-established assumptions. “You have to be aware of daily conditions on the shipping lanes,” says Jim Cafone, VP of supply network services at Pfizer Global Supply. “If you don’t know what’s happening, you can’t validate the lanes.”

He advocates monitoring each shipment. Analyzing that data can identify usual shipping conditions but may not reflect the extremes faced during unseasonable weather or delays. Delays are more common for containerized and palletized shipments than for small packages because of the shrinking fleet of wide-body aircraft, he adds.

At Amgen, “One of the big ‘ahas!’ was the need to qualify packaging systems in the same environment in which they would be packed,” says Tim Valko, executive director of risk management. “Validate the packaging on the floor where products actually are packaged — not in the lab. And, ensure the process becomes an SOP (standard operating procedure) for the scientists and for the packaging line operators. Validation must not be a paper exercise.”

Packaging Expectations are Changing
Currently, most pharmaceutical shippers use dedicated packaging solutions for summer and winter, but universal packaging for clinical trials (where the drugs being shipped) have limited stability data. “With commercial products, the cost of universal packaging is approximately twice that of dedicated packaging. So, if you’re shipping commercial products in the same climate range, is it worth the cost of universal packaging to prevent a brief excursion of perhaps 2°C?” asks Tom Pringle, principal, Pringle Consulting, LLC.

While shippers are trying to streamline their packaging options, regulators are still formulating requirements for their own countries. Currently, “Each regulatory body has different expectations. It’s a complex Rubik’s cube,” Cafone says. For example, some products stored between 2°C and 8°C may withstand temperature excursions of a few days’ duration, but some regulators allow excursions of less than three hours while others allow none. Accommodating those differences requires different package engineering and shipping solutions and, therefore, increases costs.

Ideally, pharmaceutical manufacturers would develop their products so they don’t require the cold chain. As Martin VanTrieste, RPh, senior VP of quality at Amgen, elaborates, “Many biological products are much more heat stable than we originally thought. If you perform the proper studies, you can minimize cold chain needs or ensure that minor excursions are acceptable.”

Understand Packaging Limitations
The choice of active packaging systems (that are plugged into electrical current), passive packaging systems (that rely on insulation and coolants like liquid nitrogen or dry ice), or hybrid packaging systems (that combine active and passive systems) depends upon the stability, geographic origin, and destination of the product. “For example, Brussels to Chicago has a standard elapsed, door-todoor shipping time of about 36 hours. For that, we can use passive containers with a 120-hour hold time,” Cafone says. Shipping from Brussels to an emerging market, however, is less predictable. “It may take 72 hours, or it may take 14 days. For that, we use active systems and hope handlers plug them in.”

It requires more than plugging them in to ensure products arrive in good condition, though. Although properly operating containers set to 5°C typically are accurate to plus or minus 3°C, “Shippers often overlook the importance of preconditioning the operating container — not just the air inside it — and the product to the same temperature,” says Karl Kussow, manager of quality at FedEx Custom Critical. Kussow, who is helping write the upcoming Parenteral Drug Association (PDA) technical report on active containers, says active containers can’t truly be validated. “They’re mechanical. For the report, we agreed to call the process ‘qualification.’” He says the three keys to success using active containers are proper maintenance, attention to the shipping and loading process, and ensuring active control. “Having passive protection inside is a good buffer for transfers between modes,” he adds.

For passive containers, tailored phase change materials like dry-vapor liquid nitrogen are quite effective at maintaining temperatures for several days. Although these materials may be more expensive than the packaging they replace, they can reduce overall costs by reducing weight and, therefore, freight costs.

Develop SOPs for Cold Chain Handling
At Pfizer, Cafone says, “We develop specific instructions regarding how shipments are loaded, transported, and received. We define who is responsible for each hand-off, when and how temperature-controlled containers must be recharged, how they are recharged, etc.” The documents average 45 pages and should be available to package handlers. The objective is to ensure that carriers are capable of handling the product, understand the products’ requirements, and have procedures to minimize mistakes and remediate them when they occur.

