A hot-headed decision

The transfer of pharmaceutical products with temperature requirements to clinical trials is a process in which many different players interact. Pharma companies themselves organise the shipping; transport companies handle the physical journey and ensure that products stay within the right temperature range; and the packaging industry provides storage containers designed to maintain an optimal temperature.

There are many technologies that pharma companies and their partners can turn to ensure the integrity of the cold chain. Each has its advantages, but the choice is not solely determined by efficacy. Supply chain costs are a key factor, and less sophisticated and energy-hungry cooling equipment may be preferred for that reason. Similarly, transportation solutions that require less energy bring sustainability benefits, so will be favoured by companies looking to reduce their carbon footprint.

Such factors will determine the choice between active and passive cooling solutions. Active containers are those with electrically controlled cooling and heating systems, or which cool using dry ice. Passive containers are simply insulated boxes with no active temperature control. Clearly, the risk profile of the product will be a key factor in determining the nature of the packaging that is chosen, but if there is a way to offset risk using passive solutions, then they will be cheaper, more convenient and more sustainable.

That said, there can be no compromise on performance in high-stakes situations like a clinical trial. “If the cold chain is not properly secured from end to end then it will compromise the quality of product, whether it is organs, blood, trial drugs, pharma treatments, specimens or anything else,” says Temidayo Akenroye, associate professor of supply chain management and analytics at the University of Missouri-Saint Louis, who has extensive expertise in cold chain management. “They are temperature-sensitive, so if the temperature goes too high it can damage molecules and expose substances to fermentation, as bacteria become active at different temperatures.”

Companies invest a lot in developing new medicinal products, so if the cold chain fails, they will incur a lot of waste and increase the cost of the trial significantly. “The problem might only emerge at later stages of transportation and distribution, perhaps at the point of distribution or patient use, though damage could have happened in the initial stages of transport,” says Akenroye. And it is not only the external environment that can affect temperature. Even a vehicle hitting a pothole could agitate blood samples or novel drug therapies, generating heat. So, the external temperature could be maintained within the right limits, but agitation that excites molecules can cause damage if they are not transported in the right way. The choice of passive packaging solutions is, therefore, one that requires careful consideration.

The decision matrix

The criteria used by pharma companies to select storage containers for clinical trials must be carefully thought out, as they must balance considerations of cost and performance. The logistics process can be complex, particularly as the trend towards remote or virtual trials gathers pace. “Passive cooling is often appropriate because it comes with many advantages,” says Akenroye. “It can be used in environments where there is limited access to electricity or no grid connection at all. So, it is particularly suited for use in emerging economies, where even hospitals may not have reliable electricity.”

In some instances, pharmaceutical companies take a hybrid approach based on the climate they will be traversing to reach a trial destination. Akenroye uses vaccines as an example, which are often made in developed countries and transported to those with less resources. “So, if they develop vaccines for use in a target market such as Africa, they could use active cooling in the parts of the supply chain that are in the UK, the US or [other] developed markets, but in packaging product they will need materials to redistribute the temperature and prevent effects from external heat when they leave those markets,” he says. “The cost efficiency of passive cooling and the fact that they don’t need external electricity makes it very useful indeed.”

Despite active and passive containers applying to a wide range of use cases in transporting drugs for clinical trials, there’s no such thing as a fool-proof option, as Akenroye explains. “There is always going to be a trade off,” he says. “There is no fixed option that offers the optimal solution, as it will always depend on the budget and the specifics of the trial. You could have active cooling that you are sure works, but if there is a problem with the packaging, then that problem would exist even if the product were in a freezer. There are factors that could affect the radiation of the heat, so products could be damaged even in a very cool environment.”

This, of course, is why shipment monitoring is important in the transport of investigation medicinal products, and that applies to both types of container. “If you use an active system, constant monitoring of product temperature and not just the cooling environment is very important,” he continues. “You have to link monitoring processes to the product rather than the refrigeration system.” With passive cooling, the choice comes down to the environment and access to electricity, but it could also be a strategic decision based on sustainability and the desire to reduce carbon footprint. “Constantly using electricity increases carbon emissions, so passive cooling solutions could be a good tool for reducing them,” Akenroye adds.

A hotbed of innovation

Though they have many advantages, passive cooling technologies are not without drawbacks. They work by redistributing heat and excluding external heat through natural conduction, but an over-reliance on such solutions without sufficient consideration of factors other than the quality of the insulation can lead to increased risk. “People often trust that the packaging will maintain temperature based on humidity and radiation, but there are contextual factors like agitation that could create heat and affect efficiency of passive cooling,” notes Akenroye. “There are various solutions and techniques out there, and they promise many things but there are instances in which these claims cannot be totally relied upon.” It’s for this reason that Akenroye tends to advocate the use of both systems. “This approach has been used in research trials, including some related to Ebola treatments – where all of the reagents came from the US – where active cooling was used. But as soon as the product reached Benin, it had to rely on passive cooling,” he adds. A hybrid approach optimises quality control, energy use and cost, but it won’t eliminate all the risk. For that reason, there is a constant process of innovation to improve not only the energy efficiency of active cooling systems, but also the performance of passive cooling solutions.

In 2019, space cooling accounted for almost 9% of total final electricity consumption, equal to more than one gigaton of carbon dioxide emissions. This statistic set researchers at the Massachusetts Institute of Technology (MIT) on course to develop a new passive cooling system for buildings, the principles of which could impact the way the clinical trial cold chain functions in the future. The solution, which requires no electricity, resembles a solar panel and consists of reflectors, evaporators and insulation layers to create a cooling effect as water and heat pass through the device. A sponge-like hydrogel layer is immersed in water for evaporative cooling. “There is a lot of innovation happening, and at MIT there is rigorous innovation and research into materials to help with the redistribution of heat and use natural conduction to cool a product,” says Akenroye. “There is also research happening at other institutions, including Albany University, which has developed a type of ice that not only takes longer to melt, but also reduces the likelihood that bacteria will form.”

With many options for insulation and packaging on the market, Akenroye’s experiences have led to him advising most companies to test them before use. “Do a pilot scheme to trial different systems,” he says. “I worked with the NHS in the UK for many years, and we did pilot projects for four-to-six months using all solutions from a supplier, so that we could compare different solutions and choose the best one for each application.” Another consideration when organising the supply of clinical trial drugs is whether it’s worth taking a risk-sharing approach by involving a third party with expertise in the area. “One way to manage risk is to use contractual terms and conditions with a solution provider,” says Akenroye. “I would want to guarantee 100% preservation of temperature for the required duration of the journey, and I want to be able to hold the solution provider accountable for that. The risk mitigation strategy can be in the contract, and if a supplier says no to that then you should have some suspicions right away.”

There’s a lot of innovation going on to improve the state of passive cooling, but for clinical trials, maintaining the integrity of investigational medicinal products will continue to be a shared responsibility of balancing cost, sustainability and quality control.