This morning as the group of dedicated friends ambled past I began to think of the degree of discipline and planning it takes to be that consistent; my mind began racing - as it often does in the wee hours - as I fretted over an impending deadline and struggled for an idea for this issue's column. Then it hit me: like the women's rote ritual, consistent practices, discipline, and planning are also key elements to successful and reliable cold chain distribution. And while a great deal of focus is put on the actual transportation segment of the process, there are several other areas of the process that are assumed, overlooked, or simply dismissed that can have a significant impact on the performance of an insulated shipping package. If not considered and accounted for during the operational qualification process, it can lead to a degree of misrepresentation capable of failure during the performance qualification. Overlooked or unchecked, this can put time- and temperature-sensitive healthcare products - and our responsibility to the patients who rely on them - at risk, potentially affecting drug quality, safety, efficacy, or potency.
Before I cite specific and frequently occurring examples, it's important to understand the definitions of Operational Qualification and Performance Qualification as outlined by CDER's General Principals of Process Validation and adopted by PDA Technical Report No. 39:
Operational Qualification (OQ) – Transport tests that are conducted in a temperature-controlled chamber or by other simulated test protocols. Generally, simulated testing is conducted using a temperature profile that contains the anticipated extremes for the transportation duration and temperature.
Performance Qualification (PQ) – Transport tests of product or representative product that is conducted during actual transportation or distribution.1
It is not uncommon for an organization to qualify their packaging to a temperature profile representative of their specific shipping lanes, carefully taking into account all the potential hazards of the distribution environment, while completely ignoring or disregarding what happens before and after the shipping process. This can be a costly oversight. Take for example, the preparation of the product and its packaging materials prior to shipment. This point in the process is absolutely critical to the performance of an insulated package and its ability to maintain a specific temperature range, yet it is often assumed, or worse, not included as part of the operational qualification process.
Here is a typical scenario: all the preparations for an OQ have been meticulously detailed in a pre-approved protocol and the product is removed from its storage condition (let's say 2-8 ° C), and immediately placed into a prepared shipping package and the test is begun. After successfully completing the replicate tests of the OQ, the product, packaging, and shipping configurations move to the next stage of the validation process and undergo the performance qualification (PQ). But they result in failures when the data loggers included in the shipments reveal temperatures above the allowable upper limit. Why does this happen? What went wrong?
In the real world, removal of product from storage for immediate placement into a shipping container rarely occurs. The product is likely removed from its controlled storage condition and may sit in a controlled (or uncontrolled) warehouse or manufacturing area for an unspecified period of time before it is added to the shipping container. This is completely contrary to what was performed in the OQ, and depending on the density and volume of the product it can have a significant effect on performance and temperature maintenance.
Below is an example of how even the slightest change in product starting temperatures might effect product temperature response and temperature maintenance while enclosed in an insulated packaging system during distribution. The graph depicts how identical product, in identical packaging configurations, under identical temperature profiles, experienced very different temperature responses and maintenance when the starting temperature of the product varied by only 1° Celsius. The result: product in the test which started out a mere one degree higher consistently ran 1.5° to 2.0° C higher than the identical configuration that started at just one degree less.
|Test showing the effect of product starting temperature on performance of identical packaging configurations. All data represents liquid product temperatures. Same colors represent same probe locations, but separate tests.
Given that insulated packaging systems (whether passive or active) are intended to retain temperature maintenance and not "refrigerate" or draw temperatures down, puts the entire packaging system at risk. Not only is there more heat in the package than was originally captured in the OQ, the additional heat puts a drain on the refrigerant and can affect the projected longevity of the package in distribution. The result: product temperatures not held within proper range and / or receipt of warm product.
How To Avoid or Account for This Phenomenon?
Product sitting outside its proper storage condition absorbs surrounding heat quickly. Exposure for prolonged periods of time (several minutes to hours) will only amplify this phenomenon. The result can very well mean that the product never recovers to the point where it is maintained within its specified range in the shipping container during transportation. For this reason, it is considered best practice to not only be keenly aware of this potential pitfall but account for this process and include a data logger (of the type to be used in the subsequent PQ) and / or a thermocouple within the package configurations during the OQ to record the internal air temperatures as well as probed product temperatures. Correlations can then be made in the event that a justification is needed once you have moved on to the PQ, or once the process is adopted into everyday practice.
Supporting stability data specific to the product in question, when available, is often the best line of defense and can be used to accept or reject a non-conforming shipment.
Some organizations deal with this issue by eliminating it entirely and pack product in its final distribution package within the facility that the product is stored. I used to do this for one particularly sensitive product while I was at Abbott Laboratories. The warehouse crew despised having to prepare shipments within a 2-8° C cooler, but the result was an elimination of temperature stratification within the shipment; not a single deviation for any shipment from Germany to the U.S. was experienced. Regardless of whether preparing shipments for distribution within the product storage area is an option or not (and in many operations, it's not), SOP's and proper training of personnel, the complexity of which will be based on operational limits factored into the operational qualification, must be adopted and rigorously enforced.
The same considerations need to be applied on the receiving end as well, although to a lesser extent. If the package starts off on its journey out of spec, then there is little hope or help that can result in restoring the product to its proper temperature range during transit. Once it has arrived on the receiving end, short of removing the product from its packaging and immediately placing under proper storage conditions, the damage may have already been done.
If you think that I'm splitting hairs here; I'm not. Insulated packaging systems designed for the transport of healthcare products today are very sophisticated. Most highly engineered solutions are optimized to take into account the delicate balance of performance and longevity vs. material cost and dimensional weight considerations, the basis on which shippers charge for freight. So consideration of the entire shipping and distribution process is a must in a comprehensive packaging design.
It all comes back to discipline, planning, and consistent practices from the start - elements critical to the qualification of an insulated packaging system and the daily operation of a successful and reliable cold chain process.
I considered getting up at 5:23 AM tomorrow to thank the ladies passing by my window for their inspiration, but it would take too long to explain and I wouldn't want to throw them off schedule. I think I'll sleep in instead.
1 Bishara, R. H., Ph.D., et al., PDA Journal of Pharmaceutical Science and Technology, Guidance for Temperature-Controlled Medicinal Products: Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment. Parenteral Drug Association, 2007 Supplement, Volume 61. No. S-2.