Impact of Stability and Transportation on APIs

We had a very interesting laboratory investigation last year on Nitrosamines.
Generally when we talk about Nitrosamines, we end up talking about APIs, Water and associated solvents being used.

However, we had an investigation where the environment (air) was a source of NOx leading to generation of impurities in the APIs.

No laboratory error or phase-II error could be identified for an OOS sartan API; the manufacturer claimed there was no NDEA / NDMA in their control samples which they brought in person to laboratory and were tested. The control samples gave no NDMA/NDEA, however, the couriered samples, which had sat in a warehouse for a couple of days, tested positive.

We ended up carrying out exposure studies on API samples to understand how much time and exposure is required for nitrosamines to be generated in detectable quantities.

It turns out, not much.
Day 1 - both our study samples passed with no detectable values of NDMA, NDEA.
Day 2 - we could see NDEA generation in this specific API but below the specification limit.
Day 3 - Both samples failed for NDEA.

Exposure was 30 minutes to simulated environment with nitrate vapours, and then storage in the original packing provided by the manufacturer.

It helped us prove, in this case, that there was possibility of NOx exposure in transit, if packing was not appropriate (such as LDPE bags in this case) in APIs.

Question is, how many manufacturer’s are carrying out Transport Shipment Studies specifically with this in mind.


@HimikaChoksi Thanks for sharing details of this case… I believe hearing @AndyTeasdale discussing this at a recent workshop from an audience question.
Maybe @lettieredj @AEllefsen @schlinjo1975 @timothy_curran @Ulrich @Yosukemino any experience on this particular case?

1 Like

Nitrosamines Risk Assessment is a holistic approach that should include all aspects of process development, Mfg, Packaging and testing evaluation . Packaging screening studies are an integral component of drug product stability assessments and these should be extended to API packaging screening studies if atmospheric exposure is a perceived risk

1 Like

To address this inconvenient, what I have seen and also feel should be considered is to ship/transport the testing samples under controlled conditions of at least °T and humidity and a correct packaging and sealing. Its not uncommon to have the NA testing facilities overseas or at long transit time. Its an additional cost, but avoids having the “what if” doubt or as it is mentioned in this post, increased NA content after transportation.

1 Like