Cold-Chain Validation: Emerging Vaccines for COVID-19 and Beyond Require More Extensive Evaluation

View PDF

Arktek cryostorage containers holding Ebola vaccines for distribution in Sierra Leone; in 2015, cold-chain engineering company Modality Solutions supported clinical trials for Ebola vaccines in that country.
(Photo Courtesy of Modality Solutions)

In the wake of fast-track approvals for Pfizer’s and Moderna’s respective SARS-CoV-2 vaccines, now begins the largest immunization campaign in world history. Its success will depend not only on the products’ safety and efficacy, but also on several mass-distribution programs requiring significant cold-chain infrastructure. The public has become acutely aware of the Pfizer vaccine’s demanding cryostorage specifications, generating considerable anxiety about how mass distribution will happen. Behind the scenes, however, cold-chain engineering companies such as Modality Solutions have worked alongside drug developers to ensure that vaccines can be shipped efficiently without compromising drug-product safety and quality.

In December 2020, I spoke with Gary M. Hutchinson (president and cofounder) and Daniel J. Littlefield (principal, cofounder, and head of engineering) of Modality Solutions to learn about what resources SARS-CoV-2 vaccines will require during transport, what challenges new products will impose on existing cold-chain networks, and what lessons the biopharmaceutical industry can learn from the cold-chain industry’s experiences with vaccine storage and handling. Our conversation also traverses emerging distribution models and the need for drug manufacturers and cold-chain specialists to work in parallel to optimize vaccine formulations.

Early Involvement for Shipment Success
How would you characterize your company’s role in vaccine distribution?
Hutchinson: We specialize in transportation validation. We help clients formalize and understand hazards that are inherent to shipping a biologic, vaccine, or advanced therapy through a commercial supply chain. And significant risks abound. The biopharmaceutical industry settled on temperature risks early in its development, so the idea of cold chain became the most considered factor in drug-product shipment. But when therapies such as monoclonal antibodies (MAbs) emerged, researchers discovered that other hazards posed risks to drug-product efficacy and quality.

Subsequent testing revealed a unique intersection of engineering and logistics devoted to understanding transport risks and developing methods to evaluate them. As a cold-chain engineering company, we put that information in a coherent package to explain to regulatory agencies that a therapy can be shipped safely.

Although timelines have been abbreviated during the pandemic, drug companies usually engage us late in phase 2 or early in phase 3 clinical trials — the point at which a company becomes confident about moving into large-scale manufacturing. That stage also requires transitioning a therapy from a clinical formulation to one more appropriate for commercial distribution — for instance, from a deep-frozen to a standard frozen or refrigerated formulation. Our role begins during that transition. We help clients test their commercial formulations for large-scale distribution and assist with the associated packaging and logistics.

Littlefield: Although Modality focuses on validating distribution processes, we also support emergency-response clinical trials. For instance, the US National Institutes of Health (NIH) and World Health Organization (WHO) contracted us to assist with Ebola vaccine trials in the Democratic Republic of the Congo (DRC) in 2019 and Sierra Leone in 2015.

Risk Assessment and Preparedness
How do shipping conditions for emerging SARS-CoV-2 vaccines compare with those for existing vaccines, and how prepared are cold-chain networks to accommodate distinctive transport needs?
Littlefield: Although shipping conditions differ by product, vaccines requiring cold-chain transport usually are transported at temperatures above –20 °C. Smallpox vaccines often are shipped at –20 °C, as is Moderna’s recently approved SARS-CoV-2 vaccine.
Despite media coverage of requirements for Pfizer’s vaccine, which include cryostorage at –60 °C, such low-temperature specifications are atypical. However, because we worked with Ebola vaccines, which have similarly low temperature requirements, we noticed at the beginning of the race for a COVID-19 vaccine some striking parallels between formulation and distribution specifications for those vaccine types — similarities that only now are gaining attention.

Capabilities for providing an extreme temperature range exist, in part, because drug companies want to be conservative with fast-tracked products that have not had time for comprehensive data analysis.

Hutchinson: The public continues to wonder whether rapid development has compromised the safety profiles of COVID-19 vaccines. Now the public also is asking whether we can accomplish the distribution piece. We want to make people aware that such work has been happening all along.

Figure 1: The Advantage Transport multimodal simulation laboratory validates materials for vaccine transport by exposing products to environmental hazards such as changes in temperature, pressure, and humidity as well as shock and vibration events
(Photo courtesy of Modality Solutions).

Modality has been involved in the engineering work for ~40% of late-phase COVID-19 vaccines. We perform risk assessment at our transport simulation laboratory in Bloomington, IN, where we can replicate most any environment that COVID-19 vaccines and follow-on therapies might experience during transport (Figure 1). We test for temperature, shock, vibration, pressure, and humidity hazards, stressing our clients’ molecules to the edge of failure in worst-case conditions. Based on our simulations, our clients can compare their products’ pre- and post-shipment properties to develop appropriate specifications and identify potential liabilities. Then our clients can present those assessments to the US Food and Drug Administration (FDA) to support their claims about product safety and stability.

