The pressure is on for stakeholders to continue pioneering novel engineering designs, insulation options and advanced monitoring and data analytics tools—to meet the complex demands of today’s temperature-controlled products while keeping costs low
In recent years, ongoing advances in the development and dissemination of temperature-sensitive pharmaceutical products — ranging from the Covid-19 vaccine and vaccines for other infectious diseases, biologic therapies to treat rare and chronic diseases, novel oncology treatments and cell and gene (CGT) therapies — have created more complex cold-chain requirements than ever before. These lifesaving products must be maintained at refrigerated, frozen or deep-frozen temperatures during every moment of the journey, from packaging and storage through transportation and delivery.
Biopharmaceutical manufacturers, working in close collaboration with their packaging suppliers and third-party logistics (3PL) partners, are distributing temperature-sensitive specialty medications and vaccines to more regions of the globe, with more extreme temperature profiles, longer distances and more “last-mile” challenges more than ever before. Concerning the latter—the final leg of the cold-chain journey and handoff of product—this often happens in a place or location that does not have sufficient infrastructure in place to sustain the ultra-low temperatures required.
Specifically, ongoing investments in the space aim to develop or improve:
For both parcel and bulk shipments, domestic deliveries typically have a range of 24 to 72 hours, while international transportation is usually designed to cover a range closer to 120 hours. “Any temperature-controlled delivery only has so much time in its temperature-control budget, yet that fixed time budget must last all the way until the therapy has reached the patient’s arm or mouth,” notes Adam Tetz, director of worldwide marketing for Peli BioThermal.
Globally, spending on biopharma cold-chain logistics has been rising steadily since 2018, and it is projected to grow by another 25% over the next three years, reaching $21.3 billion in 2024, according to the 2020 Biopharma Cold Chain Sourcebook published by Pharmaceutical Commerce.1
Raising the stakes on temperature and time
The unprecedented demand for Covid-19 vaccines that require frozen and deep-frozen temperatures—in parallel with growing volumes in other therapeutic categories—has upped the ante for manufacturers of shipping containers, intermediary 3PL partners and specialized trucking and airline companies. The two Covid-19 vaccines that are based on the mRNA platform have set new standards for ultra cold-chain requirements, with the Pfizer-BioNTech vaccine needing to be maintained between -80°C and -60°C (-112°F to -76°F) and the Moderna vaccine at -25°C and -15°C (-13°F and 5°F).
Even though mRNA-based vaccines and therapies have shown promise for many years, because of their extreme-temperature requirements, “no one wanted to build the critical infrastructure needed to handle them,” says Shea Vincent, senior marketing director at Stirling Ultracold, “but the Covid-19 pandemic and the rapid, high-volume rise in mRNA vaccines have blown the doors wide open.” Today, it seems that development plans for mRNA-based therapies and partnerships are being announced every day.
The many innovations that were required throughout the cold chain to enable massive distribution of the novel mRNA vaccines for the coronavirus “would typically have taken five to six years to develop and bring to market, but during the pandemic, these were completed within five to six months,” adds Gregory Demitrack, strategy and consulting manager, supply chain and operations at Accenture.
But even before the pandemic, the need to scale existing and emerging technologies to manage modern business challenges was prevalent, says Carly Guenther, Accenture’s managing director and North America life sciences and supply chain and operations lead, and will continue to be a driving factor within the pharma cold chain. According to recent research by Accenture,2 81% of supply chain executives agree that they are facing technological changes at unprecedented speed and scale, and that Covid has been their organization’s largest stress test.
To meet the exacting requirements of today’s pharma cold chain, collective effort is underway to improve the competing packaging and shipping container designs and enable novel refrigerants and PCMs. This applies to active systems that require an energy source to maintain the cold temperatures, and passive systems that do not rely on a battery power or active compressor/thermoelectric cooling to maintain their temperature setpoints during transit. PCMs are based on hydrated salts, paraffins, fatty acids, alcohols and once conditioned to the setpoint temperature, they are able to reliably store and release energy to maintain ultralow setpoint temperatures inside the container for the duration of the trip.
