A pharmaceutical product in transit may be handled as many as 15 times before final delivery, creating multiple opportunities for mishandling or exposure to conditions beyond the packaging threshold. Multiple cost-effective solutions are available to predict, prevent and detect hidden damage caused by temperature, impact or humidity. Data recorders, electronic monitors and chemical indicators are used to record excursions or to reduce risk exposure.
No matter how good the supply chain planning, the unexpected can always happen. Kevin Kohleriter, vice-president of product management and marketing at ShockWatch Corporation, reviews some of the advances in technology used in predicting cold chain incidents.
Between product safety and protection, packaging cost and preservation, it should come as no surprise that pharmaceutical packaging professionals must consider a vast number of design, validation and supervision criteria to maintain product quality. And although multiple products and services are available for evaluation, success in the cold chain comes down to knowing how to deliver a product with temperature controls adapted to shipping and warehousing circumstances; for example:
While it may be well known that transportation and warehousing conditions are essential to the chain of custody, how can a company know when and where an incident has happened? Did a door get left open on a refrigerated truck? At what point during the delivery of the crates to the dock did the product get left outside in 34°C temperatures? Who was the carrier at the time of the incident and has this happened before with this carrier?
The solution is to monitor where product damage can occur. Cold chain requirements are documented to ensure temperature conditions of pharmaceuticals and their raw materials are not exceeded even during transport and inspection.
While a product is in transit, it may be handled as many as 15 times before it is delivered to its final destination. That presents multiple opportunities to be mishandled or exposed to conditions that are beyond the product’s packaging threshold. Cold chain issues are most likely to occur when:
1. Multiple shipments of raw materials are sent from various worldwide suppliers via multiple modes of transport.
2. A pharma manufacturer picks up at the dock with various types of equipment (handcart, forklift, automation systems) and combines with other raw materials needed to create the drug.
3. An authorised distributor, wholesaler or reseller receives product and sends to the repackager via various logistics routes
4. Secondary wholesalers send to multiple retail distribution centres via additional logistics routes
5. A retail distribution centre then ships to the retail pharmacy or doctor’s office
6. The patient may store the medication in a refrigerator, pantry or even their car
But this supply chain flow does not take into account that many distributors ship product from one facility to another to balance stocking levels and some are repackaged within the supply chain. There is also the opportunity for excursions to occur while product is being loaded and unloaded from the dock via forklift or handcart.
Although visible damage – smell, dented containers, melted gel packs, leaking refrigerant – is an obvious indicator of an excursion, how do you know if, or when, transport or storage conditions have surpassed their threshold?
Multiple cost-effective solutions are available to predict, prevent and detect hidden damage caused by temperature, impact or humidity. Selecting the right solution depends on the particular company objectives.
While the objective may be obvious, the solution may not be. Solving a problem may be a matter of redesigned packaging, but it also may be as obvious as deterring employees and shippers through assigning accountability. And while any combination of these methods may be effective, they may also be overwhelming and not cost-effective. The question is where to start. Knowing how and when excursions or damage occurs allows the problem to be corrected, the risks minimised, and even accountability for the incident to be assigned via the ‘Chain of Custody’.
If the damage boundaries of the product have not been thoroughly tested throughout the entire supply chain, it would be prudent to begin with a monitoring device placed on a limited number of shipments. Data recorders, electronic monitors and chemical indicators are used by QA departments and shippers alike to identify quickly the state of temperature controls.
There are two main options to choose from:
Electronic Recorders (data loggers) have programmed limits that trip an alarm once an environmental damage boundary, such as temperature, humidity, impact or exposure to a time duration, is surpassed.
Electronic recorders can be programmed to trigger on several time/temperature events, enabling them not only to check for a single incident, but also to take multiple readings on a timed basis. The cost for such devices ranges from thousands of dollars to less than $100 (b76).
Lower cost recorders are often placed inside the packaging to monitor the actual product environment. Since data can be downloaded directly or remotely via wireless, they enable analysis and a paper trail to trace exactly when, who and even where the damage occurred.
Chemical/electronic indicators are designed to identify an alarm state visually with a change in colour as single or multiple thresholds are surpassed (e.g. <2°C for 15min and >8°C for 1hr). These highly accurate indicators are irreversible and have multiple sensitivity ranges and time-exposure durations tuned to the needs of a particular product. Because their cost is low (US$0.50–5.00 each), indicators are typically used in individual packaging. This option is helpful if the products need to be separated from the larger containers, which may be the case for wholesalers or for retail distribution. Because these indicators are ‘armable’ they can be activated at any point during the packaging and shipping process.
There is a place for both types of devices, together or combined on a shipment. Regardless of the type of monitor used, typically an LED (recorder) or colour change (indicator) alerts the receiving end of the shipment to accept or reject based on the status of documented control.
There are various packaging and warehousing considerations to take into account when deciding on a recorder versus an indicator.
