Thiomersal (also know as thimerosal, merthiolate) is an organomercurial derivative of ethylmercury that has been used very widely, and for a very long time, as a preservative in vaccines in their bulk formulations. Its primary purpose has been to prevent microbial growth in the product during storage and use. It has also been used during vaccine production both to inactivate certain organisms and toxins and to maintain a sterile production line. In recent years, safety concerns have been raised over its use in vaccines, especially those given to infants. These concerns have been based primarily on data regarding the toxicity of a related substance, methylmercury, and from data on chronic exposure to mercury from the food chain.
Such safety concerns have led to initiatives in some countries to eliminate, reduce or replace thiomersal in vaccines, both in single dose and multidose presentations. Immune-mediated reactions to products containing mercury (mainly contact allergy as a manifestation of delayed-type hypersensitivity) can occur in some humans. Although this reaction has contributed to concerns about vaccine safety, it was not a major force leading to the recommendation by the authorities in some countries for the elimination of thiomersal from vaccines. It is important to note that concerns about the toxicity of thiomersal are theoretical and that there is no compelling scientific evidence of a safety problem related to its use in vaccines, although public perception of risk has been reported in some countries. WHO policy is clear on this issue, and the Organization continues to recommend the use of vaccines containing thiomersal for global immunization programmes because the benefits of using such products far outweigh any theoretical risk of toxicity.
The primary role of thiomersal in vaccines has been considered to be that of a preservative, but data indicate that there are other effects of this additive on vaccine antigens that need to be taken into account when considering its elimination, reduction or replacement. In some production processes thiomersal is used in the inactivation of vaccine antigen together with heat, for example in the manufacture of whole cell pertussis vaccine. Should a national health authority or a manufacturer decide to eliminate, reduce, remove or replace thiomersal in vaccines, then the strategy chosen may affect not only the subsequent ability of microbial contaminants to grow in vaccine preparations, but also vaccine quality, safety and efficacy. The question therefore arises as to what evidence is needed to ensure that a vaccine in which the thiomersal content has been altered will be as safe and efficacious as the already licensed product.
A consultation attended by representatives from national regulatory authorities and the vaccine industry from both industrialized and developing countries was held in Geneva from 15-16 April 2002. The objective of the consultation was to review, in a global forum, experiences in eliminating, reducing and/or replacing thiomersal in vaccines and to discuss the potential impact of these changes on the quality, safety and efficacy of the products as well as to consider regulatory requirements and their implications. The focus was on already licensed vaccines that include thiomersal as an inactivating agent and/or as a preservative.
Making changes to the thiomersal content of vaccines containing this preservative that are already licensed is a complex issue that requires careful consideration. It should be borne in mind that any change in the formulation may have an important impact on the quality, safety and efficacy of a vaccine. Experience shows that eliminating or reducing thiomersal in an existing product can have some unexpected effects on vaccine quality, safety and efficacy. Effects on vaccine stability might also be expected. The amount of additional data required to demonstrate that a product with an altered thiomersal content is at least of the same quality as the previous licensed one containing thiomersal, including product stability, safety and efficacy, will need to be evaluated on a case-by-case basis. Any decision regarding the elimination or reduction of thiomersal in vaccines should be science-based. There should be a clear rationale for any change in the formulation that takes into account the different implications of reducing or eliminating thiomersal from the production steps and/or from the final stage of production. In some cases the resulting products should be considered as new vaccines and may require further clinical trials.
- WHO Informal Consultation on development of guidelines on procedures and data requirements for changes to approved biotherapeutic products including biosimilars, Seoul, Republic of Korea, 27-28 April 2017
- Working Group meeting on revision of WHO TRS 941, Annex 5: WHO biosafety risk assessment and Guidelines for the production and quality control of human influenza pandemic vaccines, Geneva, Switzerland, 9-10 May 2017
- Working group meeting on Hepatitis E Vaccine, Geneva, Switzerland, 11-12 May 2017
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