There has been much discussion (and confusion) regarding the applicability of MKT in the handling, storage and distribution of temperature-sensive pharmaceuticals over the past 18 months or so. Late last spring, a posse of five industry experts published a paper to add clarity to this often confusing topic. The group consisted of an Eli Lilly & Company engineer, regulatory scientist, a retired QA / Technical Support Director, and a Research Advisor, who collaborated with a Distribution QA Director from Abbott Laboratories. Their five page article was published in the May/June issue of Pharmaceutical Outsourcing Magazine.

At issue, and the answers the authors strove to assess and resolve was: can the impact of a reuslting MKT from excursions encountered over short periods of time, (excessive heat exposure during transport for example), have a significant impact on product degredation or quality?

The paper does an excellent job of illustrating the importance of establishing upper and lower limits on the use of MKT based on available stability data. The authors conclude that under certain circumstances it can be appropriate to use the calculated Mean Kinetic Temperature for a drug product as a valid means to approximate the effects of temperature variation that may occur during transport in the absence of product specific kinetic data, but that it is limited to temperatures for which there are stability data to support it, and not beyond.

The entire article has been made available in a printable pdf format (click on the paper clip icon below) thanks to the kind permission of the authors, Bob Seevers, Ph.D., Jeffery Hofer, Paul Harber, and Rafik Bishara, Ph.D. , David Ulrich; Nathan Collins, Editor Russell Publishing, and Henry Ames at Sensitech..

The temperature at which the frozen gels are conditioned have a direct and variable influence on the package's performance and longevity. Example:

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. 

You can find more on this topic in the following blog archives:

March 2009

April 2006

There was a great deal of discussion on the topic of temperature profiles last month at the PDA Cold Chain Management Conference in Bethesda, MD. Some interesting cases were presented supporting the use of MKT as one of several tools to establish profiles and failure criteria. But there can be potential pitfalls to putting all your eggs in one basket.

This month's Advanced Degrees Column in Contract Pharma explains why.

I have received many requests for links to graphs from a previous posting called "Gel Pack Refrigerants: How Frozen is Frozen?" It seems those graphs have disappeared into cyberspace when the coolerheads blog was updated. I am sorry for the inconvenience.

That posting led to a subsequent and expanded Advanced Degrees Column in Contract Pharma last April. It seems I struck a chord. Since "Gel Pack Refrigerants: How Frozen is Frozen?" first appeared (April 2006), it continues to be among the top-five read postings on this site month after month, with more than 120,000 page views over the past three years.

The following is an excerpt from the CP Advanced Degrees article - complete with graphs!

Frozen gel pack refrigerants - a critical component of temperature controlled packaging. It can also affect performance of the package and the product temperatures they are meant to protect by altering their freezing temperatures. 

            A well designed thermal package works on the principle of regulating the absorption of heat penetrating the package. Frozen gel packs in a well designed system  are able to help keep the product within a specified temperature range and duration regardless of its exposure to fluctuating external temperatures.

• But how frozen do the gel pack refrigerants have to be? 
• Is there a risk of freezing the product payload?
• What impact will conditioning gel pack refrigerants to various frozen temperatures have on overall performance longevity of a package?
• What impact might this have on the product payload temperatures?
• Is their an optimal temperature for conditioning gel pack refrigerants?
• What precondition temperature should be used for gel pack refrigerants when designing and qualifying temperature controlled packages? 

The answers to these questions provide very valuable information when designing temperature controlled packaging for pharmaceuticals or biologics for which very tight temperature ranges must be maintained.

How frozen do the gel pack refrigerants have to be? 

When gel pack refrigerants 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 pack refrigerants are removed from the freezer and immediately confined to a hermetically sealed insulated package, there is often a "thermal shock" that occurs - a brief but significant dip in internal air temperature within the package. This effect can be verified by placing a battery operated data logger monitoring device within the package or by probing the actual product within the package using thermocouple wire integrated with a temperature data logger. The lower the temperature to which the gel pack refrigerants are conditioned the more dramatic the initial dip in temperature. The effect is only compounded with the addition of the insulation. The better the insulation barrier, the more pronounced the effect and the longer the duration.

