UPDATE - April 2003
Strengthening the vaccine regulators
While vaccines procured through UNICEF meet quality standards set by WHO, the same quality assurance is not always guaranteed when governments buy their vaccines direct. As vaccine supply patterns change, WHO is working with developing countries to build their own capacity to regulate vaccines, whether locally produced or imported
BASIC children's vaccines are in increasingly short supply worldwide. Take, for example, the case of DTwP, the diphtheria, tetanus and pertussis vaccine containing a wholecell form of pertussis. Many industrialised countries now use acellular pertussis, so the interest of the big pharma in the wholecell vaccine is diminishing rapidly. Last year, only three manufacturers offered DTwP to UNICEF, with the bulk of this supply coming from developing countries. And this year, for the first time in decades, UNICEF's demand for this vaccine outstrips supply (Fig.1).
Moreover, UNICEF's purchasing requirement is only part of the total global need. More than 60 countries do not buy their vaccines through UNICEF but direct, from manufacturers within their borders or by importing. WHO figures suggest that some 90% of the DTwP available globally is now made in developing countries. Of this, only about onethird has been shown to meet WHO's quality assurance "prequalified" standards (Fig.2).
To safeguard children and to ensure an adequate future supply of highquality vaccines, WHO says that its member states should use only vaccines of assured quality in their immunization programmes. The key question is how to do this. Vaccines may be "prequalified" by WHO, that is, shown to meet agreed quality standards for purchase by the UN agencies, or they may be licensed by a fully functional national regulatory authority (NRA).
WHO has provided the "prequalification" service to UNICEF and the other UN agencies in assessing the acceptability of vaccines that they may wish to buy from a variety of different sources. The service gives purchasing agencies independent advice on the quality of vaccines and their suitability for use. WHO prequalified vaccines must meet quality, safety and efficacy standards: for example, they must show consistent potency and thermostability. They are monitored for their compliance with programme specifications on presentation and labelling, and are also monitored once in use to detect and document any possible suspected adverse effects.
|"In some countries, the weakness of the regulatory system has proved a bottleneck to manufacturers that have already invested heavily in new plant"
However, WHO has recognized that its own staff cannot assess every new candidate vaccine and that for a sustainable system to exist, governments must take responsibility for regulating domestic and imported products themselves. Since 2000, the UN agency has therefore placed increasing emphasis on building the regulatory capacity of national governments. Before a vaccine can be considered for prequalification, the manufacturer's host country must have a competent NRA in place, and this authority must be clearly independent from the manufacturing industry.
In the past, some governments have been unable to separate manufacture from regulation, and several public manufacturers in developing countries have had close, or overlapping, links with the regulatory system. In some countries, the weakness of the regulatory system has proved a bottleneck to manufacturers that have already invested heavily in new plant and highquality production processes. So WHO is investing, first, in training regulatory staff until each NRA can fulfil its necessary functions. Good manufacturing practice can then be enforced.
|1: Six functions of an independent national regulatory authority
- A published set of requirements for licensing
- Surveillance of vaccine field performance to identify any suspected adverse events following immunization
- System of lot release
- Use of laboratory when needed
- Regular inspections to allow enforcement of good manufacturing practice
- Evaluation of clinical performance for safety and efficacy
Fully functional NRAs should fulfil six specific functions, says WHO (see Box 1). Clearly, it is not realistic to expect every country, however low its income, to have the same type of authority. For a country that is host to a vaccine industry, the regulatory authority must fulfil all six functions. For a country that procures all vaccines through UN agencies, the WHO prequalification process takes care of some aspects of the process, and only the first two functions must be fulfilled. For a country that buys vaccines direct, but does not produce any, the first four functions must be fulfilled.
There is now growing evidence that some major vaccineproducing countries, such as The People's Republic of China, are strengthening their capacity to regulate the industry. Last December, an international expert team appointed by WHO went to China to review the functions exercised by its national vaccine regulatory system. The team found major advances since 1998, when a new State Drug Administration had been established as an independent authority, separate from the ministry of health and from the state vaccine manufacturers. The law on registration and licensing of vaccines had been revised. A system for monitoring the lot release of vaccines had been put in place in 2001.
|"Even in countries assumed to have robust and competent regulatory authorities, assessment can be a useful trigger for discussing ways to improve"
Inspections to check that all producers were complying with good manufacturing practice had begun, and during 2002 most vaccine manufacturers were certified. Only the system for monitoring suspected adverse events following immunization needed to improve, and plans for that were set out clearly for the first half of this year. China had shown a "very strong" commitment to build up its regulatory capacity, the WHO inspectors found (1).
The existence of an independent and competent National Regulatory Authority (NRA) is one of the requirements for vaccines to become prequalified. Once the requirements are met, China's large industry will be able to help fill the gaps in the global supply of certain key vaccines by selling to the UN agencies, and to procuring countries abroad.
By late 2002, WHO had conducted assessments of 49 national regulatory authorities worldwide, including some in industrialised countries such as Australia, Japan and Sweden, and found that even in countries assumed to have robust and competent regulatory authorities, assessment can be a useful trigger for discussing ways to improve the way these six functions are carried out. Perhaps not surprisingly, the majority of governments worldwide have still some way to go before they can be said to exercise all their regulatory functions (Fig. 3).
Obviously, countries with a vaccine industry are more likely than those without an industry to have a competent NRA, and in turn, those countries that procure their vaccines directly are more likely to have a fully functioning NRA than those that procure through UNICEF.
At this point, WHO is focusing its training initiatives on major producing countries. "Training is central to what we do," says Lahouari Belgharbi of WHO's department of Vaccines and Biologicals. WHO says it has trained more than 500 regulatory staff worldwide in the past seven years (2). The pace is accelerating as more and more new manufacturers come on line. In the coming year, WHO expects to have more potential prequalified manufacturers in India and China. Clearly, it is in the interest of governments and their WHO partners to increase the capacity for regulating this industry as soon as possible -- as China has shown to be feasible.
1. Vaccine Quality: Assessment of Vaccine Regulation in the People's Republic of China. FollowUp visit 16--21 December 2002. WHO. From firstname.lastname@example.org or WHO's regional office for the Western Pacific region.
2. Strengthening National Regulatory Authorities: A Global Overview. L. Belgharbi, WHO, address as above.
Immunization Focus April 2003 - Contents