Control of NDSRIs impurity at Drug Substance (API) specification

[Dinkar]

I have question regarding control of NDSRIs impurity at Drug Substance (API) specification.

If the LOQ value is less than 30% of limit and results are slightly upper than LOD level i.e 10 % .

Which case we follow:
Case-1: Can we propose skip lot testing
Case-2: Can we Omitting test
Case-3: Can we control in DS Specification.

Also what is the our strategy for Drug Product.

In advance thanks your support and Valuable time.

Thanks and Regards,
Dr. Dinkar Gagare

[Naiffer_Host]

This posts can be very helpful

Nitrosamine in DS and DP specifications

Dears, I want to ask if the detected nitrosamine is consistently below 30% of AI, should it be added the COA of the DS or DP. In other words, how the “skipping” should be reflected in the regulatory documents. Also, what is the regulatory criteria for the term “consistently”, is there certain number of batches to be tested? Regards, Alaa

Testing of APIs for NDSRI

I am searching reference document for implementation of skip testing for the NDSRI, if results of NDSRI is above 10% of specification limit and below 30% of specification limit. If someone can help to provide reference / strategy for the same, it will be great help.

[vsnu999]

Hi Dinkar,

Establishing LOQ at 30% is reasonably good and acceptable. If the values are consistently less than LOQ in all process validation batches and respective stability samples(ACC and LT), it is acceptable for skip lot testing. Moreover, it is important that there should be no sign of increasing trend in stability samples over the LOQ. Otherwise, you should bring in to routine testing.

Further, if the results are not detected you can omit the testing , but careful risk assessment and testing should be done appropriately as and when the process/materials are changed.

[Fatima-Ezzahra]

Hi Dinkar,

You can find the control strategy in EMA 425645/2020 Senario b.

Implementation Process_Article 5(3) Nitrosamine (europa.eu)

[Fatima-Ezzahra]

Hi @vsnu999,

Thank you for this valuable information. Can you PLZ give the referece from which you extracted this paragragh?

[Dinkar]

USFDA reference link is provided below for the same.

(https://www.fda.gov/media/141720/download)

[Dinkar]

I appreciate everyone that clarified things related to “Control of NDSRIs impurity at Drug Substance (API) specification”

[vsnu999]

Hi Fatima,
Please see the below link. USFDA.

https://www.fda.gov/media/141720/download.

[Hemant]

NDSRIs impurities are generating due to interaction of APIs with residual nitrate and nitrites from excipients, water, packing materials etc. In most of DP’s impurities are increasing during stability studies, different from classical nitrosamines. Risk assessment samples should be representative product shelf.