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. But there are a few ways to address this issue. One elegant method employed by some companies to avoid this danger is to shed the shock by allowing the gel pack refrigerants to relax for thirty minutes or so before packing or sealing the packages closed. Some wait until the frost on the outer surface of the gel pack liquefies or dissipates. The World Health Organization, (WHO) for example, communicates to their field personnel that the frozen mass inside the bag or plastic bottle, slides when shaken. This assures that the gel pack refrigerants have neared or reached 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). This is a critical step in distribution for the WHO whose vaccines cannot freeze. 

Not everyone has 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 design around it, and invest the time and expense to qualify their packages accordingly.  

What impact will conditioning gel pack refrigerants to various frozen temperatures have on overall performance longevity of a package?

[Figure 1] illustrates that the temperatures at which the frozen gels are conditioned have a direct and variable influence on the package's performance and longevity. 

The graph represents an average culled from multiple tests at each freeze temperature and illustrates:

            1.) time equilibrium at various frozen temperatures,

            2.) time to attain phase temperature of 0°C +/-1°C, and

            3.) the heat of fusion and 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.

[Figure 1]

There is evidence of an obvious performance difference. The lower the starting temperature, the more exaggerated the effects of thermal shock. It is more pronounced and of longer duration. This decreases the air temperature within the package and increases the threat of lowering the product temperature, possibly below 0°C, until the gel pack refrigerants come up to their phase change temperature. To attempt to artificially increase the longevity of the package by freezing the gel pack refrigerants at lower temperatures is a risky proposition if you have freeze sensitive product.

All gel packs contain a finite amount of energy. All 0°C phase change gel packs filled with 16 oz. of water contain roughly 179 kilojoules of energy. Regardless of what temperature the gel packs are frozen, once they reach their phase change temperature, the graph shows that they all performed the same and melted essentially at the same rate, (their heat of fusion is equal), if not the same time along the continuum. 

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).

What impact might this have on the product payload temperatures?

Suppose your company has multiple distribution sites across the country, as many do. Each site is responsible for preconditioning their gel pack refrigerants for their controlled temperature packaging shipments. Do all sites have freezers set to the same set point with the same tolerances?

The example below [Figure 2] reveals the relative changes in product temperatures when the staging temperature of the frozen gel pack refrigerant is manipulated. The data shown are theoretical and based on numerous assumptions made in order to create the following computer simulation model. The trendlines indicate there is variance between both product temperature extremes and average product load temperatures if frozen gel pack refrigerant is preconditioned at temperatures other than the commonly applied -20°C. Although design tools can theoretically predict package performance quite accurately, this is only one specific example. Results can vary depending on the input data and any theoretical modeling should be confirmed with physical test data.  

[Figure 2]

Is there an optimum temperature to condition frozen gel packs?

But before you go changing all of your freezers to lower temperatures to possibly optimize package performance, consider the mechanical impact. 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, [Figure 3] developed and published by Amgen, calculates the trade-offs in operating costs for freezing 1 Kilogram of gel. All things considered, the Amgen study concluded that the most efficient operating temperature is generally accepted to be around -18°C.  

[Figure 3]

Source: Amgen Process Development Dept.

What precondition temperature should be used for gel pack refrigerants when designing and qualifying temperature controlled packages? 

Many variables play a critical role. Therefore, there is no single, correct answer. It is important to specify and document the temperature at which your gel pack refrigerants are conditioned 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 pack refrigerants within your commercial operation. If multiple sites contain freezers with various set-points, design and qualification tests should be done over the entire range. Otherwise, you may see a difference in performance between the package configurations you qualify and those you send from your distribution sites and periodically monitor. This is especially critical for products which must maintain a narrow acceptable temperature range.

The following e-mail came to me yesterday from Tom Ferguson, former DG Manager at Delta Airlines, and a consultant to the transportation industry in the area of Dangerous Goods. Tom eloquently outlines the regulatory history of lithium battery issues and points out the concerns over their shipment with a well-balanced  look from both the shipper's and the carrier 's perspective. 

Thanks Tom, for allowing me to share this among the industry.

Kevin,

I wanted to send this email directly to you and explain some of the finer details on the ongoing issue regarding lithium batteries in cargo shipments.  I managed Delta air lines, Inc’s DG program for 7 years and recently left Delta to start my own consulting company.  I still do contract work for Delta, as well as serving as a technical consultant to both the Council on the Safe Transport of Hazardous Articles and the Vessel Operators Hazardous Materials Association.  Finally I am a current IATA Dangerous Goods Board Member.  I detail my qualifications not to impress you but to explain that I understand the issues concerned from both the carrier and the shipper sides. 

