SPECIAL FEATURE - July 2003
Vaccine vial monitors: is the waiting almost over?
A simple device could protect children from receiving heat-damaged vaccine and save millions of dollars' worth of wasted vials. Phyllida Brown investigates.
EVERY year, millions of doses of vaccines are thrown away for fear that they might have been heat-damaged, whether or not they actually are. Heat damage is not visible, so health workers have been trained to discard anything that they suspect could have been exposed, for example after two trips out to the field. More serious still, where failures in the cold chain go unnoticed, children are probably receiving heat-damaged vaccines that offer no protection.
But these problems are largely avoidable. Since 1996, a tool called a vaccine vial monitor (VVM) has been available. A VVM is a label that contains a heat sensitive material. It is placed on a vaccine vial, where it registers heat exposure over time, for example if an ice pack melts, or if a fridge suffers a short power cut. As time passes, the colour darkens. The warmer the temperature, the faster the colour changes. The label shows clearly when the cumulative heat exposure has reached the point where the vaccine should be discarded (see Figure 1). As long as the vaccine has not reached the discard point, and has not reached its expiry date, it can be used even if it has been out of a fridge several times (see "How does it work?'', Box 1).
"Used properly, this can be a miracle tool to reduce wastage and prevent the use of heatdamaged stock,'' says Ümit Kartoglu of WHO's department of Vaccines and Biologicals. In Bhutan, a study showed that wastage fell by 49% on polio vaccine where VVMs were used (1). Comparable results have emerged from studies in Nepal, Turkey, Ghana, Kenya, Sudan, Tanzania and Vietnam. The benefits are greatest during national immunization days, when large volumes of vaccine are transported into the community, but VVMs can also cut wastage in routine programmes, especially in remote rural areas where teams must travel far from base to reach children. The technology is inexpensive, with each VVM adding only a few cents to the cost of a vial and bringing net savings. UNICEF and WHO have estimated that, given typical wastage rates, the use of VVMs on the basic vaccines alone could save about $5 million a year (2). With the introduction of more expensive vaccines such as Hib and yellow fever, the savings will be orders of magnitude greater.
|Figure 1: How to read a vaccine vial monitor
|The inner square is lighter than the outer circle. If the expiry date has not passed,
USE the vaccine.
|As time passes the inner square is still lighter than the outer circle. If the expiry date has not passed,
USE the vaccine.
|Discard point: the colour of the inner square matches that of the outer circle.
DO NOT USE the vaccine.
|Beyond the discard point: inner square is darker than the outer circle.
DO NOT USE the vaccine.
Because VVMs can show up undetected failures in the cold chain, they may initially increase the number of vials that are rejected. But by identifying those failures, they will protect children and ultimately improve the quality of the cold chain as well.
So why don't all vaccines carry a VVM? Only polio vaccine, the most heat-sensitive of the vaccines used by the Expanded Programme on Immunization, has carried VVMs since 1996. Even though UNICEF and WHO have requested manufacturers to supply VVMs with all vaccines since 1999, and included VVMs in the minimum requirements for UNICEF tenders since 2000, VVMs are still only available from a minority of the 23 manufacturers that supply vaccines to the UN agencies. They appear on some, but not all, vials of BCG, yellow fever, measles, hepatitis B and tetanus-toxoid vaccines. Some multivalent vaccines also carry VVMs, including measles-rubella, measles-mumps-rubella and DTP-Hib liquid vaccine (3).
At its meeting in Dakar in November 2002, the GAVI Board resolved that all vaccines purchased by the Vaccine Fund will include VVMs after 2003. When the Board meets this month, its vaccine industry members will provide an update to the other members on action taken by industry to meet this requirement.
WHO, UNICEF and the other members of the Alliance are working with the industry and hopeful that consensus is gradually being achieved. At present, manufacturers hold differing positions on VVMs. Some, such as Chiron in Italy, Japan BCG, Green Cross Vaccine Corporation, LGLS and the Institut Pasteur in Dakar, Senegal, have introduced them for products sold to UNICEF. Other manufacturers have clear plans to introduce them. For example, says Walter Vandersmissen at GlaxoSmithKline in Belgium, the company's tetravalent vaccine DTP+HepB is expected to carry VVMs later this year, while its pentavalent DTP+HepB+Hib should follow early in 2004. The Serum Institute of India has been validating VVMs on its products but, says Suresh Sakharam Jadhav at SII, this process is now almost complete and staged introduction of VVMs will begin in January 2004.
Aventis Pasteur added VVMs to its oral polio vaccine in 1996 and says it recognizes the tool's benefits for highly heat-sensitive vaccine. But it says it has "reservations" about using VVMs systematically on all vaccines for developing countries, and it has not yet put them on any of its other relevant products. Nonetheless, Aventis Pasteur says it has evaluated the feasibility of expanding the use of VVMs to three of its products: DTP-Hib, yellow fever and measles vaccines. "Aventis Pasteur has targeted the end of 2003 to complete the feasibility evaluation, at which time it hopes to have the ability to respond to the special needs of GAVI,'' says the company.
1: How does it work?
The VVM is a coloured circle with a pale square in its centre. It can be printed on a label or attached to the cap of a vaccine vial, or the neck of an ampoule. The square gradually darkens until it matches the surrounding circle. At the point where the inner square matches the surrounding circle, the vaccine has reached its discard point.
