Nitrosamines risk assessment: step 2

In the previous videos, we explained what are nitrosamines and how to perform the risk assessment of their presence in drug products.

And when a potential risk is identified for the presence of a certain nitrosamine, what should be done?

Not necessarily the nitrosamine will be carcinogenic (that is, increase our chance of developing cancer).
So the first question to ask may be: could this nitrosamine be mutagenic or carcinogenic?
There are databases and in silico models that show us that most nitrosamines are mutagenic and carcinogenic, but not all of them.
The mechanism of the reaction which leads to mutagenicity, that is, which causes the nitrosamine to react with the DNA potentially causing a mutation, requires some structural aspects, which are not always present in the impurity.
Some groups are studying these alerts to help the industry identify the cases which are in fact of concern.
So if we can prove that the nitrosamine will not be mutagenic or carcinogenic, we can treat it as a regular impurity under the scope of ICH Q3A and Q3B.

In case we conclude that the nitrosamine is in fact a concern, it is necessary to understand if it can really be present in the drug substance or drug product - if it makes sense for us to look for it or not.
What can happen, for example, is that a nitrosamine may theoretically be formed in an initial stage of the drug substance synthesis. In this case, it is possible to estimate whether the manufacturing process is capable to eliminate the impurity before it even reaches the drug substance. This can be calculated with the purge factor. To know more, watch the video about the purge factor (Link:    • The purge factor - ICH M7 Option 4  ).

If the purge factor is correctly calculated and indicates the impurity is actually eliminated, the absence of the impurity can be justified with this approach.
In case it is not possible to demonstrate the elimination of the nitrosamine through this strategy, the recommendation is to test the drug substance, or drug product, through an analytical method, in order to quantify the impurity.

The acceptable limit for the nitrosamine must be calculated based on the principles defined in ICH M7 – the guideline which defines how to control mutagenic impurities in drug products. For this calculation, we must consider the acceptable intake of the impurity, the maximum daily dose of the drug and the treatment duration.

By using analytical testing it will be possible to evaluate if the nitrosamine is in fact present in the drug product or not. After the conclusion of this stage, the company must evaluate if it is necessary to establish a control strategy or perform any change in the manufacturing process, in order to eliminate any risk that may be confirmed.

It is now clear that this is a dynamic evaluation, and each day we learn more about nitrosamines formation, elimination and their mechanism of toxicity. So what may happen is that new information may come out and change the aspects to be considered. This is how science works.

Nonetheless, once this evaluation is completed, the industry and will have gained much more scientific knowledge about their drugs regarding the possibility of nitrosamines. Moreover, variation procedures will be taken to ensure that any risk is avoided, ultimately leading to even safer drugs on the market.