Europe: Changes to the EMA’s Q&A Document for Nitrosamine Impurities in Human Medicinal Products (v.12)

Summary:  The European Medicines Agency (EMA) has updated the questions and answers document for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products. Key updates are highlighted in red below.

10. Which limits apply for nitrosamines in medicinal products? (Updated)

• The following N-Nitrosamines’ (CAS number) have been added:
  • 4-(Methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (NNK)7
  • N-nitrosoduloxetine1
• The following limit has been added:
  • (…) Limit derived using structure-activity-relationship (SAR) /read-across approach using the TD50of NNK as point of departure

21.What is the approach to control the presence of nitrosamines until a substance specific AI is established? (New)

(…) Q&A 10 provides guidance on the calculation of the limit when a new nitrosamine is identified. If N-nitrosamines are identified without sufficient carcinogenicity data to derive a substance-specific limit for lifetime exposure as recommended in ICH M7(R1) guideline, and the class specific TTC for nitrosamines of 18 ng/day is not used for controlling the levels of the nitrosamine in the finished product, an AI agreed by the Non-clinical Working Party (NcWP) and adopted by the CHMP is required to decide on control options for the nitrosamine in the finished product.

To protect public health, to inform decisions on required market actions while ensuring at the same time availability of medicines while a formal AI is established, a temporary AI (t-AI) of 178 ng/day (total nitrosamines) can be adopted by the relevant authorities for marketed medicines identified to contain one or more nitrosamines exceeding the TTC of 18ng/day. This t-AI has been derived using TD50 values calculated in the Lhasa carcinogenic potency database and is based on a probabilistic approach that there is a 33% risk that the “true” AI is below the t-AI. It is expected that the t-AI would be used for a period of less than 12 months, as an exposure over this period of time is not expected to increase the theoretical overall lifetime risk above 1:100,000.

In practice, this means that when competent authorities are notified about a product containing a new N-nitrosamine exceeding the TTC limit of 18 ng/day, no market actions may be required for batches with N-nitrosamine levels ≤178 ng/day at the MDD pending the agreement of the AI. The adoption of the t-AI is not automatic and is evaluated by the relevant authorities at the time of notification. Use of the t-AI beyond 12 months will require additional consultation with competent authorities.

The t-AI should not be used as a target for development of validated analytical methods to quantify new nitrosamines since the long-term limits adopted by CHMP might ultimately be lower than the t-AI.

The complete document is available here.