As the administration of compounded sterile preparations (CSPs) within patient homes and other alternate care sites continues to expand in scope and volume, medications and related care are now routinely delivered to patients often at great distance from where they are prepared. This separation traditionally has been bridged through the use of delivery mechanisms that rely on common carriers such as UPS, FedEx, USPS, and/or courier services. In many cases, delivering medications in this manner can be cost-effective; mail order pharmacies have been sending medications through such carrier services for years. While the practice has been generally accepted for some time, it often fails to address concerns or account for potential factors that can influence medication integrity. When considering the transport of CSPs, maintaining the appropriate temperature range throughout the shipping cycle is often as challenging as it is critical.
Established beyond use dates derived from practice standards outlined in USP Chapter <797> and published extended stability data indicating use by dates for CSPs are predicated on the product remaining in the intended storage conditions, including room temperature, refrigerated, or frozen conditions. Factors that influence these conditions during the course of product shipment are numerous, but none may be more important than the actual shipping container itself. Commercial thermal shipping containers are commonly utilized for shipping and transport of perishable, temperature sensitive items, including CSPs. Unfortunately, product choice considerations often revolve around cost, warehouse space, ease of use, and environmental burden, neglecting actual evaluation of product performance. As such, it is critical to ensure that the shipping containers used to transport CSPs are proven to maintain the necessary environmental conditions.
Finding the Best Fit
At Providence Infusion and Pharmacy Services—part of Providence Health & Services, the largest health care provider in Washington state—the home and ambulatory infusion department decided to assess its currently utilized thermal shipping containers versus other commercially available thermal shipping containers in the market. Four primary comparison factors should be considered in assessing containers: warehouse storage space, overall cost, environmental burden, and product performance. Because significant fluctuations were found in thermal equivalence amongst the containers, we focused on assessing product performance and designed a two-phase study to determine the utility of each thermal shipping container in terms of its ability to maintain refrigerated conditions over a designated period of time.
The goal of the study was to evaluate the effectiveness of five thermal shipping containers; one of the five was the current thermal container used by our facility, while the other four were selected based on their promoted equivalency to the current thermal container by their suppliers (see Table 1: Container Characteristics). The study’s two phases employed the same methodology and differed only in whether the medication was packed into the thermal container without prior refrigeration (phase 1) or after prolonged refrigeration (phase 2).
Phase 1: Previously Unrefrigerated Preparation
In the first phase, all five thermal containers were packed in the following, identical fashion (in order from bottom to top):
The bottle of non-toxic glycol solution was oriented within each container so that it rested on top of the 0.9% sodium chloride bag and was not touching, or in close proximity to the gel packs. The thermal containers were closed as specified by the supplier and the outer boxes were taped and stored at ambient temperature within the compounding facility’s warehouse area. The digital thermometer display remained outside each package and each monitoring thermometer was calibrated and traceable to NIST standards with a specified range of -58˚F to 158˚F. The monitoring device claimed an accuracy to ± 1˚C and offered two different sampling rates—once every 10 seconds or once every 60 seconds—the latter of which was selected as the sampling rate for our study. The LCD indicated the current temperature and the device’s internal memory automatically stored the lowest and highest reading obtained throughout the observation period. Ambient warehouse temperature also was recorded at various times over a 72-hour period using the same model of thermometer, but without using the miniature bottle of glycol solution.
Phase 2: Previously Refrigerated Preparation
The second phase was performed using the same items referenced above, but the 500-mL bag of 0.9% sodium chloride had been refrigerated for 15 hours prior to packing. Both internal and ambient temperatures were recorded at various times over a 72-hour period.
Phase 1 Results: Previously Unrefrigerated Preparations
When reviewing the results of phase 1 (previously unrefrigerated bag of 0.9% sodium chloride), all of the containers had an initial recorded temperature of between 60˚ and 61˚F upon packing and sealing; the ambient warehouse temperature ranged from 66˚ to 69˚F throughout this phase of the study period. Subsequent to packing and for the duration of the 72-hour period, temperature records indicated that the previously unrefrigerated bag of sodium chloride did not reach an acceptable refrigerated temperature (36˚ to 46˚F) inside any of the thermal shipping containers. Rather, temperatures ranged from a low of 50˚F (container 1, observed after 8 hours and container 4, observed after 5.5 hours) to a high of 60˚F after 24 hours, 66˚F after 48 hours, and 66˚F after 72 hours. The high results all were recorded for container 5.
