Wider Use of Chemical Indicators Suggested

Chemical temperature indicators have long been used as vaccine vial monitors (VVM) in global immunization programs, and one provider suggests that such use suits the indicators for wider use throughout the pharmaceutical industry. Wider use could alleviate some physician concerns about cold-chain product integrity, such as those revealed in a recent Harris Interactive Research survey of U.S. physicians.

In that survey, commissioned by Temptime Corp., a majority of respondents reported that they are concerned that “heat-damaged products resulting from cumulative exposure to temperatures outside the specified temperature range pose a health risk to patients,” a press release on the study reports.

“Physicians have experienced cold chain breaks in clinical practice since we first began using medicines that required refrigeration,” said Donald T. Allegra, MD, FACP, who is not affiliated with the study. “Now, with advancements in science and medicine trending toward increased use of biologics, vaccines, and other temperature-sensitive medicines, we need far more vigilance around the cold chain to protect life-saving medicines from temperature abuse, and protect our patients from associated risk stemming from undetected temperature abuse.”

Ted Prusik, PhD, senior vice president of Temptime, believes that monitors similar to those his firm provides to support the World Health Organization-UNICEF Global Expanded Program on Immunization could be put to work in the general pharmaceutical industry to provide a better understanding of temperature exposure.

Temptime sold about a half-billion VVMs in 2009 for UNICEF vaccines, Prusik says. “Their use is part of UNICEF’s vaccine purchase requirements,” he says, pointing to a WHO-UNICEF policy statement issued in 1999. (For details, visit http://www.who.int/vaccines-documents/DocsPDF99/www9928.pdf.)

“The rational for their use was developed years ago because of known issues in the field. The program needed a low-cost solution that could help monitor product in countries with poor temperature control,” he says.

The VVM technology is based on solid-state polymerization chemistry developed at the Allied-Signal Corp. in 1983, Prusik notes. Chemical indicators have been questioned in the past because, given their single-use nature: each indicator cannot be verified or validated before use. But Prusik says even though “you cannot validate each device, we validate the process by which the indicators are made.” Temptime’s use of good manufacturing practices ensures consistency and quality, and the pharmaceutical industry routinely relies on such process validation to document product quality, rather than verifying every item, he says. "Results from a recent head-to-head study of Temptime freeze indicators vs. chemical and electronic freeze indicators confirms the consistent and accurate performance of Temptime technology. Results of this independent study are scheduled for release soon.”

Under the new USP committee chaired by Mary Foster, Prusik looks forward to a review of the USP Chapter <1118> Monitoring.
Devices—Time, Temperature, and Humidity that called chemical indicators into question. “We will ask that USP look again at that chapter,” says Prusik. The work would be timely, given industry interest in ensuring product integrity during the last mile in the pharma cold chain. “It seems as though concern about the last mile is coming up over and over again,” he says. “Even PDA is concerned about it. So we see companies looking at chemical indicators again.”

Interestingly, many of the same concerns raised in the Harris survey were those of the WHO-UNICEF program. “When building its VVM policy, it sought to address two concerns: vaccines exposed to too much heat during the last mile, and vaccines left out but actually OK,” says Prusik.

According to the Harris Interactive research, three in five physicians are at least “very concerned” about ineffective treatment and/or no relief of patient symptoms. More than half of physicians across all specialties surveyed are concerned about potential serious adverse events related to heat-damaged products. Primary Care Physicians (PCPs) and pediatricians (the top prescribers of vaccines) are most concerned of all specialists surveyed about outbreaks of preventable disease caused by administration of heat-damaged vaccines.

The Harris survey also found that cold-chain breaks are pretty common. For instance, most physicians have experienced a cold chain break in their clinical practice, the study found. More than 7 in 10 physicians across most specialties surveyed reported having experienced first-hand breaks in the cold chain in practice. And 72% of specialists surveyed including endocrinologists, hematologists/oncologists, and rheumatologists experienced a cold chain break as compared with 83% of PCPs/pediatricians.

Specialists reported more delivery-related breaks, which are thought to occur when products are in transit to physician offices. PCPs/pediatricians reported more storage-related cold chain breaks, occurring after the products arrive at the offices.
A separate study in 2006 by the California Dept. of Public Health, Immunization Branch on vaccine storage and handling, found that vaccine waste in the San Francisco Valley (10 regions) extrapolated to the state of California alone identified $2.3 million in vaccine waste, reports Prusik.

“A lot of that probably could have been saved had VVMs been used to reveal true exposure,” he says.
Of course, doctors often err on the side of caution when concerned about temperature exposure, discarding products that doctors fear could be spoiled. They do not want to administer products that may have lost potency for fear of leaving vaccinated patients vulnerable.

Such “robust and flexible” indicator technology could be used for many temperature-sensitive medicines beyond vaccines, including other protein-based products, blood products, and chemotherapeutic agents, among others, Prusik says.
Even non-cold-chain products could use an indicator to reveal other sorts of temperature exposures, he says. More and more patients are receiving pharmaceuticals through mail-order delivery, so such indicators could be used to ensure proper handling of all products, even those handled at room temperature. “Often these are high-value products, so the indicators could give patients a feeling of security.” He also suggests that they could be used to authenticate handling to fight diversion.

“Companies have advised patients not to use products because of temperature concerns. If these indicators were to be used, patients could be directed to call a manufacturer hotline in the event of a color change in an indicator that might mean the product had been heat damaged. The hotline representatives could help direct patients as needed,” says Maria Chernock, an independent consultant to Temptime. 

The specific time-temperature indicator used as a VVM is affixed to individual vials by the manufacturer after they are sealed. They are designed to withstand the heat experienced during sealing and other industrial processes. Twenty-seven vaccine manufacturers globally are currently using Temptime VVMs, Prusik reports.

The indicators can be programmed to suit individual products’ stability requirements. They can be added to prime labels, or they can be piggybacked on existing structures.