“The pandemic really shifted the way we perceive cold-chain solutions, particularly when it comes to pharma and patients receiving vaccines and medications in a quick and efficient manner,” says Wes Wheeler, president of UPS Healthcare. “We believe the industry will continue to become more optimized regarding its efficiencies, reliability and resiliency, pushing cold chain and pharma distribution forward.” UPS Healthcare recently established UPS Healthcare Cold Chain, a comprehensive suite of cold chain technologies and capabilities.
When it comes to CGTs, there is more momentum than ever to bring these innovative therapies to market. Based on the current pipeline and the clinical success rate of these products, the FDA is expected to approve 10 to 20 CGTs by 2025.3
To keep up with the projected influx of approved therapies (and the related clinical trials), stakeholders are working to build up additional capacity for cryogenic storage. Such efforts, coupled with today’s proven methodologies and processes “will enable our partners to scale their specialty CGT product shipments from many to millions,” says Albert Cooksey, SVP and general manager of 3PL services for ICS, a division of AmerisourceBergen, adding that the parent company, through its network of businesses, has supported every manufacturer that has launched a CGT product in the US to date. ICS has recently doubled it refrigeration storage capacity (2 to 8°C) and invested in additional liquid nitrogen storage capacity (-180°C). In 2020, AmersourceBergen integrated World Courier, its global specialty logistics provider, and ICS to create a single specialty logistics provider to deliver complete support from clinical trials through commercialization, including a complete cryogenic supply chain.
Advances in packaging, shipping containers
“Ongoing advances in cold-chain shipping containers are able to provide extended temperature stability against a variety of environmental conditions, enabling safe and secure deliveries to very remote communities, areas with limited infrastructure or regions with extreme climates—like winter in Moscow or summer in Dubai,” says Nick Porter, SVP and general manager (global), World Courier.
Whether the payload is a single dose of high-value CGT or a pallet worth of lifesaving therapies or vaccines, it’s a million-dollar challenge to do whatever it takes to reduce spoilage, deliver the package on time and be able to meet business objectives. One disruption along the way can have an enormous impact.
A notable recent engineering innovation is the development of highly engineered vacuum-insulated panels that outperform many traditional insulation options. Vacuum-insulated panels are constructed from a microporous core material (i.e., glass or silica fibers, foams, mineral or glass wool) that is sandwiched between two pieces of multi-layer laminate barrier film. “Compared with widely used alternative options for insulating the thermal shipping containers, these slim-profile insulation panels provide R-values (a measure of how well a type of insulation resists the flow of heat) that are 10 times higher than conventional materials,” says Tom Weir, chief operating officer at CSafe Global.
World Courier recently introduced a passive thermal packaging tool, called Cocoon (left), which allows pharma companies to transport pallet-sized shipments within a low-frozen range, over great distances, to locations where the local infrastructure may be unreliable. According to World Courier, the Cocoon shipping containers use a combination of honeycomb, vacuum-insulated panels and advanced PCM to provide stable thermal protection for 168 hours across multiple temperature ranges: controlled ambient, refrigerated and frozen, and they are 30% lighter than comparable containers, the company says. To date, the Cocoon temperature-controlled containers have been used to ship pharma products from more than 110 locations worldwide, including those with an unreliable infrastructure, and those that are prone to customs delays, extreme climate variations and more, notes Porter.
World Courier has developed another novel shipping container called PharmaCube—an active, compact, custom-built shipping container designed specifically for the ground transportation of products controlled at ambient, refrigerated and frozen temperatures. It can be stored in a van, is powered by the vehicle’s battery and performs like a mobile refrigerator.
Stirling Ultracold offers ultra-low temperature (ULT) freezers that are small (the size of a beach cooler) and transportable and are able to maintain temperatures from -20°C down to -86°C. Powered by a free-piston Stirling engine (rather than traditional compressors), these ULT freezers use less than one-third the electricity of standard compressor-based ULT freezers, and they use 100% natural refrigerants, according to the company.
“You’ll never get a compressor-based engine small enough for the size of portable units we offer, and phase-change materials don’t exist to service needs lower than -40°C,” says Vincent.
