Technology Spotlight

Temperature Effect Series

Part 1:  Identifying Cumulative Heat Exposure of Temperature Sensitive Medical Products

By Nick Puro, President, Temptime Corporation

Many biological medical products – including vaccines, large molecule pharmaceutical products, and certain medical devices – degrade with exposure to time and temperature. The degradation is usually faster at higher temperatures and slower at lower temperatures. Within certain temperature ranges, the cumulative time/temperature effect will slowly affect the potency of the product. Many of these types of medical products can also be damaged very quickly with exposure to very high heat or by freezing.

This article focuses on a method to identify mean kinetic temperature (MKT) exposure of heat-sensitive medical products and highlights the outstanding results achieved by the World Health Organization (WHO) and several Ministries of Health when a robust, miniaturized technology is used to monitor the MKT of each vial of life-saving vaccine. This technology is now adapted to monitor the heat stability of most biologicals, pharmaceuticals and medical devices.

The MKT Effect

MKT is a mathematical calculation of the cumulative thermal exposure experienced by a product for various times and temperatures (for example, from the time of manufacture until the time of its use). [MKT Information ] The MKT to which a perishable product has been exposed is the best scientific way of expressing the overall effect of temperature fluctuations on the product. For example, the shelf life for a 2°C to 8°C (Refrigerated) product is established based upon data and the assumption that the product will be maintained for its entire shelf life within the 2°C to 8°C temperature range. This is also true for controlled room temperature (CRT) products within the CRT range of 20°C to 25°C. Thus, the efficacy of refrigerated products will decrease faster as the temperature increases above the refrigerated range.  Short excursions may not harm the product to a point that will impact patient outcomes; but without monitoring the cumulative effect of all excursions and transmitting that information to the end user (practitioner/patient), it is impossible for the end user to know whether or not the heat stability profile of the medical product has been exceeded. The same is true for CRT products.

The World Health Organization Solution

The World Health Organization (WHO) began using HEATmarker^® Vaccine Vial Monitors (VVM) in response to grave concerns that children vaccinated against serious diseases, such as polio, would not adequately be protected if the vaccine lost potency due to heat exposure.  In collaboration with PATH (Program for Appropriate Technologies in Health), the WHO challenged the industry to develop an accurate, easy-to-use, cost-effective device that could monitor the cumulative heat exposure of each vial of vaccine. Following more than 10 years of research and development by major companies, the HEATmarker VVM was qualified and put into use.  HEATmarker indicators are also available for other medical products, such as biologicals, heat sensitive pharmaceuticals, and medical devices.

The HEATmarker is an MKT indicator that follows the Arrhenius equation:  The speed of the color development is faster at higher temperatures, and the color development is equivalent to product degradation over longer times at lower temperatures.     

[Heatmarker Demonstration] 

 The HEATmarker accumulates all of the temperature conditions experienced by the product to which it is affixed. It gradually, predictably, cumulatively, and irreversibly develops color to show the user, at a glance, whether the heat stability profile of the medical product has been exceeded or not. The active portion of the indicator is a square that is surrounded by a circle of fixed color. When the color of the square matches or is darker than the surrounding circle, the HEATmarker indicator is showing that the product has been exposed to potentially damaging heat.

WHO/PATH Joint Study

Major vaccine manufacturers worldwide have used more than three billion HEATmarker VVM indicators for vaccination campaigns sponsored by the WHO, GAVI, and the governments of India, Indonesia and Pakistan.  A joint study by the WHO and PATH showed that, in 2006, HEATmarker:

• Identified more than 23 million doses of vaccine that were potentially damaged by heat and therefore were not administered to patients; and
• Identified more than 31 million doses of vaccine that were exposed to potentially damaging heat, but were still effective for use – avoiding waste of those vaccines.

The WHO estimates that, over the next 10 years, HEATmarker will enable the delivery of an additional 140 million doses of vaccine, saving 140,000 lives and decreasing the morbidity rates for countless others.

Indonesia Case Study

HEATmarker VVM indicators played a significant role in saving vaccine in Indonesia after the earthquake in May 2006.  The earthquake, centered in Yogyakarta (a large city on the island of Java) significantly damaged the infrastructure, including the cold store facilities at the district and health centers.  Electricity was out for several days, and generators were either not used or not functioning.

The health workers used the HEATmarker indicators to identify, at a glance, vaccine vials that had been exposed to heat above the established temperature profile. This helped them decide which vaccines were still viable for use and which needed to be discarded. In total, vaccine in five districts and more than 50 health centers was saved from being discarded prematurely (wasted) due to the presence of the HEATmarker on the vials. Consequently, the 50 health centers were able to use vaccine to protect people from diseases rather than destroy the vaccine.   Thus, the use of the indicators substantially reduced vaccine wastage, improved the health workers’ confidence in the vaccine, and enabled the administration of the life-saving vaccine even after exposure to some time out of refrigeration.

India Japanese Encephalitis Vaccine Case Study

On September 15, 2008, The Indian Express reported that, upon inspection at an outlying storage facility, HEATmarker VVM indicators on about 450,000 doses of JE vaccine imported from China had reached the discard point. The local health officials conducted an investigation and found that the 450,000 doses of JE vaccine were stored in a walk-in refrigerated storage facility at the Government Medical Store Depot outside of Delhi.  The facility had experienced power interruptions for an unknown amount of time, and the back-up generator had failed to function properly. The HEATmarker indicator is credited with identifying the doses of vaccine that had been exposed to the excessive heat and preventing the use of this vaccine.

In the United States

The risk of undetected heat damage is greatly increased as heat-sensitive products move through the cold chain. The stringent controls followed by the manufacturer and distributors may not be maintained during shipping, at storage points, in physician offices, and by patients. Independent research indicates that 83% of primary care and pediatric physicians and 72% of physician specialists surveyed experience cold chain breaks.  More than 71% of primary care physicians and pediatricians are concerned about potential loss of product efficacy due to heat damage.  [See HARRIS RESEARCH.]  They are also concerned that they do not know if proper cold chain practices have been maintained before the products arrive at their offices. Additional challenges are faced, now that many patients are choosing to receive their medications through the mail.

Even with the most sophisticated technologies and the best intentions, breaks in the cold chain occur. Using a HEATmarker on each unit of a temperature sensitive medical product can:

• Prevent administration of medications to patients by clearly showing whether or not the product has been exposed to potentially excessive heat.
• Reduce unnecessary waste by limiting the destruction of products incorrectly suspected of heat damage.
• Support Call Center efforts by providing definitive information about potentially heat damaged products to healthcare professionals and patients.
• Enhance quality risk management and support continual quality improvement.
• Strengthen compliance with the recommendations of International Code on Harmonization (ICH) Q9 and ICH Q10.

Quality System Extension and Risk Management

Experience shows that, despite all good intentions and best efforts, temperature excursions routinely occur throughout the cold chain. While one or more short excursions outside of the recommended temperature range may not have a material negative impact on the efficacy of a medical product, the cumulative effect of time and temperature can cause medicines such as vaccines to become ineffective, creating potentially devastating patient outcomes.  Accurate, reliable and cost-effective tools exist such as HEATmarker, and can be used to support the extension of the manufacturer’s GMP quality system to the end user and mitigate risk.