The Road Ahead for the Pharma Cold Chain

The stakes are higher than ever in the bio/pharmaceutical cold chain. Whether the payload is a pallet full of lifesaving biologic therapies or vaccines, or a single dose of a customized cell-and-gene (CGT) therapy or immunotherapy agent, it’s a million-dollar challenge. Every company that takes temporary custody of these high-value shipments—as they move on and off trucks and planes, and in and out of warehouses, to reach the hospital, clinic, or pharmacy setting—must safeguard the integrity of these fragile, high-value products. Failure to ensure strict temperature requirements can create enormous financial and clinical impact, as many shipments are often valued at hundreds of thousands and even millions of dollars.

“The logistics required to ensure reliable distribution of time- and temperature-sensitive life sciences products are very complex, and there is no margin for error,” says Danny Williams, president of channel management for EVERSANA. “If things can go wrong, they will. The last two years have really pressure tested how well-prepared we are as an industry for whatever comes our way.”

Worldwide, 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 (1).As of early 2020, annual global sales of biotech drugs, biologic products and vaccines that require strict temperature control exceeded $340 billion in value, with cold-chain logistics accounting for nearly 18% of all biopharma logistics spending.

The Herculean effort to address the global COVID-19 pandemic has involved one of the largest public immunization programs ever. To date, more than 12 billion doses of the COVID-19 vaccine have been administered across 184 countries, with 588 million doses administered in the United States, according to data published in June by Bloomberg (2).

In general, the pharma cold chain is organized around three temperature ranges—refrigerated (2 to 8 °C), deep frozen (on the order of -40 to -80 °C), and cryogenic (on the order of -160 to -180 °C). Domestic shipments are typically designed to remain at the setpoint temperature for 24 to 72 hours, while international shipments are usually designed to remain at the setpoint temperature for up to 120 hours.

However, unforeseen circumstances—which may include travel delays from disruptive weather, extreme climates, vehicle breakdowns, political strife, volume volatility, staffing shortages, supply chain bottlenecks, packaging malfunctions, and more—can impact whether and when the delivery will arrive, and in what condition. “Real-time visibility is the essential as these critical shipments may involve $250,000 worth of product in one case or just one patient’s critical CGT treatment, in another,” adds Williams. “The best, most effective product does no one any good if it arrives damaged, without the necessary chain-of-custody data to verify that it’s suitable for patient use.”

Monitoring and data analytics provide critical connective tissue

“Given the sensitive nature of temperature-sensitive vaccines and therapies, all such products are given the white-glove treatment,” says Dan Gagnon, vice president of marketing and strategy for UPS Healthcare. By using next-generation solutions, smart-label technology, and other monitoring advances, many specialized third-party logistics (3PL) providers in the pharma cold chain are able to track and transmit data related to not only temperature and time, but exposure to light, pressure, vibration, humidity, tilt, and the number and duration of every open-door event and transmit the data via cloud-based platforms. Today, such monitoring systems can be applied to entire cargo containers, individual pallets, and even individual product packages, as needed. Modeling based on real-time and historic data is helping companies to both map out more effective delivery routes and to pivot quickly when disruptions do arise.

“For years, pharmaceutical companies have been collecting all types of shipping data but not necessarily finding good use for it. This has now changed significantly, given the high stakes involved in the pharma cold chain,” notes Christoph Bamert, head of sales and marketing for Elpro.

EVERSANA is piloting a variety of studies, both domestically and internationally, that are using artificial intelligence (AI) platforms, along with passive radio frequency identification (RFID) for geopositioning, to enable improved predictive monitoring on package status. “For many of these therapies—especially CGT products—the healthcare provider and the site of care that are also trying to coordinate patient care, so reliable, on-time delivery of the CGT therapy is essential,” says Williams.

“The value comes from knowing how to use the data, artificial intelligence, and other advanced modeling to drive efficiency and enable proactive interventions and constant investments,” adds Rob Coyle, senior vice president, healthcare strategy at Kuehne + Nagel, who notes that rapid, data-driven intervention is particularly critical as the volume of cold chain shipments has grown by a factor of six to eight over the past year.

Meanwhile, many pharmaceutical companies are already focusing heavily on implementing serialization tools and processes to meet US Drug Supply Chain Security Act (DSCSA) requirements. “The next development could be to link serialization data with temperature data collected along the supply chain (such as storage, transportation, last mile, and more.) to gain better end-to-end visibility and leverage stability budgets across the supply chain,” says Bamert.

Building out the infrastructure

“Ongoing investments in our systems, our people, and our standard operating procedures, along with the ability to use data-driven insights to pivot quickly, have been key to managing the unique challenges in this space,” says Coyle. Using a mix of contract logistics and warehousing and strategic investments, the company has increased capacity in -20 °C to -70 °C capabilities.

Certain vaccines (including COVID-19 vaccines) and biologic therapies require dry ice packaging during transit. To meet the demand, UPS Healthcare mapped roughly 500 new trade lanes worldwide in 2021 and scaled the production of dry ice, using more than 3 million pounds of it to help safely move vaccines in 2021, says Gagnon.

Meanwhile, to mitigate recent supply and labor shortages, Sonoco ThermoSafe, a manufacturer of temperature-controlled shipping containers and related engineered systems, has increased its inventory thresholds for both raw and finished materials. “This ensures that we are able to supply our customers on time and in full while we concurrently introduce automation within our operations where manual labor was previously relied upon,” notes Ben VanderPlas, the company’s director of engineering and R&D.“We have also qualified dual sources and/or identified alternative solutions that meet or exceed existing specifications and qualifications—while meeting our robust change-control procedures.”

