Impurities and Setting Specifications - the EMA Publishes Harmonised Policies on Its Q&A Page

There are 3 main types of impurities that are relevant to the manufacture of active pharmaceutical ingredients and must be controlled with suitable methods: genotoxic impurities, heavy metal residues of catalysts, and residual solvents. The question of how one can use a harmonised policy for setting specifications for these three possible impurities has been answered by the EMA in a recent addition to its Q&A page.
For each of the different impurity types, three identical key scenarios are outlined and the approach to setting the specifications, described. The three scenarios are:

1. The impurity is potentially (theoretically) present in a synthesis process
2. The impurity is formed or introduced prior to the final step of the synthesis
3. The impurity is formed or introduced in the last synthesis step

In the following you will find the policies for the three scenarios for the example of a genotoxic impurity as formulated by the EMA:

1. A potential genotoxic impurity
[…] If a potential genotoxic impurity is just a theoretical impurity i.e. based on theoretical considerations but not found in practice as demonstrated by studies during development of the manufacture, the impurity does not need to be included in the drug substance specification.

2. A (potentially) genotoxic impurity actually formed or introduced prior to the final step of the synthesis
If a (potentially) genotoxic impurity is formed or introduced in a step before the final synthesis step, it is considered possible to not include this impurity in the drug substance specification if it is controlled by a suitable limit in a synthesis intermediate and if it is unambiguously demonstrated by analysis results (use of spiking experiments are encouraged) that presence of this impurity does not exceed 30 % of the limit, derived either from TTC or otherwise defined acceptable limit etc, in the drug substance. If these conditions are not fulfilled, this impurity has to be included in the drug substance specification and the test has to be carried out on a routine basis. […]

3.A (potentially) genotoxic impurity is formed or introduced in the last synthesis step
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 % of the limit, derived from either TTC or otherwise defined acceptable limit etc, in the drug substance. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is not fulfilled, a routine test in the drug substance specification is needed.

The policy for heavy metal catalysts residues or solvents residues is defined by analogy.

The EMA's Q&A page can be found here.

Author:
Dr Gerhard Becker
On behalf of the European Compliance Academy (ECA)

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