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Compliance Gaps Persist In the Vaccine Cold Chain

Although a temperature-controlled supply chain is essential for the transportation of an increasing number of pharmaceuticals, particularly newer generations of complex, expensive drugs, some of the products that are most sensitive to temperature fluctuations are decades older than today’s novel oncology or rheumatology therapeutics: vaccines.

“The challenge is that vaccines are proteins with a complex, three-dimensional structure, so they will suffer more than a tablet or capsule in solid dosage form if they are exposed to temperature excursions,” said pharmaceutical supply chain expert Rafik Bishara, PhD, an advisor to the World Health Organization and a member of URAC’s Pharmacy Advisory Council.

Over the past several years, URAC’s standards have placed more emphasis on appropriate temperature control practices to ensure the proper handling of temperature-sensitive pharmaceuticals—and that includes vaccines, Dr. Bishara noted.

In version 3.0 of its specialty pharmacy accreditation guide, URAC’s PHARM-OP 7 standard for cold chain distribution requires that pharmacies have policies to address criteria for selection and testing of new packaging products, a mechanism for monitoring these products at least annually, and a means to ensure that the product is maintained within the manufacturer’s guidelines throughout the entire shipping process (www.urac.org/standards-and-measures-glance).

One Temperature Does Not Fit All

Different types of vaccines have different vulnerabilities and require dramatically different handling. Live virus vaccines, which contain weakened forms of the infectious virus, are exquisitely heat sensitive. The MMRV (measles-mumps-rubella-varicella), varicella and zoster vaccines must be kept continuously frozen at –15° C or colder until just before administration, because they deteriorate rapidly as soon as they are removed from the freezer. The MMR vaccine can be either refrigerated or frozen.

But to add a complicating factor, the live attenuated intranasal influenza and rotavirus vaccines, although they’re also live virus vaccines, cannot be frozen and must be refrigerated at the standard 2° to 8° C range. Vaccines made from inactivated viruses also are sensitive to both heat and freezing. They should be stored and transported at temperatures within the standard 2° to 8° C range. “Vaccines with an aluminum adjunct in particular cannot be frozen; they will become denatured and no longer be effective,” Dr. Bishara said.

Most of the headlines about vaccine mishandling and improper storage in recent years have stemmed from incidents in other countries, such as China. But the vaccine cold chain remains a major problem in all countries where it has been studied, according to a 2014 report from the World Health Organization (Expert Rev Vaccines 2014;13[7]:843-854).

A 2007 analysis found that accidental freezing of vaccines is “pervasive” worldwide: Between 14% and 35% of refrigerators or transport shipments were found to have exposed vaccines that were not freeze-tolerant. In studies that examined all segments of distribution, between 75% and 100% of these shipments were exposed (Vaccine 2007;25[20]:3980 – 3996). This trend has continued in the decade since the study’s publication: A 2017 update of the review found that the percentage of vaccine exposure to temperatures below recommended ranges during storage was 33% in wealthier countries and 37.1% in lower income countries. Exposure to these temperatures during shipping occurred in 38% of studies from higher income countries and 19.3% in lower income countries (Vaccine 2017;35[17]: 2127 – 2133).

Colder Isn’t Always Better

A major culprit in vaccine freezing is the misperception that if cold is good, colder is better. “From reports I have seen, some pharmacists or pharmacy techs may erroneously think that putting the vaccine next to the phase change material, or frozen block or frozen gel, ensures good cooling,” Dr. Bishara said. “But you must avoid touching the vaccine to the coolant, because that could cause freezing and denaturing.”

Staff at pharmacies that handle and/or ship vaccines should be intimately familiar with two key documents from the U.S. Pharmacopeial Convention: General Chapter <1079>, Good Storage and Distribution Practices for Drug Products (USP42-NF37 2S) and General Chapter <659>, Packaging and Storage Requirements (USP42-NF37 2S).  The latest versions of both chapters are available in volume 44, issue 4 of Pharmacopeia Forum Online (www.uspnf.com/pharmacopeial-forum).

To monitor vaccines for heat exposure or freezing, the WHO recommends vaccine vial monitors (VVM), which are marketed by Temptime under the HEATmarker and FREEZEmarker labels. VVMs are easy-to-read labels placed directly on each individual vial.

HEATmarker VVMs feature a round, lavender-colored area containing a lighter square. “By changing its color, this material indicates the cumulative heat exposure over time,” explained Denis Maire, a WHO scientist and public health specialist. “The color of the circle does not change, and is called the reference color. The color of the square, as time passes, becomes gradually darker and darker. The vaccine can be used as long as the square is lighter than the circle.”

Four different categories of VVMs are available to match the thermal stability of different vaccines (VVM 2, 7, 14 and 30—denoting the number of days to reach the vaccine’s end point if it is kept at a constant temperature of 37° C).

FREEZEmarker VVMs, on the other hand, consist of a clear plastic blister containing a green circle with a white checkmark in the middle—the “active zone.” The blister is filled with a clear liquid; after a freeze event, the liquid will turn a cloudy or opaque white, obscuring the check

Another Point of Vulnerability

Given the advent of such practical tools, staying within recommended temperature gradients during shipping becomes a less daunting task. But a 2015 survey conducted by a leading patient safety organization offers a cautionary tale about another point of vulnerability—the refrigerators that health systems use to store these medications once they’ve arrived intact after cold-chain shipping.

The Medication Error Reduction Plan (MERP) survey, conducted by the CHPSO Patient Safety Organization, which includes more than 400 members in 10 states, found evidence suggesting that vaccines often are not stored according to manufacturer’s specifications. In many cases, the sur-vey noted, faulty refrigeration occurred in several different operational areas, including emergency departments, inpatient pharmacies and outpatient clinics.

During one MERP hospital survey, 3,921 patients were identified who had received vaccines following storage at subzero temperatures, according to a report by Loriann DeMartini, PharmD, on the survey findings (www.chpso.org/newsletter/check-your-medication-refrigerators). “When vaccines are stored below freezing temperatures, the immunogen separates from the aluminum, reducing the vaccines’ potency; repeated exposure to freezing temperature will render the vaccine ineffective,” Dr. DeMartini explained, adding that temperatures at the surveyed hospital were found to be out of range for approximately 16 months.

-Gina Shaw