Temperature-Monitor Positioning within Active and Passive Insulated Packouts
Optimal placement of temperature monitors within product shipping containers that will most accurately document temperature variation during transit is important to maintaining temperature control for heat-labile pharmaceuticals and biologicals. The operating principles discussed apply to all sizes of insulated, noninsulated, active, and passive shipping containers used to protect product for the duration of transit.
Several types of temperature-monitoring devices exist: chemically activated sensors, battery-powered mechanical-recording devices, minimum and maximum temperature–reading thermometers, freeze indicators, heat indicators, and a variety of battery-powered electronic devices that incorporate an assortment of operating features including pass/fail readouts, computer connectivity, time-delayed activation, radio-frequency capabilities, data storage, and local programmability.
Design Qualification: A process that identifies a need for and the intended use of instruments, equipment or systems. Design Qualification defines the functional/
operational and/or user requirements prior to purchase.
Operational Qualification: Documented evidence establishing confidence that the equipment, software, instrument, or ancillary systems operate as intended and are capable of consistent operation within established specifications.
Performance Qualification: Documented evidence that the process or system, when operating in its environment under typical conditions, performs as intended in meeting predetermined specifications.
Temperature Monitor: A portable, independently operating device or visual indicator that has the ability to monitor and record temperatures within a specific area or container. For cGMP purposes, any data output from a temperature monitor that will be utilized for quality disposition of product needs to be validated. Portable electronic temperature monitors are usually battery powered. Visual temperature indicators are usually chemically activated. Other terms for Temperature Monitor that have been utilized in the past include Time-Temperature Indicator (TTI) and Data Logger.
A temperature monitor placed within a shipping container must be located in a position that is representative of product temperature during transit. In this way, the in-transit temperature data that are obtained can be compared to product temperature specifications and stability data. Such comparisons allow for the evaluation of any impact to the safety, potency, and efficacy of the product that may have occurred during the journey.
While the temperature of the product itself is the critical variable, it is not always easily determined within a packout during transport. A validated measurement of temperature would require a complex system of thermocouples located within the primary containers. However, since this method would destroy the package integrity, a nondestructive alternative method is required.
The most generally accepted alternative is to place the temperature-monitoring device in close proximity to the product in order to measure the air temperature surrounding the primary container while avoiding direct product contact.
Another alternative approach to determine the optimal location of a temperature monitor is to perform a “worst-case” analysis. This approach requires thermal-mapping data of the transit container derived from operational qualification (OQ) activities that, upon interpretation, delineate the range and heterogeneity of temperatures expected during transit. The temperature-monitoring device would be placed within the packout at a location that demonstrates the widest temperature variation. While active and passive insulated packouts are designed to limit such variation, temperature swings of 2°C are typically seen and are dependent upon the characteristics of the container. Although the air temperature may not be entirely representative of the product temperature, this approach is beneficial in that the device will record the widest ranges of air temperatures within the packout.
Ultimately, for an insulated packout that has passed both OQ and performance qualification (PQ), one could recommend any location within the packout to measure temperature, since all product locations will be within temperature specifications as demonstrated in the thermal map of the packout.
DETERMINING YOUR APPROACH
The strengths and weaknesses of the product-proximity approach versus the worst-case approach depend upon the specific packout under consideration. Either approach may be taken as long as the proper procedural controls and data interpretation practices are used. The optimal placement of temperature monitors in a given packout may depend upon the following
• The number of primary and secondary packages within the payload, which is derived from the minimum and maximum volume and mass studies performed during design testing.
• The amount of drug substance contained in the packout, also derived from the minimum and maximum volume and mass studies performed during design testing.
• The actual volume and mass of the payload.
• Air convection or circulation within the shipping container.
• Worst-case design characteristics of the packout.
• The position of temperature-control materials (gels) within the
In completing a satisfactory OQ and PQ for a packout that clearly defines the mass, volume, time, and temperature parameters of the container, the need for constant temperature monitoring of ongoing shipments is not a requirement. However, periodic monitoring should be a part of a qualification maintenance program.
NEED FOR MONITORING
The purpose of monitoring the temperature of product while in transit is to ascertain a level of temperature compliance and to determine whether there is a chance of any degradation or loss of potency. Such product changes might occur if the product is exposed to external ambient temperatures beyond the transit temperature specifications. The temperature monitor provides the documentation that the product temperature is satisfactorily maintained in accordance with the product stability profile described in individual country regulatory filings that support product safety and efficacy.
