Maintaining and Verifying the Cold Chain

Temperature-sensitive pharmaceuticals and biologics depend on a variety of services and technologies to establish, maintain, and verify proper storage and transport conditions. Table I lists temperature ranges for frozen, refrigerated, and controlled-room-temperature (CRT) products. With regulations evolving regarding thermal protection of these products, proof of compliance is gaining attention. Fortunately, it is becoming easier to automate data collection, analysis, and compliance reporting for controlled-temperature shipping and storage. In addition, solutions increasingly offer sustainability attributes such as reusability, recyclability, or derivation from renewable materials.

Storage type

Temperature range (ºC)

Frozen

-20 to 0

Refrigerated

2 to 8

Controlled room temperature (CRT)

15 to 25

Maintaining conditions
Protecting temperature-sensitive products from point of manufacture to point of use typically involves integration of hardware such as insulated shippers and data loggers with software for management, data collection, analysis, and proof of compliance. Clinical Reference Laboratory, a provider of testing services for clinical trials, molecular diagnostics, and toxicology, relies on hardware and software from Cryoport for a major clinical trial being conducted in four European countries. Dry-vapor, liquid nitrogen shipping protects patient samples while a web-based logistics management portal tracks and documents all shipments.

Another option for clinical trials, the reusable BioCarrier courier transit case from Intelsius shown in Figure 1, is specifically designed for local courier routes, multiple site sample collection, and “home visit” injectable transport. A rugged polymer outer with expanded polypropylene (EPP) liner maintains payloads at 2-8 C for more than 12 h (up to 18 h with dry ice). A clasp closure secures the lid, and cases can be stacked and locked together. All three sizes are regulatory compliant with preprinted UN3373 labels for the shipment of Category B biological samples.

For greater distances and longer travel times, Intelsius offers its next generation ORCA 2.0 controlled-temperature shipper. It thermally protects the payload for at least 170 h. Like many temperature-controlled shippers, it relies on advanced phase change material (PCM) that extends the protective period in extreme hot or cold environments with simple preconditioning. A variety of PCM panel configurations increases the range of shipments served and reduces costs. To help optimize container configuration, ATMOS analytical thermal modeling software, also from Intelsius, quickly assesses the suitability of a design for the intended route and payload.

To simplify specification, a number of suppliers have begun to offer prequalified temperature-controlled shippers. One recent introduction, the Aeris series from Sonoco ThermoSafe, maintains its payload at 2-8 ºC for at least 54 h. The shippers are developed specifically to address the European Union’s good distribution practice (GDP) guidelines, which took effect on Sept. 8, 2013 (1). Four sizes, ranging from 2.5 to 24 L, are optimized to minimize the number of components and shipping weight. The configurations simplify and expedite assembly and lower total cost of ownership.

Sonoco ThermoSafe also offers options for CRT shipments. “A regulatory focus on strict compliance to storage temperature limits has increased the demand for CRT shipping solutions,” explained Russell Grissett, vice-president, Sonoco ThermoSafe (2). To address this emerging market need, Sonoco Thermosafe designed the Certis Silver Universal CRT series. The expanded polystyrene (EPS) foam containers and PureTemp PCM reportedly maintain pharmaceuticals and biologics at 15-25 C for up to four days (for an 11-L payload), regardless of the season.

A Passive Vaccine Storage Device, designed to deliver vaccines in undeveloped areas, combines insulation technologies developed for space exploration and storage of cryogenic fluids with ice and data logging to overcome poor infrastructure and unreliable power supplies (see Figure 2). Invented by Global Good, a collaboration between Intellectual Ventures and Microsoft founder Bill Gates to invent technology that improves life in developing countries, the system maintains 300 doses at the required temperature for more than 30 days. Vials can be retrieved as needed without jeopardizing the remainder, and the chamber can be restocked and redeployed in the field. An onboard data logger monitors location, internal temperature, and the number of times vaccines have been removed. These data can be communicated via daily text messages and downloaded via a USB port to help plan future vaccination campaigns.

