What have you got in store?

Effective vaccine storage is the key to ensuring vaccines maintain their potency – but what’s the best way?

Vaccines now constitute one of the fastest growing pharmaceutical markets with major investment not just in research and development, but also in downstream areas such as manufacturing. The vaccine market is predicted to grow at an annual rate of 14% to generate $35.1bn in sales in 2012¹ and is set to record the highest growth of major therapy categories by 2014². As a powerful public health tool, vaccines are estimated to save 3 million lives each year³. Maintaining potency and viability during storage is therefore an essential process to ensure that all vaccines administered are as effective as possible.

The early stages of vaccine development lead to downstream clinical and subsequent validation studies, which commonly involve the screening of hundreds of thousands of lead samples. Extensive R&D is involved in the production of an effective vaccine with no off-target effects. As such, it is detrimental in terms of time- and cost-efficiency that if once manufactured, these vaccines are stored incorrectly. Any problems caused by a reduction in sample viability may mean an entire batch of vaccines are ineffective and require disposal, which can result in substantial financial loss. In clinical practice, refrigeration storage problems have been cited as a major cause for the $20 million per year wasted from ruined vaccines in the US Federal Vaccines for Children Program⁴. A recent audit in the UK found that 40% of vaccines were kept at the incorrect temperature, which has a potentially detrimental effect on potency⁵. This could be unknown of at the time, and thus some patients may have been inoculated with a sub-standard vaccine. Maintaining constant conditions for vaccine storage is undoubtedly key to improving viability and consequently the protection of a population at risk. Selecting the most efficient clinical and laboratory cold storage equipment is therefore critical to ensure sample protection.

Consumer and commercial appliances are simply not designed to maintain the requirements of high-value biological samples; whereas modern specialised laboratory refrigerators and freezers are purpose-built in every aspect, displaying advances in design and technology that can result in more efficient sample storage. As well as maintaining a consistent temperature across the entire cabinet, it is essential that temperature changes are minimal when retrieving samples. Exposure to ambient conditions, for example through multiple-user access, can result in a temperature change and subsequent recovery times to re-establish optimum conditions. Efficient compression technology, good insulation and interior cabinet design, as well as effective door seals are all important factors in improved cold storage performance. Choosing the proper equipment with proven performance that meets all government standards is now an important business decision for research, hospital, pharmacy and clinical laboratories.

There are a wide range of refrigerators and freezers available on the market, from household appliances to standard laboratory equipment and the more specialised cryogenic storage equipment. Since vaccines are biological products which are susceptible to temperature fluctuations, it is important that they are correctly stored in the appropriate, specialised equipment. The majority of commonly administered vaccines need to be stored between 2 and 8°C and must not be exposed to freezing temperatures which will irreversibly reduce the potency of the vaccine. In addition, certain freeze-sensitive vaccines contain an aluminium adjuvant that precipitates when frozen, resulting in a loss of efficiency and potency. However, the development of the Varicella vaccine in 1995 and the more recent introduction of the live attenuated influenza vaccine (LAIV) have increased the complexity of vaccine storage. These vaccines must be maintained in a frozen state, without the occurrence of any freeze-thaw⁶. Some additional examples of different vaccines which require refrigeration or freezing temperatures are shown in table 1.

Vaccine storage units must be selected with great care and it is recommended that laboratories have dedicated refrigerators and freezers, which are not used for the storage of any other sample type. Although combined refrigerator/freezer units are acceptable for vaccine storage if each compartment has a separate door, there are concerns that they produce different temperature zones – meaning that there is a lack of uniformity across the compartment. As colder air is expelled from the freezer, it enters the refrigerator space, consequently lowering the temperature of the area surrounding the cold air outlet⁶. Some vaccines (Varicella, MMRV, Zoster) must be stored in a freezer that has its own external door, since in order to reach the low temperatures required for safe storage, it is likely that the vaccines in the refrigerator compartment would freeze. These inconsistencies in temperature uniformity therefore render combined units less suitable for the storage of any temperature critical samples¹².

