Tox by Design Nitrosamine Methodology

Tox by Design nitrosamine impurities assessment reports are developed in compliance with current EMA regulation.

How to prepare a Nitrosamine Impurities Assessment report in 3 steps

A risk analysis of N-nitrosamine impurities based on ICH M7 and ICH Q9 must be performed for all products containing chemically synthesised active substances.

One Risk Assessment is requested for each formulation and each packaging.

When risk of presence of nitrosamine is demonstrated, identified testing is highly recommended.

Step 1 − Review and analysis of all materials used in the manufacturing process of the drug product from raw materials to finished product

• drug substances
• excipients
• manufacturing process
• API degradation
• packaging materials

Step 2 − Risk assessment conclusions

• for each control point, a risk level is identified
• the overall risk of nitrosamine is identified

If the risk assessment concludes that no nitrosamine impurities could be present in the drug product, there is no need to perform any confirmatory testing and therefore there is no analytical cost.

Step 3 – Testing recommendations

Based on the risk assessment conclusions, actions and confirmatory testing of nitrosamines are recommended.

How to set, for an identified N-Nitrosamine, if acceptable, an Acceptable Intake higher than the TTC

If justified, Tox by Design can set an acceptable intake for a specific nitrosamine higher than the default TTC value.

The justification will be based on a structure-activity-relationship (SAR) approach and it will adhere to the principles outlined in the Safety Working Party (SWP) document SWP, response to CMDh questions on nitrosamine (MeNP) acceptable intake EMA/CHMP/SWP/146017/2020.

According to the EMA review “Assessment report. Procedure under Article 5(3) of Regulation (EC) (No) 726/2004 for Nitrosamine Impurities in Human Medicinal Products” EMA/369136/2020:

• If N-nitrosamines are identified with sufficient substance specific animal carcinogenicity data,

     => TD50 should be calculated and used to derive a substance specific limit for lifetime exposure as recommended in ICH M7 (R1) guideline.

• If N-nitrosamines are identified without sufficient substance specific data to derive a substance specific limit for lifetime exposure as recommended in ICH M7 (R2) guideline,

     => the Carcinogenic Potency Categorization Approach (CPCA) for N-nitrosamines should be used to establish the AI, unless other robust data are available that would override this AI.

     => a negative result in an GLP-compliant enhanced Ames test allows control of the N-nitrosamine at 1.5 µg/day; for substances testing positive, the AI should be established using the CPCA method or by SAR and read across.

     => if a surrogate nitrosamine with sufficiently robust carcinogenicity data is available, the TD50 from the surrogate substance can serve as a point of departure for derivation of AI by SAR and read across.

     => a negative result in a relevant well-conducted in vivo mutagenicity study can allow control of the N-nitrosamine as a non-mutagenic impurity, i.e. according to Q3A/B limits, irrespective of the limit calculated through the above mentioned options; for substances testing positive, the AI should be established using the CPCA method or by SAR and read across.