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Outside the Box
10 essential considerations for a validated, temperature-controlled package
By Kevin O’Donnell
Whether you plan to utilize active or passive packaging systems for transporting your time- and temperature-sensitive healthcare products, there are certain aspects to qualifying the process that are essential. Some are obvious, while others are easily and repeatedly overlooked. It is no longer just about package performance. It extends beyond testing materials and components for suitability, cost considerations and implementation, to include understanding your product, your distribution network, your suppliers’ capabilities and limitations, training, and monitoring the distribution system for changes. It’s a sophisticated, dynamic, and challenging process. And as the principles of qualifying the transport and distribution of time- and temperature-sensitive healthcare products continues to closely follow established guidelines and regulation for qualifying their manufacture, regulatory authorities the world over continue to increase their knowledge as well as their expectations regarding the transport and distribution of these articles. Having a thorough and well-documented process is key to having confidence in the performance of your packaging and crucial to surviving an eventual regulatory audit.
There are a number of guidance documents within the industry that are considered best practice documents for the storage, transport and distribution of time- and temperature-sensitive healthcare products, and a list of the most commonly referenced documents is included at the end of this article. The level of familiarity, knowledge and application of these guidances throughout the industry is very broad indeed. No one document addresses it all, but among them they capture the following considerations for validating temperature-controlled shipping systems within the pharmaceutical market.
1. Understand Your Product
Surprisingly, elements of the product are often overlooked. In the not-so-distant past, it was common practice to pigeonhole commercial products into a specific “safe” storage temperature category because the pressure to launch the product superseded additional stability studies or cycling studies required that may prove the product more stable at a broader range of temperature than first thought. While time-to-market is critical, such a practice can put an undo and often unnecessary burden on those responsible for shipping the product.
The evolution of stability studies and cycling studies have reduced this practice for many of the newer products but several pharmaceutical companies have revisited and retested the stability of their more mature products, often determining greater robustness over a much wider temperature range without worry of compromising product quality. With stability data to support periodic or short-term temperature excursions beyond those listed on the product label, companies can capture considerable savings in storage, packaging, distribution, and logistics costs in the long run. Stability data to support no degradation to a product with a slight increase in temperature range can also open the door for many more packaging and distribution options. To put this in perspective — if stability data support maintaining product temperature between 0° C and 10° C during shipping, instead of the commonly default temperature of 2° C to 8° C, the temperature range has increased by 66%, and 66% of anything is a lot!
The volume and thermal mass of the product — whether it is a liquid, solid, lyophilized cake, or powder — affect package design.Also, the quantity of the units and the composition of the secondary packaging, and on a larger scale, case quantities and load configuration play a role. The drug product, all of the components in the package, and the transport package itself all have different levels of specific heat and absorb heat at varying rates. This is a particularly critical element in passive package development as there is a finite amount of refrigerant within the system to “cool down” the package and its components.
Not to be discounted is the value of the product and the value of the time required to develop an appropriate packaging system. Lastly, don’t forget the effects other environmental and distribution hazards may have on your product such as vibration, shock, compression, atmospheric pressure, light, humidity, and fragility.
2. Define Your Customer Requirements
This one is often undervalued. Who is the customer? This will likely help define specific requirements, as they often vary for internal customers, distributors, retailers or end-users. Image and presentation, brand identity and company reputation may or may not be important factors for all customers. What is the expected condition upon receipt? Will a package that arrives plastered with labels, dirty and scuffed reflect negatively on your product? Remember, perception is reality. Also, be cognizant of your customer’s delivery expectations, costs and handling procedures such as weight, size of the package, and storage space. For active systems and durable goods containers, consider the viability of closed-loop programs, without it becoming a burden to your customers. And in this age of environmental enlightenment, be aware of any disposability issues that may be incurred, and how sensitive your customer is to sustainability of packaging materials and programs for reducing, reusing and recycling.
3. Understand Your Distribution Environment
There is no greater variable on a temperature-controlled shipping system than the environment through which your product must travel. This includes modes of transport, ship-to and ship-from locations, time of day pack-out and procedures, differences in handling practices among downstream supply chain partners, various global distribution models, seasonal and hemispheric variation, and customs delays. Other influencing factors include: storage of product prior to packing, handling on the receiving end, and whether any intermediate steps need to be taken during transport such as re-icing, or recharging power units on active systems.
Know where the touch-points, wait-times, and hand-offs occur. A package in the distribution environment is most vulnerable when it is sitting still.
It is important to perform segment analysis with your downstream carriers and continuously monitor your distribution environment (and in some cases individual shipping lanes), for changes that can affect or pose a risk to your product. Sending temperature data-logging devices through your distribution lanes is an excellent way to monitor the system for changes and can reveal trends and potential threats. This initial groundwork is crucial to establishing the right “fit” for your packaging decisions. The more you understand your distribution environment, the more confidence you can have in your package choice. One of the costliest setbacks you can experience in the ultimate DQ/OQ/PQ process of package qualification which must be performed to validate a packaging system, is to go through the time and expense of Design Qualification (DQ) and Operational Qualification (OQ), only to find that the system fails during the Performance Qualification (PQ) because of assumptions you made about the distribution environment that are not representative of reality. This garbage-in-garbage-out methodology will force you to start over — from the beginning.
