NIOG and industry stakeholders discussed the 2022 NIOG workplan developments on quality, safety and procedural aspects of the nitrosamine review. In particular, the group reviewed on the recently published policy enabling the use of the temporary universal AI for managing cases where a new nitrosamine is identified and the policy currently under draft enabling the use of interim limits to be applied during CAPA implementation for known nitrosamines. Ongoing discussions on a new approach for determining AIs for nitrosamines were also mentioned.
Industry challenges with regards to complete the call for review steps (i.e. update risk assessment, testing and remediation activities) by ensuring also continuity of product supply and public health protection were acknowledged. Nevertheless, it was recognised that the policies currently adopted are expected to minimise any risk of shortages or impact to public health.
The need to develop further scientific knowledge specifically on nitrosamines safety aspects was noted. It is expected that current activities being taken by both regulatory authorities and industry stakeholders as part of different scientific consortia will bring more clarity on such aspects and will promote further policy developments.
NIOG supported further interactions with industry stakeholders, also through additional scientific meetings with the Quality Working Party and the Non-clinical Working Party experts once additional scientific developments are noted. More engagement with also with international stakeholders was supported in order to ensure global alignment.
The 456 products might be contaminated with small nitrosamines. And the 526 (526/1825 = 29%) might be contaminated with complex nitrosamines. If we ignore duplicates, the 843 (= 1825-456-526) products were considered free from nitrosamines.
And 20% of products with concerns of small nitrosamines proceeded to step 2, while most (90%) of products with complex nitrosamines proceeded to step 2. In other words, most products with secondary/tertiary amines required nitrosamines quantification. It looks like a different story from what we thought. Is that the same as your idea?
The outcome was to be expected right? Small molecule nitrosamines are more related to API process and usually, unless the contamination occurs at the last steps of the synthesis, normally the process itself is capable of purging this impurities.
Complex nitrosamines are usually more structurally related to the API, so it is quite possible that the process is not able to purge the impurity unless a specific purification is carried out. Also, there is the problem of formation during manufacturing process of the Finished Product.
Probably for two years focus was too fixated on small molecules, in many times overestimating the risk, while complex nitrosamines were understimated (and probably still are)
The industry presentation says the interim limit(178ng/day) is not viable for b blockers anymore. And nitrite level is not able to be reduced to 18ng in real. Scavengers are hypothetically available but the feasibility of application to an entire drug class is unclear. The withdrawal is inevitable without revised AI considering risk/benefit.
These are not only for b blockers but also other medicines. The underestimation of complex nitrosamines might cause fatal situations.