The latest portable unit from Stirling can be battery-operated, plugged into a car charger or operated solar power. An upright, under-the-counter model is also available to provide ultracold freezer capacity in laboratories and pharmacies. “This portability creates a lot of opportunity to manage last-mile challenge and enable the delivery of ultrafrozen vaccines and therapies to remote parts of the world,” explains Vincent, who notes that this small-footprint option is also well-suited to help support today’s decentralized clinical trials (discussed ahead). In May 2021, Stirling was acquired by biopharma CDMO BioLife Solutions.
Stirling recently partnered with Walgreens to support the company’s widespread Covid vaccine-administration efforts at its 9,000 US retail pharmacy stores. Walgreens developed a hub-model storage plan that designated many of the bigger or more remote stores as hub locations to receive vaccine shipments and help manage the ebb and flow of Covid vaccines out to individual stores. To equip the hub centers, Walgreens purchased 300 portable ULT freezers and 105 undercounter freezers from Stirling. The company’s ULT freezers have also played a pivotal role in Puerto Rico’s mass-vaccination campaign in recent months and is a key supplier to UPS Healthcare to support its cold-chain efforts.
The growth of decentralized clinical trials
While the randomized clinical trial (RCT) process remains the gold standard for demonstrating the safety and efficacy of promising investigational therapies, informing dosing strategies and supporting the regulatory-approval process, the traditional RCT approach has always been flawed in several ways—including the need for trial participants to travel to centralized locations repeatedly for drug administration, testing and observation. According to recent research from Sanofi, 70% of potential trial participants live more than two hours away from the nearest study center. 4
In direct response to trial disruptions caused by the Covid-19 pandemic, there has been growing appetite for the use of decentralized clinical trials, and this has created a paradigm shift for all stakeholders, including providers of cold-chain packaging. “Over the last year we’ve seen one of the largest shifts in the history of clinical trials,” says Wheeler. “Virtual and decentralized trials offer a pragmatic, flexible approach” that aims to allow a given trial (where appropriate) to be conducted across smaller, local clinical settings to reduce patient burden and travel requirements and in some cases, to allow patients to participate from their homes, rather than travel to any clinical site, he adds.
In a year-over-year comparison between March 2019 to March 2020 in the US, Medidata reported patient access to trial sites was reduced by 66%.5 “Now in 2021, decentralized trials have already become a reality and represent the future of the industry, offering patients, providers, sponsors and vendors another option while enhancing the overall experience for trial sponsors, contract research organizations and patients, while reducing the risk of trail failure,” says Wheeler.
While this newer model is being heralded for enabling improved participation rates and reduced burden on the patient, it is also producing additional challenges vis-a-vis the cold-chain requirements when the investigational therapy must remain refrigerated or frozen and then stored and administered properly at home. Specifically, stakeholders have had to develop more nimble packaging and shipping options, as well as logistics systems, to enable smaller, more customized deliveries, and develop the needed monitoring and support protocols to ensure that the small clinics and individual patients will then be able to play their part in the exacting chain of custody required for these experiment treatments.
Importance of monitoring and data analytics
The use of sophisticated monitoring devices, coupled with advanced data analytics capabilities, have the potential to turn real-time data into actionable insights. During the planning stages, trends and patterns gleaned from historic tracking data can help stakeholders to identify the ideal transport route— and then use tracking data to revise it regularly, as needed, to minimize the impact of transit delays, weather crises and other factors that could arise to threaten the on-time delivery of the time- and temperature-sensitive cargo.
Today, different types of monitoring devices can be embedded within the shipments—to collect and transmit real-time data related to entire cargo containers, individual pallets and even individual product packages—from the moment they begin their journey to the moment they are delivered.
“Cold-chain management practitioners are not unfamiliar with data gathering and analytics. Until recently, however, the process to generate data-driven insights from that information was costly. It required time, manual efforts, and in many cases specialized data science skills,” says Demitrack of Accenture. “However, in today’s world, that is no longer the case.”