The biopharmaceutical industry has moved quickly through vaccine development, but it also has gathered enough data concerning stability at specified temperature ranges. Those numbers are not arbitrary; they are tested and reviewed extensively. And while scientists have been developing drug products, engineers and logisticians have been working in parallel to plan for massive distribution. Based on what we know about existing products, we are confident that COVID-19 vaccines will be safe during transport. Vaccine developers are placing substantial “guardrails” around distribution, and we continue to test beyond conservative ranges to ensure product efficacy, stability, and safety even in the case of failure.

Shipping Challenges and Opportunities
What are the most difficult parts of a cold-chain operation, and how do you mitigate problems?
Littlefield: Challenges increase as a drug product moves further down the process from manufacturing. The “last-mile” logistics of getting vaccines to patients can be difficult to manage. But product damage can occur whenever there is movement. A shipment can be dropped during loading, unloading, or delivery, and shock events can damage vaccine products and packaging. Vibration from truck or airline transport can be just as detrimental as a shock event. Thus, risk assessment is critical to cold-chain success, and we work hard to ensure that our simulations are demanding and realistic. Packages will experience hazards, and companies need to know whether their products will be viable despite whatever problems arise.

Packaging typically is qualified at a certain temperature for a specified duration — e.g., for 72 hours at –60 °C. A vaccine product will be fine as long as it is packed out, shipped, delivered, and moved to appropriate refrigeration conditions within that period. But delays occur. Will a product remain viable if it sits somewhere for two days beyond that 72-hour mark? It might, because that specification is based on worst-case conditions. For that reason, we force temperature excursions during simulation. We want clients to know whether a product can be used, for instance, if its packaging reaches –50 °C instead of staying at –60 °C. Drug developers sometimes perform similar tests at their facilities, including accelerated-aging studies, during which a product is stored, for example, at –20 °C for 30 days. Combining all those data can help drug developers to determine what conditions their vaccines can and cannot tolerate.

Hutchinson: When people think about cold-chain challenges, they usually reference Pfizer’s COVID-19 vaccine. Americans wonder, for instance, about how such a vaccine could be shipped to rural parts of the United States. However, Pfizer is leveraging advantages from having its own captured network. For distribution in the United States, nearly all COVID-19 vaccine developers have contracted through Operation Warp Speed to use US Army logistics teams and the McKesson wholesale distribution network. After initial distribution through those channels, doses somehow need to be sent to healthcare providers for administration. So Pfizer’s vaccine requires deep-freezing, but the company is using a direct distribution model, whereas other vaccines may have less demanding temperature specifications but depend on multiple transitions. Last-mile logistics involve several handoffs, each adding risk into the system for a potential temperature excursion or shock/vibration event. Tradeoffs exist for both distribution models.

How might the pandemic influence transport of vaccines for indications besides COVID-19?
Hutchinson: Impacts already are manifesting in the commercial airline network. Besides UPS and FedEx, commercial airlines were the biggest movers of pharmaceutical freight. But many flights have been grounded because people are unable or afraid to travel by air. Decreases in air traffic have removed a huge amount of capacity from the shipping network, and that problem will reverberate in many supply chains. The vaccine industry is no exception.

Shipment delays are another pandemic-induced challenge. Major supply-chain integrators such as UPS and FedEx have shut down key delivery services. That will disrupt pharmaceutical distribution. Delays will have escalated significantly during the 2020 holiday season. The importance of lifesaving medicine cannot be overstated, but pharmaceuticals ultimately account for a miniscule amount of shipment volume, and that makes it difficult for integrators to prioritize packages from the life sciences. How difficult would it be to find the one box of lifesaving medicine among the millions of boxes of Christmas gifts, for instance?

That problem brings us back to basic questions about whether to choose active or passive packaging systems for drug products. Active thermal systems do not use phase-change materials (PCMs) such as water/ice or dry ice. Instead, such systems use mechanical or electrical cooling systems combined with thermostatic controls to maintain proper product temperatures. The powers of active temperature control tend to be overestimated. Some active systems run on batteries, which eventually die. They can be recharged, of course, but doing that requires an extra handling step, introducing risk.

Passive thermal control relies on PCMs, making them simpler and more cost effective than active solutions. Passive shippers also enable cold-chain engineers and logisticians to build in a safety margin. For instance, packages qualified at –20 °C for 72 hours are proven to maintain those conditions in extreme heat. If a shipment bed is cool, then passive packaging can last longer than 72 hours.

Thus, passive systems hold significant advantages. People might not recognize such benefits because they think, “My freight has been delayed. Thank goodness that I am using an active shipper that can be plugged in to last in perpetuity.” However, many things need to go right for an active shipper to perform successfully, whereas passive shippers enable engineers to set design parameters around extreme temperature profiles. If a package is delayed but experiences mild temperatures, then it is likely to perform as expected.

