Читать книгу Mutagenic Impurities - Группа авторов - Страница 59

The section relates to where a new impurity is discovered and there is “a cause for concern.” Previously, EDQM stated that structural alert alone is insufficient to trigger a concern, there must be new safety data and this point is reiterated in ICH M7: “The existence of impurity structural alerts alone is considered insufficient to trigger follow‐up measures, unless it is a structure in the cohort of concern.”

New safety data may be generated for a number of reasons and via a variety of routes. One such example is REACH testing, where chemical registration requirements require a battery of safety tests that may include an assessment of mutagenicity.

What is REACH?

REACH is a European Union (EU) regulation concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals. It came into force on 1 June 2007 and replaced a number of European directives and regulations with a single system.

REACH has several aims:

 To provide a high level of protection of human health and the environment from the use of chemicals.

 To make the people who place chemicals on the market (manufacturers and importers) responsible for understanding and managing the risks associated with their use.

 To allow the free movement of substances on the EU market.

 To assess risk, safety testing may be performed.

There are concerns over how new safety data are managed in practice. As a result of REACH, a coupling reagent 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDAC) (see Figure 2.1) was shown to be Ames positive. This chemical was widely used and at the time the data were generated there was no clear guidance as to how should authorities be informed of this new finding. Also uncertain is the impact on marketing authorization, would such a finding lead to immediate suspension of the license for the product(s) impacted or would time be permitted to make the changes needed to ensure control to appropriate levels? In the case of EDAC, the issue was minor due to the instability of the coupling agent, meaning that it was readily purged and thus presented no concern in terms of levels in associated products. Nevertheless, given the wide utility of commodity reagents like EDAC, the impact could be significant, impacting multiple products globally.

Figure 2.1 EDAC.

What is not entirely clear is how to address the scenario whereby an impurity is detected that based on its' structure belongs to the cohort of concern. It is clear based on the example of N‐nitrosamines (see Chapter 10) that detection of such an impurity would be a trigger for investigation.