The affordability of tracking devices and data-analytics capabilities has continued to come down in recent years.This allows stakeholders to cost-effectively monitor multiple parameters of importance, including not just location but ambient temperature and humidity inside and outside the shipping container; vibration; shock and tilt events; the number and duration of every open-door event and more. Transmitting that data easily via cloud-based platforms provides unprecedented insight into what’s really happening to these high-value products during storage and transit.
“We’ve come this far in terms of being able to gather so much data, but the future wave will be defined by our ability to use advanced analytics techniques to use that data even more effectively to inform and drive behavior change to hone in on the most secure packaging and transportation,” says Stirling’s Vincent.
“We use data analytics and advanced monitoring solutions to protect our clients’ products and provide them with the actionable intelligence needed to make the right decisions in real time,” adds Cooksey of ICS. In addition to monitoring devices that are able to track individual shipments, Cooksey notes that 3PL providers “can also leverage 852 and 867 sales and trade [activity] data from downstream trading partners (such as wholesalers) to provide analytics that identify customer behavior patterns to help enhance business decision-making.”
“With increased digital capabilities throughout the pharmaceutical cold chain, companies can achieve greater relevance to customers, stronger resilience to disruptions and enhanced responsibility to society and the planet,” adds Accenture’s Guenther.
According to colleague Demitrack, “When, through continuous monitoring, real-time data can be collected, conditioned with business rules and logic, contextualized, and presented to the user, it enables an intelligent response that allow stakeholders to address temperature excursions as they are happening—not after the fact.”
Specifically, manufacturers and suppliers can also use such data to spot and forecast trends, enabling better predictive and preventive intervention for all partners handling the shipment along the way.
“We’ve built internal tools that allow us to analyze past data using artificial intelligence (AI) methodologies to help predict the future, and this has really helped us in our asset-allocation solutions to get our products (active and passive containers) to the right place at the right time,” says Weir of CSafe Global. “This helps to improve planning around which products to transport in which lanes—building confidence for our customers and credibility for us.”
Similarly, these technology advances have other workplace implications as well. “Natural language processing (NLP), low-code platforms, robotic process automation and other sophisticated data-analytics techniques are democratizing the cold chain,” says Guenther. “This, in turn, puts powerful capabilities into the hands of people across the supply chain.” She believes those people closest to day-to-day business problems will be empowered to create technology-driven solutions themselves. For example, creating more accurate forecasts or squeezing more efficiencies from manufacturing processes. “We must invest in every employee in the supply chain workforce—they will be the innovators that will optimize work, fix pain points, and keep the supply chain operations in lockstep with new and changing needs,” says Guenther.
No man is an island
The global disruption and unprecedented speed of the development and deployment of Covid-19 vaccines ignited “a scramble for enterprises to reimagine their supply chain partnerships, and multi-party systems gained newfound attention,” notes Guenther.
Demitrack adds: “By leveraging with closely integrated partnerships, supply chains can gain greater resilience and adaptability; unlock new ways to approach and serve the market; and set new, ecosystem-forward standards for their industries—especially as new players come into the landscape.”
When it comes to the pharma cold chain, “owning the end-to-end supply chain is the most expensive method for bringing products to market, as you have to be an expert in all areas of the supply chain,” says Ammie McAsey of McKesson US Pharmaceutical. “A multi-player supply chain provides cost efficiencies, scale and expertise.” She notes that each distinct handoff or “touch” creates an opportunity for risk or disruption. However, the current pharmaceutical supply chain is stable and reliable. The players in the market are experts in their discipline. So, leveraging each strength and collaboration across the industry is vital.
“The Covid-19 vaccine distribution efforts have reinforced the importance of proactive planning, as well as communication and collaboration among partners across the supply chain,” says Cooksey of ICS. “By engaging 3PLs early in the commercialization process, pharmaceutical companies and their partners can design and execute a robust supply chain strategy that leverages flexibility, storage across different areas, and the right packaging solutions to maintain product integrity across all conditions.”
Cooksey goes on: “Looking ahead, it’s critical for manufacturers to identify a 3PL provider with flexible shipment solutions and robust and tested business continuity measures that can help them navigate potential challenges and protect against supply chain disruptions.”
