during the preparing of risk assessment report for nitrosamine impurity, what should we say in the stability section, how to make sure that there is no risk during the shelf life of the product? we will not go for testing. already the API does not have a secondary amine, only a primary amine functional group, so actually there is no risk for the formation of nitrosamine impurities in the finished product, especially that there is no use of nitrosating agents. so my question is how to express that the there is no risk from the stability side.
if I get it right⌠since you have concluded âno riskâ, then you are not included any spec in 32P51, and there should be no expectation to include the test during stability.
I think that assessment during stability refers to when risk is identified (step 1/ step 2).
I will be careful with what specifications and resolution you are using to determine âlack of degradationâ⌠remember the case of NDMA impurity in the Valsartan raw material testing. Many saw this impurity but it was below the reporting threshold so it got ignored by many!
I agree with you Naiffer however, here, it seems that no ndsri could be formed at first place. On the other hand , in case it would be formed and found <10% at T=0, I am also of the opinion of monitoring during stability. At least for validation batches
I agree with Naiffer and Eleni. I would probably evaluate all possibilities, even if they are purely theoretical. Now, considering that your API/ formulation contains only primary amines and you have already excluded any risk related to secondary amines in your product,âŚ
âBased on the chemical structure of the active pharmaceutical ingredient (API), which contains only primary amines, there is no plausible pathway for nitrosamine formation under typical storage or formulation conditions. From a stability standpoint, the absence of secondary/tertiary amines and nitrosating agents (e.g., nitrites) in the formulation and packaging environment supports the conclusion that nitrosamine formation is highly unlikely during the productâs shelf life.
In addition, a thorough impurity profile assessment of the API and excipients has been conducted. No known nitrosamine precursors or nitrosating agents were identified among the specified impurities. Therefore, considering both the chemical nature of the API (and excipients in case of final product) and the impurity profile, the overall risk of nitrosamine formation is considered negligible.â
I realize that I got it wrong in my reply above, however, Joao summarized it excellently. I would just add that these conclusions should be sustained by the content of the risk assessment report.
i have another case for Gabapentin, it is a primary amine, but impurity A include a secondary amine. so, when preparing the risk assessment report for the finished product also impurity A is controlled in the USP monograph. although the impurity if forms a nitoso-group it will not undergo alph-hydroxylation mechanism. after checking the stability data, the impurity is detected but within the limit. so, what to say in the report, I donât think that there is a risk.
Please correct me if Iâm wrong, but as I understand it, your API contains a primary amine, and the only potential nitrosamine-related risk youâve identified is Gabapentin Related Compound A (CAS 64744-50-9). If this is the impurity youâre referring to and experiencing stability issues with, the risk can be ruled out from a nitrosamine perspective, since this compound is an amide (pyrrolidone). Therefore, it falls outside the scope of nitrosamine evaluation and should instead be assessed under ICH M7 (mutagenic impurities) and ICH Q3A/B (impurity profiling).
That said, Iâd like to take this opportunity to open a broader discussion:
If a secondary amine is identified either as an impurity or within the API structure, my company has adopted a policy requiring additional testing before approving any API for development. This includes stability studies at both the beginning and end of the testing period. The rationale is that, even when secondary amines are controlled within impurity limits and theoretical nitrate levels are low, nitrosamine formation cannot be entirely ruled outâespecially considering the limits and potential for trace formation.
Do you or your company have experience with similar situations?
Is this approach too conservative in your view, or aligned with current industry practices?
How are you handling nitrosamine risk when secondary amines are present, even wthin the ICH q3A limits (quite high considering nitrosamines)?
Regarding new generic OSD formulations, one of our companyâs policy is using low nitrite excipients when there is a theoretical risk of nitrosamine generation. Indeed even LOQ or LOD levels of ICHQ3 limits are generally way higher than nitrosamine limits. Not sure if I understand what kind of additional testing/stability testing do you perform on the APIs before approval?
I think that precautionary measures such as internal stricter limits for API, closing monitoring of API, and continuous follow up with the suppliers could be also helpful.
As per guidance API suppliers are performing nitrosamine risk assessment and further based on assessment testing of nitrosamine impurities were performed on three commercial batches. Based on obtained results from three commercial batches if impurity found below 10% of AI limit further non inclusion of nitrosamine impurity in specification were concluded.
However risk assessment report does not contains the sufficient data for nitrosamine impurity on stability samples.
During manufacturing of finished product (OSD) most of the excipients are contains the trace levels of nitrite/nitrate, and even though if nitrosamine impurity is below 10% of AI in API due to presence of trace level of nitrite/nitrate level and degradation nature, impurity found in increasing trend throughout product shelf life.
In such cases to control nitrosamine impurity in drug product, DP manufacturer will not able to decide control strategy. As DP manufacturer does not knows the exact level of nitrosamine impurity in API.