Colder Drugs Will Prevail

Pharmaceutical companies that make temperature-sensitive products pay a lot of attention to the cold chain, which protects products until they reach their points of use. Until recently, manufacturers relied on insulated shippers based on foam and gel packs or dry ice. These designs rely on convection to cool and maintain the temperature of the air around the product.

Hallie Forcinio

Today, pharmaceutical companies are looking for longer periods of protection, and a growing number of protective packaging designs rely on conduction. In these packages, phase-change materials keep the product in the right temperature range for the required amount of time despite ambient conditions.

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Traditional "expanded polystyrene-foam shippers with water-based gel packs may still work in certain applications, but there's been a tremendous improvement in the ability to control temperature," says Eric Lindquist, president of Entropy Solutions (Minneapolis), a supplier of temperature-controlled packaging.

We will be seeing more ...

Shippers based on conductive phase-change materials typically offer several advantages over traditional packages: a smaller size, lighter weight, more consistent temperature readings from top to bottom, and a longer period of protection. In addition, these shippers are recyclable and can be used for hundreds, if not thousands, of trips. Although more expensive, shippers based on conduction often generate cost savings, particularly if their design permits a holding period that allows manufacturers to switch from overnight air delivery to two-day or ground delivery.

The envelope portion of the Greenbox Inflator Pack is suitable for one round trip before being recycled. The interior Puretemp phase-change panels can be reused dozens of times. (IMAGE IS COURTESY OF ENTROPY SOLUTIONS)

"Many companies with temperature-sensitive products don't ship on Fridays because there is no one at the destination to receive it until Monday," reports Karl Schlenker, vice-president of business development for Minnesota Thermal Science (MTS, Baxter, MN), another supplier of temperature-controlled packaging. With 72- or 96-h shippers, "companies can ship on Fridays, too," he explains.

The Greenbox Pallet Shipper withstands at least 250 trips. (IMAGE IS COURTESY OF ENTROPY SOLUTIONS)

Solstice Neurosciences (Malvern, PA) relies on a custom thermal box. The passive system incorporates proprietary high-performance insulation that offers an R-value of 45 per inch of thickness. The design not only maintains its payload at the required temperature for the required time, but also simplifies loading (AcuTemp shipper with ThermoCor insulating panels, AcuTemp Thermal Systems, Dayton, OH).

Cold-chain monitoring options from Cortegra include reusable, flexible sensors with a pressure-sensitive back. (IMAGE IS COURTESY OF CORTEGRA)

"The solution also provides us with a smaller and lighter-weight box, providing advantages in shipping and warehousing," says Alison Becker, director of customer relations and information management for Solstice. The box is also 100% recyclable.

Although virtually all pharmaceutical manufacturers perform cold-chain testing in house, several suppliers such as Coldpack (San Diego, CA) and AcuTemp operate laboratories certified by the International Safe Transit Association (ISTA). The certified laboratories provide performance data to help narrow choices or confirm in-house test results using ISTA Test Procedure 7D. The thermal-performance test measures the relative ability of a package to protect a product in conditions that simulate the shock and stress encountered during handling and transportation, including both the range and time of exposure to ambient temperatures. If test results look good, the next step is typically real-world testing. Since real-world testing often involves summer and winter trials, the process can easily take a year or more.

Custom Instapak TempGuard cold-chain packaging can accommodate the exact size and shape of the product and provide pockets for the refrigerant.(IMAGE IS COURTESY OF SEALED AIR)

A package design that protects vaccines in the last mile to point of use has won approval from the World Health Organization (WHO). Cemafroid, the French WHO laboratory, certified the design as compliant with the International Organization for Standardization's 9001:2000 standards for manufacturing isothermal packaging. The insulated packaging combines a thermal barrier with air-cushion protection that has been shown to be four times better than traditional foam insulating panels (AntiFreeze Vaccine Backpack with inflatable AirLiner insulating air cushion, Coldpack). The packaging ships and stores flat, thus saving on freight costs and warehouse storage. An illustration on the package shows how to assemble the unit, and a chart and thermometer help calculate how many ice packs are needed to protect against ambient conditions.

The modular Credo Cube surrounds the payload on six sides with panels of phase-change material. (IMAGE IS COURTESY OF MINNESOTA THERMAL SCIENCE)

The inflatable, insulating air cushion can transform any container into a cooler. The winner of a Gold Achievement Award and Special Citation for Social Responsibility from the Flexible Packaging Association, the air cushion consists of layers of reflective barrier film sealed in a proprietary design. It's available in 22 stock sizes and used by suppliers of vaccines and skin grafts.

Advice for improving cold-chain protection

Another inflatable package is designed especially for single-dose shipments that must be maintained at 2–8 °C (i.e., refrigerated temperature) for 24 h or at 20–25 °C (i.e., controlled room temperature) for 48 h (Greenbox Inflator Pack with E23 phase-change materials, Entropy Solutions). The inflatable package is reusable and recyclable and ships for less than half the cost of a traditional single-dose shipper.

