Preventing Temperature Abuse

It's hard to predict exactly what conditions a drug will experience during the distribution process. Will delivery be delayed for a day or more by a blizzard, flood, hurricane, power outage, or holiday weekend? Will the product sit in the sun for hours before it's loaded onto a plane or clears customs?

Hallie Forcinio

As air-cargo screening rules tighten, shippers fear that the frequency and length of delays will increase. Delays can be disastrous for temperature-sensitive drugs. If temperature abuse renders a drug ineffective or hazardous, it poses a danger to patients. Monetary losses can be significant, too. Because many temperature-sensitive drugs carry extremely high price tags, a single temperature-abused shipment can cost millions.

To protect products from temperature abuse, drugmakers rely on an expanding array of tools to maintain shipments at the proper conditions. These tools also identify excursions above or below the required temperature range.

The latest temperature-protecting packaging also qualifies as sustainable. Today's designs tend to weigh less and occupy a smaller footprint than previous containers. In addition, they are less likely to rely on dry ice. Thermal containers frequently are both reusable and recyclable, and may contain recycled content, too. Formalized reverse-logistics programs simplify container reuse, cut costs, automate replenishment, and ensure that recyclable components are reprocessed rather than consigned to landfills when they can no longer be reused.

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A prepaid shipping label expedites the return of the containers. Upon receipt, all containers are visually inspected, and any damaged components are replaced. Next, the containers are cleaned in compliance with 21 CFR 211.94. Before returning to service, thermal components are tracked by customer and serial number and tested to confirm that thermal performance has not degraded (AcuTemp Reusable Enviro-friendly Program Assuring Quality for AcuTemp Qualified Shippers, AcuTemp Thermal Systems).

Another program that inspects, refurbishes, cleans, and sterilizes returned containers is supported by web-based software. The software provides continuously updated reports and alerts on container status, inventory levels, and maintenance needs and allows a user to track its shipments (Credo Encore reverse-logistics services, Minnesota Thermal Science, MTS).

Temperature control

To protect temperature-sensitive shipments better, several carriers have established specialized service programs and adopted standardized temperature-control technology (Temp Control service, United Cargo, and AC Cool Chain, Air Canada Cargo).

AcuTemp RKN Temperature Management Cargo Units for air transport of temperature-sensitive goods. (PHOTO IS COURTESY OF ACUTEMP)

For air transport, this specialized service may include buying or leasing active temperature-controlled containers with proprietary air-movement, heating, cooling, and insulation systems that eliminate the need for dry ice. The compressor-equipped units, which are approved by the Federal Aviation Administration, the European Aviation Safety Agency (EASA), and Transport Canada, operate for more than 100 h on battery power, maintain temperatures between 4 and 25 °C in ambient conditions ranging from –30 to 49 °C, and provide payload space large enough to hold a full pallet. Longer hold times are possible if the unit can be plugged into an AC power outlet. The containers have successfully undergone operational qualification (OQ) at several pharmaceutical companies, including Pfizer. The OQ involved testing under a wide range of temperature setpoints, ambient conditions, shipping lanes, payload sizes, and transit durations (AcuTemp RKN Temperature Management Cargo Unit, CSafe).

A large, compressor-based heating–cooling unit capable of maintaining a temperature-controlled environment for five European-sized or four US-sized pallets recently received an airworthiness certification from EASA. It maintains internal temperature between 0 and 25 °C in ambient conditions ranging from –25 to 50 °C (RAP e2 container, Envirotainer).

The International Air Transport Association's time- and temperature-sensitive label. (PHOTO IS COURTESY OF THE INTERNATIONAL AIR TRANSPORT ASSOCIATION)

A passive pallet-shipper system for full or half pallets provides thermal protection for more than 120 h (i.e., five days) without requiring any power. The design relies on phase-change material and vacuum-insulated panels. The reusable system provides a 48 × 40 × 52-in. space with a payload capacity of 890 L (31.4 ft³ ) or a 48 × 40 × 30-in. area that holds 406 L (14.3 ft³ ) (Credo Xtreme pallet shipper, MTS). The pallet shipper is part of a range of reusable thermal containers (Credo Cube) that are used by the largest temperature-controlled healthcare transportation provider in Canada (ATS Healthcare).

Another passive system consists of a lockable trunklike unit that is durable, reusable, and compatible with security scanning. Capable of maintaining temperatures between 2 and 8 °C for as long as five days, the system is available with payloads of 36 L (1.27 ft³ ) and 11 L (0.4 ft³ ). An optional data logger records downloadable internal and external temperature data to show whether the internal temperature remained in spec throughout the shipment's travels (Kodiak Active Temperature Control Shipping Containers, Active CC Boxes).

A similar reusable design with handles and a latch relies on plant-based phase-change technology and encapsulated vacuum-insulated panels to boost performance while reducing weight. The passive temperature-controlled system produces about seven times the insulating effects of common alternatives such as expanded polystyrene and polyurethane (OrcaTherm temperature-controlled packaging, Intelsius).