Toreduce risk, “we have further diversified production across our internal manufacturing network, to ensure that redundancies are in place, and we produce products at alternative sites if issues arise at a primary site,” VanderPlas continues. “Multi-sourced strategies and opportunities for material equivalencies will continue to drive down increasing raw material costs and de-risk our own supply chain.”

Packaging upgrades

Manufacturers of both active (requiring a power source or battery) and passive (not relying on battery power) shipping containers, and the insulating materials and novel refrigerants and phase-change materials (PCMs) they rely on, have continued to innovate to maintain the required refrigerated, frozen, and deep-frozen temperatures for longer periods of time. 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 COVID-19 challenge has driven many global pharmaceutical companies and their 3PL logistics partners to reconsider packaging selection as a strategic decision,” says Vivian Berni, director, product management and strategic marketing, Sonoco ThermoSafe. Sonoco ThermoSafe recently conducted a test shipment with the organization’s new Pegasus ULD, which is said to be the first passive bulk-temperature-controlled container for pharmaceutical use that is an approved unit load device (ULD). The shipping process involved multiple segments of ground and air transportation on a journey that exceeded 130 hours. The Pegasus ULD contains a fully integrated, FAA-approved telemetry system, which provides real-time, cloud-based data on both payload and ambient temperature and other environmental factors. “This shipment has demonstrated the ability of the Pegasus ULD to address two of the key challenges for bulk passive pharmaceutical packaging technologies—providing long duration (more than five days) thermal performance and easing operational handling from trucking to ground handling to flying,” she adds.

At the end of 2021, CSafe Global acquired Softbox Systems, another manufacturer of temperature-control packaging solutions. CSafe offers highly engineered vacuum-insulated panels that are constructed from a microporous core material (such as glass or silica fibers, foams, mineral or glass, wool, and others) that is sandwiched between two pieces of multi-layer laminate barrier film. These slim-profile insulation panels provide R-values (a measure of how insulation resists the flow of heat) that are ten times higher than conventional materials, says the company.

CGT—A growing portion of the pharma cold chain

When it comes to CGT, there is more momentum than ever to bring these innovative therapies to market. Based on the current pipeline, FDA is expected to approve 10 to 20 cell and gene therapy products per year by 2025 “based on the current pipeline and clinical success rate of these products” (3).

Every CGT delivery requires a high level of customization, so it is hard to develop economies of scale. Approved CGT therapies typically involve the production of custom treatments in one of two ways:

Autologous therapies—Cells (blood or tissue) are extracted from that patient and that biological material is modified in a laboratory to produce the therapy for the same patient who contributed the starting material, one vial at a time. The process requires a complex, closed-loop delivery cycle, and as such, all starting biological materials and the finished therapy must be safeguarded at every moment in this highly choreographed process.

Allogeneic therapies—Cells (blood or tissue) are extracted from a suitable donor and that biological material is modified in a laboratory to produce small batches of therapy, which can then be infused into multiple suitable patients over time. This adds complexity in terms of the need for temperature-controlled interim warehousing and tightly scheduled cold chain deliveries to multiple patients in geographically disparate locations. When it comes to allogeneic therapies, studies show that a single donor may be able to create doses for more than 200 patients (4).

And the number and volume of approved CGT products is on the rise. According to ARM’s latest Sector Report (March 2022) (5), 2406 clinical trials were underway globally for CGT, cell-based immune-oncology therapies, and other regenerative medicines at the end of 2021. These address both prevalent diseases—59% of the total—including diabetes, Parkinson’s disease, macular degeneration, stroke, congestive heart failure, and more, and rare diseases including sick cell disease, hemophilia, multiple sclerosis, amyotrophic lateral sclerosis and more. According to ARM, 2022 is likely to be a “record year” for the approval of new gene therapies to treat rare diseases, with five such therapies up for approval in the US and Europe.

“CGT products tend to require cryogenic temperatures, often below -150 °C, which requires the use of liquid nitrogen as the cooling agent. This is commonly achieved in a reusable shipper with a structure capable of containing the liquid nitrogen vapors (a dewar) and with a design that is oriented to ship upright for optimal performance,” explains VanderPlas.“There is certainly more -80 °C storage capacity in the market than ever before. If and when such freezer farms can be equipped to be cold enough for CGT applications, that will help to enable adequate storage capacities for that growing volume of CGT products,” he continues.

“We need to not become complacent,” adds Coyle. “We need to continue planning for the next pandemic or global disruption to be sure we are ready for whatever comes our way.”

“At the end of the day, choosing the right partner can provide a stabilizing force in an inherently unstable environment,” says Williams.

References

1. Pharmaceutical Commerce, “2020 Biopharma Cold Chain Sourcebook Forecasts a $17.2-billion Logistics Market,” PharmaceuticalCommerce.com, April 2020.
2. Bloomberg, More Than 11.9 Billion Shots Given: Covid-19 Tracker (June 16, 2022), Bloomberg.com, accessed June 16, 2022.
3. FDA, “FDA Statement: Statement from FDA Commissioner Scott Gottlieb, M.D., and Peter Marks, Ph.D. and M.D., Director of the Center for Biologics Evaluation and Research, on New Policies to Advance Development of Safe and Effective Cell and gene Therapies,” FDA.gov, Jan. 15, 2019.
4. M. Lachs, O. Saulin, and B. Fletcher, “Moving from Autologous to Allogeneic ACT Paradigms,” Pharmaphorum Deep Dive Newsletter, July 2019.
5. Alliance for Regenerative Medicine, Regenerative Medicine: Disrupting the Status Quo 2021.

About the author

Suzanne Shelley is a contributing editor to BioPharm International.

Article details

BioPharm International
Vol. 35, No. 7
July 2022
Pages: 31–34

Citation

When referring to this article, please cite it as S. Shelley, “The Road Ahead for the Pharma Cold Chain,” BioPharm International 35 (7) (2022).