Phase 2: Previously Refrigerated Product
Product performance during phase 2 improved, but the overall results still showed transport temperatures higher than the acceptable range during the study period. Each of the thermal shipping containers had an initial recorded temperature of between 41˚ and 43˚F upon packing and sealing; the ambient warehouse temperature ranged from 65˚ to 68˚F throughout this phase of the study period. Temperature results indicated that two of the five thermal shipping coolers maintained acceptable refrigerated conditions (36˚ to 46˚F) for more than 24 hours. Results at 24 hours were analyzed due to the facility’s recognized standard shipping times for CSPs. Container 1 maintained appropriate refrigerated conditions for approximately 29 hours, while container 4 maintained refrigerated conditions for approximately 32 hours. The remaining three containers moved outside of the appropriate range (+9˚ to +10˚F above accepted range) within the 24 hours. Specifically, container 2 only maintained proper refrigerated conditions for approximately 2 hours, container 3 for approximately 7 hours, and container 5 for approximately 4 hours.
Study Results Drive Operational Improvements
The results of this study raised many concerns, yet provided a stimulus for our organization to more closely evaluate commercially available shipping containers and internal shipping processes. Of note, none of the refrigerated container suppliers were able to provide data to prove the temperature control capabilities of their products.
Our primary distributor for medical and surgical supplies responded to our request for data supporting temperature control claims for the cold storage thermal containers that they offered, by providing step-by-step packaging guides for each of the two cooler brands they supply. The packaging guide detailed specifics as to how the cooler should be loaded, including packing order, insulating materials required/recommended, and number and size of gel packs required given the maximum daily temperature of the originating location. In reviewing the packaging guides and comparing recommendations for the same size containers utilized in this study (12x12x12), the number of gel packs needed for each temperature range was specified. For example, moderate temperature was defined as an outside daily high ranging from between 60˚ and 70˚F, hot temperature listed with a range from 70˚ to 90˚F, and extreme hot listed at above 90˚F. The moderate temperature range best matched the temperature range in our study, and required, in order from bottom to top: two 24-oz frozen gel packs, two layers of bubble wrap, the CSP with all void space around the product filled using craft paper or bubble wrap, two more bubble wrap layers, and then two more 24-oz frozen gel packs. If ancillary supplies also were being sent they could be added to the remaining space at the top of the box (above the gel packs) after another layer of bubble wrap was used to cover the packs. For conditions of high temperature or extreme hot temperatures, for the same size box, packed in identical fashion, six and eight 24-oz frozen gel packs are suggested, respectively.
The packaging guide for the second container also delineated requirements by temperature conditions of mild, hot, and extreme hot. It recommended similar packing and insulating procedures and suggested that for a 12x12x12 cooler a total of four, nine, and twelve 24-oz packs be used when temperatures range from mild, hot, and extreme hot, respectively. It was therefore noted that if more frozen gel packs had been used in the study, results would likely have improved. Extra bubble wrap or craft paper might have better insulated the 0.9% sodium chloride bag. However, when numbers of frozen gel packs suggested for use exceed four, the practicality of effectively utilizing remaining space within the cooler becomes a factor. Therefore, identifying the coolers that require the least number of gel packs to maintain refrigerated conditions is warranted to maximize space for medication and supplies, reduce the overall weight of each package, and limit the total number of packages that the organization must send to each patient.
In addition to the packaging guides, our primary medical supply distributor provided step-by-step assembly instructions. Both the packaging algorithm and the step-by-step assembly instructions would prove useful for any organization and should be included in quality control policies and procedures for shipping to ensure uniform consistency in packing and shipping methods. However, it should be noted that even when following the provided guidance, no data was available guaranteeing CSPs would maintain a specific temperature range for the duration of transport. Thus, organizations should incorporate quality control processes that allow for verification or collection of such data internally. Initial product verification should assess differences in thermal cooling capability when previously unrefrigerated product is used versus continuously refrigerated products. Ongoing quality control plans should account for evaluating the impact of temperature changes throughout the year, monitoring various geographic shipping locations, and validating that each shipping or delivery method utilized (if multiple carriers or delivery methods are used) provides consistent results.
