The EMA has updated its quality documents with sections on genotoxic impurities, residual solvents, and heavy metal catalyst residues.
Updates come two years after the European Medicines Agency (EMA) published a question and answer document that sought to end uncertainty regarding the 2007 genotoxic impurities guidance. In the latest update the EMA attempts to clarify the setting of specification for genotoxic impurities.
“If a potentially genotoxic impurity is formed or introduced in the final synthesis step, it should be included in the specifications. However, it is considered possible to apply skip testing if the level of the impurity does not exceed 30 per cent of the limit,” the EMA wrote in its updated quality document .
To show the EMA that the impurity level falls below the 30 per cent limit manufacturers must show data from at least six consecutive pilot scale batches. Alternatively, manufacturers can show data from at least consecutive three batches produced at commercial scale.
For potentially genotoxic impurities introduced before the last synthesis step, as well as those that are merely theoretical, a less rigorous approach is needed. If the impurity is introduced part way through development the EMA recommends controlling itby a limit in a synthesis intermediate.
Having taken steps to control the impurity manufacturers should “unambiguously” show – using data from six pilot or three commercial batches – it is below 30 per cent of the acceptable limit. The EMA encourages use of spiking experiments to show the level of the genotoxic impurity.
A similar outlook is recommended for residual solvents and heavy metal catalysts. As with genotoxic impurities, the level of vigilance recommended by the EMA depends on when the residual solvent or heavy metal catalyst residue is introduced. A risk-based stance is recommended in other areas too.
“It seems reasonable that class-1 metals are the prime focus for harmonisation with the policy for genotoxic impurities while class-2 and 3 metals could be treated similarly but somewhat less strictly,” the EMA wrote.