Update of requirements for Marketing Authorisation Holders to Evaluate the Risk of the Presence of Nitrosamines

In compliance with the procedure outlined under Art. 5(3) of Regulation (EC) no. 726/2004, holders of marketing authorisations of human medicinal products containing chemically synthesised active substances and biological active substances are hereby invited to review the manufacture of their medicinal products in view of potential presence of nitrosamines.  The updated conclusions dated 18.2.2021 can be found on the EMA website.  

Should they detect nitrosamines in any of their medicinal products, marketing authorisation holders (hereinafter referred to as “MAHs”) shall be obliged to forthwith notify the competent national medicines agencies so as to allow for the adoption of appropriate regulatory measures.

The call for review has been extended to cover also all biological medicinal products for human use, in particular for the biological medicines with the following risk factors:

  • biologicals containing chemically synthesised fragments, where risk factors similar to chemically synthesised active substances are present;
  • biologicals using processes where nitrosating reagents are deliberately added;
  • biologicals packaged in certain primary packaging material, such as blister packs containing nitrocellulose.

More information is available in EMA Questions and Answers document (dated 26.2.2021) and CMDh web pages.

In the review of the manufacturing procedures employed for active substances (hereinafter referred to as “APIs”) and for finished medicinal products carried out with regard to measures to prevent the formation of nitrosamines as well as contamination or cross contamination, MAHs should cooperate with the manufacturers of active substances and of the finished medicinal products, applying also their knowledge of the manufacturing processes.

MAHs of products containing sartans with a tetrazole ring shall follow the measures arising from the referral procedure as per Article 31 of Directive 2001/83/EC dated 2.4.2019 and subsequently updated as per Commission Implementing Decision of 19. 2. 2021; for more information, please refer to EMA website (please note that the conditions arising from this referral procedure must be fulfilled within timelines stipulated by the respective implementing decisions of the Commission). A separate referral has been also carried out for medicinal products containing the ranitidine active substance (please refer to http://www.sukl.cz/lecive-pripravky-s-obsahem-ranitidinu-zahajeno-prehodnoceni) resulting in suspension of the Markething authorisations of the medicinal products concerned.  

In respect of medicinal products containing chemically synthetised active substance(s) other than sartans with tetrazole ring and ranitidine and biological active substance(s), the following steps should be taken:

Step 1
Risk evaluation:

MAHs should perform risk evaluation of their medicinal products. MAHs together with API and finished product manufacturers are required to perform risk evaluations using quality risk management principles, as outlined in ICH Q9 guideline. The principles described in ICH M7 guideline in relation to toxicology assessment, control strategy, and changes to the manufacturing processes for active substances should be applied.

MAHs should prioritise medicinal products in order to establish the sequence in which their medicinal products are to be evaluated. The factors that can be taken into account are outlined in the published Questions and Answers. For medicinal products identified as high priority, the risk evaluation should be done immediately.

The risk evaluation of medicinal products containing chemically synthetised active substance should have been concluded at the latest by 31 March 2021 (the original deadlines of 26 March 2020 and 30 September 2020 were extended following reports of the challenges encountered in meeting the original deadline, and the impact of the severe restrictions in place to combat the COVID-19 pandemic respectively). MAHs should inform the concerned competent agencies immediately if they complete the risk evaluation or identify a risk in their products.

The risk evaluation of medicinal products containing biological active substance should be concluded at the latest by 01 July 2021.

The outcome of step 1 must be a comprehensive of risk evaluation of APIs and also finished products.

  • If a risk has been identified for the API, the step 1 response template (the specimen cover letter mentioned below) should be used. In this case, the MAH is advised to proceed directly with step 2 confirmatory testing of the finished product.
  • If a risk is not identified in an API, the MAH is advised to proceed with a risk evaluation of the finished product and submit the outcome of step 1 only when a final and comprehensive conclusion is reached.

Technical aspects of risk analysis submission and its submission to regulatory authorities are specified below, under the “Detailed procedure governing medicinal products authorised in the Czech Republic” section. If a risk of presence of nitrosamines is identified as a result of the evaluation, the MAH should proceed to Step 2.

For the purposes of risk evaluation submission by MAHs, SÚKL has established a dedicated e-mail address nitrosaminy@sukl_cz. Questions and answers on this topic shall be addressed in a centralised manner by EMA and CMDh (by way of updates to document “Questions and Answers”).

