Manufacturers and supply-chain partners attempt to define and standardize shipping procedures and tests, while vendors work on reliable solutions.By Daphne Allen, Editor
and David Vaczek, Senior Editor
Maintaining the cold chain for drugs and biologics is one of the hottest topics in healthcare product packaging. “More and more pharmaceuticals are being required to stay within tight temperature ranges,” reports William Hingle, marketing manager for TCP Reliable Inc. (Edison, NJ).
In addition, “There is also an explosion in the biotech community, creating an exponential increase in demand for temperature-sensitive packaging,” reports Don Pagel, CEO of Kodiak Thermal Technologies Inc. (Houston). He estimates that there are up to 130 million shipments of temperature-sensitive medical-related products per year.
“Direct-to-patient shipping is another trend,” points out Stephen Pohlmann, general manager for NanoCool (Albuquerque). “These are relatively small payloads in need of protection.”
The now-global nature of the pharmaceutical industry also demands consistent, reliable protection throughout the now-very-long cold chain. “Formulations are now being made in India, China, Singapore, and Puerto Rico,” observes Pagel. These climates have very different temperature profiles from those in the United States.Kodiak Thermal Technologies Inc. offers the R11, a reusable 11-liter version of its R36, for clinical trials, organ transport, and smaller shipments.
Consequently, there has been a lot of activity in terms of vendor offerings. Such an array could be driven, in part, by user demand for ready-to-use shipping containers that can handle a wide range of ambient temperatures. “Many applications, such as clinical trials, require flexibility for payload size and weight and need a shipper that is qualified and ready to go,” says Hingle.
But as manufacturers consider so many thermally protective solutions, they are encountering some yet-to-be-concluded debates. Can a thermal package be validated to perform consistently and reliably throughout an unpredictable, uncontrollable cold chain? Can off-the-shelf (OTS) packaging address the most extreme conditions yet still be cost-effective? Does custom engineering better address unique product needs? And, must thermal packages be tested under real-world conditions for every possible shipping extreme?
Some experts wonder whether a standard testing profile or a standard design for all small cold-chain shipments may end all these debates. Others say that a one-size-fits-all approach may end up overpackaging some products and costing more than necessary.
THE TASK AT HAND
As manufacturers confront these issues, they need to remember that FDA is keeping a close eye on thermal packaging these days. “FDA is tuned into temperature control,” says Sanford Cook, CPP, Thermal Packaging Solutions LLC (TPS; Ocean, NJ), a consultancy specializing in analyzing and validating/qualifying the entire shipping and distribution process. “We are seeing FDA-483s given to the major pharmaceutical companies with major supplies.”
Pagel, too, speaks about regulator interest. At LogiPharma 2006 held in September in Austin, TX, Pagel had heard reports that “two major biopharma companies were just audited to USP <1079> by FDA and other regulatory agencies.”
As a result, these companies are focusing on USP <1079>, United States Pharmacopeia’s guidance chapter titled “Good Storage and Shipping Practices,” as part of their audit routine, Pagel says.
“USP <1079> is becoming a major standard that we are still learning about and understanding,” explained Rafik Bishara, PhD, chairman of the Pharmaceutical Cold Chain Discussion Group (PCCDG), a working group of the Parenteral Drug Association (PDA), to attendees at the Fourth Annual Cold Chain Distribution of Pharmaceuticals conference. “Chapter <1079> speaks to all parts of the supply chain,” he added.
Such industry guidelines along with existing regulations provide instructions for Good Cold Chain Management Practices (GCCMP). In addition to USP <1079>, PDA’s “Technical Report 39, Cold Chain Guidance for Medicinal Products: Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment,” provides further assistance. Companies should reference these when qualifying packages, said Bishara.
“The pendulum is moving. Regulatory guidance is pushing for visibility across the entire cold chain,” Bishara said. He noted that Canada, Ireland, and Brazil are among countries issuing regulations in the past 12 months. The World Health Organization in Working Document QAS/04.068 says that special storage conditions for sensitive product should be “provided, checked, monitored, and recorded.”
