Read-across/SAR posts Collection

We members are interested in how to apply the read-across method to unknown nitrosamines. However, the number of cases available is not so large. So I want to pick posts related to Read-across/ SAR from our previous discussion. We have learned a lot and understand applying Read-across/ SAR to unknown nitrosamines is not a simple road. I hope it will help you.

  1. Are all N-nitrosamines a concern? April 2021
    @David mentioned the importance of alpha hydrogen here.
  1. Q&A Nitrosamine SAR working group (23 companies and universities) July 2021
    @Naiffer_Host shared @kpcross and @David 's excellent slides. And @kpcross shared other recordings.
  1. AIs for Complex Nitrosamines by MW Adjustments, any experience? December 2021
    @Naiffer_Host introduced the concept of MW adjustment for determining the AI of complex nitrosamines. @SusanFelter and @conudel justified the application of MW adjustment. I’m not sure current discussion in the regulatory, but it may disclose in the future.
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  1. Update of the CMDh’s Q&A Document on Nitrosamine Impurities January 2022

@conudel pointed out lots of problems with guidance. We don’t have clear guidance on how to perform acceptable QSAR/read-across analysis to set acceptable intakes; the molecular weight adjustment method is not yet accepted; the criteria for the selection of adequate surrogates for the read-across method is not clear.

  1. N-nitroso-propranolol? March 2022
    Fantastic literature “Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N-Nitrosamine Impurities” was firstly introduced on this topic. But I am sorry whether this approach can apply to your nitrosamines is not clear.
  1. Using SAR to evaluate hazard and potency (Recording) June 2022
    @Naiffer_Host shared the recording of @David’s presentation, "How Concerning is your nitrosamine? Using SAR to evaluate hazard and potency”
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  1. Calculating Nitrosamine Limits (MasterClass) June 2022
    @Naiffer_Host shared the recording of @conudel 's presentation, “Setting Limits for Complex Nitrosamines”. You can understand how to decide the limit of NDSRIs.
  1. Nitroso Flecainide July 2022
  2. N-nitrosoamides - a horse of a different color July 2022
    We discussed the difference between nitrosamines and nitrosamides/carbamates/urea/guanidine. These look confusing, but they should be distinguished.
  1. Officially used surrogates for read-across method July 2022
    I visualized surrogate compounds used for read-across by EMA. I think we need more examples.
  1. AI Limit for Nitroso Nebivolol August 2022
    @David shared deep insight for selecting a suitable read-across analog. I think the current read-across surrogates in 10 focus mainly on local similarity. I hope it will be improved in the future.

If you want to add your favorites, please do not hesitate to post. Let’s enjoy this journey with us!

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  1. AI for small nitrosamines not listed in EMA, FDA or Health Canada October 2022
    Points to note for calculating TD50 are shared in this thread. As @SusanFelter focused, a robust bioassay is important. NDBA and NDPA with TD50 values are in LCDB, but limits are extrapolated from NDEA.
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Sharing our paper about DARAN (Defined Approach for Risk Assessment of New Nitrosamines). This defined approach uses lines of reasoning based on structure-activity relationship (SAR) patterns and Read-Across (RAx) to set transparent, interpretable, and acceptable limits for new N-nitrosamines for which no toxicological data exist. The approach is based on the regulatory criteria defined in the report EMA/369136/2020 for structure-activity relationship (SAR) and Read-across (RAx):

  1. Structural similarity criteria
  2. RAX hypothesis
  3. Influence of structural differences
  4. Detailing and assessment basis

We used an example case with not API-like, but we are working with
Nitrosamine drug substance-related impurities (NDSRIs), proposing some additional SAR steps and methods.

Access:
dos Santos, C. E. M., Dorta, D. J., & de Oliveira, D. P. (2022). Setting limits for N-nitrosamines in drugs: A defined approach based on read-across and structure-activity relationship for N-nitrosopiperazine impurities. In Regulatory Toxicology and Pharmacology (Vol. 136, p. 105288). Elsevier BV. https://doi.org/10.1016/j.yrtph.2022.105288*

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Hi Sir,

Iam unable to find an appropriate tox data for N-Nitroso-N-methyl benzylamine?

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Can it be read across with NMPEA with a AI of 8ng?

Hi, @Iyappan.

Thank you for asking me. I searched the following compound on the substructure search of LCDB.

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18 compounds are included in LCDB but do not look good as a surrogate for N-Nitroso-N-methyl benzylamine. Then CPCA is a better way compared to read-across from NMPEA. 18ng or 26.5ng/day is applicable.

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Thank you so much Sir for taking time and replying to my question…

Can we apply CPCA approach for small molecule Nitrosamines also?

As far as I know, there is no clear line between NDSRIs and small nitrosamines. The AI of MeNP(1-methyl-4-nitroso piperazine) contained in Rifampin was calculated as 26.5 ng/day by read-across in the previous version of EMA Q&A, but now CPCA is available, 400 ng/day. Unless there is an appropriate surrogate, I expect the application of CPCA justified.

image

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Remember that CPCA approach is not mean to justify a higher limit that was already published or accepted by NRA.

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In this case, I believe that the change also comes from the fact that non-compliance of “26”.
Applying any of these limits implies recall from the market. And they (EMA FDA etc) must have been thinking about what to do with this structure.
I am also referring to nitrosopiperazine, which comes from something as common in pharma as piperazine solvent.

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