"Approximately 15 to 20% of our medications must be kept at room temperature. If they get warmer or cooler, they lose their efficacy," says James Soucey, director of clinical services for Wal-Mart Specialty Pharmacy, an early adopter of the Greenbox Inflator Pack. "Keeping a medication at controlled room temperature during shipment has been mandated by federal and state regulatory commissions for years, but it just wasn't possible given the options on the market," he continues. "Wal-Mart did the very best it could, but now we have an increased level of confidence," he concludes.

For many frozen shipments, dry ice has been the refrigerant of choice. However, it may alter the pH of some drugs, and many carriers consider it a hazardous material because it can cause burns and requires special handling during packing and unpacking. Dry ice also emits carbon dioxide.

A phase-change material was introduced several years ago as a replacement for dry ice in less stringent applications. The US Department of Agriculture lists the material in its Biopreferred purchasing program, and it is now available for frozen products currently shipped with dry ice. The phase-change material can be reused more than 20,000 times, produces no emissions, is 100% renewable and biodegradable, and is 20% lighter than dry ice (PureTemp -40 phase-change material, Entropy Solutions). Amgen (Thousand Oaks, CA) uses it in conjunction with a pallet-size container (Greenbox Pallet Shipper, Entropy Solutions). "We were looking for a solution that addressed the adverse effects of dry ice, while providing a more cost-effective, environmentally friendly option," explains Donnie Wilson, senior manager for engineering at Amgen.

Launched in spring 2009, the pallet shipper features an injection-molded outer container with a built-in 48 × 40-inch pallet. A modular design makes it easy to replace the phase-change material so the container can maintain a different temperature range.

Another new passive thermal container surrounds the payload on six sides with phase-change material that features precision-formed beveled edges for a tight thermal seal. The modular design is available in five sizes (i.e., 6 × 6, 9 × 9, 12 × 12, 15 × 15, and 18 × 18 in.) and supports four temperature levels (i.e., –50, –20, 4, and 22 °C) for a minimum of 72 h. The modular design means that sizes can be coupled to create a 9 × 18-in. container, for example (Credo Cube, MTS).

Significantly lighter than traditional insulated shippers, the container cut tare weight almost in half at one beta test site and doubled payload capacity. "As a result, the new shipper weighs less when fully loaded than the previous shipper weighed empty," reports Schlenker. Lighter weight means lower shipping costs. The container's cube is smaller, too, so more of them fit on a truck or storage shelf.

The container yields additional savings because packout is simpler, and containers and components can be used repeatedly and then recycled. In a two-year trial, 1500 shippers completed 10,000 trips with no losses resulting from temperature excursions and kept at least 8500 one-way shippers out of the landfill.

Frozen products previously shipped with dry ice benefit even more. Eliminating the dry ice not only results in a smaller, lighter package, but also eliminates handling concerns and the charge that carriers add to the freight bill for dry-ice shipments.

Phase-change material and gel packs are conditioned before use, a step that requires time and energy for chilling or freezing. Protective packaging that eliminates conditioning provides cooling by evaporating water under vacuum. Once switched on, it takes less than 5 min to operate at full efficiency. To indicate that the unit is working, a label printed with thermachromic ink turns blue as the temperature cools. The cooling system is designed for one-time use, but the insulated shipper it fits into can make multiple trips (NanoCool protective packaging, NanoCool, Albuquerque, NM).

Although most developments in cold-chain packaging focus on conductive systems, new high-performance convection systems are worth considering. One relies on polyurethane-foam insulation to keep shipments cold longer than would be possible with polystyrene foam. This higher insulation factor reduces the amount of dry ice or gel packs needed to protect the payload and may allow shippers to switch from overnight delivery to more economical two- or three-day service. High durability means the foam insulation can be reused (Instapak TempGuard Cold Chain Packaging, Sealed Air, Danbury, CT).

Condition monitors

Data loggers have long been used to monitor shipment conditions. In recent years, these devices have been supplemented by thermochromic labels, radiofrequency identification (RFID) tags, and electronic sensors that can be read through cell phones and global positioning systems.

New features on traditional data loggers include the ability to generate reports in PDF format within the unit, thus eliminating the need to install and qualify separate software. The user simply plugs the unit into the USB port on a personal computer to download the report (Libero cold chain monitor, Elpro, Marietta, OH).

A new family of devices monitors variations of 1 °F for temperatures ranging from –15 to 50 °F, tracks temperatures for days or as long as two years, collects temperature data at intervals ranging from 2 s to 9 h, and provides a history of how long the product experienced temperatures outside the recommended range. (Cold chain sensors, readers, software, and support, Cortegra, Fairfield, NJ).

A battery-powered RFID tag operates at ultrahigh frequency (868–960 MHz) and measures temperatures between –30 and 85 °C with ± 0.5 ° accuracy between –5 and 15 °C and with ± 1 °C accuracy below –5 and above 15 °C. Other features include memory that stores 4096 readings, an integrated clock, and two-year battery (RF Thermochron sensor, Maxim Integrated Products, Dallas).

