Read-across/SAR posts Collection

[Yosukemino]

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.

Are all N-nitrosamines a concern?

There’s one category of dialkyl nitrosamines that has been explicitly stated as to not be of concern - the EMA have indicated that at least one alpha-hydrogen is required (EMA, https://www.ema.europa.eu/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf ); however at the moment all others should at least initially be considered as part of the Cohort of Concern. Note that not having an alpha hydrogen does not guarantee a negative result - nitrosodiphenylamine (NDPhA) is carc…

2. 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.

Q&A Nitrosamine SAR working group (23 companies and universities)

#OpenQ&A This PPT was presented by Kevin P. Cross, PhD (Instem PLC) @kpcross and David J. Ponting, Ph.D. (Lhasa Limited) @David at QSAR 2021 and describes Lhasa and Instem’s collaborative efforts in the area of N -nitrosamine assessment, including the nitrosamine SAR working group - currently comprising of 23 companies and universities. QSAR2021 Cross Nitrosamines SAR FINAL.pdf (790.9 KB) [image] [image] [image]

3. 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.

AIs for Complex Nitrosamines by MW Adjustments, any experience?

With the recent publication of FDA’s Updates on possible mitigation strategies to reduce the risk of nitrosamine drug substance-related impurities in drug products | FDA A new concept have emerged: ‘nitrosamine drug substance-related impurities (NDSRIs)’ a class of nitrosamines sharing structural similarity to the API For this class of nitrosamines, the read-across when setting limits can be quite challenging. We have seen the case of N-nitroso-varenicline (37 ng/day). This afternoon Dr. Nudel…

[Yosukemino]

4. 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.

Update of the CMDh's Q&A Document on Nitrosamine Impurities

CMDh added an option to to introduce a limit in the specification of the FP as a possibility for lifting the condition on the risk assessment (RA) for the finished product. It would be nice if we could get some guidance from CMDh on how to actually set limits, particularly for complex nitrosamines. Until now we don’t have clear guidance on how to perform acceptable QSAR/read-across analysis to set acceptable intakes (AIs); a negative Ames test is not currently accepted (even when using the modif…

5. 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.

N-nitroso-propranolol?

Thanks for the information. I attach the link to the mentioned paper, it is a really good one. Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N-Nitrosamine Impurities | Chemical Research in Toxicology (acs.org) Coming back to the topic, that is interesting for sure, because is not the same to have NA above the 18 ng/day limit than to 440 ng/day. This will need careful evaluation for al LOLs.

6. 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”

Using SAR to evaluate hazard and potency (Recording)

At the recent USP’s China Nitrosamines Workshop, Dr. David Ponting @David lead the presentation “How Concerning is your nitrosamine? Using SAR to evaluate hazard and potency” @jxl To understand questions like: How can DATA sharing benefit the entire industry on correlating and identifying trends when it comes to SAR evaluation? How good is the AMES test? How about Carcinogenicity Potency of Nitrosamines? The importance of the Activation Mechanism? Does SAR feature play a role when predicting mu…

[Yosukemino]

7. 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.

Calculating Nitrosamine Limits (MasterClass)

At the recent USP’s China Nitrosamine Workshop, Dr. Raphael Nudelman @conudel lead a true master class on ‘Setting Limits for Complex Nitrosamines’ If you want to understand how to approach limit setting, I encourage you to invest the time to watch the presentation. It will be a very well-invested time! @jxl [image] Click here to watch! Please feel free to add your questions below via reply…

8. Nitroso Flecainide July 2022
9. 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.

Nitroso Flecainide

Anyone having idea about AI limit of Nitroso Flecainide? What could be the AI limit as per QSAR and read across approch?

N-nitrosoamides - a horse of a different color

Of late, I am seeing an alarming trend where people are mislabeling impurities as nitrosamines, when they are really nitrosamides/carbamates/urea/guanidine. Let us understand thatthe N-nitroso compounds can be divided into two categories, the M-nitrosamines and N-nitrosamides** (Figure 1). N -nitrosamines are formally derived by the reaction of secondary and tertiary amines with nitrous acid or other nitrosating agents. These can be formally considered as “amides” of nitrous acid and are stable.…

10. 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.

Officially used surrogates for read-across method

I want to visualize surrogate compounds used for read-across by EMA. [image] NDEA NDEA applies to five compounds. NDEA is well-known and has sufficiently robust toxicological data. [image] NDMA NDMA applies only to NMBA, despite its robust toxicological data. [image] NTHP There are compounds for NDSRI from here. NTHP is used for two, NNV and N-nitroso sitagliptin. The double bond of NTHP is the key feature. [image] N-Nitrosopiperidine N-Nitrosopiperidine applies to NMPH. T…

11. 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.

AI Limit for Nitroso Nebivolol

No limit has yet been published, as you observe; this may well be due to the difficulty of selecting a suitable read-across analogue, and I would be hesitant to do so myself without a lot more information. It may be that without further analysis (ongoing) of the complex nitrosamine data to allow us to understand how to make the extrapolations from small molecules, selection of a suitable analogue for this compound would be an impossible task. I do not believe that the compound will be potent en…

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

[Yosukemino]

12. 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.

AI for small nitrosamines not listed in EMA, FDA or Health Canada

Hello everyone, I would like your help once again on the following dilemma we are facing as a team. We are now dealing with small nitrosamines testing which are not listed in any of the guidelines but are included in CPDB (Carcinogenic Potency Database) and LCDB (Lhasa Carcinogenicity Database) and have a TD50 value. Specifically I refer to the nitrosamines: 1-Nitrosopiperazine (NPZ), 1,4-Dinitrosopiperazine (DNPZ), N-Nitrosodiethanolamine (NDELA) and 1-Nitrosopyrrolidine (NPYR). In some cas…

[carlosematos]

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*

[Iyappan]

Hi Sir,

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

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

[Yosukemino]

Hi, @Iyappan.

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

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.

[Iyappan]

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

Can we apply CPCA approach for small molecule Nitrosamines also?

[Yosukemino]

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.

[Naiffer_Host]

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

[IreneNS]

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.