The evolution of lithium batteries has caused great concern and confusion within the transportation regulations, not just domestically but internationally.  Significant changes to lithium metal and ion battery transport have just gone into effect (Oct 2008 and Jan 2009) that now regulate materials never before regulated.  Additionally, the exceptions to the regulations have changed.  There are differing opinions regarding what is regulated and what is not, and that disagreement is what led to the Cold Chain issues.  Let me detail some of the issues:

Excepted Lithium Batteries

While Delta focuses on air shipments of lithium batteries, the US PHMSA just modified their exceptions in Oct 1, 2008.  Industry is still trying to understand their requirements of marking and labeling.  To make matters worse, DOT regulations are different than International transport regulations issued by the International Civil Aviation Organization for air transport.  Shippers of lithium batteries worldwide are having to revamp their training and transportation programs to account for new marking and packaging requirements that were not in place 4 months ago.  

Lithium Batteries Contained in Devices

The shipment of lithium batteries is heavily restricted.  Bulk shipments of lithium metal batteries are forbidden on passenger aircraft, and shipments of devices containing lithium metal and lithium ion batteries must now be marked and offered with accompanying documentation stating that fact.  During discussions last fall with the IATA Dangerous Goods Board and US PHMSA, there was disagreement as to whether devices DESIGNED TO OPERATE DURING TRANSPORTATION were in fact subject to the hazardous material regulations.  IATA was of the impression that if they were excepted from the regulations, they were not.  However, PHMSA disagreed and stated Competent Authority Approval would be required for all such shipments, even excepted batteries.

Subsequent discussions with Henry Ames, IATA, and Delta led to the request for clarification from PHMSA regarding their specific product and the batteries contained therein.  This discussion put the issue in front of PHMSA and allowed all the facts to be reviewed.  The final outcome of those discussions you are already aware.  However, you may not realize the clarification applied only to the batteries that were referenced in the letter.  Larger batteries which do not meet the exceptions in 49 CFR 172.102 Special Provision 188 are regulated as hazardous materials and would have to be offered as such.  Additionally, if they are to be operational during transport, they would still required Competent Authority Approval to do so. 

FAA Involvement

To this point, all the public knowledge I have seen has been regarding the exception of the Sensitech devices to hazardous material transport regulations.  While that was a significant hurdle, the public has failed to realize it is not the final step.  Indeed, the FAA, regulating under a different set of regulations (14 CFR, or the Federal Aviation Regulations) requires all air carriers to test and certify that any electronic device operating aboard an aircraft does not interfere with navigation equipment by creating electromagnetic interference or power drain.  Since these are battery powered devices, the power drain is moot.  However the EMI testing is required.  Typically, this is accomplished by reviewing testing completed by the manufacturer against the RTCA 160 D, E, or F standards.  All devices, laptops, portable oxygen concentrators, MP3 players, all devices expected to be used aboard an aircraft during flight MUST be approved.  While the carrier provides the approval, the FAA must be consulted, usually through the operators FAA Certificate Management Office.

If all relevant data is provided by the manufacturer, the process can take less than 4 weeks depending on workload and availability.  If all the required info is not available, the process can take an indefinite amount of time.  And this approval is required for EACH device, not for just a representative supplier. 

As you can see, the process is not as cut an dry as appears from the surface.  Nor is it limited to only a hazardous material nature.  This problem stretches across two US governmental administrations and multiple industry business units.  I have not provided an in depth technical discussion either but regulatory hair-splitting is at the heart of the issue.  I assure you, no company wants to refuse potential revenue, and certainly not in this economic climate.  However, it is also the responsibility of any air carrier to ensure their passengers and cargo are transported safely and compliantly.  The regulations are in place to ensure that happens.  Ignorance of the regulations does not mean a company is safe or compliant.  It means they either are not aware of the regulations or do not have the resources to investigate the issue fully.

The opinions stated in this email are mine alone.  I am not representing or defending Delta’s actions in this issue although I have been intimately involved from the beginning.  My reason to respond to you is more to open a line of communication between industry and the carriers.  Finger pointing from either side does nothing but generate frustration.  Open dialogue leads to safer shipments and airplanes, fewer frustrated shipments, and happier shippers and carriers.