Does any of you observed level of NDSRIs follow different growth patterns with respect to age in the same drug product?
For example, after analyzing let’s say 30 or 40 stability batches of a drug product, few batches shows linear trend across the shelf-life while few other shows non-linear and some batches does not follow any trend [Note: Test method for NDSRIs is validated].
Anyone observed such scenario in any or your drug product? If so, I will be happy to connect with you to discuss further.
I would suggest nitrite testing apart from precursor amine testing. You may find that levels differ greatly from one batch to another. Having significant higher levels of nitrites in some batches may lead to faster formation of nitrosamine overtime, and also may seem that it is a different trend. Remember that formation of nitrosamines depends on different factors
Agree with Javier, the cases I have seen is due nitrites in the excipients. @schlinjo1975 demonstrated in his Metformin paper how diverse the nitrite content space is in excipients, even from batch to batch, from the same manufacturer.
excellent answer Javier!! and in most cases, nitrite quantity is the ‘‘driven factor’’ of the nitrosamine formation as the precursor amine is usually in an excess
Differences in the levels of NDSRI’s across multiple batches may be due to various reasons (differing levels of precursor, nitrites, process impact etc)
However if you are seeing different stability trends across different batches (linear, non-linear), then that is an odd observation. The first step would be to confirm that the results are correct.
Assuming that there is no stability excursion, I would probably relook into the method. Probably a co-eluting peak is impacting the results.
You can use some additional transitions to evaluate this behavior or work on your method (may be try HRMS). Or you could try some orthogonal technique to confirm these results.
As you have said that results are within specification, I am assuming that the values are above LOQ since values below LOQ may not be precise and may show abnormal trend.
We observed similar effects. We were able to identify nitrite as the primary driver of nitrosamine formation during stability testing. The nitrite content varied considerably between batches.
However, I also noticed that some people tend to forget that nitrosamine testing is essentially residue analysis, which means that several factors can strongly influence the measured values. For example manual integration (if allowed, but even algorithms have problems depending on peak shape and dwell times) or differences in recovery (which are usually not determined on each analysis run, but based on experience will vary on each sequence), or many other reasons.
If you “normalize” the data using acceptance criteria for precision (for example RSD), does the trend remain?
For me, values like 0.15 (T1), 0.16 (T2), and 0.18 (T3) do for example indicate a trend, but I would interpret it cautiously, considering typical analytical variability.
This is not meant as criticism . I don’t know your data. It’s just something I have noticed quite often in similar cases.
As has already been mentioned, NA levels depend on many factors, which can vary from one batch to another or even from one sample to another within the same product batch.
Sometimes, commercial lots of an excipient are a blend of different manufacturing lots, so nitrite levels can vary from drum to drum within the same lot. Slight differences in moisture content between different parts of your finished product batch can also affect the mobility of nitrites within the formulation and the rate of NA formation.
Another common source of analytical variability is the in situ formation of NA during sample preparation, or the formation of relatively stable adducts from trace amounts of Na or K that are difficult to control. Or something as simple as the fact that, due to a heavy workload in the testing lab, the sample is removed from the chambers at 3M and analyzed 1M later; during this time, the NA may have grown.
In the event of unusual results, it is always advisable to repeat the analysis to confirm the result.
On the other hand, NA formation is not a typical degradation reaction; rather, it is a reaction in which there is a limiting reactant, which can be the nitrites or the precursor amine when impurities are involved. Therefore, it is most common to observe asymptotic growth—faster at the beginning and gradually slowing down as it approaches the asymptote (whose value may vary depending on the concentration of the limiting reactant). However, far from the asymptote, the growth may appear linear. A linear increase can also be observed when the precursor amine is formed as a degradation product of the API. In the first phase, when there is still an excess of nitrites, the formation of the impurity will be the factor that determines the growth kinetics.
But regardless, we must keep in mind that sudden increases in NA formation can also occur due to various factors; for example, if an excipient containing nitrites is not in direct contact with the API, the nitrites may migrate through the formulation until they reach the API and then begin to react. This migration of nitrites in a solid matrix is difficult to predict and can vary from one stability sample to another.
The formation of nitrosamines in solid pharmaceutical formulations is a very complex process that we need to study, and we are still far from fully understanding it