4. Know Your Packaging Options
Active or passive? It is more than just personal preference, like paper or plastic, or boxers or briefs. It is a fundamental question with two very different logistics paths (see number 3) and cost structures. Is one better than the other? There is no single, universal solution applicable to all circumstances. Both have their levels of risk, merits, and drawbacks.
Active systems have come a long way over the last decade with several companies recently rolling out new and improved products and services and stepping up their quality management systems to compete in the biopharmaceutical market. Generally speaking, active systems can be a practical solution for shipping large volume, high-value products — particularly upstream in the supply chain and between international airport hubs such as Chicago, Miami, London, Frankfurt, Dubai and Singapore. But going further afield can be a bit more difficult, with equipment availability and returnability often an issue. While most active units are quite readily qualifiable to meet the rigorous demands of the biopharmaceutical industry, it is a mechanical device and as such there is a level of risk failure that must be considered. On the plus side active systems are rugged and larger containers are built to optimize space aboard wide-body aircraft. Units are generally leased, not purchased, so there are no warehousing implications, and they load quickly. A cost/benefit analysis should be performed for the total cost of active containers, including fuel surcharges, pick-up / return fees and other logistics charges to determine if this is a viable solution over a passive packaging system.
Passive systems also have unique benefits. They can be shipped essentially anywhere in the world within a defined period of time using gel pack or phase change materials as a refrigerant. Their performance is very repeatable without the need for human intervention and they can be designed to meet a range of external environmental demands. There are a variety of materials to choose from, with varying degrees of performance and cost. Most passive systems are comprised of disposable materials although environmental considerations should be factored into this design choice. These types of packaging systems usually contain multiple components, and gel packs need to be conditioned to the proper temperature before use, requiring warehousing considerations not experienced with most active systems. They can be configured in a tremendous array of configurations at relatively low cost and can be shipped across town or across the globe.
Refrigerated trucks for short haul transport can be a viable alternative. However, there is no consensus within the industry as to how to qualify them. Refrigerated ocean containers are often considered, but the luxury of long delivery times — spending days or weeks on the open seas — is not a risk most companies are willing to take with their high-value pharmaceuticals.
Somewhere between active and passive systems is a category of packaging utilizing rapid evaporation technology, Pelletier devices, thermally activated switches to regulate temperatures within containers, and other novel concepts. These certainly have their niche. Not necessarily economical, these can be practical solutions for specific applications, particularly for small packages and low-volume shipments.
5. Know Your Suppliers' Capabilities
Aside from the goods and services your suppliers can provide, what else do you know about them? They are not all created equal and not everyone can meet the extraordinary demands and expectations of the biopharmaceutical market nor understand and appreciate the regulatory implications. Consider your suppliers’ industry reputation, customer service, locations in proximity to your own, quality management practices, and local and global supply, if needed. Foster and maintain close relationships with your suppliers.
Fortunately for the healthcare industry, the quantity of providers and the level of quality and expertise required to safely and efficiently transport time- and temperature-sensitive drug products has grown by pandemic proportions. Packaging companies, 3PLs, airlines, freight forwarders, data-logging manufacturers and data management companies, consolidators, thermal testing laboratories, specialty warehousing facilities, and platform providers offer more choice than ever before. This evolution has been most noticeable at so-called - and seemingly ubiquitous, “cold-chain conferences.”I attended the first IQPC Cold Chain Distribution for Pharmaceuticals Conference in Philadelphia in 2002. There were six exhibitors plying their wares to a few dozen attendees in a tiny basement banquet room of a downtown hotel. Last month, IQPC’s 7th Annual Cold Chain Distribution for Pharmaceuticals Conference held at the Philadelphia Convention Center, drew hundreds of delegates and 45 exhibitors.
Providing to the healthcare industry can be an attractive and lucrative prospect. You would be wise to avoid companies that “dabble” in healthcare packaging and logistics or pander to the market. Consider those with primary focus and expertise in transport and distribution specific to the vertical drug market. After all, having an awesome set of tools at home doesn’t necessarily make you Norm Abram. Experience counts.
6. Set Realistic Goals
It will probably cost more and take longer than you think. It may even take longer than you’ve got. Don’t panic. You can take remedial, documented steps to ensure the safe transport of your drug products while formulating, executing, and implementing a long-term strategy for qualifying your packaging and your processes. And any experienced packaging provider or service provider worth its salt will be more than willing to help you navigate through the process. Call it a “continuous improvement approach.” While this may cost more initially, it will pay multiple dividends in the long run. The overarching consideration is to do it right and document what you’ve done.
