New cold chain solutions meet regulatory, shipper requirements

Fig. 1. Savsu’s PHD shipper for small volumes. Credit: Savsu

Upholding cold-chain integrity and regulatory compliance standards are morphing into major issues, experts say, with the explosion of temperature-sensitive pharmaceutical products, new global and regional manufacturing mandates, and supply chains extending worldwide. These are among the primary drivers affecting the development of specialized shipping boxes and containers used for transporting these drugs to market.

The stakes are high, as an estimated $243 billion worth of cold-chain biopharmaceuticals will be in worldwide distribution by 2016, up 55% from 2010, according to the Biopharma Cold Chain Sourcebook published by Pharmaceutical Commerce. The majority of biotech products require refrigerated (2—8°C) storage and transportation, as do most vaccines, blood products and other injectables. Meanwhile, regulatory requirements for what has traditionally been called “controlled room temperature” (CRT) storage (15–25°C) and transportation are tightening—and that covers the majority of pharmaceuticals.

Last year, Pharmaceutical Commerce listed more than 35 suppliers of temperature-sensitive packaging solutions (March/April Cold Chain Directory), and each year, a handful of new companies show up at industry events offering novel combinations of packaging materials, insulation and refrigerants.

Among the most significant policy changes made in the past three years are “Good Distribution Practices” (GDPs). These regulations exist in various forms and numerous countries or regulatory jurisdictions, and their principles are in place in many contractual agreements between manufacturers and service providers. Many GDPs share the same basic principles: document and verify work processes; test and monitor equipment (including temperature mapping of containers); and document actual performance of cold chain tasks.

“Prior to the regulations, companies were not required to ship CRT drugs in temperature-controlled packages,” notes Stu Krupnick, global marketing manager, Sonoco ThermoSafe (Arlington Heights, IL), a provider of assurance packaging products. “With this change, temperature-controlled shippers are needed, which can significantly add to a company’s cost.” To address this requirement, Sonoco ThermoSafe launched a number of parcel- and pallet-sized CRT shippers in 2013, with more in development to address specific logistics needs in Europe.

EU GDP takes hold

The latest jurisdiction to implement a regulatory change, the European Union (EU), has already created a stir, industry members say. Implemented last July, the GDP places an emphasis on taking temperature-controlled distribution management from a prescriptive process of selecting appropriate packaging. As a result, shippers are re-examining their current practices and packaging and often finding problems with their current solutions.

Many are finding that their packaging is non-compliant or there are more cost-effective solutions available, experts say. “Products that formerly were shipped in the ambient environment now must have further proof that the shipping environment does fall within their stability,” says Karl Kussow, manager of quality and validation for FedEx Custom Critical (Uniontown, OH), which specializes in expedited freight shipping and solutions for transporting sensitive shipments. “If not, then appropriate packaging or containers must be used.” FedEx Custom Critical recently launched a service called Temp-Assure Shipping Studies which enables customers to improve the quality of their temperature-control supply chain through a combination of research, evaluation and recommendations related to specific shipping methods and lanes.

The EU GDP specifies that for temperature-sensitive products, qualified equipment—such as thermal packaging, temperature-controlled containers or vehicles—be used to ensure correct conditions are maintained between the manufacturer, intermediate points and ultimately the customer. It calls for staff to be properly trained and written procedures for assembly and handling. “The extent to which this affects package selection cannot be determined,” Krupnick says. “It does imply, however, that users understand how their packaging performs, that they can document that it performs as expected, and that the implementing parties within the supply chain can be held accountable if they do not.”

Observers say the requirements emphasize the importance of selecting high-performance insulated packaging and increases the relevance of developing a partnership with packaging manufacturers and suppliers. With increased monitoring and tracking requirements, there is expected to be an increased need for packaging that performs to tight specifications, even in harsh ambient environments or through unanticipated delays. “Companies will need packaging that is proven to maintain temperatures consistently and for longer periods of time, in some cases, using this packaging to control temperature throughout the last mile,” says Christy Ogrean, director of marketing, American Aerogel (Rochester, NY), a producer of aerogel-based insulation products used in thermal packaging systems.

