The assessment report of the CHMP’s Article 5(3) of Regulation (EC) No 726/2004 opinion on nitrosamine impurities in human medicinal products provides general guidance and recommendations on mitigating and preventing the presence of nitrosamines in human medicinal products. EMA recently updated the Q&A document (Questions and answers 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) with the emphasis on the approach how to control presence of nitrosamine exceeding the AI during CAPA implementation.

In accordance with the regulatory steps taken by authorities following the identification of an N-nitrosamine exceeding the AI and outlined in Q&A (question No. 20), the less than lifetime (LTL) concept or the use of interim limits may be considered by the lead authority and NCA’s on a temporary basis to inform market actions and at the same time ensure availability of medicines. MAH’s are expected to establish and implement corrective and preventive actions (CAPAs) in authorised medicines without any delays to ensure patients safety and product quality. Nevertheless, it is recognised that implementation of CAPAs may require some time before the MAH is able to mitigate the presence of the identified N-nitrosamine below the established AI. Therefore, to avoid unnecessary risk of supply disruptions, a harmonised approach promoting the establishment of interim limits in a streamlined way is agreed.

The approach is applicable to all authorised products that have:

• a duration of treatment not exceeding 10 years; and
• CAPA implementation timeline of up to 3 years from the establishment and publication of the AI.

Treatment duration Up to 12 months >12 months up to 10years

Interim limit

13.3 x AI*

6.7xAI*

* in any case the limit should not exceed 1.5 μg/day unless the established AI (Table 1, Q10) is > 1.5 μg/day.

The approach is not applicable to the below instances:

• Authorised medicines taken for a lifetime (>10 years);
• CAPA implementation exceeding 3 years from the establishment and publication of the AI;
• New/ongoing regulatory applications.

The above interim limits are based on the LTL approach outlined in the ICH M7 guideline, using the two most conservative adjustment factors (6.7 and 13.3 x AI).

The application of these adjustment factors would not be expected to exceed a theoretical excess cancer risk of 1 in 100,000 during the period of CAPA implementation. MAH’s are expected to ensure that the implementation of adequate controls for the detected nitrosamines is done as a matter of priority. During the use of the interim limit, monitoring measures may be evaluated by the lead authority as required. However, it is not the expectation that MAHs’ include these interim limits in specifications via variation.