I came across a situation recently that worst case molecule with regards to cleaning (this molecule dont have nitrosamine risk) MACO acceptance criteria in a sterile site is relaxed and more than Nitrosamines limit of a potent molecule manufactured in the site. Due to this even if the cleaning worst case molecule passes the test after the batch manufacturing it may fail for nitrosamines impurity check but we will only know it if we have the impurity testing in release or stability spec. Also, there is a risk of carry forwarding nitrosamines risk material in to product batch with non-nitrosamines in a multi product manufacturing facility. I just want to ask this forum do you also see the same risk as i see which needs to be addressed by bringing site cleaning MACO acceptance limit same as worst case nitrosamines impurity limit of products manufactured in site?
I came across a situation recently that worst case molecule with regards to cleaning (this molecule dont have nitrosamine risk) MACO acceptance criteria in a sterile site is relaxed and more than Nitrosamines limit of a potent molecule manufactured in the site. Due to this even if the cleaning worst case molecule passes the test after the batch manufacturing it may fail for nitrosamines impurity check but we will only know it if we have the impurity testing in release or stability spec. Also, there is a risk of carry forwarding nitrosamines risk material in to product batch with non-nitrosamines in a multi product manufacturing facility. I just want to ask this forum do you also see the same risk as i see which needs to be addressed by bringing site cleaning MACO acceptance limit same as worst case nitrosamines impurity limit of products manufactured in site?
My opinion: since the molecule though itself is non NA but is manufactured in a multi-product facility - there could be risk that a residual NA molecule from previous manufacture can be carried over to the current molecule. This, combined with the fact that all health authorities prefer the most conservative approach in case of unknown risk from molecules that are not fully characterized (so CPCA approach cannot be applied) and lack of toxicological data- hence TTC or 18 ng/day. Thus MACO for the cleaning process should target 18 ng/day to be on the safe side and avoid regulatory queries.
Since there is a risk of carryover to the next product, it would be better to apply the worst case scenario (Lowest AI of the nitrosamine, lowest batch sizes, higher daily doses and safety factors). Otherwise a regulatory query/audit may trigger checking all the products manufactured on the same assembly for the particular nitrosamine which would be cumbersome.
Thank you Parthamuk2003, i also believe the same MACO of worst case molecule in the facility has to be same as worst case nitrosamines AI limit in the facility. But, i am getting pushback from client as this correlation between Cleaning limits and NDSRI limits were not mentioned in any regulatory forums. Do you know any literature where these two topics were discussed in relation?
I believe a comprehensive risk assessment would be beneficial in this context.
Such an assessment should take into account all products manufactured at the facility, as well as the sequence of manufacturing processes. Key factors to consider include:
The theoretically possible nitrosamines and their respective acceptable intake (AI) limits.
The presence of nitrosating agents in any process, which could potentially react with vulnerable amines carried over from previous batches.
The highest risk scenario involves the carryover of vulnerable amines followed by exposure to nitrosating agents in the first step of the subsequent process, rather than carry over of nitrosamines which in worst case would be traces in traces.
The interaction between cleaning agents and product residues should also be evaluated, as this may influence impurity formation or detection.
Cleaning methods have to be developed using LCMS/GCMS considering the conservative AI that will be used. Also cleaning methods can be separate from the drug substance/drug product methods. They can have lower run times as cleaning samples generally are extensive in number (running into hundreds of swabs)
If the sample fails then it can surely be problematic. Unless there is a specificity issue it will demonstrate inadequate cleaning method.
There are ways it can be justified. For example if the nitrosamine levels in the targeted drug products are say not detected (even at ppb levels) then the risk of carryover for next products may be negligible. Or if the nitrosamines are volatile then a justification based on volatility can be attempted. But these have to be properly justified on a case by case basis.
Thank you Amit, if the new stringent MACO limits are less than previous cleaning samples test results either way it is going to be an issue with regards to cleaning method failure or nitrosamines carryover point of view. Logically it is making sense. If you have any relavent literature regarding applying of NDSRI limits in cleaning samples MACO please share, that would be a great help.