Facilty Design & Management

All Aboard the Cold Chain

As liability risks increase, drug manufacturers are assuming greater ownership of the “cold chain” for transporting valuable biologics. Stability testing, data logging and other technologies are helping to ensure product safety as the industry moves toward a whole new distribution model.

By Angelo De Palma, Ph.D., Contributing Editor

Globalization, economics, and the rise of biotechnology have vastly complicated pharmaceutical distribution and logistics. Of the $400 billion worth of pharmaceutical products sold worldwide in 2003, approximately 10% were cold-chained biologicals. Sales of biotech products between 1999 and 2003 grew nearly twice as rapidly as those of small-molecule drugs.

The U.S. Food and Drug Administration emphasized the need for a safe, secure drug supply through its February 2004 document, “Combating Counterfeit Drugs.” Every one of the top 30 counterfeiting targets have some cold-chain component.

As manufacturers consider anti-counterfeiting strategies, they are beginning to recognize that the cold chain is a key component of authentication. “A product adulterated through tampering is just as dangerous as one that has suffered temperature abuse,” says Henry Ames, director of marketing for Sensitech (Beverly, Mass.). “In fact, FDA includes temperature abuse in its definition of adulterated product.”

A validatable temperature data logger such as Veriteq's VL-1000 can help protect sensitive products in the cold chain.
Historically, manufacturers were satisfied to manage the cold chain within their facilities. Today, their desire for greater control over the cold chain during handling, storage, and distribution necessitates close relationships with distributors and third-party logistics/ transportation providers. “Manufacturers who do a really good job while the product remains within their manufacturing or filling plant often wash their hands [of it] when product ships,” says Carla Reed, a VP at Chainlink Research (Cambridge, Mass.). “But if you own the brand, you own it until the patient consumes it and you’ve achieved a good result.”

Of the major distributors, just three — Cardinal Health, AmerisourceBergen, and McKesson — control approximately 90% of drug distribution in the United States. Their traditional business models were based on both a “buy and hold” strategy and a secondary arbitrage model. Distributors hoarded expensive product and held it as prices rose, thereby enjoying an inventory profit. At the same time, manufacturers were able to enter revenue earlier on than if purchases more closely tracked patient demand.

For the arbitrage model, the distributors bought and sold among themselves based on expected price increases and or regional differences in supply and demand. Terry Hisey, U.S. managing principal for Deloitte Life Sciences (Philadelphia, Pa.), refers to these practices as “cannibalization of high-value products by distributors.”

FDA's push for safe, secure supply chains has jeopardized this business model, which directly affects who “owns” the cold chain. It has also opened the door for nimble, technology-savvy logistics and shipping companies to pick up some of pharma’s cold chain business.

“It’s going to take some time for the new distribution model to kick in,” says, Henry Ames. “Eventually we’ll reach the point where distributors will be held to a higher standard with respect to drug storage and handling.”

One thing that will not change is the burden of responsibility for delivering effective products unadulterated by extremes of temperature. “If there’s a problem with a drug shipment people will remember the manufacturer’s name, not the distributor’s,” Ames notes.

Like many long-established pharmaceutical business practices, the current logistics model is probably unsustainable. Large distributors and manufacturers view the “happy medium” of current cold-chain pricing radically differently. Drug makers look longingly to the day when competition drives shipping costs down, while distributors attempt to raise prices through outright increases or by adding services.

Bioburden

Biotechnology has been the driving force behind cold-chain innovation. “Just a few years ago hardly anyone was aware of the cold chain as a significant force in pharmaceuticals,” notes Bob Townsley, managing consultant for global life sciences and healthcare for PA Consulting (London, U.K.). “Today, 244 products approved in the U.K. are handled, shipped, and delivered under controlled temperature conditions.”

A related driver will be the emergence of novel cell-based therapies, points out Peter Berry, CEO of CryoPort (Brea, Calif.). Vaccines consisting of live or attenuated cells have, of course, been “cold-chained” for decades.

