Drugs must be transported, stored, and ad-ministered in non-ideal environments. However, the stability labeling for many
refrigerated drugs often allocates zero time for handing outside of the refrigerated norm of 2 to 8°C. Similarly, the labeling
for "room temperature stable" drugs often allocates zero time for storage outside of about 2 to 25°C.
Stephen E. Zweig, Ph.D
In the real world, drugs are transported to where they may rest in uncontrolled storage or loading areas for some period of
time. They may also be handled by healthcare workers who don't normally work in environments that meet these fictional "ideal"
temperatures. To what extent is this disconnect between stability labeling and practical reality medically significant? Clearly
this depends upon the drug in question. Many of the classical "small molecule" drugs are quite temperature stable, but other
drugs, such as beta-lactam antibiotics and biotherapeutic proteins, are quite unstable. In this later example, undetected
or undocumented temperature fluctuations can cause medically significant problems.
Here, recent experience cited from the vaccine field may prove relevant. Vaccines are biologic products and somewhat resemble
therapeutic proteins in overall stability and other characteristics. Like therapeutic proteins and other temperature-sensitive
drugs, vaccines can be rapidly destroyed by temperature extremes such as freezing or storage at elevated temperatures.1 Unlike therapeutic protein drugs, however, vaccine effectiveness is fairly easy to measure. After vaccination a blood sample
can be drawn, and the presence or absence of antibodies against a particular vaccine antigen can be measured.
Vaccine researchers first realized that temperature control was a major concern as a result of large-scale, third-world immunization
programs. Follow-up studies typically revealed that a large percentage of the population failed to respond to the vaccine.
These vaccination failures drew attention to the high incidence of "cold-chain" breaks in the third world. Studies indicated
that in the journey from the manufacturer to the ultimate end user, the vaccines passed through many hands (links in the chain),
with numerous opportunities for the vaccines to be stored improperly. As a result of these studies, the World Health Organization
(WHO) now requires that all WHO vaccines incorporate an easy-to-read time-temperature indicator (TTI)2 on the vaccine's label.3 This TTI lets users know at a glance if the vaccine is still viable.
Cold-chain breaks are not just a third-world problem. Surprisingly, a large number of follow-up vaccine storage studies have
demonstrated that cold-chain breaks are also common in the United States and other first-world countries.4 Because vaccine deterioration (i.e., vaccination failure) is fairly easy to measure, vaccine workers are very sensitive
to this issue. As a result, there are strict vaccine storage rules, including documenting the storage temperature on a twice-daily
basis and strict standards for vaccine refrigerators.
But are vaccines and therapeutic drugs really all that different? Is the rate of cold-chain and stability failures for therapeutic
drugs somehow substantially better than that of vaccines? This appears to be unlikely. The primary reason that cold-chain
awareness is significantly lower in the pharmaceutical sector may be because drug failures caused by cold-chain breaks are
harder to detect.
PROBLEMS WITH PRESENT DRUG- STABILITY PRACTICES
Over time, drugs can deteriorate into inactive, or even potentially harmful forms due to oxidation, hydrolysis, or any number
of other side reactions. Each of these reactions advances in a temperature-dependent manner. At higher temperatures, these
reactions usually speed up, and at lower temperatures they usually slow down. With certain exceptions, such as the denaturation
of protein-based biotherapeutic drugs induced by freeze-thaw phase transitions, the actual rate of drug deterioration changes
only slowly with temperature. Thus, a drug will generally deteriorate only slightly faster at 9°C than it will at 8°C.
Present drug labeling and stability testing almost universally ignores these basic chemical facts. At present, most temperature-sensitive
drugs typically have labeling such as: "Store at 2°C to 8°C, do not freeze."