Packaging Addresses Cold-Chain Requirements

As temperature-sensitive drug products travel worldwide, packaging serves as the barrier to a potentially hostile ambient environment. Temperature-controlled shippers not only maintain payloads within frozen, refrigerated, or controlled room-temperature (CRT) ranges, but also help brand owners and other supply-chain participants meet good distribution practice (GDP) standards. The careful control of payload temperature not only protects product quality, but also reduces losses due to temperature excursions and ensures profitability.

“There is plenty of evidence that suggests that a product’s temperature (and the associated fluctuations) can have profound impacts on a product’s stability, and therefore, its therapeutic effectiveness,” explained Désirée Valentine, senior supply-chain manager at BioConvergence, a contract service provider offering formulation development, testing, production, and supply-chain services, in a statement associated with a presentation at the 11th Annual Cold Chain GDP & Temperature Management Logistics Global Forum, organized by IQPC, Sept. 30-Oct. 4, 2013 in Chicago, IL (1).

“We are seeing growth in the number of temperature-sensitive shipments due to the increasing cold-chain regulations and expansion of generic products,” said Dirk Van Peteghem, vice-president of UPS Healthcare Logistics, in an announcement discussing UPS’ participation at the same meeting (2).

Other driving forces in the temperature-controlled packaging marketplace include an expanding number of biologics, more attention to CRT distribution, and rapidly growing drug sales in emerging markets. The 2014 Global Cold Chain Report, published by IQPC/Cold Chain IQ, predicts more than 50% of the world’s best-selling drugs will require cold chain protection by 2016. As a result, the study forecasts dramatic growth for the cold-chain logistics market through 2017 with increases of 57% in emerging markets, 46% in Asia, 21% in Europe, and 18% in North America (3).

Another market study anticipating strong growth, Global Healthcare Cold Chain Logistics Market Report & Forecast (2013-2018) by IMARC Group, projects an increase in market value from $7.3 billion in 2013 to $11.4 billion by 2018 (4).

Despite advances in temperature-controlled logistics technology and best efforts by manufacturers and other participants in the supply chain, problems still occur. For example, Ampio Pharmaceuticals experienced a disruption in its clinical study of Ampion, an injectable anti-inflammatory for knee pain associated with osteoarthritis, when both the study drug and placebo experienced exposure to temperatures below 15 ºC and may have frozen during shipment to clinical sites in January 2014. “Pivotal clinical-trial drug specifications dictate precise temperature and handling conditions for all study drug product in order to assure that the conclusions about the safety and effectiveness of the tested drugs will be accurate and repeatable during routine clinical use,” reported Michael Macaluso, CEO of Ampio in a statement. “The drug temperature specifications were set because Ampion may lose potency if it is exposed to temperatures approaching freezing” (5). Although the cold-chain lapse delayed the release of the analysis of single-injection study data, other aspects of the clinical trial are proceeding as planned, and Ampio is working with FDA to provide accep-able data to support a biologic license application (BLA). As a result, the company anticipates it will file its BLA for Ampion on schedule by the end of the first quarter of 2015 (6).

Trends in temperature-controlled logistics include growing availability of prequalified shippers, which simplify the validation process, more sophisticated supply-chain services, rising interest in reusable packaging, and advances in temperature-monitoring technology.

Prequalified shippers
Prequalified systems, offered by a growing number of suppliers, simplify adoption of temperature-controlled packaging. The FlexSystem from American Aerogel, for example, offers prequalified configurations for CRT, refrigerated, and frozen payloads. Each shipper relies on the same 19x14x15-in. plastic corrugated outer shell with a built-in strap for easy handling, plus a corrugated fiberboard layer, Aerocore vacuum insulated panels, and phase-change material (PCM). The interior compartment may be divided to match payload size and required temperature range. Maximum payload size is 30 L. Specified temperature ranges can be maintained for either 24 or 48 hours, and the design is durable enough to make multiple trips.

