One of the most read articles of this blog (over 4,000 views to date) is a posting I made on May 10th, 2006 where I referenced a FREE downloadable program for calculting MKT.

Several of you have contacted me to tell me the link in the article no longer works. Try as I may, I can't keep up with all the latest versions of links I have provided on this site over the past two years.

Now for thee good news! ScienTek Software, Inc., who developed the complimentary calculation as a "community service to the pharmaceutical industry worldwide" has recently released a new (2.0) version called STABILITY SYSTEM II. Now you can calculate til your heart's content! Enjoy.

Sorry for any frustration this may have caused you...

Fast, Cheap and effective. Too often these are (in descending priority) the requirements employed by the well-intentioned when selecting distribution packaging for temperature sensitive pharmaceutical products. It may be the result of poor planning, a project afterthought, an accelerated launch schedule, or just plain ignorance that causes the panic. In any case, it seems that distribution operations - those required to get the product out the door - are the last to be notified - and while the hot potato of blame and responsibility gets tossed around the organization, the scramble for transport packaging begins. 

I have not only been the victim of this scenario, I have seen it played out repeatedly across the breadth of the pharmaceutical industry. What I have learned, and what I have observed (other than it is the worst of all approaches) is that there is no such thing as fast, cheap and effective when it comes to insulated packaging. You can only ever meet two of these criteria, never all three.

~ Fast and Cheap will not be effective

~ Cheap and Effective will not be fast

~ Fast and Effective will not be cheap

Which combo you choose depends greatly on who within your organization has the most influence, and who is making the decision. Distribution/Operations wants it fast. Procurement/Purchasing wants it cheap. Engineering/Quality wants it effective. So, what's it going to be? All are less than desirable - and all have consequences. It's as if you had to decide whether or not to leap from the third story window of your mistresses burning, oceanfront apartment building just to avoid being swept away by the oncoming tsunami.

The Fast and Cheap combo will allow you to get product out the door under a tight time line but its ability to effectively protect the product from temperature extremes in transportation is minimal, at best. I call this the "Minnow Bucket" solution. The type of insulated container you can buy at your local grocery store or bait shop - thin wall, low density, inferior quality, manufactured  by who-knows-who, who-knows-where. The same goes for the gel pack refrigerant - minimum mil thickness polyethylene bags filled with a solution that may or may not be homogeneous, microbe-free, or filled to a consistent volume.

The Cheap and Effective combo, or the "David Copperfield" solution is nothing more than an illusion. The illusion is derived from the assumption that the product must be protected from temperature extremes because of its novel components. The "perception-deception" may include "space age materials", foil liners, temperature indicator strips or gels that perform "better than ice". Test data to support their claims of performance, if it exsists, is usually weak, sketchy, poorly documented - and often biased. They give the appearance that the integrity of the product has not been compromised when, in fact, they do little to eliminate the heat bridge between the environment and your precious product.  

The Fast and Effective combo is probably the best short term solution. Expensive? Yes. But is it the costliest? This is the "Penalty Packaging" solution - where development, testing, qualifying and implementing an optimal solution is something for which you have neither the time, resources, nor budget. There are several reputable companies who have off-the-shelf, pre-qualified thermal packaging solutions for the tightly controlled temperature requirements inherent to pharmaceuticals and biologics. These are sophisticated, highly engineered packages with more complex configurations, that have passed rigorous, and well documented transportation and thermal tests. They often include phase change materials (PCM's) in addition to; or in place of regular gel packs. All offer a high degree of assurance that your product will be protected from temperature extremes during transit and come in various sizes, designs and shipping durations. Pay the penalty. And continue to use these pre-qualified packages with confidence until such time you can develop a custom package that fits your specific need without the added pressure of getting / keeping your product on the market. The benefits will be: a qualified, long-term solution consisting of a properly engineered package from a reliable supplier that reduces material cost, labor, weight and freight expenses.

Ultimately, your company's reputation depends on the decisions you and your organization make, the packaging solutions you choose, and suppliers with whom you have partnered. Temperature sensitive drugs have a unique vulnerability. We all have an obligation to provide the safest, highest quality drug to the end user - one day, that will be you and me. 

Frozen gel packs - a critical component in the performance of temperature controlled packaging. By regulating the absorption of heat, frozen gel packs in a well designed system are able to help keep the product within a specified temperature range regardless of its exposure to fluctuating external temperatures.

But how frozen do the gel packs have to be? 

Is there a risk of freezing the product payload?

Will conditioning gel packs to various frozen temperatures have an impact on the performance of a package?

Is there an optimum temperature for conditioning frozen gel packs?

What temperature conditioning should be used for designing and qualifying  temperature controlled packages? 

The answers to these questions can be very valuable information to have when designing a temperature controlled package.

How frozen do the gel packs have to be? 

When the gel packs are removed from the freezer they immediately begin to transition to their phase change temperature, roughly 0°C in the case of water-based gel packs, those most commonly used. If the gel packs are removed from the freezer and immediately confined to a hermetically sealed insulated package, there is often a "thermal shock" that occurs, evidenced by a brief but significant dip in internal air temperature within the package. The lower the temperature to which the gel packs are conditioned the more dramatic the dip in temperature. The effect is only compounded with the addition of the insulation. This can be verified by placing a battery operated data logger monitoring device within the package or directly, by probing the actual product using thermocouple wire integrated with a temperature data logger.

Recordings of  this phenomenon have been the cause of countless deviations, non-conformances and subsequent explanations among quality organizations within the pharmaceutical industry.

Is there a risk of freezing the product payload?

