By Susan Marrano and Gary Savvas
In the clinical supplies business, you need to be capable of handling and distributing the drug supply both domestically and internationally within very specific temperature ranges. The percentage of investigational drug supplies requiring specific temperature control is far greater than for approved drug products, due to limited stability data and the development of new molecules by the biopharmaceutical industry.
While planning for the distribution of clinical supplies, the final component in a long chain of events is often overlooked as a potential source of last-minute delays. For example, a clinical site has received its shipment of investigational drug product and has reported a temperature excursion. Now, the site needs to know if the product is acceptable for use before the scheduled patient visit. This is the point where any unresolved questions about dealing with temperature excursions come to light, usually with little time to clarify any outstanding issues.
Even with the use of the best shipping materials and temperature monitoring technology in the industry, reports of temperature excursions are still a possibility. Careful planning ahead of time will help to reduce the chance of actual excursions and will ensure that false excursions are significantly reduced or resolved efficiently.
Identify Packaging That Is Suitable For Specific Temperature Ranges
Temperature control, capacity, availability, and economy are all factors to consider when selecting suitable packaging. For product that is highly temperature-sensitive, a prequalified shipper (i.e. container used for shipping) may be the only option. Manufacturers of prequalified shippers have performed their own testing in accordance with industry-accepted standards. If validation is required for specific products with varying payloads, additional testing can be outsourced or performed in-house. Prequalified shippers hold temperatures within specific ranges for varying durations, up to several days. A potential drawback is that payload space can be more limited, and options may be further reduced depending upon the dimensions of product shipped. Prequalified shippers with phase-change refrigerant material may offer larger capacity relative to shipper size. Many prequalified shippers may be reusable, but the logistics become more involved since shippers need to be returned and accepted back into inventory. If product stability permits, a nonprequalified insulated shipper may be sufficient for project needs. It is the most economical option, with a variety of readily available sizes.
The distributor can select the appropriate shipper size based on volume and dimensions of supplies being sent. Shipper capability may vary widely; therefore, product stability is critical to shipper selection. Even when the appropriate shipper has been identified, it may not be available in all countries where the study is being conducted. When equivalent shippers are unavailable, source and forward supplies to the distribution depot. Careful selection of packaging supplies will help ensure that product remains within acceptable temperature ranges.
Active vs. Passive Units
Pallet-sized active units are self-regulating and will hold temperatures within a tight range for as long as necessary, provided that batteries are in good working order and that power for recharging is available along the route. Be sure to confirm with your courier their access to power and proper electrical connections before allowing them to ship an active unit. Although most active units have built-in temperature monitoring capability, it is highly recommended to use additional monitors for redundancy.
Prequalified pallet-sized passive units are generally less expensive than active units, weigh less, and therefore are less costly to ship. These and smaller prequalified shippers might be ideal for short trips overseas to areas where import delays are unlikely. For longer overseas shipments where delays are possible, a thorough understanding of shipper handling is necessary. Establish close communication channels with the courier to ensure it adheres to special handling requirements. Replenishment of gel bricks, if possible, needs to be arranged with the courier.
Specialty services can include the use of certain prequalified shippers not readily available at the depot, with preconditioned gel bricks delivered on-site; special transit routes and shipping arrangements to ensure the fastest possible delivery domestically and internationally; or the use of refrigerated trucks or vans. Specialty couriers will be highly trained in the use of their products and will have a solid understanding of handling along the entire route to ensure temperatures remain within range.
Potential Issues That Arise During Transport
Even for shipments within the continental United States, delivery time can be much longer than originally anticipated. Real-life examples include: planes grounded by storms or mechanical issues, shipments bumped from overscheduled flights, delivery to incorrect locations, or shipments unpacked by people not directly involved in the study. In the last case, product may not be placed into appropriate storage conditions immediately, and temperature monitors may be handled incorrectly. Creating bold labels for the outside of the shipper with information identifying the product’s temperature requirements and indicating that a temperature monitoring device is enclosed is a good first line of defense.
In order to facilitate a quick resolution in the event of a temperature excursion, develop procedures, acceptance criteria, and communication channels for determination of product acceptability. This is the most critical step and the one most often overlooked — until patients are scheduled at the site and product needs to be approved for use immediately. For example, a site may call the distribution depot to report the excursion, but it is not for the depot to decide whether product is acceptable for use. The depot must pass along the information as quickly as possible to the sponsor. The responsible personnel will determine acceptability based upon scientific review of stability data. Delays occur when it has not been made clear who will decide whether product is acceptable and who will relay that information back to the site. Additional delays can occur when the decision-making parties are located several time zones away.
To increase site compliance during receipt of temperature-controlled shipments and reporting of temperature data, ensure that clear instructions and related forms are included with every shipment. Instructions can include required temperature for storage, directions for deactivating and reading temperature monitoring devices, and appropriate contacts in the event of a temperature excursion.
Temperature reporting can be expedited with the use of USB temperature monitors that create their own PDF files. Readouts can be downloaded and forwarded via email to contacts immediately. Although we are in a digital age, analog chart recorders are reliable and provide immediate readouts. If non-USB temperature monitors are used and need to be returned to the depot for download, plan to include mailers and preaddressed air waybills with each shipment. This will simplify the process for sites and ensure that monitors are returned quickly.
Understanding False Excursions
False excursions at the end of transit are where the majority of excursion contingency plans come into play. For example, a site may report an excursion when the acceptable range is 2 to 8 degrees C and actual transit temperatures are 4.9 to 5.2 degrees C. Why? Often, an “excursion” occurs just after delivery is made and a digital temperature monitor is removed from the shipper. The final reading is taken at room temperature just before the monitor is turned off. In other instances, sites fail to turn off the monitor and keep it at room temperature, even if the product has been placed into a refrigerator immediately. In these cases, confirm the time the site placed the product into refrigeration. Use this information to justify the event as a false excursion. With chart recorders, sharp spikes will appear if the shipper is bumped during transit, and sites may interpret the spikes as excursions and report them as such. False excursions can delay product use; therefore, it is crucial to project success that temperature excursion procedures are in place before study start-up. The same rules apply for false excursions as for actual excursions: Communication channels need to be determined ahead of time, return of temperature data needs to occur as quickly as possible, and product acceptability needs to be determined based upon defined acceptance criteria.
Sponsors of clinical trials invest time and money to set up clinical sites, recruit patients, and manage studies. Delays in getting the drug to patients can negatively impact timelines and even discourage patients from continuing with treatment. Therefore, it is important to select appropriate packaging materials, define responsibilities, and establish clear communication channels prior to the first shipment to minimize excursions. Despite the best efforts of all parties to prevent temperature excursions, they still may occur. With forward thinking, careful planning, and attentive management, the entire process can flow smoothly and efficiently.
About The Authors
Susan Marrano is a distribution project manager at Xerimis. She has 15 years’ experience with clinical supplies and is primarily responsible for temperature-controlled distribution.
Gary Savvas is director of operations at Xerimis. He has 10 years experience in the biopharm industry and has held positions in quality assurance and manufacturing.