Vaccines excipients

Vaccine excipients (adjuvants and other substances used in the formulation) are treated in the same way as chemical substances. If new substances are introduced, a full safety assessment is required. It may be necessary to assess their toxic potential separately from the vaccine, since the vaccine formulation may interfere with a proper testing. In addition the normal pharmacological and safety tests for vaccines must be performed with the final, formulated product. 

Many factors have to be considered when developing combination vaccines. First the selected components need to be given on a similar schedule and all components should already be licensed in the United States. The excipients contained in the individual vaccines may interfere with another component when combined, altering a component s immunogenicity. Finally, the immunogenicity of the combination must be similar (within 10%) to the immune response when the components are administered separately. This has been problematic with combinations containing Haemophilus influenza type b vaccine, for which the immune response has been significantly blunted in some combinations.13... 

Figure 3.9. Generalized overview of the industrial-scale manufacture of recombinant E2 classical swine fever-based vaccine, using insect cell culture production systems. Clean (uninfected) cells are initially cultured in 500-1000 litre bioreactors for several days, followed by viral addition. Upon product recovery, viral inactivating agents such as /i-propiolactone or 2-bromoethyl-iminebromide are added in order to destroy any free viral particles in the product stream. No chromatographic purification is generally undertaken as the product is substantially pure the cell culture media is protein-free and the recombinant product is the only protein exported in any quantity by the producer cells. Excipients added can include liquid paraffin and polysorbate 80 (required to generate an emulsion). Thiomersal may also be added as a preservative. The final product generally displays a shelf-life of 18 months when stored refrigerated...

The intended human formulation of the vaccine is administered to the animals in order to ensure exposure to all of the vaccine components, including the protein or carbohydrate antigen, adjuvant, excipients, and impurities. 

Certain additives, salts, and bulking agents may be added primarily to improve vaccine stability upon storage (19,20). These excipients such as mannitol, glycine, and trehalose have a direct impact on the stability of the polypeptide or conjugate and are investigated for this purpose. 

EXCIPIENTS USED IN VACCINE FORMULATIONS CURRENTLY IN CLINICAL TRIALS... 

ANALYTICAL ASSAYS AND QUALITY CONTROL OF EXCIPIENTS FOR VACCINE FORMULATIONS... 

In conclusion, excipients to be used in vaccines must be very carefully selected and justified to the regulatory authorities because these are to be used in millions of healthy subjects. Their safety and compatibility with other vaccine components are of prime importance. Because vaccines of the future will be more and more complex, the need for suitable excipients is also likely to grow. It must be ensured that the excipients do not compromise the immunogenicity of the vaccine and accord maximum stability upon long-term storage. 

Vogel FR, Powell MF. A compendium of vaccine adjuvants and excipients. In Powell MF, Newman MJ, eds. Vaccine Design The Subunit and Adjuvant Approach. New York Plenum Press, 1995 141-228. 

Independent use patents offer the weakest patent protection. They almost invite others to seek possibilities to circumvent them and they do not cover the products that result from the invented new use. Wherever the necessary requirements are fulfilled, product patents should be applied for. In the first example given above, it seems hardly justified to construct product claims for (all) products made by the modified fermentation process. The excipient with adjuvant effects could probably be patented as a product patent, claiming "vaccines containing substance X as a novel adjuvant" with the non-obvious advantage of a better tolerability or efficacy over existing adjuvants. As for the third example, any advantageous characteristic of the resulting product may be used to justify a product patent. 

User safety-related investigations are unlikely for most biological products. However, some excipients and special vaccines (e.g. poultry live vaccines for spray applications) may warrant studies addressing the user safety during application. 

The development of veterinary products for cattle, pigs, sheep, poultry and other food producing animals also includes residue testing of all new pharmaceutical products, including adjuvants or other excipients in vaccines. Residue safety studies address the potential risk to humans due to the consumption of food from treated animals. Accordingly, the test substances in these toxicity studies are applied orally. Residue depletion studies (pharmacokinetic studies) in the target species must be carried out to define the occurence, concentration and elimination of the substance and its metabolites in edible tissues, milk and eggs. 

Applications for MRLs for excipients in currently registered vaccines have to be made before 1994. The procedure and the MRL limits do not apply to products and ingredients for cats and dogs or for other animals, which are not used for human consumption. However, substances which are banned because of their toxicity for humans, could also be critical for those species. 

Vaccine adjuvants and other excipients may require independent or further pharmacological and safety studies. 

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