🤷‍♂️ FAQ: How do I calculate the CPCA of my Nitrosamine Impurity?

[Naiffer_Host]

CPCA Calculation

EMA Q&A Rev. 16 EMA/409815/2020 - MAJOR UPDATE

Dear @Diego_HM, Thank you for sharing the information. I’m so excited to read it. It’s amazing!! According to the revision history, the updates are as follows; Amendment to Q&A 10 to include the Carcinogenic Potency Categorization Approach (CPCA) and the enhanced Ames test (EAT) for establishing AIs for N-nitrosamines. Addition of Appendix 1, listing the nitrosamines for which AI have been established by the Non-clinical Working Party (NcWP), including new AIs for N-nitrosamines determined us…

Example of How to calculate CPCA

Case Studies for CPCA Scoring

Let’s try CPCA Scoring!! If you want to post cases, the following PDF may be available to convert and custom. And images of compounds may be available in the visualization thread. And you can request the scoring, and then someone may help you. [image] Example of CPCA Scoring.pdf (71.4 KB) I’m not sure I can respond to all requests correctly. I’m looking forward to your participation!!

[Yosukemino]

Visualization of categorized compounds

Visualization of Categorized Compounds by CPCA

I want to visualize categorized compounds by CPCA in EMA Q&A rev.16. [image] Category 5 [image]

Calculation of α-hydrogen score (Illustration of @David’s description)

EMA Q&A Rev. 16 EMA/409815/2020 - MAJOR UPDATE

Dear @David Thank you for your helpful and informative explanation. Of course, I remember you helped us in this community many times. And I want to illustrate your explanation to understand nitrosamines deeply. If the most-hindered side is CH2, then whether the right-hand side is CH2 or CH3 makes little difference, both sides can react and highly-reactive diazonium ions can form, hence the score of 1 - reflected in a number of potent carcinogens that match this unhindered pattern. [image] I…

About the exception of CPCA (Nitrosamides and others)

EMA Q&A Rev. 16 EMA/409815/2020 - MAJOR UPDATE

As EMA was starting to look at nitrosamides, I wrote a white paper in a hurry to indicate that these are not nitrosamines but “Nitrosamides”. I have a posting here “Nitrosamides - horse of a different color”. These products are direct acting carcinogens and should not be treated as nitrosamines. So, you can do a general Ames assay to see if they are positive. also, treat them as mutagenic impurity and use SAR. Most of them will have higher limits. Again, they are not nitrosamines. So, dont apply…

[Yosukemino]

About the exception of CPCA (Nitrosamines where the N-nitroso group is within an aromatic ring (e.g., nitrosated indole))

EMA Q&A Rev. 16 EMA/409815/2020 - MAJOR UPDATE

For the nitrosated indoles, they aren’t nitrosamines per se; the indole nitrogen is not a secondary amine. Definitely still worth mentioning in the assessment if you consider there is risk of formation or have evidence thereof (don’t conceal anything is normally good advice!), but the implausibility of diazonium formation means that I would argue very strongly for treating these as conventional impurities under ICH M7 rather than as part of the cohort of concern. I recently summarised this on a…

EMA Q&A Rev. 16 EMA/409815/2020 - MAJOR UPDATE

As I see, David has provided a response to your questions. There have been a lot of studies on nitroso indoles which are well known. Many of them are mutagenic. My recommendation will be to look for surrgates with do have nitroso indole group and again, they are not “nitrosamines”. So, dont mix them up and provide separate analysis. Like the nitroso carbamates and nitroso guanidines, they do not need metabolic activation to show their mutagenicity in Ames. Look at this paper, which may give you …

An example of deactivating feature (a 6-membered ring fused with another ring)

EMA Q&A Rev. 16 EMA/409815/2020 - MAJOR UPDATE

For this structure, I would say: The hydrogen count is indeed (2,2) for one point The six-membered ring is not strictly a piperidine, because of the aromatic thiazole fused to it (and the six-membered ring is definitely not aromatic itself, fails Huckel’s rule) - piperidine implies all ring bonds are single. However, the CPCA rule gives two points both to piperidines and to all 6-membered rings other than sulphur-containing and morpolines, so still two points That fused thiazole, though, mean…

[Yosukemino]

Difference of guidance between EMA and FDA

FDA - Recommended Acceptable Intake Limits for NDSRIs Guidance for Industry

Some things I noticed right off the bat about differences with other guidance documents which are important: • FDA says to provide a “scientifically justified rationale” if the CPCA is not met. However, they lack the clarity HC and EMA had. o No mention on what to do with a negative Ames. They mention the EAT protocol, but what do you do with a negative? EMA and HC says TTC is appropriate. o No mention of what to do with a negative in vivo study. EMA and HC says apply ICH Q3A/B. o The re…

FDA - Recommended Acceptable Intake Limits for NDSRIs Guidance for Industry

My contributions to the highlights of the guidance: Overall, the U.S. FDA approach is harmonized with the EMA’s guidance on NDSRI detection and mitigation. The updated EMA guidance introduces a new Carcinogenic Potency Categorization Approach (CPCA), which is a basis of the new approach both regulators are taking to determine the AI of a given NDSRI and aid in risk assessment for various APIs. Manufacturers of approved or marketed drug products should, if they have not done so already, eva…