Links in the cold chain

31 October 2019

Due to extremely delicate formulations, temperature-controlled packaging is crucial in the distribution of drugs to ensure that pharmaceuticals are at an optimal state for use. Will Moffitt speaks to Giulia Carlucci, principal packaging engineer at Teva Pharmaceuticals, about the risks involved, the options for passive and active shipping, and how new technologies are enabling more efficient and intelligent delivery systems.

The name Fredrick McKinley Jones is rarely mentioned in the ranks of notable inventors. In a dream dinner party guest list for worldaltering geniuses, the Cincinnati-born autodidact would do well to nab a corner seat beside the likes of Tesla and Edison. That said, his invention of portable air-cooling units for trucks in 1938 was a landmark feat, allowing perishable foods and medicines to be transported around the world.

As renowned economist Tim Harford explains in his book Fifty Things that Made the Modern Economy, Jones’s invention ‘revolutionised healthcare’, allowing drugs and blood to be transported to injured soldiers during the Second World War, and vaccines to reach remote corners of the globe.

The proportion of medicines worldwide that are counterfeit, with sales of illicit drugs amounting to roughly $30 billion between 2013 and 2017.
World Health Organization

Thanks to Jones and a few others, this global supply line is now a vast, intricate network of refrigerated production, storage and distribution that transports pharmaceutical products around the world.

It’s a growing market, with temperature-controlled healthcare products selling at more than double the rate of other medicines, one that is set to be worth $16.8 billion by 2025, according to a new report from consulting group Grand View Research.

Among other factors, a key driver has been the increasing demand for biopharmaceuticals such as vaccines and blood components that require specific temperatures in transit, along with precision medicines, such as cellular therapies, biomarker testing and regenerative measures like organ creation.

Increased regulation

For Giulia Carlucci, principal packaging engineer at Teva Pharmaceuticals, such measures have made pharmaceutical packaging a more rigorous art form, with regulations becoming increasingly complex and demanding.

“Not only are we seeing different types of medicines and pharmaceutical products, but we’re also witnessing stricter regulatory processes in terms of how those items are then packaged and transported,” Carlucci says. “Previously, you would order from supply, check the dimensions of the product, check the required materials and that was enough. Now that’s no longer the case.”

As Calucci explains, most of these products fall into two camps: active and passive. The former ranges from individual packages in a full container to entire trailers and aircraft, all of which rely on their own thermostatic-controlled energy source to protect products from temperature and climate deviation. Meanwhile, passive packaging uses conventional materials combined with wet ice, gel packs, dry ice and liquid nitrogen.

As one of the largest suppliers of generic pharmaceuticals in the world, Teva’s products go to myriad destinations; some risk being exposed to high temperatures and humidity in tropical climes, while medicines bound for colder climes risk being frozen.

$7.8 billion
Value of smart packaging market by 2021.
Smithers Pira

“In the past, selecting custom boxes or trays, leaflets and labels happened at a very late stage of our development projects,” Carlucci says. “Now everything starts much earlier. We’re performing simulated studies on products that enable us to better ensure that the packaging will work under specific travelling conditions.”

Naturally, it’s important that these items arrive unharmed, but a deeper look at the type of products entering the market shows that there is more at stake; at times, the consequences of improper transportation can be life-threatening.

In August 2017, for instance, a shipment from a single lot of Intralipid 20% IV fat emulsion was exposed to sub-freezing temperatures on its way to a distribution facility. Two months later, the company Baxter International recalled the product, warning patients to dispose of their supplies. When frozen, the product’s emulsion droplets enlarge, forming aggregates that can obstruct pulmonary circulation, leading to serious health problems and, in some cases, death.

There’s also the slippery problem of transporting radioactive drugs, which contain active ingredients that sport half-lives. Consider Bayer HealthCare Pharmaceuticals’ FDA-approved Xofigo injection, formerly known as Alpharadin. The drug is one of the first radioactive agents with a high relative biological effectiveness to treat men with prostate cancer. The total shelf life of radium 223 is roughly four weeks, and its half-life is about 11 days. If the product is not delivered within a 28-day window, it ceases to be an effective treatment source.

Smart money

To better monitor these goods in transit and ensure they arrive in pristine condition, Teva and other pharmaceutical companies are embracing smart labels equipped with radio-frequency identification technology (RIFD).

Advances in RIFD and falling costs – an RFID tag was priced at about $1 in 2003, and is roughly $0.10 today – mean that items can be tracked across the cold chain, ensuring they remain secure, while tags automatically update stock and inventory databases.

“In the past, we would use two data loggers per palette, but these days we can use incredibly small monitors in each of our labels to track all sorts of things: temperature, pressure, humidity, UV exposure… ultimately, it’s a more transparent way of ensuring product safety and reliability,” Carlucci explains.