Large crates or reefers: How is the product packaged, insulated and what does the product weigh? Temperature-controlled packaging comes in two forms: active and passive. Active containers may use a compressor with heat exchanger, reversed sterling engine or politer element. Typically, the larger the container, the more likely it is to have an active cooling system; this means it has a higher chance of reuse (a closed loop system) and is a better candidate for a data logger. Distributors delivering and shipping multiple types of drugs may find this useful.
While the container itself may play an active role in assuring quality, the type and number of carriers in addition to the long-term storage conditions may affect the length of time monitoring is needed. Pharmaceuticals shipped via ocean transport may need to be in transit or storage for many months. Electronic data loggers of any kind will have a battery life that is affected by the length of use as well as the environmental conditions. Electronic monitoring devices with a 30% longer battery life than the expected shipping and storage duration will ensure the entire length of transit is recorded and that there is no data loss.
Battery life can also be affected by how the monitor is set to record. Just like a cell phone that is constantly pinging the network, a data logger that is constantly recording on a time-only basis will record everything, good and bad, making it difficult to filter the damaging incidents and also wearing heavily on the life of the battery. Choosing monitors that are set to trigger in the event of threshold-based incidents – i.e. it should trigger only on those excursions that are concerning – can extend the battery life by as much as 12 months.
Data recorders provide information, not just indication and therefore represent a good way to obtain detailed information to improve the design of packaging or reduce risk exposure.
Smaller packages: These often utilise a passive container with dry ice, gel packs, eutectic plates or even phase-change materials on a non-water or wax basis. Because these containers tend to be non-recyclable and non-returnable, a temperature indicator may be the best method.
Labels, inset cards and caution tape can inform carriers and recipients that goods require specific thermal conditions
Since temperature packaging indicators come in a wide variety of temperature thresholds, most do not have to be customised for internal tracking or compliance regulations. Due to the volume of a standardised product, production costs can be kept lower.
Indicators can be mounted to any surface, either on the product itself or external to the packaging to create a visible deterrent to mishandling. If exposure has occurred, once activated, the indicator is irreversible and tamperproof, providing a permanent record of exposure. To ensure that products ‘weather the storm’, make sure the indicators are field armable (i.e. can be activated at any point along the route) and moisture- and tamper-resistant (i.e. adhere regardless of condensation level).
It should also be noted that if breakage due to dropping is a concern, impact indicators could be used in conjunction with temperature indicators. These devices are tuned to specific g-forces and follow the same strict testing standards as temperature indicators to ensure their accuracy.
As mentioned above, indicators are not only used to detect potential spoilage, but are also used as a means of deterrence through accountability. Why use an indicator rather than a recorder as a deterrent? A very common gap in the supply chain for sensitive drugs is the lack of understanding of the regulatory requirements related to product exposure in the last mile of the chain.
Placing condition indicators (temperature, impact or tilt) outside the packaging with a companion label increases visibility of the indicator. The threat of being caught is an effective deterrent to mishandling and is a constant reminder that quality is being monitored.
|Table 1: Devices for testing and validating a cold chain|
|Device||When to use||Characteristics to consider|
|Recorders||Highly valuable shipments
Difficult shipping lanes
Transport lane qualification
Facility monitoring/ mapping
Closed loop environment
|Full-journey profiling, single or multiple events, and enable data analysis|
Measure, record, store and timestamp (humidity and atmosphere pressure environmental conditions)
Moderate to expensive output to monitor a period of time or support validation testing
Technical parameters: sample rate, battery life, temperature range to be monitored, data archiving memory requirements
|Monitors||Known stability data to be matched
Indication of time/temperature for multiple temperature
Packaging needing to be monitored
Mixed product loads
Open or closed loop environments
|Track temperature, humidity, impact or other excursions at predefined thresholds
Lower cost than recorders, making them ideal for distributors shipping and delivering multiple drug types and/or needing a disposable recording solution for open loop shipping
Can record single or multiple events
May or may not have a digital display showing: total number of excursions per threshold, duration of the longest, and cumulative duration of all excursions
|Indicators||Quick, easy method for monitoring a single key temperature
Low cost approach for use with validated package to ensure the package has not degraded
Open loop environments
|Irreversible, visible indication that temperatures have fallen or risen outside of acceptable range|
High accuracy sensing performance
No external power source required
Small footprint for interior container temperatures
Less expensive than electronic monitors and recorders
Newer types of indicators do not require pre-conditioning
Long shelf-life (1–3 years)
Refer to Table 1 when deciding which monitoring devices to test and validate a cold chain process. All three product types are used worldwide and are tested to comply with multiple quality standards.
It is the last mile that counts and the shipment has run out of gas. The manufacturer has done everything expected in their role: selected the right packaging, validated and inspected the warehouses and personally selected the carriers. What could possibly go wrong? A dropped package, ignorance, faulty refrigeration equipment – any or all of these.
A monitoring programme may reduce packaging costs, assure compliance standards, and make that last mile of the cold chain as good as the first.