For less stringent applications, a passive system maintains an 11 × 11 × 5.5-in. (0.4 ft³ ) payload area in the 2–8 °C range for 72 h. It consists of gel packs, expanded polystyrene (EPS) panels, and an outer plastic or corrugated case. The unit holds 1 to 7.5 lb of product (TimeSaver 72, Cryopak). All components of the packaging are recyclable, and the EPS insulating panels contain as much as 20% postindustrial recycled content.

Another advantage of the design, which won a Greener Package Award in 2010 from Summit Publishing, is the energy- and time-saving nature of the phase-change material used as the core refrigerant. It freezes and thaws at 5 °C and does not need to be pre-conditioned in a refrigerator or freezer (Engineered Phase 5 phase-change material, Cryopak).

For smaller quantities that are delivered quickly, an inflatable thermal envelope maintains the contents between 2 and 8 °C for as long as 24 hours. Patented construction blocks heat transfer and cushions the product, too. Delivered inflated, the reusable pouch features a zipper closure and dual compartments: one for product, and one for cooling-gel packs. It's available in 1-, 3-, and 5-L sizes (One Day pharmaceutical pouch, Coldpack).

Temperature monitoring

Data loggers provide a warning if the contents of an insulated package or container experienced heat or cold beyond acceptable parameters. The devices permit immediate decisions about product quality. The ability to upload temperature data from the monitor as soon as the shipment arrives eliminates delays and quarantine time associated with waiting for a monitor to be returned for analysis or a report to be faxed (Shipping Temperature Electronic Monitoring System, Almac Clinical Services).

A specialty courier service tracks the temperature and movement of sensitive shipments in real time through a customized global positioning system (GPS)-based device. It also can provide chain-of-custody data (GPS Tracking devices, GTX, for MNX).

Integrating a satellite network with tracking software achieves similar functionality. The two-way communication between shipping container and shipper or recipient enables real-time product tracking and management and provides an early warning if temperatures deviate beyond desired parameters (SmartLink Platform, Axeda, and satellite network, ORBCOMM).

Yet another way to track temperatures inside shipping containers relies on an active radio-frequency identification (RFID) tag equipped with a satellite modem and GPS receiver. If an RFID reader is within range, the tag communicates with it. If not, it uses the satellite modem to upload environmental data and location coordinates (GlobalTag ST-694 and SmartChain software, Savi Networks).

Another RFID-based data logger also relies on an RFID tag–temperature sensor combination. The semipassive tag is compatible with most Gen2 ultrahigh-frequency RFID readers and features a thin profile, easy-to-use manual interface, and 16 configurable temperature ranges between –20 and 70 °C. As many as 4000 data points can be collected. Algorithms calculate the product's remaining shelf life to provide data to support a decision to deliver or return a product that has experienced temperature abuse. Deutsche Post DHL has adopted the technology for its Smart Sensor Temperature service for temperature-controlled shipments (RT0005 easy2log Temperature Logger, CAEN RFID).

RFID technology also is the basis for a label that records temperature information. At any point during the distribution process, a wireless reader can collect data from 30 labels located within 60 ft (20 m). Reading distances as great as 300 ft (100 meters) are possible if the line of sight between reader and label is unobstructed. Available in both the United States and Europe, the flat labels are about the size of a credit card (Ultra Wireless Label and Ultra Wireless Reader, PakSense).

Similar capabilities are provided by high-frequency 13.56-MHz RFID tags and readers designed for humid environments (SensTag sensor, Phase VI Engineering, based on the MLX90129 sensor IC, Melexis Microelectronic Integration Systems; 13.56-MHz reader from Proxima RF).

A temperature-control process, designed especially for clinical-trial shipments, consists of an RFID tag for recording temperature, a dedicated compartment for a mobile phone for high-speed data transmission, and a secure web-based portal. Designed to record temperatures between 5 and 35 °C at configurable intervals, the device can track more than 8000 data points and operate for nearly 60 days. If the data show that the temperature remained within specifications during shipment, the drug can be released immediately for use (RFID tag, Stora Enso; multimodal communication, MediXine Oy; Clinical Logistics Services, Parexel International).

Standards

Several groups, including the Parenteral Drug Association, the International Safe Transit Association (ISTA), International Air Transport Association, and the US Pharmacopeia are working on tools, guidelines and regulations to support Good Distribution Practices. ISTA recently released its Standard 20: Design and Qualification of Insulated Shipping Containers. It includes multiple appendices and worksheets to support the design, testing, and validation of insulated shipping containers. ISTA's new Standard 7E: Thermal Transport Packaging Used in Parcel Delivery Systems updates Standard 7D.

With the development of Standard 20 and Standard 7E A, ISTA also established new certification categories. A handful of laboratories have completed or are working to be designated as ISTA Certified Thermal Transport Laboratories, and personnel have begun the process to earn Level I or Level II status as ISTA Certified Thermal Professionals. Laboratory certification must be renewed every two years.

Thermal packaging, developed and tested according to the ISTA standards, is designed to simplify the sourcing process and provide confidence in its performance. "Drugmakers will be able to buy ISTA-certified thermal packaging off the shelf with all the necessary documentation and validation information," predicts Ed Church, president of ISTA.

Hallie Forcinio is Pharmaceutical Technology's Packaging Forum editor, 4708 Morningside Drive, Cleveland, OH 44109, tel. 216.351.5824, fax 216.351.5684, editorhal@cs.com.