The cold chain started as a breakthrough in the pharmacy field. Now, it needs more development. The cold chain helped immunize millions of children for three decades, but this specific process – whereby vaccines are kept within 2°C to 8°C (36°F to 46°C) from manufacturing to administration – remains as a difficult path for immunization programs to reach children of remote places. 

The cold chain is costly. The use of high quality refrigeration, cooling technologies, and the constant need for electricity, contribute to why 20 million children in the world are yet unvaccinated, and two million die every year from vaccine-preventable diseases. The price of the vaccines is not the problem anymore. NGOs have purchased them from manufacturers and sell them cheaply to developing countries. The difficulty lies in their delivery and storage, which always rely on electricity and cooling materials. The interruption of heat means the loss of vaccine potency.

controlled temperature chain drugs

This inherent risk in vaccine handling called for a better option—hence the development of the controlled temperature chain (CTC). Also known as a flexible cold chain, CTC is the process of allowing vaccines to be stored beyond the recommended cold chain requirement. Growing evidence shows that vaccines can remain potent even if stored outside the cold chain for multiple days prior to vaccination. This flexibility has potential benefits such as cost savings, preventing vaccine damage, and most importantly reaching children from in remote areas.

What is CTC?  

Vaccines are temperature-sensitive biological substances. If exposed to high heat or freezing temperatures, vaccine stability is compromised. Once they lose efficacy, it can never be regained. The cold chain was designed to prevent this from happening. Manufacturers require handlers of vaccines to keep temperatures within 2°C to 8°C (36°F to 46°F). When the temperature drops or exceeds  specifications for a long time, then the vaccines must be disposed of immediately.

Not all levels of sensitivity, however, are the same. Some vaccines are more heat-sensitive than others. For example, Oral Polio Vaccines (OPV) are one of the most sensitive to high temperature, while Rabies vaccines, pneumococcal conjugate vaccines (PCV), human papillomavirus vaccines (HPV), hepatitis B vaccines, and tetanus toxoid vaccines are the least sensitive to heat.

That’s where the controlled temperature chain comes in. The CTC allows some least heat-sensitive vaccines to be stored outside the cold chain requirement for a few days prior to administration. In a CTC setting, vaccine temperatures can reach the ambient temperature up to a specific threshold, for instance, 40°C (104°F) for most vaccines. CTC however will not disregard the cold chain, as vaccines need to still be stored within the traditional cold chain most of the time.  

Counting the Costs: Why the Need for CTC?

In a health review published in 2007, 35% of vaccines in developing countries resulted in accidental freezing for extended periods of time. UNICEF 2011 audits showed that $1.5 million worth of vaccines were damaged in five months alone, due to freezing temperatures. Moreover, the GAVI Alliance estimated that cold chain equipment for 2020 is worth $650 million. Adhering to cold chain requirements can be very costly.

The use of CTC for most vaccines provides a cost-savings potential. A study in 2014 estimated that the use of MenAfricaVac, a meningitis A vaccine, accounted for a cost of only $0.12 per person, reduced from $0.24, a half amount saved because of inexpensive CTC requirements. If replicated to mass vaccination, then this represents a massive cost reduction.

For resource-limited settings like the ones in developing countries, delivering vaccines requires the use of passive cooling technologies. Instead of electricity, frozen water-packs cool the vaccine carriers. These ice packs must be frozen for 24 hours and must be conditioned to prevent freezing damage. In the case of immunization campaigns, where thousands of people in remote areas need to be vaccinated, all these preparations and equipment add an immense burden to logistics.

In a CTC, where no cooling is required for a limited time, frozen water-packs can be eliminated. Without that cooling requirement, there’s no need for time-consuming preparation of conditioning, no risk of freezing, and increases in available space for more vaccines also reduces the weight of the carriers by half.

cold chain chest

Challenges of a Flexible Cold Chain

After all these years, why does CTC remain in the sidelines? Just a small percentage of vaccines are being tested for CTC. Only the meningitis A vaccines, and MenAfriVac, are WHO-prequalified for CTC storage and transport.

Re-licensing or re-labeling could be a reason for the slow development. For a vaccine to be authorized for use, it must be approved by the regulatory agency where the manufacturers are located. Then, the vaccines must also be authorized by the regulatory agencies of each country where the vaccines will be used. Any modification in the vaccines’ packaging, administration, formulation, new storage conditions also needs to be authorized by the same regulatory bodies. Such a complicated process pushes manufacturers away from aiming for a CTC license.

Some authorizations are also country-specific. For instance, HPV vaccines are mostly manufactured by Merck in the United States. The US Food and Drug Administration (FDA) approved the storage of HPV vaccines at or below 25°C (77°F) for 72 hours. While this seems a stretch from a traditional cold chain requirement, it can only be applied to the US settings, where they are always equipped with air-conditioning, but not to resource-poor settings where the ambient temperature goes higher than 25°C (77°F). Since most HPV vaccines are manufactured in the US, the situations of developing countries remain neglected.

Apart from the cycle of regulation, re-licensing incurs additional costs. When applying for a relicensing, manufacturers must conduct numerous stability studies that prove their vaccines can remain stable despite ambient temperatures higher than the cold chain range.

Some vaccine manufacturers use this roadblock as an excuse for inaction. The worldwide roll-out of the global polio eradication plan prompted the need for more oral polio vaccines (OPV). Sanofi Pasteur’s IPV, one of the leading products in polio vaccines, has a very good thermostability profile. Sanofi, however, claims that re-labeling for extended temperature conditions is not necessary as the regulatory process would take years.

What Needs to Be Done?

Vaccine purchasers play a pivotal role in the development of CTC-labelled vaccines. UNICEF, GAVI Alliance, PAHO, and the Gates Foundation have huge purchasing power. They can focus their attention and purchase more from manufacturers who address the issues of the developing countries. Plus, these NGO donors could reward manufacturers with financial premiums, prizes, or becoming a large part of their market, only if they develop CTC vaccines with the developing countries’ unique situation in mind. 

The vaccination community must push for current vaccines to maximize their full thermostability profile, while developing more vaccines in their required cold chain range.

All manufacturers of vaccines such as Sanofi-Pasteur, Pfizer, Shantha, and Serum Institute of India must conduct more heat stability studies and disseminate their results in public. They should also strive for more re-labeling of new generation and old vaccines so developing countries get better access to them without the need for costly cooling devices and electrical connections.

Developing countries are not the only ones that can benefit from a flexible cold chain—developed countries can, as well. Without the need for expensive equipment and the fear that vaccines may lose its potency along the way, manufacturers, mostly from developed countries, will spend less money on storage and transport.

The improvement of CTC benefits everyone. Above all, children, the most vulnerable members of society, will have the chance to live.


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