Fig. 2. ThermoSafe’s family of passive shipping containers.

Credit: ThermoSafe

Passive cooling heats up

Over the past five years or so, the momentum for innovative shipping solutions has been in “active” containers—essentially mobile, battery-powered or plug-in refrigerators. The field was pioneered by Envirotainer (Upplands Vasby, Sweden); CSafe (Akron, OH) is a rising competitor, as is PharmaPort, exclusively licensed to UPS. The units are generally regarded as reliable, but expensive when used as “unit-load devices” (ULDs) in the bellies of widebody aircraft. More recently, there are the beginnings of a countermovement back to “passive” (non-powered) containers, including ones that can hold a pallet-size shipment.

Innovations in passive containers include hard-cased and reusable systems, vacuum-based insulation panels, composite container walls that are more compact, and a growing variety of phase-change materials, which are used in gel packs to provide cooling. “Advanced technology such as vacuum insulated panels and phase change materials, if designed and handled properly, are proving to be a superior method of providing passive protection,” says Kevin Lawler, VP of sales and marketing, Minnesota Thermal Science (Plymouth, MN; Minnesota Thermal is now a subsidiary of Pelican Products, Inc.). “The technology allows for efficiency advantages, results in much more cost-effective solutions, and in regards to use, results in a much simpler container to prepare and pack out.”

Each type of passive cooling system provides its share of benefits and drawbacks, experts say. “For many shipments that do not require strict temperature performance, one of these passive systems may provide cost savings over an active solution,” says Brian Kohr, CEO at CSafe (which also markets the AcuTemp line of passive containers). “It all depends upon the payload size, desired thermal performance, dimensional weight charged by the airlines, whether the system needs to be repositioned in transit.”

Sonoco ThermoSafe offers innovative passive solutions for the cold chain industry, as evidenced by its patented convection and Stratta technologies. “A great deal of our research and development focuses on new insulation materials and refrigerants,” Krupnick says. “Ultimately, we want to provide our customers with the lowest total cost of ownership solutions available to meet their exact requirements.”

Weight and size are among the biggest cost determinants in air freight, and being able to optimize the balance between container size and actual payload is key to providing a cost-effective solution, experts say. Minnesota Thermal Science’s Credo Cube reusable thermal packaging allows clients to ship product or clinical trial materials in containers that can be 50% smaller in outer dimension, with up to 50% larger payload areas and 30%+ lower tare weight. “Combined with the advanced performance of the packaging, it allows the client to ship more product with less packaging, at a lower service level, that in the end can save 30 to 50% on transportation,” Lawler says.

Further cost reductions are being realized through greater use of bulk or pallet-sized shippers. The trend is driving packaging manufacturers to expand their product offerings to cover additional sizes, durations and temperature ranges. “This is due to the globalization of the pharmaceutical industry which is requiring more products to be shipped to various locations worldwide in bulk,” Sonoco ThermoSafe’s Krupnick says. “Meanwhile, outsourcing trends in manufacturing and the growth in clinical trials in BRIC countries are also contributors.”

In addition to cost, sustainability initiatives to reduce waste from used packaging materials are also impacting selections by pharma companies. “We are seeing increased interest for our reusable passive packaging,” CSafe’s Kohr says, “as our ability to ensure packaging performance prior to each re-use ensures the integrity of a qualified solution while providing the cost savings that supply chain managers seek.”

Cryopak Industries, a division of TCP Reliable (Edison, NJ), a packaging solutions provider, reports clients are being asked to implement qualified packaging faster that best addresses their green initiatives. “This includes packaging that is smaller, lighter and simple to condition and pack out,” says Bill Hingle, marketing director. “These needs are coupled with the continued need to be cost effective to implement and be done in a short timeline for development.”