The temperatures seen during transit should be in alignment with those experienced during the OQ of the packaging and shipping materials.
The Design Qualification (DQ) parameters for a shipping container specify the correct shipping and distribution temperature range for the product as delineated in stability reports.
The OQ testing calls for alignment with the DQ requirements, i.e., the temperatures supported by product testing data. During OQ testing, thermocouples measure the product temperature directly, either by placement within the primary container in direct contact with the product, or contiguously attached to the primary container.
Consequently, the OQ testing data accurately describe the product temperature inside the insulated package. Frequently, an “air” probe thermocouple has been utilized in the OQ phase of testing that measures the air surrounding the product in the payload, thereby approximating the readings that a traditional temperature monitor will record during shipment. During OQ testing, there is usually a small difference in temperature between the air surrounding the secondary package and the product within the primary container. This is due to the insulating characteristics of air itself, as air has little density. As stated in the laws of thermodynamics, heat only passes from the hotter to the cooler. Within the packout, heat transfer occurs because of the air movement or convection flow within the packout, the insulating properties of the secondary packaging, the conduction of heat across the surfaces of the primary container, and the insulation property of the air itself.
The OQ report specifies the minimum and maximum mass and volume for the shipper and reflects the performance capabilities of that shipping container for the times and temperatures for which the shipment was designed in the DQ. The PQ document defines the specific container, unit, case, carton, or individual market packages shipped. The temperature monitors contained within the PQ shipments are representative of actual product shipments.
The absolute need for temperature monitoring is based upon the known product stability data, its regulatory filing, the label storage condition, and the ambient temperatures to which the product will be exposed during transit.
Considerations for the use and placement of temperature monitors include the following:
Initial time delay of the temperature monitor. The time delay programmed into the validated temperature monitor allows for the time required to achieve an equilibration of temperature within the packout. The OQ may call for the packout to be assembled with the shipping container, coolant gels, product, dunnage, and other packing materials such that ambient (room) temperature air is initially enclosed within the packout. Depending upon product and component volume and preconditioning, plus the length of time required to complete the packout, several hours or longer may be required for the air inside the shipper to equilibrate to the expected internal shipping temperature once a container is sealed. During this package equilibration period, the actual product temperature may drift toward ambient conditions, depending upon the package configuration. This can be seen by evaluating the temperature data in the associated OQ tests. The air being measured immediately next to the product may read outside of the product shipping temperature specification until all the contents within the shipping container fully equilibrate. A time delay programmed into the temperature monitor helps to eliminate or limit false positives that can occur during equilibration.
It is important to evaluate and understand the packout and shipping fulfillment process prior to implementation of a time delay in order to retain proper temperature control of the product. The packout equilibration time and product temperature impact should be in conformance with the stability profile of the drug.
Guidance for acceptable locations to position the temperature monitoring device. Consider the
• The temperature monitor should be placed as close to the product as practical. It is generally more important that the temperature monitor be located in a position that is representative of the product’s temperature than to be located in a worst-case position.
• The top center position in a packout is frequently utilized as a worst case. Hotter air in the container rises because of internal convection and gathers more readily toward the center of a packout. Applying heat transfer principles, a worst-case cold position in a packout may be seen at the bottom where there is settling of colder air.
• Secondary packages should not be disassembled or destroyed in order place the temperature monitor closer to the product.
• Temperature monitors should not be buried in the payload such that they are thermally protected by other product packages and do not represent the worst-case position within the payload. For example, the temperature monitor should not be placed at the base of a case or carton of product near a cooling source (gel), which would insulate that location from temperature variations within the packout.
• Temperature monitors should not be placed immediately next to a coolant gel, which is not representative of the product’s true temperature. The exception to this situation is when the packout design calls for gel wraps to encase secondary finished packages directly. While the temperature monitor is in contact with both the gel and the product, it will capture the worst-case situation within the packout as the gels warm from the outside-in. The product will be the final point in the packout to succumb to warming or cooling from exterior ambient temperatures.
• Where a corrugated payload box defines the maximum volume of a payload, the temperature monitor should be placed inside the corrugated box. Again, product should not be displaced in order to fit the temperature monitor into a complete corrugated product shipper. In this case the temperature monitor should be attached to the exterior of the full corrugated box to approximate the product’s temperature.
• If a protective plastic bag is used to isolate the product from contact with other products or gels, the temperature monitor should be placed inside of the bag to better represent actual product temperature. Alternatively, placement of the temperature monitor outside of the plastic bag would represent the air within the packout.