The cold chain is a critical element in product authentication — in fact, FDA considers temperature-abused product to be "adulterated." Photo courtesy of Sensitech.

Serono’s (Geneva, Switzerland) cold-chain requirements are typical in biotechnology; more than two-thirds of the firm’s finished products ship cold. After production, the company transfers bulk actives to another site for final formulation and filling. This “first leg” journey involves small quantities of highly concentrated, potent material that is packed in dry ice and shipped. “As long as it reaches its destination within a certain time frame we’re certain the product has arrived at full potency and quality,” explains Werner Bucher, who directs Serono’s Packaging and Distribution Center of Expertise.

Bucher sees shipment of finished products as significantly more problematic than for unformulated active because physical volumes are much higher for the former (pallets of several cubic meters vs. several liters), and maintaining and validating freezing temperature is significantly easier, even for long trips, than keeping within the magic 2-8°C window. Difficulties arise as the distribution chain sprouts to hubs and distribution centers, where variables begin to pile up, multiply, and cause logistical headaches. “This is the most challenging part of our cold train,” Bucher admits.

FluMist, MedImmune’s (Philadelphia, Pa.) innovative nasal influenza vaccine, must be stored and shipped at -15°C or lower. “Although freezing temperatures are generally easier to maintain than the 2-8°C normally employed to ship biologicals, the challenge with frozen products is maintaining temperature even as you ‘pick and pack’ — not just while shipping, but during routine handling,” observes George Cox, director of supply chain operations.

For shipping FluMist between its two Philadelphia manufacturing sites and a distribution center near Louisville, Ky., MedIimmune employs the services of Total Quality (TQI; Mecosta, Mich.). TQI is typical of the new breed of logistics firms, offering satellite tracking, redundant refrigeration systems on its trailers, and through a contractor, rapid-response maintenance for when problems arise.

The most elaborate cold-chain strategy melts to mere protocol without extensive stability data. Manufacturers need to determine, in detail, stability at a range of temperatures over time to minimize precautions taken during storage and shipping. When temperature fluctuations occur, it is far more comforting to defer to temperature-time-stability curves than to guess or retest a lot.

Claude Ammann, Ph.D., quality assurance director at Apoxis (Lausanne, Switzerland), says manufacturers need to establish “acceptable” reductions in purity or potency resulting from temperature excursions, and stick to those limits. It helps if the appearance of degradation products, a measure of quality over time, is correlated in some way to an efficacy assay.

For Ammann, whose company will begin shipping biologicals for an oncology clinical trial next year, 2% to 5% of degradation products is acceptable, although he admits that the cutoff point is unique to each product. “If you can assess degradation through appropriate stability curves you’ll be in a much better position to decide whether to release a product or not,” he says. “It all comes down to where the product in its present form falls on the curve.”

One possible way to simplify drug logistics is to design products so they ship and store more easily. This is already done, to some extent, with lyophilization and formulation strategies. However, the expense of one or more additional unit operations must more often than not be justified by a significant improvement in stability and/or efficacy. “Dosage forms and formulations tend to drive logistics, not the other way around,” observes Terry Hisey of Deloitte Life Sciences.

Where’s the Beef?

Food and other perishable products have been shipped for years over long distances, begging the question: Why the fuss about pharmaceuticals?

“The main difference between food and drug shipments is dollars and cents,” notes Larry Gordon, president of Cold Chain Technologies (Holliston, Mass.). “When Purdue Farms sends out a reefer [refrigerated tractor trailer] and someone forgets to flip a switch, they lose $15,000 worth of chickens. When the same thing happens to a pharmaceutical shipment, the loss may be in the millions of dollars, not to mention potentially adulterated product slipping through to consumers.”

Which raises a related puzzler: If these shipments are so valuable, why not ship any quantity of product valued at, say, $20,000, in refrigerated trucks? Many food manufacturers maintain entire facilities, including loading docks and tractor trailers awaiting loading, under strict temperature control. European biotechnology companies are beginning provide similar treatment to their high-value products.

