Consider how important it is for the physicians administering your drugs to have a good perception about your company. And by good perception, I don’t mean that they just are satisfied with the drugs you produce, I mean they like the drugs and your company in general; they feel confident that you’re top-notch. Sure, there is a lot of marketing that goes into creating that perception, but what you may not realize is that your cold chain processes and technologies can have just as big an impact on a customer’s perception as any advertising or marketing campaign. Imagine a physician who receives a batch of antibiotics that are required to be kept at a cold temperature but are warm to the touch when received. Although the drugs may have been delivered from a distributor that is many steps removed from the original manufacturer, the doctor is still going to blame the manufacturer. The pharmaceutical cold chain is receiving a lot of attention these days as increased counterfeiting and diversion practices throughout the distribution channel are uncovered.
The cold chain is also being more closely scrutinized due to the increase in the manufacture of biologics and other temperature-sensitive medicines such as:
- diagnostic and laboratory reagents
- blood fractions
- blood reagents.
In response, regulators are asking pharma/biopharma companies more detailed questions about how their products are transported and stored from the point of manufacture to final delivery. Auditable records of what process was used to transport a drug and what materials were used to protect and control the temperature of the shipment are becoming the norm.
In 2008, the FDA conducted inspections of drug warehouses of varying sizes. Forty-two inspections were conducted, and 16 inspections resulted in the issuance of an FDA 483. The most common observations included:
- a lack of equipment calibration
- a lack of procedures or documentation for investigations into excursions
- a lack of documentation that labeled conditions were maintained during transport.
“Regulators are also beginning to consider that ‘ambient’ products should be distributed in a more temperature-controlled environment,” explains Karl Kussow, manager of quality and validation at FedEx Custom Critical. “So, the ‘cold chain’ is beginning to also include more ambient or room temperatures.”
Where Breaks Occur In The Cold Chain
Proactive pharma/biopharma companies are starting to analyze their cold chains to determine where improvements should be made. Often this includes a review of the two types of container technologies — active and passive. “Both types of containers are designed to maintain a stable temperature, but they go about it in different ways,” explains Kussow. “An active container responds to external temperatures to remove heat from the cargo area so that the temperature around the cargo is stable. Recent technology also has enabled the production of active containers that are able to both heat and cool. These compressor-powered containers are particularly effective in maintaining the desired shipping temperature regardless of changes in the external temperature environment. In designing a passive package, the engineer predicts the temperature environment during transport and builds a package that will hold a stable temperature for the expected duration of the shipment.”
According to Dan Gagnon, director of UPS Healthcare Logistics, there are many common breaks within the temperature-sensitive product supply chain, starting at the shipper’s location through to delivery. Each stage of the chain must be managed with strict adherence to accurate, standard operating plans (SOPs). Gagnon says the following are a few key areas to review:
At the shipper’s site — Packaging materials that are not preconditioned (i.e. precooling all packaging materials, such as cardboard, coolants, and styrofoam, when they are prepared for packing) or active containers that have not been tested pose significant threats to solutions designed to hold temperatures. Pack-out SOPs must be strictly adhered to, as even a simple deviation from block dry ice to pellet dry ice can be disastrous for a shipment.
At the airport/freight facility — Freight facilities and airports that are congested with cargo create a risk for excursion (i.e. temperatures falling out of the recommended range). Freight staged in open freight facilities or on a ramp can be exposed to extreme temperatures if left unattended. Freight must move directly from the freight facility to the aircraft for loading. Delays on the ramp during the aircraft loading process become a key concern, especially in winter when using an active container without a heat source.
On the aircraft — Passive or active containers positioned in the belly of an aircraft or near a door could be exposed to freezing temperatures. Faulty door seals and poor airflow within the body of the aircraft can contribute to temperature excursions. At 35,000 feet, the air temperature can get to minus 50 C, which can have a significant negative impact on containers without heating sources. Many 2- to 8-degree Celsius products become completely destroyed when frozen, which is why freezing is one of the biggest concerns of pharmaceutical shippers.
At customs/FDA holds — The most common break occurs because of issues stemming from brokerage and customs. These unexpected delays often occur at an inconvenient time in the night that requires the freight to be staged prior to resolution. This is a common issue which must be addressed with preplanned and pretested contingency plans.
“Most of the time the cold chain supply is successfully maintained through extensive planning,” explains Robert Donnell, business development manager at Dubin PLC, a provider of cold chain supplies for the pharmaceutical industry. “Breaks in the cold chain can also occur due to unforeseen circumstances experienced during transportation or dramatic weather changes. In less developed countries where the infrastructure can be less reliable, planning and expertise is crucial to minimizing disruption.”
Maintaining Cold Chain Integrity
As the number of temperature-sensitive medicines increases, so too do the number of solutions and technologies used to transport those drugs. And since no one solution is best for all drugs, you need to carefully evaluate your cold chain’s capabilities and match them accordingly to your product. Better yet, enlist the help of an expert who is used to procuring, shipping, and distributing cold chain products.
FedEx’s Kussow says that internationally, a best practice is to containerize the temperature-sensitive product in a package that can maintain the desired temperature range throughout the lane it will travel from shipper to consignee. This can be done with active and passive technologies, both of which are being advanced, but the use of passive seems to be growing, probably due to active containers being heavier and more expensive.
Beyond new combo heating/cooling technologies that can sometimes even remove the need for dry ice, there are many new devices that capture a shipment’s location, temperature, humidity, and light and send that data back to the shipper through GPS/cellular technology. “Many of these devices are being tested to ensure they do not interfere with aircraft technology,” says UPS’ Gagnon. “The pharmaceutical industry sees promise in this technology, but is still trying to figure out how to get the right return on investment. Collecting shipment information in real time can be expensive. This expense can sometimes be justified when the carrier has the ability to intervene when excursions occur; however, service levels in the 99% range challenge the overall value. As costs for the devices come down and the industry figures out how to use the information being collected, investments in this technology will increase.”
Going back to the example of the physician who receives the drugs, temperature-tracking technologies applied at the unit dose level can also be very helpful in creating and maintaining that positive perception of your company. For example, Temptime makes miniaturized, self-adhesive time-temperature indicators which are permanently affixed to individual units. These markers inform users if the product has been exposed to potentially damaging temperature ranges during its travels through the cold chain.
In March 2009, Temptime worked with Harris Interactive on a survey of physicians regarding the proper storage and handling of temperature-sensitive medicines. “Things can get very complex in the cold chain, and there are many ways a product can be mishandled inadvertently,” says Ted Prusik, Ph.D., senior VP at Temptime. “The thrust of the research was to understand if physicians had concerns if a temperature-sensitive product at the unit level was stored and handled correctly from the manufacturer to their door.” The physicians’ fear, of course, was that heat-damaged medicines could lose efficacy, potency, or even lead to adverse effects.
Two hundred fifty-one doctors responded, with all stating they were very concerned about the status of the pharmaceutical cold chain. In fact, 83% of the primary care physicians and pediatricians and 72% of the specialists (e.g. endocrinologists, hematologists, oncologists, and rheumatologists) reported having experienced a break in the cold chain. Furthermore, four out of five of the physicians surveyed said they felt there was a need for a device to track temperature at the unit level and that they would have more confidence in the companies that produce medicines with such tracking capabilities. Now that’s the type of perception you want your end users to have of your company.