Toxicity Threshold Determination for Batch Release Impurities

Problem: Your drug has an impurity above the qualification thresholds

With the maximum daily dose ("MDD") of the drug, this amount of impurity found is compared to the ICH Q3B threshold limit value

  • If % qualification< % ICH Q3B limit → no evaluation
  • If % qualification > % ICH Q3B limit → toxicological evaluation

Toxicological evaluation and risk analysis

Determination of the toxicological profile of the impurity (CMR, acute toxicity, chronic toxicity, etc.) by studying bibliographic data or using in silico models (QSAR, Read-across): a NOAEL or LOAEL value will be chosen.

  • Calculation of the threshold of toxicity, Permitted Daily Exposure ("PDE")
New Specification Formula
New specification (%) =
NOAEL or LOAEL (mg/kg/day) × Body weight (kg)

F1 × F2 × F3 × F4 × F5
  • Calculation of the new specification

    New Specification Formula
    New specification (%) =
    Toxicity threshold (mg/day)

    mg impurity in MDD (g/day)
  • If ratio > 1qualified impurity

You can check Tox by Design methodology for Out of Specification reassessment, signed by an European Registered Toxicologist expert here.

In the event you are performing this exercise for innovative compounds GMP scale up manufacturing, please be noted Tox by Design is duly accredited for the French Research Tax Credit CIR.

Feel free to contact us using this email link to receive a quotation for Out of Specification reassessment, before or after Marketing Authorisation.