Incorporating process improvements to verify the quality measures related to maintaining refrigerated conditions during transit of CSPs is paramount. USP Chapter <797> notes that “inappropriate processes or techniques involved with packaging, handling, and transport can adversely affect quality and package integrity” of CSPs. In addition, TJC states in standard MM.03.01.01 that medication storage is designed to assist in maintaining medication integrity, promote the availability of medications when needed, minimize the risk of medication diversion, and reduce potential dispensing errors. Interpretation of this standard, in combination with MM.05.01.11, which outlines safe dispensation of medication, indicates the need for operational systems that address shipping and delivery challenges. Therefore, incorporating the utilization of available tools for temperature tracking into standard operating procedures is warranted.
An array of temperature monitoring devices is available for transporting CSPs. The devices vary in their level of complexity, cost, and monitoring approaches. Basic solutions include time and temperature tags, which utilize heat- or cold-sensitive chemicals and indicators. These disposable, relatively inexpensive tags are available in versions that allow for detection of prolonged exposure to either freezing (<32˚F) or room temperature conditions >77˚F. However, these indicators lack any continuous monitoring capability for assessing the maintenance of refrigerated conditions.
Other available devices provide the ability to continuously or intermittently sample temperature. These devices are often reusable, are about the size of a credit card or a deck of cards, and come in both electronic versions with downloadable data points when attached to a computer, or as non-electronic devices that create a permanent, internal strip-chart report that is removed by breaking the seal and pulling the strip-chart out. These information sources are then returned to the compounding facility for interpretation and verification of cooler performance. Such devices are capable of recording temperatures within a range that expands well into freezing (≤ -20˚F) and also into extreme high temperatures (≥100˚F). Other less robust but useful monitoring devices include those that report the high/low temperatures during the delivery period. The downside to high/low monitoring systems is that there is no data availability detailing when temperatures may have exceeded or dropped below the acceptable range.
Continuous or intermittent temperature monitoring devices that monitor other potentially important parameters also are available. In addition to temperature, one device, utilized in conjunction with a common shipping carrier, includes the option to also monitor package location, light exposure, relative humidity, and barometric pressure. Custom settings for each measure can be programmed and the sender will receive alerts if one or more of the monitored variables are outside of a predetermined range.
Identifying the correct cold storage thermal shipping container to utilize for transport is critical to ensuring product integrity. While ease of use, storage space, and cost are commonly considered, the most important consideration should be product performance. Request all available data from manufacturers and critically evaluate this data for applicability. We now refrigerate our CSPs prior to shipping whenever possible, to ensure the best possible outcome. Adopting standard operating procedures that include detailed algorithms for packaging and applicable cooler assembly ensures consistency among staff practices; consider utilizing staff competency testing for packaging policies and procedures.
The implementation of routine quality control checks of continuous or intermittent temperature monitoring devices is needed in order to verify actual cooler performance. Quality checks also allow for the comparison of delivery methods to ensure consistency among carriers. Finally, organizations should determine how much risk they are willing to accept and balance the pros and cons of each delivery method. Methods that decrease package misadventures can have a significantly positive impact on patient care outcomes and can reduce overall financial risk to the organization.
Jason L. Iltz, PharmD, is the pharmacy operations manager for Providence Infusion and Pharmacy Services in Spokane Valley, Washington, as well as a clinical associate professor of pharmacotherapy at Washington State University College of Pharmacy. Jason received his doctor of pharmacy degree from Washington State University. He has more than 15 years of experience in infusion pharmacy practice and is also a certified immunization provider with a collaborative practice agreement for the prescribing and administration of vaccines in Washington State. In 2011, Jason was named pharmacist of the year by the Spokane Pharmacy Association.
It is imperative that CSPs maintain both purity and integrity throughout the shipping cycle, yet unforeseen disruptions or circumstances can have a significant impact on patient safety and operational efficiency. Receiving a medication deemed to be unusable or having delays in medication receipt can negatively affect patients who rely on these medications to sustain life or recover from severe illness. Operational impacts include both time and cost considerations in remaking an unusable preparation and redelivering the package. Such issues should be taken into account when choosing suitable delivery and shipping options. Special handling by courier services can significantly decrease damage rates and other shipping misadventures.
The organization also should determine how much financial risk it is willing to accept. Capital insurance programs are available from common carriers that cover perishable loss for shipped packages. Options for coverage vary including the choice to cover some or all packages that leave the facility. Other add-on or rider policies that cover perishable loss can be added to existing business insurance plans. These policies vary significantly in coverage terms and should be examined closely before a decision is made to increase coverage.
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