The super-insulated device successfully completed field trials in Senegal in 2013 and will undergo additional field testing in Africa before broader manufacturing and distribution in 2014. Under an agreement announced in July 2013, AUCMA, a refrigeration company based in Qingdao, China, will manufacture and distribute the device to strengthen the vaccine supply chain in underserved regions.

Enhancing sustainability
To reduce waste, Fairview Pharmacy Services has switched from EPS coolers to insulated shippers made of biodegradable, cornstarch-based Green Cell Foam material. The conversion to the compostable shipper from StarchTech will keep about 44,000 EPS coolers out of landfills in 2013. Because EPS is rarely included in curbside recycling programs, the shipper also simplifies disposal for the estimated 12,500 patients who receive temperature-sensitive medications from the pharmacy each year.

Enhancing the sustainability of refrigerated truck trailers, Emerald Technology Partners has launched the patent-pending Wedway refrigeration power system. The system replaces fossil fuel with kinetic power and eliminates related emissions. A WedLink temperature monitoring and management system from InTouch Technologies makes it possible to view trailer location in real time and remotely manage all refrigeration and mechanical systems from any computer or mobile device equipped with an Internet connection.

Confirming conditions
It’s not enough to establish and maintain frozen, refrigerated, or CRT conditions; data must be collected to confirm parameters were met or provide a warning that a deviation occurred so a decision can be made about the viability of the product. Wireless devices are gaining popularity for this task.

One example, the Automated Temperature Monitoring System (ATMS) from Cargo Data Corp., relies on radio frequency (RF) technology to automate collection, retrieval, and archiving of in-transit temperature data captured by the company’s data loggers. The ATMS automatically posts the data to Cargo Data’s website, where any interested party may view and print it, so that supply-chain partners do not need to manually download or distribute temperature-recorder data.

Another wireless device, FreshLoc SA mobile temperature monitor from FreshLoc Technologies, works with a calibrated thermometer and text or email messaging to automate documentation of conditions in storage environments and support compliance with regulatory requirements. “Many of the people we have talked to have complained about the difficulty of staying compliant with manual temperature monitoring and inventory checks but are not ready to move to a fully automated system because they only have one or two refrigerators,” explained Dick Fettig, executive vice-president of FreshLoc (3). Once deployed, the FreshLoc SA software sends a phone or email message to remind the operator to record the temperature or make the inventory date check. The operator inputs the data on a Smartphone, tablet, or personal computer and sends it in real time to a server where it can be accessed at any time. Each entry is signed with an email or text-message address for 21 CFR Part 11 compliance. The reminders reduce the chance that scheduled checks will be missed or product will experience temperature abuse and become unusable. If the reading entered is out-of-specification, the system issues an immediate alert and suggests corrective action.

A fully automated system, the VTMS vaccine temperature monitoring system from MadgeTech, shown in Figure 3, provides continuous, remote monitoring of sensitive products such as vaccines or pharmaceuticals in refrigerators, freezers, and coolers. The system provides the tools needed to comply with the Centers for Disease Control and Prevention (CDC) guidelines for storage and temperature monitoring of refrigerated vaccines, which stipulates accuracy of +/- 0.5 °C and specifies use of a glycol-encased, detachable probe along with a digital data logger to provide temperature-buffered readings and prevent false alarms (4). MadgeTech’s VTMS consists of an NIST traceable RFTCTemp2000A data logger equipped with two-way wireless communication plus a thermocouple and glycol bottle. A liquid crystal display on the data logger displays minimum, maximum, average, and current temperature readings. Alarms light up and sound if temperature drifts above or below the safe range. E-mail or text alerts also can be sent so action can be taken before goods are compromised. Two-way wireless technology permits remote starting, stopping, and downloading of the device. Data can be transmitted in real time to a central personal computer or downloaded periodically. Accompanying MadgeTech 4 software preserves original records and includes customizable analysis and reporting tools.

