NDSRI growth with respect to age

Root Causes
1

Dear Nitrosamine assessors,

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.

Thanks in advance

2

dear Krishna,

for the batches that does not follow any trend, have you tried retest?

3

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

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4

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.

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5

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

thank you

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6

Retest wasn’t performed as there is no trigger for it since products are meeting the limit.

7

Thank you for refreshing by referring to Joerg Schlingemann @schlinjo1975 articles.

8

let me ask. is this observation made in different time points for the same batch or at one time point (end of shelf life) among several batches?

9

Hi Krishna,

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.

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10

Hi Krishna,

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.

11

Hi Amit,

Yes the values areabove LOQ

Thank you

12

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.

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