The European Medicines Agency (EMA), the Heads of Medicines Authorities (HMA) and the Coordination Group on Mutual Recognition Procedures and Decentralized Procedures (CMDh) have published documents related to the implementation of the Article 5(3) procedure of Regulation (EC) No 726/2004 on nitrosamine impurities in human medicinal products. These documents are updated on a regular basis. The latest versions are published on the CMDh homepage: Heads of Medicines Agencies: Nitrosamine impurities (hma.eu)

2023.08.04 - Information for marketing authorisation holders: Submission of the update of step 2

EMA and CMDh updated the Q&A document on the Article 5(3) procedure on nitrosamine impurities in human medicinal products in July 2023. This update included new and revised Acceptable Intakes (AIs) for some N-nitrosamines and new methods for determining the limits for newly discovered nitrosamine impurities. Marketing authorization holder (MAH) of products concerned by those nitrosamines are requested to resubmit their step 2 response in the updated template to (re-) confirm under which scenario their products should be classified under the newly published AIs. This is particularly important in case a step 2 scenario A or D response was submitted (see CMDh press release, July meeting). The resulting necessary update of step 2, if a step 2 was already submitted, is to be submitted to the BfArM by the marketing authorization holder via the PharmNet.Bund portal. For this purpose the SKNR 6364 (Step II - Update: new limit. The nitrosamine risk was analytically confirmed by the finding of impurities with nitrosamine.) was established for the upload of the notification template. SKNR 6362 or 6363 should continue to be used for the initial step 2 submission. The SKNR used for submission should not be combined with any other SKNR. The submission is free of charge and will not be considered as a variation.
Updated submission forms and the current Q/A document are published on the CMDh homepage.

2020.11.25 - Information for marketing authorisation holders: Submission of step 2

In step 2 of the risk assessment procedure, additional testing will be carried out on those medicinal products for which a risk of N-nitrosamine formation or a possible (cross)contamination has been identified in step 1. Analogous to step 1, the results of the investigations are to be submitted to the BfArM by the marketing authorisation holder via the PharmNet.Bund portal. For this purpose, the SKNR 6362 (The nitrosamine risk was confirmed analytically by the discovery of contamination with nitrosamine.) and the SKNR 6363 (No contamination with nitrosamine was found in the tests of the medicinal product.) were set up for sending the feedback form. The SKNR used for the feedback should not be combined with another SKNR. The submission is free of charge and will not be considered as a variation. If the risk of N-nitrosamine formation or a (cross)contamination has been identified in step 1, the testing should be carried out as soon as possible.

PharmNet.Bund

The submission forms are available on the homepage of the Coordination Group (CMDh) at: https://www.hma.eu/620.html

2020.10.07 - Information for marketing authorisation holders: request to evaluate the risk of the presence of nitrosamine impurities – deadline extension

The European medicines regulatory network has agreed to extend the deadline to complete step 1 (risk evaluation) as described in information on nitrosamines for marketing authorisation holders (see below) now for chemically defined medicinal products to 31 March 2021. EMA and CMDh have provided further information on this. Please note that there may be updates to the Coordination Group's (CMDh) Question and Answer document and that you should therefore always refer to the current version of this document. For biological medicinal products the deadline is 1 July 2021.

This follows reports of the challenges encountered in meeting the original deadline of 26 March 2020, and the impact of the severe restrictions in place to combat the COVID-19 pandemic.

The European medicines regulatory network encourages marketing authorisation holders to submit the outcome of step 1 before 31 March 2021 if they complete the risk evaluation or identify a risk in their products.

Marketing authorisation holders should inform the national competent authorities as soon as possible if tests confirm the presence of nitrosamine, irrespective of the amount detected. The immediate risk to patients should be assessed and appropriate action taken to avoid or minimise the exposure of patients to nitrosamines.

2020.08.06 - Information for marketing authorisation holders: request to evaluate the risk of the presence of nitrosamine impurities - Q&A document and PharmNet.Bund portal

EMA and CMDh have updated the Q&A document on the Article 5(3) procedure to prevent nitrosamine contamination in medicinal products for human use. This document includes potential sources of nitrosamine contamination identified to date and is intended to support marketing authorisation holders in the ongoing review of their manufacturing processes. Please note that there may be further updates to the Question and Answer document and that companies should therefore always refer to the current version of this document.

Further information is available

• on the homepage of the European Medicines Agency (EMA)
  Nitrosamine impurities
• and the Coordination Group (CMDh)
  Advice from CMDh – Nitrosamine impurities

The feedback of the marketing authorisation holders according to step 1 shall be provided for the medicinal products authorised by BfArM via the PharmNet.Bund portal. For this purpose the SKNR 6360 (The risk evaluation of the medicinal product revealed a risk for nitrosamine formation) and the SKNR 6361 (Based on the risk assessment of the medicinal product, a risk for nitrosamine formation can be excluded) were established for the upload of the notification template. The SKNR used for feedback should not be combined with another SKNR.

The PharmNet.Bund portal intended for the submission of responses will be available again from 13.08.2020 after a temporary shutdown due to the technical conversion of the AMIS drug database to the successor system AmAnDa. Instructions for the feedback via the PharmNet.Bund portal can be found below under the entry of 20.12.2019.

2020.03.26 - Information for marketing authorisation holders: request to evaluate the risk of the presence of nitrosamine impurities – deadline extension

The European medicines regulatory network has agreed to extend the deadline to complete step 1 (risk evaluation) as described in information on nitrosamines for marketing authorisation holders (see below) to 1 October 2020. EMA and CMDh have provided further information on this. Please note that there may be updates to the Coordination Group's (CMDh) Question and Answer document and that you should therefore always refer to the current version of this document.