To monitor air shipments, the wireless Sentry FlightSafe system from OnAsset Intelligence combines sensors for environmental conditions such as temperature, humidity, pressure, shock, and vibration with GPS, wireless transmitters, and analytical software to collect environmental data and track location in real time. Envirotainer is testing the Sentry FlightSafe system on its RKN e1 and RAP e2 air cargo containers, which are equipped with compressor-based cooling and electric heating. Successful tests will lead to commercialization of integrated systems and required approvals and certifications. Until now, data on shipment conditions were gathered continuously but not available for review until a container reaches specific destinations. With the patented, Federal Aviation Administration-compliant FlightSafe communications platform, the RKN e1 and RAP e2 containers transmit location, condition, and environmental information whenever the containers are on the ground. Immediate access to data provides peace of mind regarding product condition throughout transit and helps supply-chain partners take action if conditions drift out-of-specification or maintenance is needed. This knowledge also can expedite returns.

Once fully deployed, The Sentry FlightSafe system will provide Envirotainer’s Active Container Data and Transport Evaluation services with position and sensory data for each shipment. These enhanced information services will help supply-chain partners verify supply-chain performance and confirm product quality.

UPS provides similar proactive shipment monitoring and risk management capabilities with its UPS Proactive Response Secure service. The service helps ensure temperature-sensitive shipments achieve timely arrivals at their destinations and guarantees up to the retail value, plus other costs, when unexpected events (including weather delays) occur. “This is the highest level of service we offer,” says Bill Hook, vice-president of UPS Global Healthcare Strategy (5). The 24-h/7-day service provides end-to-end visibility and is available throughout the United States and Puerto Rico and for outbound shipments to 12 countries in the European Union. Other service enhancements for temperature-controlled shipments include Next Flight Out expedited delivery from UPS Express Critical, installation of dry-ice replenishment and refrigeration infrastructure at more destination locations, and addition of UPS Proactive Response control towers in Europe and Asia.

SenseAware, a sensor-based logistics system from FedEx, uses sensors to detect temperature, light, humidity, barometric pressure, and location. The system communicates these data in near real-time so supply-chain partners can take action as needed.

Automating reporting
As regulatory guidance and requirements evolve, so does the need for compliance reporting. However, data gathering and analysis can be cumbersome. The latest cold-chain technology platform from Dyzle BV not only automates the process, but documents the data to meet requirements outlined in the European Union’s GDP guidelines (1).

The open, independent platform collects data from multiple sensors and monitoring systems, including proprietary and legacy devices, and provides automatic registration and interpretation of environmental parameters like temperature, humidity, carbon dioxide, and energy consumption in real time. “With one view, we provide complete end-to-end visibility of the cold chain on any Internet-enabled device, enabling automatic registration that is needed to meet the new GDP guidelines,” explains Bert Zandhuis, CEO of Dyzle (6). Another benefit of the software is its ability to organize data into dashboards customized for specific job functions. For example, the senior management dashboard might present the financial impact of any excursions in the cold chain.

References
1. EC, Guidelines on Good Distribution Practice of Medicinal Products for Human Use 2013/C 68/01 (Brussels, Mar. 2013).
2. Sonoco ThermoSafe, “Sonoco ThermoSafe Launches Certis Silver Universal CRT Design-Qualified Shippers,” Press Release, Mar. 14, 2013.
3. FreshLoc Technologies, “New Mobile Solution from FreshLoc Promotes Safety and Prevents Non Compliance,” Press Release, Jan. 15, 2013.
4.Centers for Disease Control and Prevention, “Guidelines for storage and temperature monitoring of refrigerated vaccines,” www.cdc.gov/vaccines/recs/storage/toolkit/toolkit-resources.pdf, accessed Sept. 6, 2013.
5.UPS, “UPS Launches Industry-First Service for High-Value Time- and Temperature-Sensitive Shipments,” Press Release, June 26, 2013.
6. Dyzle BV, “Dyzle’s Latest Version of Proven Cold Chain Solution Sets the Standard for Global GDP Compliance,” Press Release, June 18, 2013.

Hallie Forcinio is Pharmaceutical Technology's packaging editor, editorhal@cs.com.