Cold-Chain Challenges Heat Up

By John Conroy

If you’re a pharmaceutical manufacturer or wholesaler, you want the insulin that you shipped Monday to arrive at the doctor’s office on Tuesday, ready for patient appointments. You don’t want the containers perched on pallets in the sun outside a cargo terminal at Pittsburgh International Airport for two hours on Tuesday afternoon, waiting for refrigerated trucks.

As the global market for insulin and other bioengineered drugs continues to grow, this scenario and others are putting a strain on all the links in the supply chain for temperature-controlled products— pharmaceutical manufacturers, wholesalers, packagers, and third-party logistics (3PL) providers alike.

Given the growing global reach of biologics, the problem is even more acute outside the United States. David Bang, CEO of LifeConEx LLC (Plantation, FL), told Future Pharmaceutical magazine that a typical international delivery of cold chain pharmaceuticals can involve “three airports, three ground handlers, two different airlines, two truckers, one freight forwarder, and one customs broker.” Different regulations in two countries and three different climate zones compound the complexity, he noted. A joint venture between DHL Global Forwarding and Lufthansa Cargo, Bang’s company was established to help alleviate this problem by offering end-to-end transport of temperature controlled drugs.

The industry is responding with several solutions, among them efforts like DHL’s to reduce the number of handover points needed to move a product to its final destination. Customers have been involved in an ongoing effort to outsource “noncore business or logistics related work” to shippers for the past six years, says Angelos Orfanos, vice president, Americas, life sciences and healthcare for DHL (Plantation, FL).

In December 2007, FedEx announced a pilot program in collaboration with AmSafe Bridport (Phoenix) to use AmSafe’s compressor-driven technology container. The temperature-controlled shipping container “has the ability to dial in temperatures between 4° and 25°C,” capturing “70–80% of all temperature controlled refrigeration products being shipped,” claims Jeff Sitzlar, manager of business development for FedEx.

Freight transportation giants such as DHL, FedEx, UPS, and other 3PLs are confronting several converging trends, according to Orfanos. With biotech leading the way, industry forecasts from LEK Consulting, McKenzie & Co., and DPWN Inhouse Consulting report growing revenues for the pharmaceutical industry’s life sciences market, he points out.

A 2001 forecast by LEK Consulting predicted the life sciences segment of the pharmaceutical industry will grow at a compound annual growth rate (CAGR) of 12% through 2007, with the temperature- controlled portion of the segment estimated to grow at a CAGR of 22% during the same period, Orfanos says. A more recent forecast by DPWN Inhouse Consulting estimates an industry CAGR of 6.6% through 2012, he notes.

In addition, 39% of all life sciences products were forecast to be temperature- controlled drugs by 2007, with the remaining 61% dry, noncontrolled products. In 2001, those figures were 15% for the former category and 85% for the latter. Temperature-controlled products can include those kept at the controlled room temperature (CRT) of 15° to 25°C, Orfanos says.

“The whole concept of maintaining temperature during transport is a huge part of the industry, and it’s going to grow,” says Eric Isom, manager of warehouse operations for Sentry Logistic Solutions (Indianapolis). The 3PL distributor operates a foreign trade zone that allows international pharmaceutical and biotech clients to bypass importation regulations such as “customs, paperwork, dues, and tariffs,” he says. One sign of the explosive growth in the cold chain that Isom has seen since joining the industry in 1998 is the number of conferences on the topic. “From 1998 up to 2001 you may have been able to find one seminar a year that was talking about this,” he says. “Now if you search the Internet, I would venture to say you could find 50 to 100.”

Many of the seminars no doubt focus on the welter of state, federal, and global compliance regulations governing coldchain operations that are figuratively and literally all over the map. Canada, for instance, “has very strict guidelines on their product coming in as far as the cold-chain parts, says Isom. “In the United States, there are lot of guidelines telling you to do it, but there’s not always a lot of detail telling you how to do it.”

A British health official for the Medicines and Health Care Products Agency, known as MHRA, emphasized the deleterious effects of temperature excursions at a recent conference Orfanos attended. John Taylor, MHRA’s group manager for regulatory assessment, remarked that 43% of all major deficiencies recorded by an agency inspector in 2004 and 2005 were related to storage and transportation temperatures, according to Orfanos.

“There’s been a huge change in the market’s product profile,” he says. “Many of the new products are bioengineered products and bioengineered products have larger molecular structures, which makes them much more susceptible to temperature and humidity variations.” Bioengineered drugs include insulin, coagulants, interferons, cytokines, enzymes, hormones, and interleukins. The protein-based drugs are used to treat diseases such as hemophilia, diabetes, cancer, cystic fibrosis, and hepatitis.

Additional trends affecting the cold chain include the emergence of new markets in countries such as China and India, regulatory challenges, security concerns, and a run of mergers in the healthcare and 3PL spaces, Orfanos says. India is now producing generic drugs, including biologics that require temperature control, Orfanos notes. “That’s creating new challenges,” he says, because the supply chain is now stretching “to new manufacturing sites in the rest of the world.”