Progress is being made toward harmonizing this growing body of world standards.
PCCDG and its European counterparts, the Cold Chain Committee C3 and the Pharma Logistics Forum (PLF), have formed the Temperature Controlled Pharmaceuticals Group (TPG). The groups will continue operating as distinct entities under the umbrella organization, Bishara said. PCCDG is developing a consensus list of best industry practices.
The Cool Chain Association (CCA) is promoting the Cool Chain Quality Indicators (CCQI) standard to logistics providers. CCA aims to make CCQI part of the selection criteria when shippers are choosing logistics companies, said Steven Boyd, CCA director-at-large and AmSafe Bridport (Los Angeles) director of sales and marketing.
“Customers are asking for and regulators are demanding cold-chain policy with precise quality standards. We are making our members aware of this proven standard and how they can benefit from it,” he added.
CCQI was developed by CCA and Germanischer Lloyd Certification (GL-C; Hamburg, Germany). GL-C performs a risk-based audit that checks processes for conformity with state-of-the-art practice.
QUALIFICATION AND VALIDATION
Best practices described at the Cold Chain Distribution conference include that shippers must provide documented evidence to show that temperature ranges were maintained through transport. “An ongoing temperature and humidity monitoring program is essential for data-based quality decisions,” said Bishara.
But does such a program validate packages or simply qualify them? “Recent publications and cold-chain conferences have once again elevated the topic of qualification versus validation and understanding the difference between the two,” says Kevin O’Donnell. O’Donnell is director and chief technical adviser to industry at SCA Packaging N.A., ThermoSafe Brands (Arlington Heights, IL), and was formerly with Abbott Laboratories for 26 years. He created and hosts the first-ever blog site dedicated to pharmaceutical cold-chain distribution, www.coolerheadsblog.com.
“The terms qualified and validated have been interchangeably misused for as long as I can remember,” he says. “The confusion lies with what we know as the definition of these terms, which are often contradictory, and how they are applied to a controlled process, such as equipment operation or a manufacturing operation, versus an uncontrollable process, such as the environment and distribution practices. You cannot validate what you cannot control. Given the environment and the widely variable distribution process, validation only partially applies.” For more on this debate, please see the sidebar on page 48.
BUT WHAT IS A STANDARD?
Talk of standardizing shipping containers can be confusing—What is actually being standardized, you ask?
Standardizing could refer to the work of PCCDG, which is developing a consensus list of best industry practices. The working group is hoping to standardize a shipping profile for domestic shipments in small-parcel distribution enviroments, reports O’Donnell.
Standardizing could involve deciding between USP <1079>, PDA Technical Report 39, ISTA 7D, and others or harmonizing them all as a joint standard. One set of standard procedures for designing and testing thermal packages could show users what exactly is expected.
Others say standardizing involves determining a particular temperature profile with all the peaks and valleys of temperature extremes and coming up with one set of package design specifications. But “there is no standard temperature profile,” says O’Donnell. Even though domestic shipping profiles are pretty consistent, he says, and fall within the range of 18–26ºC a majority of the time, they are vastly different in South America, Europe, and the Far East because of differences in distribution models.
The quest for standardization may lead some interested parties to search for (or develop) a standard prequalified design. “Companies try to compensate for what they don’t know about their distribution environments and processes, and prequalified containers provide good peace of mind,” O’Donnell adds. “Prequalified containers are often bulletproof in that they are tested against a robust ambient profile and protected against extreme cold and extreme warm.” Some prequalified designs are referred to as “universal packouts” instead of “seasonal packouts,” he notes.
But could prequalified containers built to follow one “standard” meet all of industry’s needs? “No. There is no holy grail of packaging,” adds O’Donnell. “There are simply too many other variabilities and customer-specific requirements—but it could go a long way to solving many companies’ challenges for distributing temperature-sensitive product.”