• For active containers with full or partial pallets of product, the method of conveyance is based upon the PQ testing of the truck, ocean container, or air cargo container. Temperature monitors should be placed in either a worst-case position as determined by OQ thermal mapping and reflective of the entire container where multiple pallets are involved, or placed in close proximity to the product to capture temperature more directly.
• For active pharmaceutical ingredient (API) and bulk drug substance (BDS) containers, consideration should be given to the shape and size of the primary container such that proximity to product, protective secondary container, interior air convection, cooling elements, and interferences (i.e., valves, closures, inlet and outlet lines, gages, or sterile enclosures) are accounted for in capturing accurate worst-case temperature results for the shipment.
• If the packout container is designed to have divided internal compartments to separate the temperature assurance materials (such as frozen phase-change bricks) from the product, the temperature-monitoring device should be positioned in the compartment where the product is located, not in the compartment with the temperature-assurance materials.
• The temperature-monitoring device should not be placed in direct contact or in close proximity with any frozen temperature-assurance materials, such as phase-change bricks, since this may result in a false negative temperature reading. The temperature-monitoring device should be separated from these
temperature-assurance materials with an insulating material delineated in the OQ.
• The temperature-monitoring device should not be placed in direct contact or close proximity with temperature-assurance materials such as gel packs used for controlled room temperature thermal mass, since this material may insulate the temperature-monitoring device and result in false high temperature readings that are not reflective of the temperature of the packout and the product.
• The placement of the temperature-monitoring device should include ease of use considerations. Since packout timing is important in keeping product within the proper temperature range, the placement of the monitor by the shipping site as well as retrieval by the receiving site should be considered so that the product itself is not exposed to room ambient temperatures for an extended period of time. The sending site should be able to efficiently activate and place the monitor into the packout quickly. The position should be such that the receiving site can locate and deactivate the monitor quickly upon receipt. Reducing the
complexity of the packout helps to drive consistency in training and to enhance compliance.
Product payload. The minimum and maximum payload sizes are defined in the OQ report. Because the quantity of product is bracketed between the mass and volume, the exact position of the temperature monitor may vary slightly depending on the number of product packages contained in the packout.
Laboratory chamber testing for every conceivable variant of product package numbers and positions contained in the payload is impractical. Therefore the precepts of temperature-monitor placement are important to follow.
Number of temperature monitors. The number of temperature monitors used during a shipment depends upon of the mode of transportation being used, the volume of product being shipped, the number of individual pallets or containers in the shipment, and the commensurate value of the product. The guidance for the number of temperature monitors placed into a PQ shipment is defined in the PQ protocol. The minimum number of temperature monitoring devices is defined in the Conformance Standard for Shipping and Distribution.
The thermal mapping process is performed during OQ and provides the core data from which to best evaluate temperature-monitor or data-logger placement.
Many operational errors involving temperature monitors or data loggers happen through mishandling of the units themselves. For example, devices may be left activated outside of a cold vault after a shipment is completed and the product itself securely placed in proper cold storage. During the excursion investigation process, this possibility should be taken into consideration.
For active containers (e.g., trucks and ocean containers), it is critical that sufficient airflow is present throughout the container.
Overloading or “wall-loading” will restrict that air flow. Blocking and bracing methodologies should therefore take into account the need for container wall clearance. The vehicle loading plan standard operating procedures (SOPs) is a viable communicative method for addressing air circulation in active container.
The number of temperature-monitoring or data-logging devices placed in an insulated shipping container should be described in operational documents such as SOPs. That number of devices utilized in regular shipments should be based upon the DQ, OQ, and PQ results.
The purpose of placing a temperature-monitoring device within a container that is used to protect product in transit is to monitor the temperature of the product as accurately as possible. The placement of the temperature-monitoring device should be either as close to the product as possible to best represent the actual temperature of the product, or be in the worst-case location within the transit container, where the temperature swing is the greatest.
Based upon OQ thermal mapping for each packout, all areas within the payload are defined as thermally acceptable; therefore, those areas are equally justifiable and are valid locations to place the temperature-
Following the above guidelines for placement of temperature monitors in temperature-controlled packouts will increase the accuracy of product data–capture during transit. Once temperatures are accurately obtained, they can be compared to transit temperature specifications and pertinent product stability data, allowing for the evaluation of potential temperature-related impact on product safety, potency, or efficacy at the end of the journey.
Geoffrey Glauser is Director, Global Packaging Technology, for Wyeth Pharmaceuticals (Collegeville, PA).■