Back in the States, post-9/11 security concerns are having an impact on the cold chain as well. In November 2001 the United States launched the Customs- Trade Partnership Against Terrorism (C-TPAT), a voluntary antiterrorism program designed to smooth cooperation between the industrial supply chain and U.S. Customs and Border Protection.

“That’s not only a trend, it’s a current event that puts pressure on all the parties,” Orfanos says, noting that a product in the cold chain has a “defined timeline” to get to its final stop. A company that is out of compliance with C-TPAT regulations or FDA and USDA guidelines may find its product delayed, and it’s easy to imagine the consequences for the cooling medium inside the containers. “You may not be able to afford to get stuck at the airport waiting for a product to be released as your dry ice is melting,” Orfanos says.

Changes in the regulatory climate are also putting some heat on the industry. Regulators worldwide have expanded the definition of a temperature controlled product, Orfanos says. While historical cold-chain temperatures range between 2° and 8° C, the industry has recently seen “an evolution to the 15° to 20°C range.” Considered room temperature, this range “has evolved in regulators’ minds as a controlled-temperature zone” referred to as temperate or ambient, he notes.

The expanded definition of temperature- controlled product has led many countries to pass laws mandating that manufacturers ensure that drugs are kept in the range stated on the label, according to Orfanos. “Those governmental bodies are saying if this product needs to be kept at that temperature then you, the manufacturer, have delegated the temperature requirement for that product,” he says. “If you’re going to ship it from Point A to Point B you need to maintain [the product’s] efficacy.” Regulators around the world have taken the label designations and said, “‘Okay, fine, but now you’ve got to meet that requirement.’”

And if you don’t? “A product could potentially be delayed in reaching its destination, requiring analysis, or in the worst case, being deemed spoiled,” Orfanos says. Spoilage could occur when a combined accumulated range of temperature excursion reaches a certain length of time deemed unacceptable by the manufacturer’s quality assurance department.

“A number of regulatory and standards-based guidance documents have been published over the last two years,” says Henry Ames, director of strategic marketing for Sensitech (Beverly, MA), which specializes in cold-chain solutions for monitoring temperature-sensitive products from the beginning to the end of the supply line. These include the November 2005 publication of USP <1079>, the general guidance document covering good storage and shipping practices by the U.S. Pharmacopeia. Other documents addressing product efficacy and patient safety include Technical Report 39 (“Guidance for Temperature-Controlled Medicinal Products: Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment,” revised in 2007), by the Parenteral Drug Association, as well as regulatory publications from Canada, Ireland, and other countries.

Revised by a cold-chain working group within the Parenteral Drug Association, Technical Report 39 harmonizes supply-chain best practices with EU regulations. One of the key recommendations is that transportation companies establish quality management systems with a designated decision maker. USP <1079> offers a range of storage and shipping guidelines and recommendations. The 15-page document covers areas such as establishing temperature profiles, monitoring during shipping, qualifi cation protocol, and receipt of pharmaceuticals. On this last topic, USP <1079> recommends transfer of arriving product to “a manufacturer-designated storage environment within two hours of receipt,” for instance.

“All supply-chain partners need to work together to ensure product quality and patient safety,” Ames says. These twin goals have led Ames to argue that streamlining the cold chain and the pharmaceutical industry’s push for an anticounterfeit electronic pedigree system are linked. The majority of counterfeited drugs tend to be temperature-controlled products, he notes, because those typically cost more than noncontrolled drugs.

“You need to look at all pressures to streamline the pharmaceutical supply chain, which would include a desire to reduce counterfeit drugs as well as drugs that have been adulterated through temperature abuse,” Ames asserts. “There is a strong correlation between counterfeit drugs and temperature-sensitive drugs. Adulteration includes external factors such as temperature, shock, vibration, humidity, and pressure.”

An authentic product that’s been “temperature abused,” even though it’s the genuine article, “is worthless,” Ames reasons. “You really have to [be vigilant about] both to maintain product safety, and streamlining the supply chain helps to reduce the risk and address some of the issues with either diverted product entering the supply chain in complex distribution channels or thermal excursions that may occur.

“The benefit to streamlining the supply chain can help address both problems,” he concludes, “and there are a number of supply-chain partners that have recognized the growth in this market and the need for more specialized service offer ings. FedEx Customer Critical, UPS Health Care Shared Network, and DHL LifeConEx are all good examples.”

Similarly, Keith Sinclair believes the cold chain and e-pedigree matters are “two distinct but related things.” The director of operations for biopharmaceuticals distributor FFF Enterprises (Temecula, CA), Sinclair agrees the industry has been paying greater attention to maintaining product integrity throughout the supply chain. “Once it gets out of the manufacturer’s hands, it’s a matter of how the wholesaler is handling it,” he says.

As a result, the regulatory spotlight has shifted to the wholesaler, and “there’s been talk of FDA stepping in,” Sinclair says. “I think what’s happening is confusion between pedigree and channel integrity. Pedigrees do not create channel integrity. They just document who has handled a product, but not how. And how a product is handled, whether it’s a cold-chain product or not, defines the integrity of the channel. When [FDA] is talking about getting involved, they’re really talking about pedigree.”