Cryopak offers Cryo-Gel gel packs, which are re-usable, and said to last longer than ice, while the refrigerant gel is designed to protect products from freezing or over-heating for safe transport of healthcare products. It is available in a durable, laminated, plastic pouch, or a Cryo-Gel 2 “no-sweat” paper material to protect against condensation touching the product.

Fig. 4. American Aerogel’s vacuum-panel shipper.

Credit: American Aerogel

Pre-qualified containers save time, money

One way pharma companies are reducing shipping costs and increasing speed to market is by “pre-qualifying” insulated shipping packages. This means the entire solution—box, insulation, coolant/PCM—is validated to maintain a specific temperature range under discrete conditions within a laboratory testing chamber. “These conditions may be ambient profiles as described by a regulatory agency such as ISTA (International Safe Transit Assn.) or they could be profiles designed by the manufacturer or customer,” American Aeogel’s Ogrean notes.

Pre-qualifying provides assurance the insulated packaging, when used as prescribed, performs to stated specifications. “For some clients, these pre-determined requirements fully comply with their specific needs,” Cryopak’s Hingle says. “Many times, a client will ask us to verify the design performance against their specific shipping lanes to best assure the actual performance of the design.” Cryopak offers a pre-qualified line called the TimeSaver, which offers a wide variety of selection options, Hingle says, including time and temperature performance ranges, single use and re-use options.

Pre-qualification is also used by pharma companies to segment available products in the marketplace, providing a means to identify the highest performing solutions and giving them a basis of comparison between suppliers. “In some cases, pre-qualified packages can truly be an out-of-box solution,” American Aerogel’s Ogrean says, “allowing them to simply follow the directions of the supplier rather than have to test and determine the right mix of insulation and coolant/PCM needed.”

Cold Chain Technologies (Holliston, MA) offers new pre-qualified thermal packaging such as KoolTemp GTS for the transport of small to pallet-sized loads of temperature-sensitive products. The environmentally-friendly parcel and pallet solutions are said to offer a high-performance option to increase payload while decreasing expenses due to lightweight materials, optimized DIM and patent-pending PCM systems. The temperature range is 2°C—8°C, 15°C–25°C and frozen applications.

Pre-qualification assumes a sort of one-size-fits-all approach, which will work for some shippers but not all. “We continue to see a trend toward customized qualified solutions,” CSafe’s Kohr says. “This is because it enables customers to optimize costs by ensuring a box is not over- or under-designed for the payload, duration and ambient profile.”

Still, not every company has the time, resources, facilities, equipment, or expertise to fully qualify such packaging, industry members say. Generally speaking, the level of regulatory acceptance for a fully qualified package consists of a design qualification (DQ), an operational qualification (OQ), and a performance qualification (PQ), performed in triplicate against heat and cold profiles, using minimum and maximum quantities of product. Occasionally, some packaging modifications are made to meet user requirements.

The process of qualifying a packaging solution for shipping a specific biopharma product can be outsourced to many of the packaging vendors, and air carriers as well. Besides FedEx Custom Critical’s Temp-Assure program, testing labs exist at TCP Reliable (via its DDL subsidiary), the ISC Labs business unit of Sonoco ThermoSafe, Cold Chain Technologies, Inmark (Austel, GA), DGP Intelsius (York, England; US HQ in Indianapolis), Minnesota Thermal Science, Sofrigam (Rueil-Malmaison, France) and many others. UPS provides package testing within its network, and Modality Solutions (Indianapolis) is an independent testing lab. Some of these labs are certified by ISTA, but ISTA standards are only advisory from an FDA perspective.