“There’s a lot of mythology surrounding pharmaceuticals,” observes Bob Townsley, “that they’re so different from other products, and that regulations get in the way of innovation. In fact, pharma regulations are not much tighter than for shipping and storing food and drink. The real problem here is that until recently pharmaceutical companies didn’t look seriously or critically enough at their supply chain logistics. They never got their act together, which is why they are still well behind foods and other industries.”

Logging in Temperature Security

Pharmaceutical shipments vary tremendously in size, from several cubic-meter pallets to single doses. Transport by refrigerated trucks (“reefers”) makes sense for high-volume products, but most drug orders do not justify renting an 18-wheeler and actually ship better in small, insulated containers.

For decades, biologists and medical labs have used cold-ship technologies to send samples across town or across the globe. Microelectronics have enabled a new group of products, temperature loggers, which provide a validatable, 21 CFR Part 11-compliant temperature record for containers of almost any size.

Loggers fill a “knowledge gap” in cold chain implementation, allowing shippers to document what was previously taken as an article of faith. In the past, manufacturers would assume a shipment was fine as long as dry ice remained on delivery. Loggers change that by providing downloadable plots of temperature versus time, an essential bit of knowledge when releasing labile product to the marketplace.

Temperature loggers eliminate any doubts and supply a record suitable for framing (or submission to regulators). Loggers make sense for larger packages, where dry ice cannot be counted on to stay put, and for very valuable products. But their cost can only be justified when the recipient returns the devices to the shipper.

Loggers have found another interesting use: validating and testing shipping containers, routes, and carriers. “Shipping product manufacturers use multiple loggers to validate refrigerated units, and after servicing, to re-validate,” says Kevin Bull, CEO of Veriteq Instruments (Richmond, B.C.). “Companies designing new shipping containers also use them to validate performance under a variety of conditions.”



GETTING SHIPPING DOWN COLD

Several of our cold chain experts volunteered tips on what it takes to deploy a successful cold chain strategy.

“Implementing a successful cold-chain strategy requires coordination and communication,” says Richard Street, Manager of Abbott Global Supply (North Chicago, Ill.). From preparation time to delivery, formalized procedures and communication plans, including escalation matrixes, must include everyone who comes in contact with a shipment. “Proper timing of order dispatch and receipt is essential to ensure products arrive before weekends and holidays, and for international shipments, that they clear customs quickly.

“Mapping out the entire supply chain maximizes the positive impact of cold chain,” Street adds. “At Abbott, this is achieved through collaboration between logistics, quality assurance, and packaging.”

George Cox, director of supply chain operations for MedImmune (Philadelphia, Pa.) offers the following check list:
  • Logistics and R&D should hook up early, during product development, to establish a product’s stability issues and propose how to deal with them.

  • Don’t try to re-invent the proverbial cold-chain logistics wheel. Logistics companies have much more experience in cold shipping and handling than almost any pharmaceutical or biotech company. “There’s plenty of help out there,” says Cox.

  • No matter how satisfied you are with your cold chain strategy, never stop trying to improve it.

  • Be flexible and open to new technologies: What works well in dead of winter may not protect product on a sweltering tarmac in mid-July.
From Serono’s Werner Bucher:
  • For tighter control over temperature and other shipping/storage variables, limit the number of logistics partners to the absolute minimum.

  • Audit all logistics partners, no matter how minor their role.

  • Change shipping providers with great caution. Remember: the product may be out of your control, but it is still your responsibility.

  • Choose the best transport containers possible, preferably those that accommodate temperature monitoring and/or control.

  • The weak link in logistics is probably package handlers at airports. To assure they know what they’re supposed to do, print or label handling directions plainly and visibly in several locations on the shipment.

  • Have a plan for dealing with temperature “excursion.” Corollary: Good long-term stability data equals peace of mind.
And last, but not least, from Carla Reed:
  • Packaging and documentation should account for the literacy skills of everyone who comes into contact with the shipment. Warning labels should contain explicit language, even icons, to indicate special handling needs.

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