“We spend a lot of time teaching service providers and encouraging them to invest in education and equipment to maintain the cold chain, based upon the requirements of the products they handle. That includes identifying destination conditions and ensuring that customs offices and the final recipients have the equipment and procedures to protect shipments from thermal excursions. You have to examine the whole chain of custody,” Cafone emphasizes.

Know the Shipping Environment
Understanding the partners and their resources, as well as the product’s chemistry, becomes even more critical when switching transportation modes. Some companies are moving part of their air cargo to ocean freight, reducing costs but altering risks. Logistics experts talk about reefers disconnected from ships’ power and never reconnected, and about partially charged batteries that were drained during handoffs. “Ocean shippers aren’t good at handoffs,” Cafone says. Therefore, they prefer to avoid transporting pharmaceuticals. They are, however, doing it — particularly for products that don’t require close temperature control.

“Active containers for ships may not operate within the same tolerances expected of air carriers,” says Jamie Chasteen, product development manager at Cold Chain Technologies. Part of the issue relates to the larger sizes of marine containers. To help remedy this potential temperature differential, Kussow recommends loading products in active containers so air flows around the product’s sides.

Active containers also are at risk when disconnected from ships’ power. That risk can be mitigated by deploying passive packaging as a buffer inside the active containers. Amgen’s products are shipped in intermodal reefers and lifted from trucks to the ship, where they are plugged into the ship’s power. “The reefers have batteries, and all of ours have temperature indicators inside the containers. We know the key profile the product experiences and can reject it if it experienced temperature excursions,” says VanTrieste. Advanced monitors incorporate wireless and radio-based communications and real-time monitoring that can alert shippers to pending excursions. Although intervention is possible, it’s often impractical because the containers may be inaccessible inside the cargo bay.

Colder Isn’t Better
“Distributors and wholesalers often have the mindset that colder is better. It’s not,” Chasteen says. Freezing substantially diminishes the efficacy of many compounds. “That concept is new to various segments of the industry.”

Shipments packaged to withstand extreme heat may be damaged when they are used in less severe situations. “A very common problem we see is customers using data loggers who have had no problems with multiple shipments, but who suddenly have a cold excursion. Approximately 95% of the time, when the temperature suddenly hovers between 0° and 2°C, the package was placed in a refrigerator. Invariably, a new employee was stressed about keeping the package cool until the carrier arrived.”

Consider the Laws of Thermodynamics
Solar radiation also is just beginning to be considered in packaging. Chasteen recalls one pharmaceutical shipment that sat on a tarmac at 25°C. “The temperature monitor on the package registered more than 50°C.” The differential was caused by the reusable, clear plastic covers that protect pallets from the weather and from abrasion from cargo netting. “The covers created a greenhouse effect.”

Even without the covers, solar radiation has an effect. “Historically, more than 90% of temperature-sensitive boxes were white lined corrugate,” Pringle says. That’s changing as shippers realize that white marks packages as high value. The less expensive brown lined corrugate, however, absorbs more solar radiation than white and must be factored into cold chain decisions.

Positioning matters, too. “High-density products may exhibit the right temp on the surface but not in the center,” Cafone notes. Palletized products, too, will have temperature differences between products at the center of the pallet and those along its exterior. “We conduct studies to understand how long to prechill products to achieve the correct, consistent temperature gradient throughout the pallet.

“We also work with surface carriers and airlines to ensure products are placed in the right position in cargo bays. For example, if a refrigeration unit is at the front of the truck, cargo in the front will be colder than cargo near the back. Also, it’s warmer over the wheel wells,” Cafone says. Aircraft have similar issues, with hot spots near heating elements and toiletry equipment. Depending upon placement, temperatures may range from 8°C to 25°C in a cargo hold. The differences vary even among the same model of plane, so no single solution is effective fleet-side. Some carriers, like FedEx Custom Critical and Panalpina, can control temperatures inside their cargo planes. But, temperature-controlled packaging is still required to ensure proper temperatures are maintained.

“The packaging environment is very dynamic, as companies validate new technologies and put them in place,” Valko says. “The key is to understand the science behind the packaging, the product’s sensitivity, and the complexity of moving that package, and to ensure that material handlers are qualified and understand how temperature excursions affect people’s health.”