This follows reports of the challenges encountered in meeting the original deadline of 26 March 2020, and the impact of the severe restrictions in place to combat the COVID-19 pandemic.

The European medicines regulatory network encourages marketing authorisation holders to submit the outcome of step 1 before 1 October 2020 if they complete the risk evaluation or identify a risk in their products.

Marketing authorisation holders should inform the national competent authorities as soon as possible if tests confirm the presence of nitrosamine, irrespective of the amount detected. The immediate risk to patients should be assessed and appropriate action taken to avoid or minimise the exposure of patients to nitrosamines.

2020.03.13 - Additional information for marketing authorisation holders

The PharmNet.Bund portal intended for the submission of the above mentioned risk assessments has to be temporarily shut down (presumably for a period of 4 weeks) already on 13.03.2020 at 5.30 pm due to the technical conversion of the national drug database AMIS to the successor system AmAnDa for technical reasons.

For more information see:
https://www.bfarm.de/EN/Drugs/licensing/ZulRelThemen/eSubmission/eSubmission_AMIS-replacement.html

eSubmissions can therefore only be submitted after the transition phase when the PharmNet.Bund portal is available again. The BfArM will inform on its homepage when the portal will be available again.
We therefore request that risk assessments not yet submitted by 13.03.2020 within the scope of the Article 5(3) procedure are only submitted after reactivation of the PharmNet.Bund portal, even though this may result in exceeding the deadline for feedback according to step 1.
When submitting the application, it should be taken into account that feedback can also be grouped. Up to 99 ENRs can be entered simultaneously in the portal; these can also be grouped in the corresponding template of the CMDh.

2019.12.20 - Information for marketing authorisation holders: Request to evaluate the risk of the presence of nitrosamine impurities in human medicinal products containing chemically synthesised active pharmaceutical ingredients

In June 2018 a contamination of valsartan with nitrosamine N-nitrosodimethylamine (NDMA) was detected. Subsequently, another nitrosamine, N-nitrosodiethylamine (NDEA), was detected in valsartan and other sartans were implicated in the review. NDMA and NDEA are classified as probable human carcinogens.

An Article 31 review of sartans at risk of containing nitrosamine impurities (i.e. sartans with a tetrazole ring) concluded that manufacturers must review and make necessary changes to their manufacturing processes to minimise nitrosamine impurities as much as possible. In addition, strict limits were set for nitrosamines in these products.

The findings of the review indicate that there is a potential for nitrosamines to be present in APIs for other medicines (i.e. non-sartans APIs), depending on the API and the finished product manufacturing processes.

It should be noted that nitrosamine impurities have been identified in some batches of pioglitazone and in batches of ranitidine. An EU-wide review of ranitidine has been initiated. As the nitrosamine levels found in pioglitazone were within the interim limits established in the sartans review, no market action was deemed necessary. As a precaution, companies using certain reagents to manufacture pioglitazone have been requested to test their products and check their processes to rule out the presence of nitrosamine impurities.

Nitrosamines are not expected to be formed during the manufacture of the vast majority of APIs outside the class of sartans with a tetrazole ring. However, it is now known that these impurities can form during production under certain conditions and when certain solvents, reagents and other raw material are used. Therefore, despite the low risk of nitrosamines being present, all marketing authorisation holders are asked to review their manufacturing processes and take precautionary measures to mitigate the risk of nitrosamine formation or presence during the manufacture of all medicinal products containing chemically synthesized APIs.

A scientific evaluation by the Committee for Medicinal Products for Human Use (CHMP) was initiated in September 2019 in accordance with Article 5(3) of Regulation (EC) No 726/2004.
The European Medicines Agency (EMA) has initiated an Article 5(3) procedure in this regard and has approached the associations of the pharmaceutical industry with a letter coordinated at European level. Further information is available

• on the homepage of the European Medicines Agency (EMA)

  EMA advises companies on steps to take to avoid nitrosamines in human medicines

• and the Coordination Group (CMDh)
  Information on nitrosamines for marketing authorisation holders

Following the publication of the notice to MAHs in September 2019, the CMDh and EMA have updated the related Q&A document for MAHs who are currently reviewing their medicines for the possible presence of nitrosamines and testing products at risk. The updated document lists potential sources of nitrosamine contamination that have been identified to date. This new information can support companies in their ongoing review of their manufacturing processes.

The Q&A document was again updated and supplemented in December 2019. The most important additions in the document are the limits for nitrosamines in medicinal products based on lifetime and less than the lifetime use.

Questions and answers on “Information on nitrosamines for marketing authorisation holders”

The CMDh and the EMA further agreed on templates for MAHs to submit their feedback in step 1 (risk evaluation) and step 2 (confirmatory testing).
In addition, the CMDh agreed a practical guidance for non-centrally authorised products which provides more information on the procedural details of the submission.
All updated and new documents will be published on the CMDh website under

Information on nitrosamines for marketing authorisation holders

The feedback of the marketing authorisation holders according to step 1 shall be provided for the medicinal products authorised by BfArM via the PharmNet.Bund portal. For this purpose the SKNR 6360 (The risk evaluation of the medicinal product revealed a risk for nitrosamine formation) and the SKNR 6361 (Based on the risk assessment of the medicinal product, a risk for nitrosamine formation can be excluded) were established for the upload of the notification template. The SKNR used for feedback should not be combined with another SKNR. Submission is free of charge and will not be considered as notification of change.

PharmNet.Bund