Omission of specification <10% AI

Hi all,

I wanted to question what the general in applying the <10% rule to omit the inclusion of a specification. To me, it is not clear in the EMA Q&A.

My understanding is that, even if you are <10% at release, you should be able to show that the product will comply at the end of the proposed shelf-life. But do you have then to be <10% at end of shelf-life?

For drug products that are already well established in the market, this is feasable and according to the Q&A you should test batches up to expire date, but for products that are going through registration, in many cases you won’t have batches old enough to be tested.

Sometimes on risk assessments you would see risk discarded without any stability data

What is your experience on this topic so far?




In that case you should for products in development treat it as a normal impurity, test the nitrosamine in accelerated stability studies to ensure at least 24 months shelf life can be obtained. If it do not complies, test at intermediate conditions, if again the data is not matching you will need to re-puropose your product or wait until long term data is available (formula mod. etc.).


The <10% limit meaning that there was no requirement for a clause on the specification, and the 10-30% meaning that periodic testing should be carried out to ensure compliance were always a little bit odd in the context of nitrosamines to me.

Limits like that were initially introduced for ICH Q3d, elemental impurities, and for this it makes sense - the level of mercury, for example, could vary based upon batches of raw materials used in the manufacture of a particular product, but once that product is manufactured then that level of mercury is fixed, it is not going to increase or decrease on stability.

Nitrosamines on the other hand can and do increase throughout the shelf-life of the product, and this is why the limits of 10% on release make little sense. There could be many situations where the level of nitrosamine is less than 10% upon fresh manufacture, but storage at elevated temperatures and humidities could increase the level of nitrosamine to above the AI by the end of the shelf-life. Conversely, there could be products that form 60% of the AI upon manufacture, but are not susceptible to increase nitrosamine formation on stability (due to improved packaging/moisture barrier/formulation) and so never reach the AI. Which of these scenarios should be of the greatest concern and monitored and controlled closely?

In reality, it will come down to real time stability data, potentially supported by ASAP stability data, and the finished product manufacturer should be setting a specification limit on release, if necessary, to ensure that the product will remain within the AI, if there is shown to be the potential for nitrosamine formation on stability. The 10% could be a useful guide to justify not having a release specification clause for the nitrosamine only if the data supports that limit. The question remains as to how much data is sufficient to justify and support.