Cold-chain logistics

To prevent gaps in the pharmaceutical cold chain, many logistics providers offer specialized services. One joint venture supplies a compressor-driven refrigeration unit designed for air transport. It can heat or cool to maintain user-selected temperatures between 4 and 25 °C at ambient temperatures ranging from –30 to 50 °C. The container can maintain a constant temperature more than four times longer than dry-ice-based systems and sustain a controlled temperature environment for as long as 100 h. The system also records payload, temperature, access, and power status. This information can be downloaded through a USB port (AcuTemp RKN cargo container, CSafe, Dayton, OH, joint venture between AmSafe, Phoenix, AZ, and AcuTemp).

An airline offering cold-chain services provides priority handling and a coordinated shipment process with multiple checkpoints throughout the journey. Other components of the program include cool-room facilities, dry-ice-based containers and thermostat-controlled containers equipped with heating and air-conditioning units to maintain an interior temperature of 2–20 °C (Pharma LIFT, Cathay Pacific Airways, Hong Kong).

For truck shipments, two firms have partnered to integrate fleet management with cold-chain management. The solution includes wireless sensors as well as software and delivers the data it collects to the user's computer (Mobius TTS system from Cadec Global, Manchester, NH, with TempTracker module based on PIMM Cold Chain Management System from Procuro, San Diego, CA). The integration makes it possible for shippers or other stakeholders to monitor conditions inside tethered and untethered trailers in real time. In addition, if temperatures vary from expected levels, the system sends an alert so corrective measures can be taken.

One international shipper is strengthening its cold-chain support with Competence Centers in emerging markets and regional hubs in Panama, Istanbul, Dubai, and Singapore that are certified to comply with good manufacturing practice and good distribution practice. The shipper provides warehouse and transportation services customized for clinical trials and pan-European, less-than-truckload, temperature-controlled cold-chain road freight capabilities (Life Science strategy, DHL Global Express, Bonn, Germany).

Refrigerator monitors

An automated, paperless system closes a cold-chain gap by monitoring refrigerator temperature in pharmacies and dispensing areas operated by the South Eastern Health and Social Care Trust in Northern Ireland. Wireless sensors regularly check the temperature of refrigerators where vaccines, erythropoietin, and chemotherapy drugs are stored. Deviations from preset temperature parameters trigger audiovisual alarms onsite, as well as text messages and emails to key staff members. With the system, the Trust will be able to develop an archive of historical temperature data and corrective actions to form an audit trail (Wireless to Web, Kelsius, Belfast). To provide full traceability, the Trust also uses portable data loggers to monitor temperature-sensitive products during transit to primary-care locations (Portable data loggers, Kelsius).

Another diagnostic toolkit monitors refrigerators and freezers to provide early warnings if temperatures deviate from norms and also serves as a predictive-maintenance tool. Monitoring labels are activated and positioned at various points inside the refrigerator or freezer and collect data at intervals even during a power outage. Data are downloaded through a wireless reader for review and transfer to a personal computer, where they can be stored permanently and analyzed (Ultra TK diagnostic tool kit, PakSense, Boise, ID).

Conditions in refrigerated truck trailers can be checked through a system that automates remote monitoring of their internal temperatures as well as the status of the refrigeration units and fuel levels. Based on a mounted passive RFID tag, the system transmits data in real time, eliminates repeated manual checks, and can be configured to provide alarms if temperature or fuel levels drift outside predefined thresholds (Yard Hound Reefer yard-management software, PINC Solutions, Berkeley, CA).

On the horizon

The pharmaceutical cold chain remains largely self-regulated. "Everyone puts together their own protocol," says Etienne P. Snollaerts, chief executive officer of Coldpack.

Many packaging engineers take a conservative stance and overengineer their protective packaging, he notes. For example, many protocols specify a 2–8 °C temperature range. This narrow window can be challenging to meet and can increase costs if it requires additional refrigerant or insulation. Although it's generally imperative to prevent freezing, many products suffer no loss of quality at temperatures slightly above 8 °C, thus making a temperature range wider than 2–8 °C feasible in some cases. "In fact," says Snollaerts, "up to 16 °C is acceptable for vaccines, according to WHO."

The adoption of less stringent protocols may be supported by work underway on standards. In the United States, a division of the Parenteral Drug Association is working with ISTA to develop test profiles for the cold chain. Parameters include minimum load, maximum load, and orientation. If successful, "a 96-h box would meet a standard set of guidelines," explains Lindquist. He predicts the groups will publish a finalized document before the end of 2010 and that it eventually will serve as the basis for mandates by the US Food and Drug Administration or the US Pharmacopeia.

He also expects a rising level of regulatory interest in enforcing controlled room-temperature conditions. Maintaining products at controlled room temperature has been difficult because of a lack of sufficient protective packaging. This situation is changing as new conductive systems are marketed.

Another change likely to affect cold-chain packaging is the phase-out of disposable packaging. It's already occurring in Europe, Japan, and China, and Lindquist predicts that similar requirements eventually will be adopted in the US.

"Convincing the pharmaceutical industry to change takes time, but we're sure it's coming," says Snollaerts.

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