Although Sinclair agrees with the need for “a good pedigree system,” he says this endeavor has mostly been left up to states’ boards of pharmacy. FFF’s method of narrowly defining the channel—from manufacturer to distributor to healthcare provider—contributes more to channel integrity than any pedigree can, he says.

Sinclair does note that monitoring of temperature during shipping “could tie back to electronic pedigree” if RFID technology were successfully developed. There’s been industry talk that the PHARMA-BIO “RFID chip could potentially even track temperature,” he says. “If pedigree is put in place using RFID, the technology could also be used to track temperature in transit.”

This prospect raises exciting possibilities in terms of cold-chain streamlining. “Imagine treating yourself at home, and you have an RFID scanner,” Sinclair says. “You get the product from the pharmacy, scan it right there,” and determine whether you received the correct drug and whether the drug stayed within the manufacturer’s stated temperature range. No one’s holding his breath, however, as adoption of the technology has been slowed by concerns over cost, standards development, and the impact of radio waves on proteins, Sinclair points out.

As Ames notes, all links in the supply chain need to collaborate for the greater good, but in the United States at least, ultimate responsibility for product safety rests with the pharmaceutical manufacturer. In his position as director of marketing and business development for packaging company Tegrant Corp./ThermoSafe Brands (DeKalb, IL), Richard Ellinger has observed that 3PLs “are taking more responsibility when handling the repackaging end of the business because the 3PLs are following the lead of the manufacturers.” He notes that USP’s General Chapter <1079> requires shippers and distributors “to follow the proper storage and shipping requirements, as indicated by the manufacturers.”

ThermoSafe’s mail-order fulfillment customers, in particular, have shown increased interest in pursuing opportu - nities in the 3PL space, Ellinger says. He adds that the company’s business has seen “nothing dramatically different from what we’ve faced in the past.” However, in terms of ThermoSafe’s market, he notes that the company services pharmaceutical and biotechnology manufacturers “the same way we service the 3PLs, because their needs are more similar than they’ve ever been before.”

Those needs involve a high level of complexity, says Rob Brown, vice president of specialty sales for Cardinal Health (Dublin, OH). Cardinal Health’s 3PL division, special pharmaceutical services, has “17 clients selling therapeutic biologicals requiring coldchain distribution. “The key thing that presents difficulty in the cold chain, more than product characteristics, is the delivery requirement,” he says.

Cold-chain products stored with a wholesaler “may have 20 days worth of inventory, and if they go through wholesale channels, the requirements are complex,” Brown says. “The morecomplex need is shipping directly to a physician’s office for a scheduled ad - ministration. Some clients get orders at 10 A.M. on Monday that need to be shipped overnight because at 11 A.M. the next day the patient is showing up for administration.”

For a 3PL transporting products to a wholesaler, “it is a very expensive piece of the cold chain,” Brown explains. “Most everything goes overnight in cold chain, so you’re mostly shipping UPS or FedEx parcel shipments. If it’s a biotech [product] the volume is not as high as traditional [drugs], so you’re spending a lot of dollars in overnight shipments versus Less-Than-Truckload (LTL) shipments.”

However, Cardinal Health believes there are plenty of opportunities to consolidate transportation because its 17 cold-chain clients “pretty much ship to the same people,” Brown says. “We think there’s an opportunity around consolidating the transportation to those similar customers.” Counting the cost of validated shippers, overnight transportation costs, and conversion to truckloads, consolidation could be up to 15–20% less expensive, Brown says.

Brown says a 3PL can usually limit liability exposure if it follows the manufacturer’s quality assurance instructions defining “the packaging configuration. As long as we follow that configuration, we’re not liable.” Causing a product to freeze by putting it in a gel pack for shipping when the customer’s SOP calls for an ice brick is an example of a lapse that could lead to the manufacturer filing a liability claim with the transportation provider, he says.

Variability is most common in the transportation link for 3PLs, Brown notes. Studies by companies such as Sensitech “show what happens when product goes up in a plane. It is amazing the variance of temperature in the hulls of those planes,” he says.

Reducing those variables and decreasing the number of handoffs will mitigate product risks, asserts Donald Nolde, vice president of sales and marketing, Cold Chain Technologies (Holliston, MA). “The fewer people handling product, the better off you’ll be,” says Nolde, whose company specializes in cold-chain shipping containers. “We have seen the need for third-party logistics increase over the last few years, and I believe that will continue with the biotech sector. Our task at Cold Chain is to make their job easier and with better compliance by providing improved and simplified packaging solutions.”

Says Nolde: “We’re focusing on the fact that at the end of the day, whether you’re a 3PL, or a pharmaceutical manufacturer, or a biotech company, it’s your responsibility to ensure that small molecule or large molecule [products] arrive in unadulterated and safe condition. I’ve got two daughters. Do I want them to receive a drug that’s not in good condition? Obviously, I do not.”

And those words are bound to reassure patients as well.