Adjuvants are a specific group of vaccine/medicinal product compounds, since they are not classified as active substance but have more than just a stabilising activity. According to the EMA guideline EMEA/CHMP/QWP/396951/2006 (Guideline on excipients in the dossier for marketing authorization of a medicinal product), adjuvants, being no active substance, are categorised as excipients like antioxidants, preservatives, stabilisers, and many other. In the EMA guideline EMEA/CHMP/VEG/134716/2004 (Guideline on adjuvants in vaccines for human use) adjuvants are described as components that potentiate the immune responses to an antigen and/or modulate it towards the desired immune responses. Adjuvants can be classified according to their source, mechanism of action, or physical or chemical properties.
The EMA guideline on adjuvants further clarifies that the major means by which adjuvants may exert their activities are presentation of the antigen, antigen/adjuvant uptake, distribution, immune potentiation/modulation and/or protection of the antigen from degradation and elimination.
A manufacturer has to adhere to strict rules and guidelines regarding the manufacture and use of adjuvants. The same EMA guideline on adjuvants describes all the quality requirements, where the adjuvant should fulfil to. Depending on the type of adjuvant, additional guidelines are in force and should be followed. Non clinical testing with the adjuvant alone and in combination with the antigen should be thoroughly studied and documented. Finally, regarding clinical studies, the inclusion of an adjuvant in a vaccine must always be justified. The required clinical trials depend on whether it is a new adjuvant in a new vaccine, or rather a change to an already licensed vaccine.
Adjuvant type specific monographs described in the European Pharmacopoeia should also be followed by the manufacturer (e.g. Aluminium hydroxide and Aluminium phosphate). At the FDA, also guidelines on adjuvants are present and at the level of the World Health Organization (WHO), a guideline is under development.
All the above mentioned guidelines and monographs are also in force during the assessment of the marketing authorization application submitted by the applicant and should be taken into account by the regulatory assessors.
At the level of batch control and release by official medicinal control laboratories (OMCL's), the testing on adjuvants is very limited and for most vaccines not performed. At the Belgian Scientific institute of public health, MPL content is determined for batch release of a human papilloma virus vaccine and a hepatitis B vaccine. Testing by OMCL's on other adjuvants for other vaccines can be performed for information only.
Manufacturer's are continuously developing new complex vaccines with new complex adjuvants. Some of these adjuvants have strong immunological properties like receptor stimulation. In the near future, it might become necessary to create more detailed guidelines on the manufacture and control of these adjuvants and it might also be found necessary that OMCL's perform more testing on (new) adjuvants to better control the quality of vaccines.