McKesson has played a pivotal role in supporting the US government’s efforts to distribute the Covid-19 vaccine. “From our partnership with the Centers for Disease Control and Prevention (CDC), the manufacturers of the vaccines and various technology partners, we’ve built a best-in-class approach to handle the different temperature requirements of the frozen and refrigerated Covid-19 vaccines,” says McAsey. As of early September, McKesson has delivered more than 199 million Covid doses all over the world, according to the company.
“We know that—despite tremendous progress to date— the global vaccination rollout is still in its early stages and a tremendous amount of work is still needed to ensure these vaccines reach communities around the world,” says Porter of World Courier, which has worked with partners to distribute millions of coronavirus vaccines to more than 20 countries over the past year. “As the vaccine supply increases, our teams will continue to work with partners across the supply chain to design and optimize logistics strategies and identify how we can best leverage our global network and temperature-controlled solutions to support successful distribution efforts.”
Executives stress that it is critical for cold chains to have a certain level of flexibility and adaptability to attend to unforeseen circumstances, including changing weather patterns, packaging or hardware malfunctions or vehicle breakdown. Using next-generation sensors, smart-label technology and other tracking advances, can help create those dynamics, says UPS Healthcare’s Wheeler. “We are now able to monitor a given package down to 10 feet anywhere in our network, and that has enabled us to achieve a 99.9% on-time delivery rate for our vaccine shipments.”
For some cold-chain situations, single-use (disposable) packaging options make more sense; for others, reusable shipping containers that may allow 40 to 50 shipments before they need to be retired are a more financially and environmentally sustainable option. “In the last two years, we have noticed a drastic change in sustainability leading strategy and many of the actions behind cold-chain decisions, ranging from packaging considerations to 3PL service agreements, and we expect to see more aggressive commitments in this arena, as the sustainability theme continues to grow in relevance,” says Vivian Berni, director of product management for Sonoco ThermoSafe.
“These days it is very popular to offer environmentally friendly, sustainable options—especially in certain geographies—and some of today’s newer cold-chain packaging products are both recyclable and curbside compostable,” adds Tetz of Peli BioThermal. While some current compostable packaging options may not be as robust with regard to extreme temperature control, they are still likely to find a niche in the direct-to-patient model that is growing in decentralized trials, where there is a small window of time but a relatively short distance to distribute the refrigerated or frozen medications. “This would allow the patient to safely dispose of the single-use packaging at home and not require the pharma company to keep track of and retrieve the shipping container from each patient,” says Tetz.
When it comes to the ability to reduce the overall carbon footprint associated with individual cold-chain shipping efforts, today’s model for leasing reusable shipping containers has also continued to evolve, experts contend. “Shipping containers that may go from New York to Tokyo will be managed in such a way that they travel back full,” says Tetz. “We work closely with our global network of service centers to balance out the travel schedules, in order to ensure that there will be the fewest possible number of empty travel legs as possible as these shipping containers are moving around the globe.”
All of these changes have continued to shape the landscape throughout the biopharma cold chain. “Traditionally, the supply chain has almost always been considered a back-office, transactional function, but increasingly, this activity—especially as it relates to time- and temperature-sensitive pharma products—is being recognized as a critical pillar in an organization’s success,” says Berni of Sonoco ThermoSafe. “It directly informs and shapes the strategic direction, growth and competitive positioning of that company, and ensures that patient access to therapy will not be upended.” As a result, she adds that proper investment needs to be funneled all throughout various levels of leadership, “supported by the right tools to manage dynamically—not Excel spreadsheets.”
Such technological approaches go hand-in-hand with today’s larger mindset among the C-suite when managing the supply chain in the life sciences. “Historically, pharma companies tended to worry about the cost of one package, but today, stakeholders are taking a much broader view of all risks, considering the entire infrastructure and advanced technology options that are required to ensure reliable delivery from end to end, and making their decisions more smartly,” says CSafe’s Weir.
Adds Berni of Sonoco ThermoSafe: “The ongoing changes throughout the pharma cold chain will continue to create both challenges and opportunities—and potential competitive advantage—for those willing to break from the status quo.”