Cold chain packaging can be a hard thing to get right. Not only must it comply with an array of regulations, but it must be capable of protecting the shipment all the way to its final destination. This means maintaining its temperature within a relatively narrow window, no matter what complications arise in transit.

In recent years, the demand for such packaging has increased significantly. More drugs than ever require temperaturesensitive packaging, not least biologics – a category that grows year on year. According to a report by Grand Report Research, the global biologics market size is predicted to surge from $276.6 billion in 2015, to $399.5 billion by 2025.

On top of this, the emerging biosimilars market is expected to have major implications for logistics. Slow to get off the ground, biosimilars are now appearing at a record pace: in 2017, the European Medicines Agency approved 15 biosimilar products, more than in the previous five years combined.

Since these products require cold chain handling – of which the temperature range is 2–8°C – many pharma companies are looking to specialised technologies to reduce the risk of temperature excursions. This is perhaps most important when their drugs are being shipped globally – many emerging markets have extreme temperature ranges, requiring stringent temperature control.

Protect the product

For German pharma company Grünenthal, these kinds of issues are critically important. Specialising in pain treatments, it supplies drug products to customers worldwide with the help of its logistics partner, Kühne & Nagel. Many of these products are shipped in cold chain.

“The end-to-end supply chain ensures on-time, in-full deliveries so that patients receive the products when needed,” says Jorg Grigo, director of Grünenthal. “In accordance with standard product portfolio, transportation and warehousing have to meet regulatory and quality requirements to store and ship controlled substances. Any cold chain transportation risks have to be mitigated.”

Grünenthal, he explains, like many companies, provides assembly, packaging and vial-labelling services for a number of biopharmaceutical products. As more biosimilars enter the market, the demand for these kinds of services continues to increase.

“In order to accompany the growth in biopharmaceutical demand, Grünenthal has increased its cold-storage capacity as well as its vial labelling and packaging lines,” he says. “Cold chain is also becoming more important to Grünenthal’s contract manufacturing customers.”

So, what does this mean from a packaging standpoint? After all, one may have the best logistics and monitoring processes in the world, but if the container isn’t up to scratch, the product won’t be adequately protected.

As Grigo explains, the company has broad experience in developing packaging designs for temperature-sensitive products. When working on a new design, it takes many considerations into account.

In accordance with standard product portfolio, transportation and warehousing have to meet regulatory and quality requirements to store and ship controlled substances.

“First of all, packaging designs must meet drug safety requirements for the patients. This is our top priority,” he says. “The design process for packaging material considers supply chain requirements for delivering the product to the patient. The packaging design also contributes to meeting productspecific temperature requirements during manufacturing.”

For instance, pharma companies need to meet time out of refrigeration (TOR) requirements, which are designed to ensure that the drug isn’t kept out of its recommended storage conditions for too long.

If temperature excursions do occur, there is a chance that the product will become unusable or unsafe, leading to supply shortages. According to the Centers for Disease Control and Prevention, around $300 million worth of vaccines alone are destroyed each year due to improper storage and transit.

“Just as important is the manufacturing and supply process, which ensures optimised product yield,” says Grigo. “Grünenthal has demonstrated a proven track record in creating and maintaining strong yield results for temperature-sensitive products.”

The company, together with its contract manufacturing partners, has developed various secondary packaging materials for use with temperature-sensitive biopharmaceuticals.

He adds that the choice of packaging varies significantly from product to product, depending on patients’ requirements and dosage forms. With so many factors to consider, this choice is too important to leave until the last minute. In fact, Grünenthal’s partners start thinking about the secondary packaging as early as the R&D phase.

“Grünenthal’s contract manufacturing customers own the R&D process of biopharmaceutical product, and the secondary packaging keeps evolving throughout pre and post-launch timelines,” says Grigo. “Throughout the product life cycle, Grünenthal supports the secondary packaging development in the best interest of the patients.”

Serial stuff

Of course, these kinds of requirements must be considered alongside serialisation regulations, which are designed to protect patients from falsified medicines.

“Grünenthal has supported serialisation requirements from the very beginning,” says Grigo. “[All our] packaging processes will fully comply with the European Falsified Medicine Directive. Also, we already supply serialised drug products to markets in China and the Middle East.”

With so many new logistics requirements – and so many new products on the market – it seems likely that packaging will remain top of the pharmaceutical agenda for some time to come.

On the opposite page, we run through some of the recent innovations that are changing cold chain technology.

Phase change materials

Compared with older methods of insulation, such as polystyrene and foams, phase change materials (PCMs) are an ‘intelligent’ means of ensuring temperature control. They allow the temperature to be controlled more precisely, minimising the risk of temperature excursions even over a long period of time. Typically, they are made from a salt solution or a form of paraffin placed in a sealed box.

In essence, PCMs are materials that can change between states – from liquid to solid and back again – at a certain temperature, releasing or storing large amounts of energy in the process. This keeps the temperature within a designated range. While a common melting point is 0°C, it is now possible to purchase PCMs with a more desirable melting point of 2–8°C.

Many pharma companies are looking to specialised technologies to reduce the risk of temperature excursions.

First used for cold chain purposes in the mid-2000s, PCMs are around five to seven times more effective than polystyrene, and are more reliable over long journeys. Although they cannot maintain their temperature range indefinitely, they do perform well for all practical purposes, especially when used alongside vacuum insulated panels and, although they are still considered a pricey option, they are arguably more economical in the long run.

Vacuum insulated panels

Vacuum insulated panels are a sophisticated form of insulation that allows packages to retain their cool temperatures for up to ten days. Unlike traditional forms of insulation, which work by trapping pockets of air within the material, vacuum insulated panels eliminate the air altogether. A porous material is packed in a metallic barrier film and a high vacuum is achieved.

Much thinner than polystyrene, these panels are compact and lightweight, saving space inside and outside the package. They are especially useful, then, where space is at a premium, and give a far greater payload efficiency than bulky foam.

Like PCMs, vacuum insulated panels are much more expensive than traditional insulating materials. They can also be quite fragile, which can give them a lower shelf life.

Evaporative cooling

Evaporative cooling is fast emerging as an eco-friendly alternative to traditional refrigerating systems. A container of water is pierced and subsequently evaporates, absorbing heat and cooling down the product.

Since this system needs no preconditioning, it has been touted as a possible solution for developing countries, where electricity supply can be limited. It does not require gel packs, and can be stored at normal warehouse temperatures ready for activation at any time.

Evaporative cooling systems can save space and materials, and work for around 96 hours. They could theoretically be used as an on-demand option; for instance, in a particular section of the supply chain that is likely to lack electricity. They are not, however, suitable for large shipments and work less well in cold or humid climates.

Liquid nitrogen and ULT transporters

For certain shipments, it is necessary to have temperatures far lower than the typical 2–8°C. For instance, certain vaccines and biological samples must be stored at cryogenic temperatures, sometimes below -130°C.

Liquid nitrogen-based shippers enable this, maintaining ultralow temperatures for up to ten days. Although leaks are always a concern, recent product innovations have improved the safety profile significantly. For instance, in one new packaging technology, the liquid nitrogen is held in a matrix in suspension.

Ultra-low temperature (ULT) transporters are another option – the containers are filled with dry ice, which is readily available and relatively cheap. Newer models include inserts that minimise the amount of ice required for cooling.