Fig. 3. ThermoSafe’s pallet-size shipper. Credit: ThermoSafe

Reliability questions

The challenge with reliance on pre-qualified containers is that pre-qualification is predicated on specific criteria, including ambient conditions, pack out volumes, methods and procedures. “Any variation of these conditions will change the resultant performance of a container,” notes Bruce McCormick, president and CEO, Savsu Technologies (Santa Fe, NM), a designer and builder of high-performance shipping containers. “Pre-qualification can be helpful for general comparison. But the challenge is to be able to compare all the conditions used in each pre-qualification test.”

Companies will often perform their own pilot tests even though the packaging has been pre-qualified. This is to ensure performance will be maintained in real-world situations and in specific shipping lane environments. “Clients ask about pre-qualification test data,” McCormick reports. “But when we examine their needs, it often turns out that the best approach is to run pilot tests under the conditions they will be experiencing.”

There are several components at play, including size/design of the package, type/quality of materials used, and type/quantity of refrigerant. If a box is designed and qualified properly, customers should be able to rely on the qualification process and supporting data. However, this assumes the selected ambient protocol is appropriate for the geographies, shipment routing, seasonal variations, duration of shipments, product payload sizes and product type.

“There is no accepted industry standard for temperature profiles, so it is impossible to make an ‘apples to apples’ comparison,” Sonoco ThermoSafe’s Krupnick says. “ISTA is attempting to standardize this by providing a universally accepted and uniform test protocol for qualifying temperature-controlled packaging called Standard 20.”

Regardless of whether a package is pre-qualified or not, regulatory expectations and nearly all industry guidances advocate the need for performance qualification. “If done properly, solutions can be designed to achieve the performance required at an overall cost savings,” CSafe’s Kohr says. “This is why CSafe’s custom designed solutions are becoming more popular than off-the-shelf.”

Cryoport (Lake Forest, CA) has taken an approach that combines prequalified protection for clinical materials with integration with shipping procedures. In a proprietary dewar that employs liquid nitrogen as the refrigerant, the Cryoport container can provide upward of 10 days of -150°C refrigeration. In the past year, the company partnered with FedEx to provide quick, simple delivery of the charged container to the shipper, pickup and delivery to its destination, and return (to Cryoport) for re-use. Nitrogen has the advantage of avoiding the “dangerous goods” designation among air carriers (for which dry ice is so designated); in addition, as FedEx has noted, the latest generation of high-efficiency cargo aircraft can run afoul of limits on the amount of carbon dioxide permitted in the aircraft’s interiors.

New technology

The next generation of highly effective insulated packaging are said to protect temperature-sensitive payloads from uncontrollable and sometimes unpredictable factors, such as ambient temperatures and transportation delays. Vendors say these solutions will help pharma companies comply with the latest standards and regulations. At the same time, the new technology introductions are aimed to make cold chain shipping more economical and less environmentally problematic.

For example, American Aerogel insulated packaging is marketed as high performing passive solutions. Because of its proprietary insulation, customers can ship more, with less coolant, in smaller containers, and over a longer period of time. “Our premium product line, AeroLite, is a pre-qualified, vacuum insulated panel solution that contains all necessary PCMs to maintain payload temperature in the frozen, refrigerated and CRT temperature ranges,” Ogrean says. “Also, because we design, manufacture, and test all of our products ourselves in our ISTA-certified laboratory, we have complete control over the process.”

High-performing insulated packaging can also be an important component in the risk reduction plan against product loss and noncompliance. “New finished pharma products, drugs in trials, assays and stem cells require strict temperature management, whether it is CRT, 2—8, frozen or cryo frozen,” Savsu’s McCormick says. “Packaging thermal performance must provide robust protection throughout the cold chain.” All Savsu containers feature easy pack-out, rugged construction and reusable systems designed to reduce packing and shipping costs while delivering high thermal performance, he says.

Sonoco ThermoSafe claims its two patented product technologies—convection pallet shippers and Stratta composite shippers—meet the industry’s primary need for smaller and lighter shippers with greater payloads and higher performance. “2014 should continue to be a year of firsts with many new products to be launched using these novel technologies,” Krupnick says.