The ICH Guideline Q3C defining the limits for residual solvents as impurities in active pharmaceutical ingredients (APIs) and finished medicinal products as well as the methods for establishing their exposure limits has already been revised four times. The revisions concern among others provisions for calculating the PDEs (PDE = permissible daily exposure, denoting the maximum amount of a solvent that may be taken in with a medicinal product) for the solvents N-Methylpyrrolidone and Tetrahydrofuran. Now the guideline is about to be revised once more, the reason being that new toxicological data have been collected on the solvent Isopropylbenzene (called "Cumene" in the guideline). Hitherto, this substance has been categorised as Class 3, i.e. as a solvent with low toxicity. In general, these solvents have PDE values of 50 mg per day or more. Recent toxicity studies conducted in rats and mice clearly showed a heightened carcinogenic potential so that it has become necessary to assign Isopropylbenzene to the higher Class 2 and to calculate the PDE accordingly.
On 26 March 2010, the ICH Draft Consensus Guideline "Impurities: Guideline for Residual Solvents - PDE for Cumene" was published (Step 2 in the ICH process) and has since been available for commenting by the public. This guideline now requires the calculation of the PDE for Isopropylbenzene according to the rules for Class 2 solvents. After two further steps in the ICH process, this guideline will be integrated into the core document, which will then bear the name ICH Q3C(R5).
This new regulation might require manufacturers of APIs and medicinal products using Isopropylbenzene to make a considerable effort in changing their registration dossier (e. g. as a consequence of changes to the manufacturing process, the analytical methods etc.).
Dr Gerhard Becker
On behalf of the European Compliance Academy (ECA)