2.1. Impurities controlled by EP monographs

Impurities controlled by EP monographs

Perhaps the most essential part of a quality standard of an active substance is the section on impurities.

Active substances of medicines are pharmacologically active due to the structure of the chemical molecule. No substance can be 100% pure. A certain amount of impurities will always be present. Such impurities may come from:

  • The manufacturing method, i.e. how the substance is produced or ‘synthesised’.
  • Degradation of the active substance molecule, i.e. if it breaks down or falls apart.

Some impurities may have a chemical structure more or less similar to the active substance itself. Such an impurity may also be pharmacologically active, similar to the active substance or in a different way. The impurities may have an unwanted effect, for example they may be toxic.

One purpose of a monograph is to present analytical methods that can detect the impurities and set limits for their level. The monograph lists precisely all the impurities that can be detected by the method and defines the acceptable level for each of them.

Some impurities will have been present at the time when the originator company tested the substance for effectiveness and safety. This means they have been part of the toxicological and clinical trials together with the active substance. Therefore, their presence at that level will be acceptable.

If the method of synthesis is changed, or if another company produces the substance after patent expiry, the level of impurities may change. It is important to evaluate what implications these changes could have on the quality of the manufactured product:

  • Could new impurities appear?
  • If yes, could the methods in the monograph detect them?
  • What would an acceptable level be?

Answering the questions above is a complicated process. The company producing the substance may need to submit documentation for the suitability of the EP monograph to control the purity of the substance. Such documentation should be presented to the regulatory authorities when applying for approval of a new medicine or when changing an existing medicine containing that substance.

The suitability of a monograph in relation to a specific method of synthesis may also be documented to the organisation producing the EP and the individual monographs. The EP is elaborated at the European Directorate for the Quality of Medicines (EDQM), based at the Council of Europe in Strasbourg, France. The manufacturer of an active substance could submit documentation to the EDQM for evaluation. See the procedure for Certificates of Suitability (CEP), described in the next section.