Yes. One elegant method employed by companies to avoid this danger is to shed the shock by allowing the gel packs to relax for thirty minutes or so before packing or sealing the packages closed. By allowing the gel packs to near their phase change temperature, the risk of thermal shock, if not eliminated entirely, is significantly reduced by the time the product is placed into the package with the gels so as to stay within the acceptable range, (2-8°C for example).

Not all companies however, have the ability to do this within their daily operation. Others don't employ this solution due to an inability to control and document the process. Still others allow for the dip to occur and invest the time and expense to design and qualify their packages accordingly.  

Will conditioning gel packs to various frozen temperatures have an impact on the performance of a package?

By linking to the following graph, you can see that the temperature at which the frozen gels are conditioned have a direct and variable influence on the package's performance and longevity. 

The graph is an average culled from multiple tests and illustrates 1.) equilibrium at various frozen temperatures, 2.) time to attain phase temperature of 0°C +/-1°C, and 3.) the consequent longevity of the gel pack. In each test, identical 16 oz., 0°C phase change gel packs were probed with thermocouples and conditioned simultaneously in freezers set at -10°C, -20°C, -30°C and -80°C. They were removed simultaneously after 48 hours and placed into a controlled temperature chamber at 23°C +/- 1°C. Data were then logged at 15 minute intervals over a 48 hour period.

There is evidence of an obvious performance difference. The lower the temperature, the more exaggerated the effects of thermal shock. It is more pronounced and of longer duration, decreasing the air temperature within the package and increasing the threat of pulling the product temperature out of specification, possibly below 0°C. Attempting to artificially increase the longevity of the package by freezing the gel packs at lower temperatures extends the thermal shock curve but does nothing to extend the duration of the heat of fusion. Each gel pack contains a finite amount of energy, called enthalpy. For instance, all 16 ounce 0°C phase change gel packs contain roughly 179 kilojoules of energy. Regardless of what temperature the gel packs were frozen, once they reached their phase change temperature, the graph shows that they all performed the same and melted essentially at the same rate, if not the same time. 

Practitioners of insulated package design attempt maximum utilization of the phase change portion of the graph while minimizing the effects of what happens before and after (the curves on either end of the graph).

Is there an optimum temperature to condition frozen gel packs?

Beyond performance differences, there are mechanical considerations when it comes to optimizing the freezing of gel packs. One of the more remarkable properties of water is that it has the highest specific heat of any common substance, 1 calorie/gm °C = 4.186 J/gm °C. It's cheap, abundant and easy to work with - which is what makes it such an attractive source of coolant in insulated packaging systems. It does however, require a significant amount of energy to freeze. The table below, developed by Amgen, calculates the trade-offs in costs for freezing 1 Kilogram of gel. The most efficient temperature is generally considered to be around -18°C.

Source: Amgen Process Development Dept.

What temperature condition should be used for designing and qualifying  temperature controlled packages? 

It is important to specify and document the temperature your gel packs are conditioned to for design and qualification tests. Make certain that the conditioning temperature and tolerances of the freezers are commensurate with the freezers used for conditioning gel packs within your commercial operation. Otherwise, you may see a difference in performance between the package configurations you qualified and those you send to your customers.

For a related topic, see the posting Effects of Refrigerated Storage on Assembled Insulated Packaging in the January Archives.

I came across a quick, painless, flexible and FREE program that calculates MKT using the formula published in USP 27. This free 2 MB zip file, compliments of ScienTek Software, is provided as "a community service to the pharmaceutical industry worldwide". The program is self-documented with complete validation information for meeting compliance requirements of 21 CFR part 11. 

USP's Activation Energy value of 83.144 kJ/mole is provided as a default but if you can justify a different value, the program gives you the flexibility to recalculate. This latest version (1.2) also allows for the unit preference of kilojoules or kilocalories.

The MKT.exe is developed using Microsoft Visual Basic 6 (SP5) and requires a 32-bit Windows platform to install and execute. 

To learn more click here. To download and unzip the file directly, click here.

It was an interesting, diverse and exciting trip to New York City this week. I'd like to thank all of you who took the time to stop by the booth at Interphex and chat about the blog and discuss what you've been working on, issues you're dealing with, or packaging conundrums you're trying to resolve.

One of the more interesting technical questions I was asked came from a bio-tech researcher from Cambridge, MA. Although I could not answer his question directly, I assured him I would post it to the blog and with over 1,700 visits here a month, hopefully he can check back and see if anyone has any information they would be willing to share and post.

Question: What, if any, are the effects of gamma radiation sterilization on temperature data logger performance? How does this affect the componentry, memory chip, battery, etc.?

Apparently, his company packages their temperature sensitive product (complete with data logger) into distribution packaging and zaps it afterward. Currently, they use a TempTale 4 Dual Sensor with a flexible external thermocouple, and place the logger outside the box in a lead pig before sterilization.  I'm sure any information you can share would be appreciated.

A second question was asked by a fellow member the . He broadcast it to the members of the cold-chain discussion group and I thought I'd post it here as well to see if any of you can provide him with the information he is requesting.

Question: "I am currently working on a new project where we are looking at standard 5 and 10 Liter bags that will be filled with various Biological and culture media products.  We will be transporting these between sites, potentially at -70C.  Trying to get a benchmark on what everyone is doing. Specifically, the type of secondary packaging, totes, cages etc., quantities currently shipping, and experiences, if any, with bag materials at these low temperatures".

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Next week I'm off to Bethesda to moderate at the inaugural PDA Cold-Chain Management Conference. There should be plenty of information to share when I return...