Cold Chain: Going the Extra Mile

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Shipping temperature-sensitive pharmaceuticals such as biological products, has never been easy. Today, changing global requirements and a more complex supply chain are driving more conservative approaches to temperature control. For products such as cell therapies and tissue culture, cryogenic shipping is now preferred.  Other biopharmaceuticals are being shipped at lower tempertures, and even small-molecule-based pharmaceuticals that might have been shipped at ambient temperatures a few years ago, must now be kept at controlled temperatures.

Transport has become much more than simply moving product from one place to another.  It’s now being seen as a “mobile form of storage,” says Volker Kirschner, director of temperature control solutions for World Courier Management Co, part of Amerisource Bergen. This is especially true in Europe, he says, where the European Union (EU) began strengthening its good distribution practice (GDP) guidelines three years ago.

Nothing can be taken for granted.  “From political unrest to pandemic concerns, the possibility of changes in shipping patterns and logistics strategies is quite real,” he says, and developing a global transport strategy has become more complex.

Specialists in cold-chain shipment are responding to regulatory challenges and uncertainty by investing in new technology and IT, and strengthening partnerships with specialty logistics providers. For their pharmaceutical and biopharm customers, they caution, careful risk-assessment is the only way to avoid costly product shipment problems. Many are adding services and products to help make this task easier.  

The rise of good distribution practices
The most pronounced recent change in the cold-chain market has been more complex global regulations, from the EU’s GDP guidelines for pharmaceuticals to the Drug Supply Chain Security Act in the United States. “It can be difficult for companies, especially smaller ones, to know where to begin, and how to revamp compliance processes to stay ahead,” says Wanis Kabbaj, director of global healthcare strategy for UPS.

Additional requirements (e.g., for controlled room temperature) have increased compliance challenges. Many drugs that were once shipped at ambient emperatures must now be shipped at 15°F to 25°C, increasing costs at a time when most pharmaceutical companies are trying to reduce logistic and supply chain operations budgets, says Ariette Van Strien, chief commercial officer at Marken Global Life Science Supply Chain Solutions, which specializes in cold chain and logistics.  

Compliance has become especially challenging for clinical trial supply shipments, she says, noting that suppliers must scrutinize their global network, enhance tracking capabilities, and improve quality standards.

Of utmost importance, says Kirschner, are quality management systems (QMS) and documentation, personnel and training, and risk management, especially regarding standard operating procedures (SOPs); facilities and storage requirements; and transport. “Quality departments within manufacturers’ supply-chain operations are gaining more and more influence,” he says, noting that regulatory agencies expect pharmaceutical manufacturers to take a risk-based approach and enforce audits and quality agreements.

Managing risk
The most critical aspect to maintaining stability and integrity is choosing the most appropriate temperature conditions for the product and, consequently, the best packaging for maintaining those conditions, says Mark Sawicki, chief commercial officer at the cold chain specialist, Cryoport.

A perfect example, Sawicki says, is the distribution of critical biomarker samples. Under currently accepted practice, these samples are shipped on dry ice. However, he notes, this shipping method has been connected with a 15-30% product compromise or failure rate. As a result, more companies are opting to use cryogenic temperatures to ship biomarkers, to help eliminate potential risks associated with transit times and temperature excursions.

PCI Pharma Services, a diversified contract services firm that offers cold-chain expertise, has seen a dramatic increase in demand for storing product at ultra-low temperatures, from -40°C down to -196°C, and has adapted its products and services to focus on supporting these temperatures for storage, packaging and shipments, says Samantha James, associate director of clinical services.

Pharmaceutical manufacturers need to conduct more critical, comprehensive shipping studies on all materials transported in support of a clinical program, says Sawicki, not only looking at sample failure but the impact of the selected transport medium on assay or product performance.

“We consult with every client to select the best system and temperature-control solution, whether dry ice, liquid nitrogen, or phase-change materials (PCMs) to ship pharmaceutical products, diagnostic specimens, biotherapeutics, and tissue samples, says Van Strien.  

Generally, the most crucial factors to consider include therapeutic indication, route, mode of transportation, and product sensitivity, she says. “Because a pharmaceutical’s stability is not always known in early trial phases, additional caution may be necessary, and protection for any changes in environmental conditions.”  

Van Strien advocates developing a thorough risk assessment to help ensure product stability from origin to destination, including studies of the following:

• Packaging

• Payload configuration

• Temperature monitor placement

• Transport routes (modes and nodes)

• Potential risks and mitigation strategy

For clinical products that are only available in small samples, incorrectly handled shipping and transportation can put millions or even billions of revenue dollars at risk by compromising clinical studies, potentially delaying product commercialization, notes Kirschner. When minimizing risk, it is important for manufacturers to consider the package type and choice of temperature-control mechanisms, environmental concerns, value of the ingredients in the product, temperature requirements and variables, and overall shipping costs.

Suppliers need to master nontechnical issues as well, including local politics and security issues, especially when conducting clinical trials in new geographic markets. Proactive planning is required, Kirschner says, to help protect the integrity of products and, ultimately, the safety of patients who use those pharmaceuticals.

Generally, he notes, up-to-date methods should be used to assess risk.  For example, he says, failure mode and effects analysis (FMEA) can be conducted, and risk priority numbers (RPNs) assigned, based on the probabilities and severities of certain adverse events occurring during transport.  These RPNs would help determine whether mitigation is required, and what type would work best for the specific product, market and application.