The colour change is due to a chemical reaction known as polymerization. With heat and time, the initial agent, a monomer, is converted irreversibly to a polymer. The chemical reaction speeds up when the temperature is raised. As different types of vaccines have different levels of heat sensitivity, VVMs come in four types whose rates of colour change at specific temperatures have been designed to reflect these different heat sensitivities. The type of VVM that is attached to a particular vaccine is the type appropriate for that vaccine's heat stability. For example, VVM2 is designed for oral polio vaccine, the least heat-stable of the vaccines used in the Expanded Programme on Immunization, which reaches its discard point after two days at 37ºC. At the other end of the spectrum, VVM30 is suitable for certain types of hepatitis B vaccine, which are relatively heatstable and survive undamaged up to 30 days at 37ºC.
A VVM does not measure the potency of a vaccine, but simply its heat exposure. Heat exposure is one of the main factors that can affect vaccine potency. VVMs do not provide information about whether a vaccine has been frozen, another potential source of damage, especially for hepatitis B.
Some manufacturers have expressed doubts about the technical accuracy of VVMs and their validation. But VVMs are validated rigorously, both in the laboratories of both the VVM manufacturer, LifeLines in New Jersey, USA, and the laboratories of vaccine manufacturers that currently use them. Each batch is tested by exposure to heat in water baths and using a colour reflectance densitometer, to ensure that the VVM changes colour correctly in response to heat exposure. Vaccine manufacturers also conduct tests before accepting each shipment from the VVM manufacturer. WHO has also commissioned various independent laboratory tests, for example at the UK National Institute for Biological Standards and Control, to compare these results with those of the manufacturers. "We have shared the results of these studies with all industry members, and none of them raised any questions,'' says Kartoglu.
Still, some in the industry fear that manufacturers could be held liable for products bearing "healthy'' VVMs that were later blamed for adverse events. However, says Kartoglu, concerns about liability are nothing new. All vaccine manufacturers risk being held liable for adverse events attributed to their products, and VVMs do not change this. If anything, a VVM should reduce the risk that a manufacturer will be held liable for adverse events, because heat-damaged products are less likely to be used. The risk that a VVM will fail in the field is only theoretical, says Kartoglu: it is a validated device that is checked, lot by lot, by the producer. Manufacturers that use VVMs already perform regular audits on the producer. And, just like any other material used in a vaccine production line, the vaccine manufacturer checks every lot as part of its acceptance process. In six years of use, with more than 800 million vials of vaccine bearing VVMs, there has been no documented case of a child receiving heatdamaged vaccine due to a faulty VVM.
For some vaccine manufacturers, the strongest objections are not technical but logistic or economic. Aventis Pasteur told Immunization Focus that its reservations about universal use of VVMs for developing countries include the size of the investment relative to the expected returns, and concerns that there is currently only one manufacturer of VVMs. Aventis Pasteur also has concerns about how to manage its own inventory, given that VVMs are required only on vaccines supplied through UNICEF, and not currently on vaccines supplied through the Pan American Health Organization (PAHO).
Firm contracts for vaccines
Vandersmissen at GSK says the company may lose flexibility in the use of its filling-line capacity if it has to add VVMs to some vaccines. He says that manufacturers would be encouraged to devote space and capacity to VVMbearing products if they had firm contracts from public-sector vaccine buyers to purchase a given quantity of vaccine. At present, only a "gentleman's agreement'' is in place until the vaccines are bought, and this uncertainty makes manufacturers wary of risking wasted capacity.
Some manufacturers are reluctant to introduce a new technology that they believe will need to clear yet further regulatory hurdles. WHO says it is the responsibility of the individual manufacturer to contact their national regulatory authority about any approval it may need for VVMs. However, WHO has already taken steps to find out the position in some countries, and will continue informally to work with national regulatory authorities on this issue. France and Belgium have told WHO that VVMs do not require regulatory approval from their national authorities. In the US, for vaccines licensed for distribution in the US, manufacturers would need a supplement to their licence application, and vaccines not licensed for US distribution have to meet export regulations. However, these are not seen by WHO as difficult to achieve.
UNICEF, as a key public-sector buyer of vaccines, is responsible for sending clear messages about VVMs to its suppliers. "We are working with all manufacturers to ensure the implementation of VVMs at the earliest opportunity,'' says Shanelle Hall at UNICEF Supply Division. She points out that because there are so few suppliers of certain vaccines, UNICEF does not always have a choice; to ensure enough doses are bought, UNICEF must sometimes buy vaccines without VVMs at present. "But by having VVMs as part of the technical specification for vaccines, and through continuous communication with manufacturers, we are building up the number of vaccines we receive with VVMs.'' Hall points out that it would help if all buyers also required VVMs. Steps are being taken towards indroducing VVMs in the PAHO region. Programme managers from PAHO countries will meet in Peru later this year to discuss the options.
Mercy Ahun, formerly the manager of Ghana's national immunization programme, and now with the GAVI Secretariat, is clear. "VVMs are currently one of the best contributions that vaccine manufacturers can make to the lives of children''.
- Vaccine Vial Monitor Impact Study Results. Kingdom of Bhutan. July 1997 through November 1998. Program for Appropriate Technology in Health, Seattle, 1999.
- Quality of the cold chain. WHOUNICEF policy statement on the use of vaccine vial monitors in immunization services. WHO/V&B/99.18
- United Nations Prequalified Vaccines (June 2003). www.who.int/vaccinesaccess/quality/un_prequalified/ prequalvaccinesproducers.html
- Getting started with vaccine vial monitors. WHO, 2002. WHO/V&B/02.35