Request to all Marketing Authorisation Holders of medicinal products containing active substances in the form of mesilates, (di)isetionates, tosilates or besilates to assess the risk of occurrence of contamination with mesilate esters and related compounds.

03 April 2008

Following recent discussions at QWP and CMD(h), marketing authorisation holders of medicinal products containing active substances in the form of mesilates, (di)isetionates, tosilates or besilates are requested to undertake a risk assessment on the occurrence of mesilate esters and related compounds as impurities in their medicinal products.

Preclinical studies with certain mesilate esters have revealed that their DNA alkylation action can
induce mutagenic, carcinogenic and teratogenic effects. This has been reported for methyl and ethyl mesilate and it is not unreasonable to suspect that similar toxic effects may exist in alkyl esters of other low molecular weight sulfonic acids, e.g. tosilates. Although there are no data showing the toxic effect of such esters in humans, there is nevertheless a potential risk that genotoxic substances as described above may be present as impurities in medicinal products containing active substances in the form of sulfonic acid esters.

For this reason the IMB requests all marketing authorisation holders concerned to undertake a risk assessment on the occurrence of these impurities in their preparations. Guidance on how to perform this risk assessment is available via the following link:

CMD(h)/QWP letter

If the outcome of the risk assessment is that the risk is not satisfactorily controlled taking into account the requirements of the Guideline on the limits of genotoxicity impurities (EMEA/CHMP/QWP/251334/2006) the market compliance section of the IMB should be immediately informed using the following email address: kevin.odonnell@imb.ie If consequentially amendments to the registered manufacturing process/control of active substance and/or finished product are required, a variation to the marketing authorisation should be submitted within 3 months.

All concerned marketing authorisation holders are requested to carry out this risk assessment as soon as possible but not later than 30/06/08. Following this date confirmation that this risk assessment has been carried out may be requested during inspections of related manufacturing sites.