Would prequalified designs need to be so robust that they could also be reusable? Would companies be at risk of overengineering or underengineering their thermal packaging?
Kodiak’s approach is to create durable, rugged containers, which Pagel argues are more reliable in protection than expanded polystyrene (EPS) and gel packs boxed in cardboard. He likens the drug industry’s current struggle to insulate the cold chain to that of the ocean shipping industry in the 1950s. “It took a while, but that industry eventually reached a standard for shipping, choosing reusable containers. The drug industry, too, needs a rugged, durable container with a long life that follows some sort of industry standard.” A reusable solution is the best way to meet an industry standard, Pagel argues. He acknowledges that there are different reusable solutions available from vendors.
Kodiak’s approach involves a self-contained unit that maintains a certain temperature range without the use of power for up to five days. Still using phase-change gel, but segregated in the removable lid along with a patented thermal switch, the system “protects payloads from ambient temperature spikes,” says Pagel. The lid is designed to freeze on a Kodiak-supplied rack in a commercial freezer before use. After put in place, the lid relies on its temperature-regulating switch to begin cooling or to cease cooling, depending upon the payload’s needs and the shipping environment.
A thermal shield consisting of an aluminum envelope around the entire payload area is sealed against a convection plate. Vacuum insulation panels (VIPs) surround the whole unit. It features data-logging capabilities to record temperature and humidity. “FDA is warning through quiet channels that such records may be required,” Pagel says. The R36 refrigerated container maintains a payload temperature between 2° and 8°C for more than five days with no power or dry ice. The D36 deep-frozen container maintains temperatures below –22°C for up to five days based on the amount of dry ice placed in the lid.
TCP Reliable, which has offered thermal packaging design for years using EPS and traditional gel packs, has launched a reusable solution in its new product line, the TimeSaver. “By reducing size, weight, and incorporating reusable features in the design, our TimeSaver also helps in the reduce-and-reuse initiatives that many pharmaceutical companies are practicing to be more environmentally responsible,” says Hingle. “The TimeSaver 72 has been prequalified by TCP using the ISTA 7D standard for thermal performance. It is designed to transport and maintain payloads at 2–8°C for periods up to 72 hours and longer.”
Hingle says that reusability is becoming “more and more of a hot-button topic that is used in considering package design. There are many levels of this that can be incorporated into the packaging, all with various cost impacts to the packaging and shipping. We look to identify with the customer at the front end of the project the importance of this to them relative to the value of the product and how this relates to their reduce-and-reuse initiatives. Usually we are able to find an effective solution that balances costs versus benefits.”
The TimeSaver 72 incorporates Phase 5 phase-change material engineered to phase at 5°C encased in patented plastic panels that fit together to form a cube around the payload. (This design won an Ameristar award from The Institute of Packaging Professionals in 2004.) “Phase-change materials can be thermally more effective than traditional gel packs in critical applications such as 2°–8°C,” says Hingle. “Less of the refrigerant is required, comparatively, thus keeping the overall size and weight of the shipper down. This translates into potentially big savings in shipping costs,” he says.
NanoCool’s solution features a proprietary technology in the lid that cools the payload through water evaporation. VIPs are used to insulate the package. While the lid is designed for one-time use, the VIP-insulated container can be reused with a new lid.
“Our answer is to offer our OTS system or to build a custom design if needed,” says Pohlmann. “An OTS system must meet your requirements. If it doesn’t, you step away from it.”
Cook says that working toward a standard approach for shipper design is “admirable.” However, “our experience has been that most applications have different minimum and maximum product quantities in a single package. Many single packouts have products of mixed characteristics, such as primary container size, mean kinetic temperatures, label temperatures, and materials (lyophilized, liquids, solids packaged in blisters, vials, cards, syringes, etc.). All must be evaluated as to temperature characteristics during the transit events.”
