Nitrosamines risk assessment: step 1

Nitrosamines are compounds to which we are exposed daily through many sources, and they can also be impurities in drug products.
In the previous video we talked about the risk that these compounds can be and the reason why it is necessary to perform an assessment of drug products for the risk of nitrosamines presence.
In September 2019, EMA determined that all pharmaceutical companies must perform an evaluation in 2 steps:
Step 1 is an assessment of the theoretical risk in the drug, and step 2 is the confirmation of the risk when identified, using analytical methods.
But how should this evaluation be done?
In step 1, the whole manufacturing process must be considered and all the potential sources of nitrosamines must be identified.
The manufacturing process of a drug product begins with the manufacture of the drug substance. The pharmaceutical company then adds together the drug substance and excipients to produce the drug product, which will then be packed.
Hence, this evaluation must include the potential for formation of nitrosamines during each of these stages:
- the manufacturing process of the drug substance must be evaluated, considering also the possible contaminations that could happen at this stage;
- the stability of the drug substance must also be considered, which can have an impact on the stability of the drug product as well;
- and the chance of formation during the manufacturing of the drug product must be evaluated, which could be due to the interaction of the drug substance with the other components of the formula, or even with the packaging system.
In this evaluation, all sources of amines and nitrosating agents must be considered, keeping in mind that both precursors must be present for the nitrosamine to be formed. Other reactions which can form nitrosamines are being studied by some groups, and may also be considered in this evaluation.
Some of the cases which caused the recalls were valsartan and ranitidine. In the case of valsartan, both precursors were used in the route of synthesis of the drug substance, and their reaction led to the formation of the impurity.
For ranitidine, on the other side, the precursors were part of the drug substance molecule itself, so that the nitrosamine was formed through the degradation of the ranitidine molecule. So this was a stability issue.
Although the most obvious risk for nitrosamine formation may reside on the drug substance, in theory there could also be an interaction of the drug substance with an excipient, packaging material, or even with another drug which may also be added to the formulation, in case one contains the amino group and the other contains a nitro group.
If both the precursors are present in the formulation, there is a theoretical risk of forming a certain nitrosamine.
This is the evaluation that should be done, considering the entire process.
And what should we do when the risk of forming a nitrosamine is identified?
Watch the next video to find out. Not necessarily the theoretical nitrosamine will be carcinogenic, and even if it is, it may not be expected to be present. So the next step is when we will investigate whether there is an actual risk or not.