Temperature is not the only variable to consider. Many pharmaceuticals and biopharma manufacturers require a great deal of stability protection from temperature, shock, vibration, humidity, and light, explains Kabbaj.  “Healthcare logistics has little room for error, so specialized packaging, advanced temperature and location monitoring leveraging global control towers, and in-transit intervention are all critical.”

In addition, Kabbaj says, extended time in transit when product is being transported inland may expose the packaging to temperature fluctuations that increase risks. Ocean transportation risk factors include container placement on the vessel, sunlight exposure, container insulation, and dwell time on the dock -- all introducing additional packaging stressors.  

He suggests that pharmaceutical manufacturing professionals take the following steps to ensure that they are covering all the bases required for risk mitigation:

• Test packaging, including seals, for endurance, and put prototypes through compression, impact, vibration, temperature, humidity, and shock tests. Package optimization should include validation through design qualification, operational qualification, and performance qualification protocols.

• Optimize packaging and transportation together. Do not develop a cold-chain solution sequentially with assumptions based on transportation, and then the transportation solution that comes with pack-out expiry. Pairing a lighter and cheaper cold-chain packaging with expedited air transportation, for example, may prove to be more effective than opting for a slower mode of transportation (e.g., ground shipping) with complex, heavy, and bulky packaging.

• Innovate continually to create better efficiencies. Optimize the shipping carton, minimizing unused space, and select more precise packaging configurations.

“Pharmaceutical manufacturers that do not continually review, evaluate and update packaging best practices leave themselves open to product risk and cost inefficiencies,” Kabbaj says. “Leave room for new ideas, material innovations, and new packaging manufacturers by engaging cold chain partners in a collaborative mode.”

Technologies enable faster response
Cold-chain service providers have been developing new technologies to help pharmaceutical companies better manage risk and respond to problems.  “New requirements are driving developments in packaging and monitoring technologies,” says Kirschner.  As an example, he points to newer semi-active packaging technologies that allow for longer durations of temperature control with lighter materials that have less environmental impact.

In addition, he says, passive packaging  solutions have been developed that can provide proven temperature control over long distances. Independent testing has shown these solutions to perform five to seven times more efficiently than semi-active solutions, he says. Kirschner also points to new phase-change materials (PCMs), comprised of paraffin or salt-based solutions, that allow for more precise temperature control to maintain product stability over long distances or through extreme climates.

Many packaging manufacturers are now developing their own vacuum-insulated panel (VIP) containers, combined with PCM solutions, for easier handling and storage. Additionally, he says, on the monitoring side, developments in global positioning software (GPS) and tracking equipment now include automatic start-up and shutdown mechanisms that can provide a real-time view into a shipment’s status. Many technology providers have invested in real-time, GPS-enabled data loggers. Combined with improved data access, through customer portals and better IT, the technology offers immediate insights into bottlenecks and delays.

Logging more than just temperature
“These data loggers provide the ability to track both condition and chain-of-custody, in real time,” says Sawicki.  They can track, not just temperature, but also monitor the impact of external influences on container integrity including orientation and package damage, he adds, and can also tell whether the container has been opened.

Examples of new cold-chain data loggers include Sensitech’s TempTale and Nexleaf’s ColdTrace systems. Contract service suppliers are also offering enhanced IT connections. PCI Pharma Services, for instance, has developed a portal to allow clients to access real-time data, 24/7. “They can monitor stock levels, and view and trace all live shipments associated with their project, with direct links to courier tracking,” says James.

Last year, Marken introduced Sentry, a GPS-enabled sensor platform, designed specifically for pharma with real-time track and trace capability through custom-designed software that monitors, records, and reports on location, temperature, motion, shock, exposure to light (i.e., when the box opens), atmospheric pressure, and remaining battery life. The device transmits in real time and communicates through customized cloud-based software that connects with Marken’s Maestro IT system, says Van Strien.

Today, major cold-chain trends include increased use of temperature- managed shipping, and an interest in evaluating transport  methods and equipment critically, to maximize sample integrity, says Sawicki. There is also an increased emphasis on protecting the products of cell, gene and immunotherapy, says Van Strien, and the complex supply chain logistics that these products require.

Cryogenic shipment for cell therapies
A growing number of biopharm companies must now ship cell- and gene-based therapies, says Kabbaj.  Such products require cryogenic storage at temperatures -238°F and below. In the past, shippers relied on dry ice (which performs best at approximately  -108.4°C), he explains, but dry ice emits carbon gas, which can damage proteins in biologic shipments, and might be harmful to handlers and to the environment. “Not only is dry ice shipping subject to a wide range of international regulations, it simply does not provide a cold enough temperature for many new specialty therapies” he says.

Yet another important trend, says Van Strien, is increased demand of remote shipping, for example, of clinical trial dosages to patients’ homes. “We will continue to develop further services to allow patients to participate in clinical trials from home, or remote sites of their choosing,” she says.  

Marken has also introduced an enhanced online booking app for investigator sites that is pre-programmed by study. It has also integrated enhanced scanning technologies throughout its global network. “More mobile technology will help treat patients at locations of their choosing,” says Van Strien.  

Article DetailsBioPharm International
Vol. 29, No. 3
Pages: 45–48

Citation:
When referring to this article, please cite it as A. Shanley, “Cold Chain: Going the Extra Mile," BioPharm International 29 (3) 2016.