Nitrosamine risk assessment process:

The nitrosamine risk assessment process is a systematic, multi-step framework required by global regulators to detect, evaluate, and control N-nitrosamine impurities and Nitrosamine Drug Substance-Related Impurities (NDSRIs) in active pharmaceutical ingredients (APIs) and finished drug products.

The Mandatory 3-Step Process

Step 1

Risk Evaluation: Theoretical Assessment - MAH must perform risk assessments for all products.

A theoretical nitrosamine risk evaluation involves a structured, science-based investigation into the potential presence, formation, or carryover of N-nitrosamines and Nitrosamine Drug Substance-Related Impurities (NDSRIs) in active pharmaceutical ingredients (APIs) and finished drug products.

Evaluating the simultaneous presence of a vulnerable amine (secondary, tertiary, or quaternary), a nitrosating agent (such as nitrites or nitrates), in API,excipients (via nitrite databases), packaging components (e.g., nitrocellulose-containing printing inks on blister packs), and favourable environmental conditions (such as low pH or acidic microenvironments).

Step 2

Confirmatory Testing If risk is identified, the testing shall be performed on API and FP batches with using validated and highly sensitive methods i.e. (LC-MS/MS),

- Testing should be conducted on 10% of annual batches or 3 batches per year, whichever is higher.

- If fewer than 3 batches are manufactured annually, then all batches should be tested.

- This includes, testing not only of newly produced batches but also retained samples which are still within shelf-life period.

Step 3

If impurities exceed limits, submit variations to the FDA or EMA with modified process or modified formulation.

Changes to Marketing Authorization: Reformulation & Control: Adjusting formulation pH to prevent nitrous acid formation, adding antioxidant scavengers (like ascorbic acid or alpha-tocopherol), screening excipients for low-nitrite grades, or modifying synthetic steps

Reporting mechanism to health authorities

For new Submission - risk assessment for the presence of nitrosamines must be submitted at the time of submission,

For already authorized medicinal products - risk assessment for the presence of nitrosamines must be submitted

 

Submission of step 1 outcome: Risk Evaluation: Theoretical Assessment

-        Inform to HA risk evaluation (step 1) outcome using the dedicated templates.

-        If a risk identified, the expected timeline for the testing activities should also be provided and proceed with step 2 confirmatory testing

-        If no risk identified, the outcome of step 1 to submit one email notification with identical outcome in the dedicated template

 

Submission of step 2 outcome: Confirmatory testing

-        MAHs should inform to the competent authorities if tests confirm the presence of nitrosamine, irrespective of the amount detected and by utilising the dedicated reporting templates.

-        If impurity levers are more than 10 % of acceptance limit, then updated specification shall be submitted to agency by using suitable Post approval variation.

-        MAHs are expected to continue to review and re-visit the outcome of the risk evaluation as and when new information becomes available.

Submission of step 3: Update marketing authorizations

-        Submission of appropriate variation(s) to the HA with the regulatory guideline on classification of variations.

-        MAHs should submit their variation applications as soon as they conclude their investigations

 

Re-assessment of Nitrosamine Risk assessment of Step 1 and Step 2

For below changes in formulations will required the Re-assessment

-        Change in API source

-        Change in API intermediates

-        Change in Raw material source/starting material

-        Change in manufacturing process

-        Change in Packaging material or composition

 

Reference: EMA Guidance : Article 5(3) of Regulation (EC) No 726/2004 regarding nitrosamine risks.