Enabling Global Vaccine Distribution
What issues arise with shipment of biologics and vaccines to underresourced countries?
Littlefield: Such places need to develop sufficient infrastructure to support cold-chain operations. Most countries in sub-Saharan Africa still lack dry-ice capabilities. Countries affected by the Ebola virus — the DRC, Sierra Leone, Guinea, and Liberia — have developed some capability for cryostorage at –60 °C. Those countries will need either to construct additional capacity for the Pfizer vaccine or use Moderna’s product. Large vaccination programs are already in place for diseases such as diphtheria and polio, so those programs, which provide for –20 °C storage, could be adapted for Moderna’s vaccine. But large-scale implementation of vaccines requiring lower temperatures will be a challenge.

The NIH, US Agency for International Development (USAID), Bill and Melinda Gates Foundation, and World Health Organization (WHO) provide much support for cold-chain operations in developing countries. But the challenge is a bit like giving someone a guitar; doing that doesn’t make that person a musician. Giving clinicians a –60 °C freezer doesn’t make them cold-chain experts. My experience is that pharmacists and physicians in those countries are incredibly smart and talented but don’t yet have experience with cold-chain engineering. Developing adequate infrastructure will require a training component that until now has been neglected.

The Future of Vaccine Distribution
What is the COVID-19 pandemic teaching the biopharmaceutical industry about vaccine distribution, and how might distribution change in the future?
Hutchinson: Vaccines are “mission critical,” but distribution still relies on a business-to-consumer (B2C) commercial network. Biologics and vaccines have special requirements and great need for expedited service, yet we throw them into the same networks as every other shipment, introducing several hazards. Shipping companies try to protect against temperature excursions and shock/vibration events by overpackaging drug products using four-inch–wall polyurethane boxes that end up in landfills and gel ice made with nasty additives. Such tactics are inevitable when shipping drug products in networks that are not fit for purpose.

An idea that has emerged — one that I am trying to evangelize — is to build a distinctive life-sciences distribution network. Using a specialized network would be much more efficient than handing off a vaccine shipment to UPS or FedEx and hoping for the best. Of course, those carriers respect and support the biopharmaceutical industry, but transferring sensitive products with special requirements into a high-volume network can beget mistakes. Such problems will continue for as long as the biopharmaceutical industry remains a miniscule part of a huge network.

We need to try something different. The pandemic should be a wake-up call. And if another pandemic happens soon, it would be a shame if we did not learn anything from our current conditions and found ourselves lamenting the same problems as we have now because we did not make fundamental changes.

The vaccine industry will learn several lessons as Pfizer’s and Moderna’s vaccines are distributed widely and as more candidates advance through clinical trials. But genuine change will start within trade associations. Creating a distinctive life-sciences logistics network will be difficult because the companies comprising that industry are competitive. Large companies with sufficient volume and capacity will need to cooperate to establish a network.

A commercial opportunity exists in creating such a network. Integrators such as UPS use life-sciences–specific warehousing for storage but then throw all those packages into their general delivery network. Maybe vaccine developers could leverage an industry-specific network within a large integrated carrier. Amazon already has provided a model for creating our own captured network, and the biopharmaceutical industry ships enough product to make something like that work; it just needs to find a suitable shipping partner and then commit to shifting resources to specialized logistics.

Littlefield: The industry is learning that many activities that traditionally have been performed sequentially can be done in parallel. Until now, vaccine development has taken many years. Now we are witnessing vaccines move from discovery through commercial distribution in under a year. Part of that stems from acceleration on the part of research and development (R&D), but rapid development still requires appropriate checks on vaccine efficacy and stability. In terms of distribution, that means that transportation validation needs to be performed earlier and more effectively than it has in the past.

Hutchinson: Some companies already have learned that lesson and have aligned their development and manufacturing capabilities with their end products in mind. It is no accident that the Moderna vaccine can be stored at warmer, more conventional freezer temperatures and enjoy longer viability a refrigerated temperature than other formulations can. Decisions about those requirements were made early. Our goal, as a cold-chain engineering company, is to set up vaccine companies for success by engaging them relatively early in the clinical process to consider what challenges will come during commercial transport. Then we help them assemble datasets that they will need to minimize cold-chain risks going forward.

Brian Gazaille is associate editor at BioProcess International, part of Informa Connect; brian.gazaille@informa.com. Gary M. Hutchinson (ghutchinson@modality-solutions.com) is president and cofounder, and Daniel J. Littlefield (dlittlefield@modality-solutions.com) is principal, cofounder, and head of engineering at Modality Solutions; 2600 South Shore Boulevard, Suite 364, League City, TX 77573; https://www.modality-solutions.com.

Leave a Reply