Selecting the correct refrigerator or freezer is also dependent upon the number of vaccine doses required by the laboratory each year. Laboratories with a low volume of 500 or less doses per year will need a stand-alone laboratory refrigerator or freezer unit. In comparison, a laboratory which processes a very high volume of >10,000 doses per year requires a pharmacy- or biology-grade refrigerator only unit and/or a stand-alone freezer unit⁷.

Cold-chain practices have a tendency to prioritise the protection of vaccines from heat damage, often at the risk of inadvertently exposing them to freezing temperatures instead⁸. As a result, the accidental freezing of vaccines, which should be stored between 2 and 8°C, is a largely overlooked problem; yet freeze-sensitive vaccines represent over 31% of the $439 million USD UNICEF spent on all vaccines in 2005⁹. The maintenance of accurate and uniform temperatures is therefore of significant importance. Since vaccines are protein preparations, temperatures above or below the optimal range will cause unfolding and denaturing of the protein. Exposure to heating or freezing conditions will weaken and subsequently break the hydrogen bonds holding the tertiary structure together, causing the vaccine to lose its specific shape and become ineffective.

When temperatures deviate, either above or below, the optimum range, the integrity of the vaccine becomes compromised. If undetected, patients are subsequently administered with a sub-standard vaccine. Although this does not have major implications on patient safety and no adverse effects have ever been observed, this is still a public health threat since young children inoculated with under-strength vaccines are unprotected against dangerous diseases⁴. As such, re-vaccination programs have been initiated in instances where this has been identified as an issue. This is not only costly, but can also be a traumatic experience, especially for younger patients. In addition, vaccination is generally a stressful situation to put children through and an additional level of angst can result from having to repeat the discomfort a second time⁴.

Proper temperature monitoring is key to maintaining uniform, optimised conditions throughout the storage unit. US CDC guidelines state that thermometers should be placed in a central location within the storage unit, adjacent to the vaccine. Temperatures need to be read and documented twice each day – once when the office or clinic opens and again at the end of the day⁶. Temperature logs should remain on file for at least three years, unless state rules stipulate a longer period. Immediate action must be taken to correct storage temperatures that are outside of the recommended range and mishandled vaccines should never be administered to a patient.

Vaccine refrigerators and freezers both require an automatic de-frost to ensure that the units are free from any water, ice, frost or coolant leaks, which could have an adverse effect on the stored samples. Clinics need to make significant allowances for the largest possible batch of vaccines that they will need to store at one time. This can be problematic as pandemics, such as the recent H1N1 (swine flu) outbreak, are not easily predicted. However, since individual doses need to remain 2-3 inches away from all walls, doors, drawers and cold air vents (as these are most likely to have temperature extremes), the footprint of available space needs to be decided with care⁷.

After exposure to temperatures outside of the optimal range, there are no visible signs to alert researchers that there may be a reduction in potency⁶. As such, strict quality assurance measures must be adhered to in an attempt to identify any potential decrease in efficiency. Studies have demonstrated that educating at least one staff member about correct monitoring and reporting of the refrigerator temperature significantly improves the maintenance of storage conditions, with fewer deviations from optimal temperature ranges going un-reported^10,11. Furthermore, a working National Institute of Standards and Technology (NIST) certified thermometer, or built-in monitoring system should be used to provide highly accurate and reliable temperature readings.

A number of additional measures can also be implemented to aid the maintenance of optimal temperatures. Incorporating alarms to alert users to a deviation in the temperature will enable stricter monitoring and control, since it provides a real-time warning, which cannot be ignored. The storage units themselves also need to be of a high quality and therefore not require frequent maintenance and repairs. For example the door seals must be intact, with no visible damage to provide a tight and secure closure. This ensures that no cold air can escape to the external environment and result in an increase in the internal temperature. In addition, every clinic should have a written Disaster Recovery Plan that identifies a refrigerator with a back-up generator in which to store vaccines in the event of a power outage or natural disaster¹².  

Recent developments in storage equipment have enabled the quick and simple monitoring of temperature fluctuations during vaccine storage. This, in combination with a degree of education on quality control measures can help to ensure that vaccines remain viable after storage, eliminating the need for costly losses and the implementation of revaccination programs.