At a time when manufacturers are increasingly turning to third parties to transport pharmaceutical products, the ability to monitor medicines in transit is an invaluable tool, not only to keep watch over products, but to ensure that the operators themselves can be trusted.

“We use third parties that can track products in their vehicles,” Carlucci says, “so they might have their own data-logger inside their shipping van, for instance. The printout of the average temperature then serves as proof that everything went well, or in some cases, that it didn’t.”

In theory, the collected data can be used to improve quality control, meet regulatory requirements and reduce costs. But with so many hands packing, lifting, hauling and delivering products, maintaining efficient cold-chain operations is never that simple.

“We’re performing simulated studies on products that enable us to better ensure that the packaging will work under specific travelling conditions.”

“Data integrity can be an issue, along with getting third parties in the supply chain up to speed with what a pharmaceutical company requires in terms of certification and data accessibility,” Carlucci says. “A big risk is that you give a third party a job to shift a product from A to B, the third party is either unaware of the correct legislation or can edit the data to lie and make it seem like they’ve done a good job.”

International adoption

While Teva and other pharmaceutical bodies have been using RFID technology in an attempt to monitor products more efficiently, more advanced track-and-trace capabilities are now becoming a legal requirement in a number of countries.

This is mainly being driven by concerns over drug counterfeiting, with the World Health Organization estimating that 10% of all medicine worldwide is counterfeit, with sales of illicit drugs amounting to roughly $30 billion between 2013 and 2017. To minimise the chances of counterfeit medicines entering into established supply chains, both the US and Europe are developing more stringent labelling methods, and have ordered manufacturers to switch to 2D identification codes on individual packages.

In the US, these changes are a major part of the Drug Supply Chain Security Act, a 10-year project that began in 2013 to create a transparent electronic database to better trace the legitimacy of drugs through the supply chain.

“Data integrity can be an issue, along with getting third parties in the supply chain up to speed with what a pharmaceutical company requires in terms of certification and data accessibility.”

Europe has followed suit, with the EU enforcing a similar system based around 2D identification that began in February 2019. Known as the ‘falsified medicines directive’ (FMD), the new labelling method means that data can be stored on a centralised database managed by the European Medicines Verification Organisation, which checks the authenticity of individual products.

For Carlucci, these efforts are emblematic of the general direction pharmaceutical packaging is heading, with technology allowing companies and regulatory agencies to keep a watchful eye on the great variety of products entering the supply chain.

“Because of these regulations, you need to verify every product, and technology is driving that, allowing larger regulatory agencies to become more involved in these procedures,” she says. “It’s becoming clear that technology and data management are going to play an increasingly important role in the cold chain.”

The search for solutions

Moreover, as Carlucci notes, these forms of trackand- trace logistics are the tip of the iceberg when it comes to more advanced operations. Bioscience researchers are even looking to the molecular level of drug manufacturing for answers to temperature control issues.

Oregon start-up StoneStable is experimenting with coating viruses in silica, rendering them impervious to hot and cold temperatures, before returning them unharmed to their original state. The company is in the first phase of testing the process with the influenza vaccine.

Over 3,000 miles away, Vaxess Technologies, based in the Harvard Life Lab in Boston, is experimenting with silkworms to alter the behaviour of vaccine molecules and save these drugs from degradation.

Then there’s the looming possibility that drone delivery will become the chosen form of transport for large pharmaceutical companies. In September 2017, Timothy Amukele, assistant professor of pathology at Johns Hopkins University School of Medicine, along with drone engineer Jeff Street, set a medical record for drone delivery, sending blood samples 161 miles in three hours across the Arizona desert. The samples, kept at an average of 24.8°C inside the drone’s refrigerator, remained viable.

While still in development, drones could play a major role in shaping the cold chain of the future. For now, however, the focus will be on improving quality control, meeting regulatory requirements, and reducing costs, as the market for temperaturecontrolled pharmaceutical products look set to grow in the coming years, with more unorthodox forms of medicine entering the cold chain and developing companies requiring higher numbers of vaccines.

In light of these predictions, RFID and smart packaging is set to become an even more integral aspect of cold-chain operations, with market researcher Smithers Pira predicting that the smart packaging market will reach $7.8 billion by 2021.

For many in remote corners in the world, smart, temperature-controlled packaging is providing greater access to innovative and potentially lifesaving forms of treatment. Ultimately, as Carlucci says, it’s about making sure more medicines arrive safe and sound in the hands of the user. 

Vaxess Technologies is experimenting with silkworms to alter the behaviour of vaccine molecules in order to prevent degradation.

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