Cold Chain Technologies has expanded its KoolTemp GTS line to handle larger payloads while decreasing system cost, size, and weight. The KoolTemp GTS Rx, Express, Excel, Extreme, and Evolution shippers are based on KoolDesigns Thermal Modeling and proprietary Koolit Advanced PCM. Payloads range from 4 L to pallet load.

Another prequalified line of temperature-controlled shippers, the PharmaTherm line from Intelsius, maintains CRT, refrigerated, or frozen payloads for up to 72 hours. Common coolant and packout configurations for multiple sizes simplify usage (see Figure 1).

Sonoco ThermoSafe has added a frozen (less than -20 ºC) configuration to its Envoy Series of prequalified shippers. Available in four payload sizes, ranging from 2.5 to 24 L, the shippers keep contents frozen for a minimum of four days.

Reusable versus disposable
Temperature-controlled shippers must not only protect the product, but also be sustainable. Sustainable designs may involve recyclable components, components made of renewable materials, or reusable systems.

Reusable systems offer the best environmental profile, according to a lifecycle analysis by Minnesota Thermal Science, maker of the Credo Cube reusable shipper with recyclable vacuum insulation panels and PCM. The study concludes that the reusable Credo Cube reduces global warming potential by 75% and post-consumer waste by 95% and results in a lower environmental burden across five lifecycle stages: material extraction, component manufacturing, component assembly, use, and end-of-life. The study compared the 12-L Credo Cube 4-1296 reusable shipper to single-use expanded-polystyrene (EPS)- or polyurethane (PUR)-based shippers with similar payload space and 2-8 ºC temperature control for 96 hours. Other study parameters were predicated on a typical clinical trial: a two-year time frame with 30,000 individual shipments within the continental United States (7).

With a closed-loop reverse logistics system, only 772 Credo shippers are needed compared to 30,000 single-use containers. As a result, the Credo Cube shippers generate 64.9 metric tons of cradle-to-grave carbon dioxide emissions versus 752.4-754.5 metric tons for the single-use designs. In addition at 9.49 kg, the Credo Cube shipper weighs about 50% less than the single-use containers to more than offset the transportation-related emissions and costs related to the reverse logistics step (7).

The reusable system also offers advantages at end-of-life because recycling is included in the closed-loop reverse logistics process. In comparison, recycling options for PUR- or EPS-based disposable shippers are not readily available in the US at the present time. As a result, the study concluded that the global warming break-even point between the reusable and single-use containers occurs after nine shipments (7). Pelican Products, the owner of Minnesota Thermal Science and Cool Logistics, has established a temperature-controlled packaging division, Pelican BioThermal.

Temperature monitoring
The Xsense cold-chain management system from Israel-based BT9, which established a US office in Los Angeles in 2013, tracks multiple parameters: temperature, dwell time, and relative humidity. With that information, the web-based system identifies deviations from specifications and provides guidance for corrective action.

A sensor suitable for monitoring dry-ice shipments, the LyoTemp Lyophilization Data Logger from MadgeTech, operates at temperatures from -60 to 75 ºC. A 48-inch-long flexible cable houses the hermetically sealed thermistor temperature-sensing element. Features include password protection and user-configurable alarms. Light-emitting-diode indicators inform users of logging status or alert when thresholds are exceeded. The unit records in real time or can be programed for delayed start. Downloadable software stores files, maintains a database of original records, creates reports, and analyzes data.

A USB-based device, the Q-tag CLm doc data logger from Berlinger, collects temperature data and displays them when plugged into a personal computer. Available in single- or multiple-use configurations, the logger also integrates with web-based SmartView cold-chain data management software from Antaris Solutions, which was acquired by Berlinger in June 2014.

Another USB device, the Escort iMini USB logger from Cryopak, is preprogrammed and ready for immediate use. The unit collects data and stores it in a PDF format, eliminating the need for additional software for viewing. The report generated includes a summary, temperature graph, statistics, and out-of-specification details regarding time spent outside specified parameters.