Cook says that “all of the events, such as handling time and ambient temperature exposures from the time the package is actually taken from the refrigerated storage units, queued for packaging, sealed, and shipped through, including the final mile at delivery, must be considered in safe and properly validated shipping studies,” explains Cook. “After the study is completed, we first try to source off-the-shelf insulated protective containers. We will design new geometry and characteristics only when nothing we know of is available at a reasonable cost. Since there are so many variables, we believe the only defendable use of a shipping container that will adequately and efficiently protect temperature-sensitive products is to test it, only as a component of the entire event, and have certified documentation attesting to the package’s efficacy.”
When asked whether reusable, durable off-the-shelf designs built to meet a standard could meet industry needs, Cook says that question has different answers depending on the supplier’s products and capital equipment investment. “Normally, traditional foamed plastic like EPS and urethane offers the least-expensive one-way shipment. More-expensive hardware systems that rely on structured, returnable frameworks or reversed logistics, whether rented or purchased, may turn out to be significantly more expensive in the long run, even when factoring in warehouse storage space and handling. Having said that, they should be considered in single-destination repeatable applications.”
NanoCool’s Pohlmann says that when considering thermal packaging options, companies should look at the costs of designing, assembling, and shipping a package. “The cost of our system requires you to look at entire costs. While our system may be more expensive up front, it is lighter, so you save on shipping; it has a less complex packout, and there are no gel packs to store on the packaging line.”
AcuTemp (Dayton, OH) custom designs reusable containers, tailoring the insulation capabilities and dimensions to customer needs. The firm’s ThermoCor insulation can be employed in both single-use or reusable shippers, or battery-powered mobile VaxiCool refrigerators could be employed for up to five days. The firm’s newest offering, the RKN Thermal Pallet, holds products between 4° and 25°C for more than 90 hours thanks to battery power and ThermoCor. It is currently going through FAA certification.
Plastilite (Omaha, NE) is sticking with EPS for insulated shippers for temperature-sensitive products. According to Rick Drew, Plastilite is focusing on ways to mold EPS that extends shipping times and reduces weight and coolant, all by 25%.
Cold Chain conference participants discussed the potential of RFID. One pilot program reported on how receiving warehouses can obtain an instant read of RFID-tagged shipments before trailers hit the loading dock. Inventory and temperature data were downloaded at the same time into the inventory management system.
Bishara called on industry to be more open about RFID cold-chain pilots in order to share experiences as the technology is tested.
Intelligent Devices Inc., a subsidiary of Information Mediary Corp. (IMC; Ottowa, ON, Canada), announced the Log-ic Temperature Tracker that it said offers a lower-cost RFID cold-chain monitoring and tracking solution. American Thermal Instruments Inc. (Beavercreek, OH) markets the product. “The market requires easily usable, cost-effective, and safe and reliable electronic content–monitoring solutions. Sensor tags have to meet disposable price points,” said Michael Petersen, chief operating officer, IMC.
RFID enables capturing tag data without the need for human intervention or opening the temperature-sensitive shipment. Temperature thresholds can be programmed to tags via two-way RFID communication, Petersen said.
The solution processes time and temperature points in real time, time-stamping and displaying excursion durations and maximum temperatures reached. Shipments are tracked and documented using CertiScan RFID readers. The RFID sensor tags are active Class 3 RFID tags operating on high frequency, offered in disposable and reusable versions. Tags are 2 in. sq. and weigh less than 1oz. IMC CertiScan software displays tag data in line and pie charts, and histograms show the time product experienced in each temperature range.
The important thing is for companies to understand their distribution environments so they do not over- or underengineer their shipping containers. When it comes to transportation packaging, “companies often struggle with product and package failure and the desire for cost savings,” says Ondrea Kassarjian, professional services development engineer for Lansmont Corp. (Lansing, MI). “The data they receive from our testing services provide facts that they can base decisions on to increase durability and cost savings. Lansmont developed the Six-Step method, which is a scientific approach to optimize the development of a product-package system. This method includes monitoring the damaging effects of the distribution environment, bare product testing, and package testing. This methodology is used to confirm the validity of a product-package system so that compliance can be maintained.”