Be prepared to make some hard decisions. The scope of any qualification process as complex as this is rarely without compromises. Your original goals, as lofty and well-meaning as they may be, are likely to change over the course of the project. Cost realities tend to be the most persuasive. Draw a line in the sand on the levels of risk you are willing to take and the confidence levels you are willing to accept. On the flipside, know when good enough is good enough.
7. Qualify Your Package System
You can’t expect to win on a shaky platform. That only works in politics. A one-off approach to qualifying a packaging system will never stand up in an audit. Instituting a DQ/OQ/PQ process to qualify your packaging and validate your process, is overwhelmingly considered the industry’s current best practice. This process for validation was adopted from CDER’s Principles of Process Validation, a familiar and readily-accepted method among FDA investigators. The principles of this process as it relates to packaging are well-defined in PDA Technical Report No. 39. The process is “system neutral.” In other words, it applies to active and passive packaging systems alike. It first requires documenting the critical parameters of the product, packaging and transport systems — all the things we’ve discussed to this point including: duration, routes and modes of transportation, product stability, packaging material, minimum and maximum loads, thermal mass, expected ambient temperature profiles, restrictions, marketing requirements and user requirements. From this, component specifications can be made documenting that all components in the packaging system are capable of consistently performing within established limits and tolerances.
The Design Qualification is performed before the Operational Qualification and ensures that the aforementioned functional requirements are met. It is during this design process where you can easily get bogged down. Consider the following scenario: the requirements call for three sizes of containers, (let’s say small, medium, and large), each containing a minimum and maximum product load, two different temperature profiles (high and low, hot and cold, winter and summer, or however you want to define them). The OQ testing matrix would look like this:
| Container | Min.Summer | Max. Summer | Min. Winter | Max. Winter |
| Small | 3 | 3 | 3 | 3 |
| Medium | 3 | 3 | 3 | 3 |
| Larger | 3 | 3 | 3 | 3 |
The latest advancements in testing technology employed by some testing labs includes thermal modeling using sophisticated analytical programs and prediction models to gain a more intimate understanding of the thermal dynamics of packaging systems, and speed-up the design process. These often include finite element analysis and thermal fluid dynamics programs with customized software for performing rapid simulations without using environmental chambers. Their three-dimensional analysis can accurately predict time over temperature by performing millions of calculations through the interactions of all the elements in the packaging system, and they can quickly build virtual prototypes, and run concurrent designs over a matter of minutes rather than days, weeks, or months. While not a substitute for actual OQ testing, collaborating with a reputable test lab employing such processes can reduce time lines, material expense, and laboratory costs (not to mention frustration) during the design process.
The Performance Qualification or “real world test” is performed upon successful completion on the OQ to demonstrate that the process is accurate, effective and reproducible. It should include actual ambient temperature variations (such as seasonality), representative product load configurations, a sufficient number of shipments to assure repeatability, calibrated temperature monitors and other cogent environmental data collection devices, if required.
8. Implement
Transfer the qualified process to routine operations formally by means of clearly written and approved standard operating procedures. Training the relevant personnel should be done prior to implementation of the process and in-line with the procedures documented to carry out the PQ. All training should be documented. Feedback from the downstream supply chain partners and stakeholders can be vital to the success of implementation. Notification should be communicated between applicable parties if any changes to the carrier’s routes, modes or methods occur.
9. Audit Your Suppliers and Let Them Know Your Expectations
| Commonly Applied Guidance and Regulation Affecting Temperature-controlled Packaging, Storage, Transport and Distribution of Time- and Temperature-Sensitive Medicinal Products The following list is by no means complete, but is pertinent to the discussion above:
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Most current guidance documents addressing storage, transport and distribution of time- and temperature-sensitive healthcare products include a section on quality systems. A formal and documented quality agreement is necessary to ensure that there is a common understanding about materials or service, quality specifications, responsibilities, guarantees, and communication mechanisms. They should include traceability to their raw materials when applicable and ensure that processes are repeatable. They should also specify minimum standards of performance, operation or other service attributes. A quality agreement (sometimes referred to as a service level agreement) generally includes purpose, objectives, commitment dates, duration and definitions, scope of work, performance and reporting metrics, an audit program, problem management (including escalation procedures), compensation, duties and responsibilities, training, warranties and remedies such as a CAPA program. Bear in mind, that your material and service providers may not operate or be familiar with cGMP standards. Efforts should be made to align their standards to your own.
10. Monitor the System for Trends and Changes
Now that you have successfully implemented a packaging system that assures your temperature-sensitive medicinal products arrive at their destination(s) safely, be wary of system changes. Work under the principle that “the only constant is change” and keep a watchful eye on the transit environment. Periodic monitoring (as defined by your quality systems) using calibrated data-logging devices is an excellent way to check for trends and changes that might otherwise go undetected. It may require you to re-qualify your package system.
The work necessary to maintain the quality of the drug products you deliver is never over. Look for ways to improve the process, alleviate bottlenecks and avoid unnecessary risks to your product.
I never said this would be a simple process. If it were, I wouldn’t have been able to make a 28-year career out of it.