Alerts about temperature excursions also can be provided by time-temperature indicator labels. Timestrip supplies labels capable of monitoring time periods from a few minutes to 18 months. These “smart” labels cost less than a data logger or radio frequency identification tag and also can present promotional messages or batch/control identifiers to help authenticate product and discourage counterfeiting. Activation occurs by pressing a button to release a liquid to the indicator window. Labels are supplied by piece or in rollstock form. Unactivated labels can be stored in ambient conditions for up to two years. A unique serial code on each label provides traceability. Different designs monitor specific conditions. The most versatile version, the Timestrip Complete label, measures how long temperatures exceeded the specified range (above and below). For less stringent applications, the Timestrip Plus label indicates how long the storage temperature exceeded maximum, while the Timestrip Minus label shows how long it fell below the minimum level. If only elapsed time needs to be measured, the basic Timestrip label can be specified.

Supply-chain services
Temperature-controlled shipping that avoids any excursions outside of the targeted temperature zone depends on a number of supply-chain practices. At BioConvergence, implementing best practices resulted in a 99.7% excursion-free rate, decreased average days in transit by more than one day per shipment, reduced days in transit (50% reduction in “delivery past qualification” time), improved coordination internally and externally, and established processes for continual improvement.

Travis Hudson, associate process engineer at BioConvergence, explained, “We began by having a clear picture of the results we wanted to see: improvements to key performance indicators and partnerships, as well as reductions to excursion rates. Next, we began an in-depth analysis of our existing processes and flagged five specific root causes that were interfering with outcomes. After strategically addressing each of these items, we began to see improvements in our metrics. This process has become the standard at BioC in promoting continual improvements” (1).

UPS, a logistics service provider, has expanded service levels for temperature-sensitive products. Three tiered-service levels balance the speed of air transport with the economy of ocean shipping. UPS Temperature True Plus for active and passive shipments maintains the strictest of temperature ranges with maximum in-transit monitoring. UPS Temperature True Standard is designed for shipments with less stringent monitoring needs. UPS Temperature True Saver, a standardized ocean freight solution, combines cost management and regulatory compliance for large volume shipments.

References
1. BioConvergance, “BioConvergence Presents Case Study on Temperature Controlled Pharmaceutical Products,” Press Release (Bloomington, IN, Oct. 18, 2013).
2. UPS, “UPS Introduces New Shipment Service Levels for Its Temperature True Portfolio,” Press Release (Atlanta, GA, Oct. 2, 2013).
3. IQPC/Cold Chain IQ,2014 Global Cold Chain Report, p. 4, accessed Aug. 12, 2014.  
4. MarketReportsOnline.com, “Healthcare Cold Chain Logistics Industry 2018 Forecasts Research Report Now Available at MarketReportsOnline.com,” Press Release (Dallas, TX, Dec. 26, 2013).
5. Ampio Pharmaceuticals, “Ampio Reports That Due to Temperature Deviations Below Product Specifications During Shipments to the Ampion STEP Study Clinical Sites, Release of Data Will Be Delayed,” Press Release (Englewood, CO, August 21, 2014).
6. Ampio Pharmaceuticals, “Letter to the Ampio Shareholders in Regard to the STEP Study and Ampio’s Plans for the Ampion BLA,” Press Release (Englewood, CO, August 25, 2014).
7. Minnesota Thermal Science, “New Life Cycle Comparison Analysis Demonstrates Environmental Impact Difference Between Reusable Thermal Shipper and Single-Use Container” White Paper (Plymouth, MN, 2013), accessed Aug. 26, 2014.

About the Author
Hallie Forcinio is Pharmaceutical Technology's Packaging Forum editor, 4708 Morningside Dr., Cleveland, OH 44109, tel. 216.351.5824, fax 216.351.5684.