⚙️🌎CPCA: the gestation, birth, and development -Pub

This is one of those articles that delves into the behind-the-scenes of science. You will be able to follow the gestation, birth, and development of CPCA. Check out this article:


it covers the entire birth of CPCA. Here is a general analysis:

  1. Introduction:
  • The article describes the approach of CPCA, a structure-activity relationship methodology adopted in 2023 for international regulatory guidance on assessing the safety of nitrosamine impurities in pharmaceutical products.
  • CPCA utilizes structure-activity relationships to determine acceptable intake limits for nitrosamine impurities in pharmaceutical products.
  1. Development of CPCA:
  • An international Nitrosamine Working Group (NITWG) was established to develop CPCA, involving experts in pharmacology, toxicology, chemistry, computational toxicology, and structure-activity relationships.
  • The goal was to create a methodology that didn’t rely on robust data for a single surrogate compound in each Acceptable Intake (AI) assessment, allowing AI identification even when specific compound data isn’t available.
  • CPCA builds upon previously published works and an evaluation of structure-activity relationships from a larger dataset of nitrosamine carcinogenicity.
  1. Dataset and Model Development:
  • The training dataset included 81 nitrosamines with carcinogenicity data.
  • Activating and deactivating structural characteristics of carcinogenic potency were identified, used to assign a Potency Category (PC) to each nitrosamine.
  • Potency categories range from 1 (high potency) to 5 (low potency), with thresholds defined based on regional AI limits and toxicological concern limit for mutagenic impurities.
  1. Application of CPCA:
  • CPCA allows consideration of the relative effects of multiple activating and deactivating characteristics on the molecule to predict carcinogenic potency and recommend an AI limit.
  • Examples of applying CPCA to hypothetical impurity structures related to the active substance (NDSRIs) are provided in regulatory guidance.
  • The applicability domain of CPCA is limited to compounds with a carbon atom directly linked to both sides of the N-nitroso group.
  1. Conclusions:
  • CPCA serves as a practical tool to quickly determine recommended AI limits for nitrosamines based on structural characteristics.
  • Further development of CPCA will be facilitated by the availability of new experimental mutagenicity testing data and metabolism studies.
  • CPCA was developed to address situations where there were insufficient carcinogenicity data or where a structure-activity relationship assessment did not identify a suitable surrogate for cross-reading assessment.

Kudos to the authors!

Link: https://www.sciencedirect.com/science/article/pii/S0273230024000813


By @jbercu


Swiss medic referred the paper on its website. :grinning:


I think it is quite innovative but still needs to be confirmed by experiments. I wish that at least 10 NDSRIs were subjected to carc. testing to confirm that what is being proposed by CPCA is close to what the AIs are.


Looking forward to seeing this go in print and accessing the supplementary data as well.

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This paper is in print now, so the supplementary tables with more listed compounds considered during CPCA design is accessible on the publisher website now.

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