33ème Congrès annuel de la SFT - Montpellier, 25-26 octobre 2007
Alertes toxicologiques
Excipients, Adjuvants, Additifs, Impuretés

General Principles for the Safety Assessment of Excipients

Pr Jean-Roger Claude

Faculty of Pharmacy, Paris, France

Excipients in medicinal products cover a large range of products structurally very simple to very complex mixtures, used for technological reasons. Normally they have no pharmacodynamic or therapeutic activities, can be used by various route of administration and must exhibit a large safety margin. Several classifications have been proposed, the most relevant in view of the safety assessment being the IPEC. classification: a new excipient can be either a new chemical entity or a chemical entity previously used as a food additive, a compound of cosmetics, an excipient of veterinary medicinal products or of human medicinal products but a lower exposure or via a different route of administration.

For industry, very broadly speaking, there are three possibilities to conceive a safety program for an excipient:

  • New compound, no data: a full toxicology program

  • Product of well-established use worldwide (pharmacopeias...): no studies

  • Halfway situation: on a case-by-case basis elaboration of a safety program taking into account the previous knowledge of the product, plus, if necessary, bridging or complementary studies

Nevertheless many difficulties occur: excipients of well-established use cannot be considered definitively as safe in all cases, scientific informations are sometimes scarce and poor, the kinetic and metabolic profiles are difficult to evaluate, the human data sometimes debatable, etc.

When a full toxicology program, or when bridging or complementary studies are necessary, an IPEC guideline was proposed in 1997, but a FDA guideline: “Non-clinical studies for the safety evaluation of pharmaceutical excipients”, close of the IPEC guidelines, was implemented in May 2005. The original feature of this guideline is to recommend a study program depending of the duration of human exposure. Special requirements are provided for use in pulmonary, injectable and topical products.

For the EMEA, the existing guidelines are related to the informations about excipients in the dossier for marketing authorization of a medicinal product, and to the label and package leaflet (“excipients à effets notoires”). Other general guidelines (Genotoxic impurities) apply to excipients. New requirements are conceivable in the next future.