The FDA published a document yesterday around the detection of small molecule nitrosamines, specifically NDBA being detected in infusion bags, potentially from printed overwraps and packaging.
august-18-2025-emerging-scientific-and-technical-information-on-leachable-ndba.pdf (205.0 KB)
Interesting the CDER are considering an adjustment factor for the lifetime AI limit of four to ten-fold of total nitrosamine exposure.
Interesting,
See also: Anyone experienced low level interference/ contamination issues with NDBA during method development? - #2 by IreneNS
Would be useful to know if NDBA leaching from IV bag is demonstrated also when no IV bag ports (cf. possible rubber seal NDBA risk, linked with zinc dibutyldithiocarbamate) are used to sample the liquid for testing (and which IV bag types have shown a risk, as there are many polymer types).
But I guess indeed inkjet printing is sufficiently common for IV bags, and dibutylamine use in inkjet inks as well to support the plausibility of the root cause (probably liquid sampled from unprinted bags have been tested as well to shown absence).
Similar to the new guidelines for ICH Q3E on extractables and leachables, where there is a requirement to consider the impact of labels applied to semi-permeable bottles etc. - the whole package needs to be thought of as a potential source of impurities within the product, sometimes when not even in direct contact.
Of course, meaning that to know for sure if the NDBA cause is the printing or the seal, you have to omit one of both.
@Amitkumar any experience on this specific source?
Critical update coming from the agency
If printing is identified as the root cause, the potential impact on other packaging configurations can be reasonably predicted.
This was due for a long time. Also, it is good to see that the agency is slowly acknowledging the issue of less than lifetime.
I think that you have pointed out something that FDA’s information misses. A significant source of NDBA is butylated rubber seal. While ink could be a significant source too, but leachable NDBA from rubber stoppers have been known forever and I think the rubber seal is more in contact with large volume parenteral than the ink.
I agree compounds like dibutylamine and Dibenzylamine have been reported in literature as an extractable from polyisoprene stopper and both are precursor of Nitrosamine impirities N Nitroso Dibenzylamine and N Nitroso dibutylamine
Which type of butylated rubber seals, Bromo, Chloro or both?
Iilun Murphy, the director of the US Food and Drug Administration’s Office of Generic Drugs (OGD), issued a warning to manufacturers regarding a recently identified leachable nitrosamine in certain drug products that are packaged in infusion bags.
She stressed that manufacturers of affected products must conduct thorough risk assessments to confirm that their bags do not contain this substance. These risk assessments are required to be completed by 16 November 2025.
Could you please give me the literature references you refear to?
Hi, Please refer slide 14 of presentation https://www.nelsonlabs.com/wp-content/uploads/2021/03/Karen-Pieters-Testing-of-packaging-systems-for-Large-Volume-Parenterals-Extractables-Study-Design-and-Challenges.pdf. Hope this helps!
Can someone please clarify on the calculation of limits of these small molecule nitrosamines, whether we have to consider total volume of drug product for the calculation of limits for leachable nitrosamines? or same like NDSRI we have to use API MDD for calculation?
Bonjour
Je suis amenée à rechercher la N-Nitrosodibenzyl amine dans des poches pour perfusion à des taux très bas vu son AI calculée de 18ng/jour. une méthode permettant de descendre à 36ng/l est elle disponi
ble ? Quelqu’un a t il pu derisquer cette impureté ?
Hi,
As per my understanding, as the nitrosamine is leaching from the infusion bag, the correct way to calculate this would be using the total volume of the drug product, as MDD of DP, not API. Just like in NDSRIs the source of nitrosamine is the DS and therefore the amount of DS intake is used for the calculation, here the maximum daily amount of product as the matrix where the nitrosamine is going to be concentrated is used for the calculation.
Thanks a lot for your response
