Stress condition in COC impurity


We are screening the COC impurities in some of the products. We were started work on development samples, but we also want to estimate on stress samples.

For Actual stability will take time, so please suggest which stress condition is the best for generate the data for Nitrosamine.

Thank you.

I have read in several publications the use of nitrosation assay procedure (NAP Test). The NAP test was originally designed in 80’s by the International Agency for Research on Cancer of the WHO to simulate in vivo formation of nitrosamines in the stomach.

In the publication below, All samples were incubated at 37°C for 4 h with an API concentration
of 10 mmol/l in a 40‐mol/l sodium nitrite solution at pH 3.5 (with 1 mol/l hydrochloric acid). The pH was adjusted in the sodium nitrite solution, measured (pH 3.5 ± 0.5), and corrected if necessary after the addition of sample material. After incubation, samples were centrifuged and the particle‐free supernatant was analyzed.

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Thank you for the information.
Please also suggest stability condition for stress condition, like 40°C\75%RH or 50°C\75%RH for 7 days or 15 days or else for nitrosamine and product nitroso.
Is there any specific condition required or suggested by any of the agency ?
This will help me estimate stability of the products.

Thank you.

Any lead will be appreciated.

@1234 @Sarada.jena Not sure if you had the opportunity to read Joerg et al (@schlinjo1975) recent paper “Avoiding N-nitrosodimethylamine formation in metformin pharmaceuticals by limiting dimethylamine and nitrite”

Section 3.8 Stability of Metformin drug products, explained the stress study conditions for Metforming drug product investigation in stability.

Open access: Avoiding N-nitrosodimethylamine formation in metformin pharmaceuticals by limiting dimethylamine and nitrite - ScienceDirect

Still, I am awaiting for answer. please suggest condition.

@1234 Did you had opportunity to read the recent update on Health Canada Nitrosamine Q&A?

38. Number and types of drug product batches as part of confirmatory testing for marketed products and new market applications (updated)

For marketed products, the number of batches to be tested should be commensurate with the risk. Examples of high risk include:

  • late-stage formation/introduction of a nitrosamine impurity in a manufacturing process
  • presence of nitrosamine precursor functional groups in the API
  • potential for nitrosamine formation on storage

MAHs and manufacturers should test a representative number of batches of the drug product as appropriate based on the risk assessment (for example, batches that are representative of sources of components, manufacturing processes/sites, manufacturing dates).

If the root cause for nitrosamine risk has been identified and scientifically demonstrated, and impurity levels are expected to be consistent from batch-to-batch (for example, as demonstrated by spike-purge studies), testing should be conducted on 10% of annual batches, or 3 per year, whichever is highest. Testing should include both newly produced batches as well as retained samples of batches still within the expiry date. If fewer than 3 batches are manufactured annually, then all batches within the expiry date should be tested.

Testing plans or protocols (for example, a protocol for the number and type of batches to be tested) do not need to be submitted to Health Canada for assessment and approval before initiating confirmatory testing.

If nitrosamine impurities are detected at significant levels (approaching, at or above AI limits), additional batches of the drug product on the Canadian market and within the expiry date should undergo confirmatory testing. In such cases, MAHs may be requested to test all lots on the Canadian market that are within the expiry date.

For NDSs, ANDSs, Supplements and Notifiable Changes (for quality changes that may impact the potential presence of nitrosamines in the drug substance or drug product, refer to number 13), at least 6 pilot or 3 commercial-scale batches should undergo confirmatory testing where a risk of nitrosamines has been identified. A higher number of batch results should be submitted for assessment where the risk of nitrosamine presence is high. Examples include:

  • the late-stage formation/introduction of a nitrosamine impurity
  • nitrosamine precursor functional groups in the API
  • stability concerns exist for nitrosamine formation over the retest period/shelf life

Testing results of stability batches for a nitrosamine impurity should be conducted where:

  • a risk has been identified that nitrosamine levels could increase in the API or drug product over time or
  • the potential for increases over time is unclear

A minimum of 6 months of accelerated and long-term stability data in the proposed container closure system(s) should be provided in the drug application.

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