Specimens cover letters that should not be changed by MAHs:

Specimen cover letter, Step 1, no risk identified

Specimen cover letter, Step 1, risk identified

Specimen response template Step 1, risk identified

Note: In case the Step 1 response was submitted in an older template version, the updated template is not needed.


Step 2
Confirmatory Testing:

In the event that a risk of presence of nitrosamines is identified as a result of the risk evaluation, confirmatory testing should be carried out using appropriately validated and sensitive analytical methods in accordance with the prioritisation deriving from the risk evaluation conducted in Step 1. Medicinal products identified as high priority should be tested as soon as possible. Confirmatory testing of all medicinal products identified to be at risk of presence of nitrosamines and submission of required changes in the manufacturing authorisation dossier should be concluded at the latest by 26 September 2022 for chemically synthetised active substances and by 01 July 2023 for biological active substances.
 
If tests confirm the presence of an nitrosamine impurity, irrespective of the amount detected, MAHs should forthwith inform the competent national agencies (such cases shall be reported to SÚKL using the quality defect reporting procedure and sent to: zavady@sukl_cz).

Specimen cover letter, Step 2, no nitrosamines detected

Specimen cover letter, Step 2, nitrosamines detected  

Specimen response template Step 2, risk identified


Step 3
Changes to the marketing authorisation:

MAHs should apply for a variation or variations to marketing authorisation in a timely manner to introduce any required changes, such as amendment of the manufacturing process of the active substance or the medicinal product, amendment of active substance or product specifications, and amendment of control methods of the active substance or product.

The competent agencies should be forthwith informed should the finding suggest an immediate risk for public health.

Detailed procedure governing medicinal products authorised in the Czech Republic

Responsibility for the collection of information in respect of medicinal products authorised via the centralised procedure lies with EMA; risk evaluation shall be sent solely to EMA, without copy to SÚKL.

In respect of authorisations via the MRP/DCP with the Czech Republic acting as the Concerned Member State (CMS), the risk evaluation addressed to the Reference Member State (RMS) shall be sent, in the format required by the respective RMS, to the RMS, with a copy to SÚKL sent to the following address: nitrosaminy@sukl_cz. If the respective RMS allows for the collective submission of several MRP numbers, the submitted list shall clearly indicate which of the medicinal products have been authorised in the Member States, MRP numbers and MA numbers.

In respect of authorisations via the MRP/DCP with the Czech Republic acting as the Reference Member State (RMS), the evaluation can be submitted for more MRP numbers of the concerned MAH as attachment to the cover letter as per the specimen referred to under Step 1 (either the “no risk identified”, or “risk identified” having the same testing dates) by e-mail to the following address: nitrosaminy@sukl_cz. The template as linked above must be used for sending the list of medicinal products with identified risk. The submitted list shall clearly indicate which of the medicinal products have been authorised in the Member States, MRP numbers and MA numbers of all medicinal products included in the evaluation. The e-mail should have the following subject: “Outcome of risk assessment nitrosamines – Step 1 (or step 2 respectively)” + “no risk“ or “potential risk“ + the name of the MAH + eventually MRP/DCP number; it is necessary to cc the CMSs. The e-mail should be sent by the MAH or the entity representing the MAH.

In respect of national authorisations, there are 2 options how to submit the risk evaluation:

1. Submit the evaluation for each medicinal product separately, using the specimen cover letter (either the “no risk identified”, or “risk identified” version including the response template linked above) by e-mail to the following address: nitrosaminy@sukl_cz, with the following subject: “Outcome of risk assessment nitrosamines – Step 1 (or Step 2 respectively)” + either “no risk” or “potentional risk” + marketing authorisation number of the product. 

OR

2. Submit a summary list of all medicinal products of the concerned MAH authorised via the national marketing authorisation procedure in the Czech Republic as attachment to the cover letter (either the “no risk identified”, or “risk identified” version), i.e. in this case, there would be one e-mail message with the cover letter and the list of products (using the template linked above) for which a risk has been identified, and another e-mail message with the cover letter and the list of products for which no risk has been identified. In such a case, the subject of the e-mail should read: “Outcome of risk assessment nitrosamines – Step 1 (or Step 2 respectively)“ + either “no risk”, or “ potentional risk” + the name of the MAH. Below please find a list of products authorised via the national procedure, incl. MAHs; this list should be used to filter the concerned products.  

Also, this list can be used to report the medicinal products concerned with no risk identified (in column N, please specify: NO – i.e. no risk has been identified). The list of medicinal products where a risk has been identified should be provided using the specimen template linked above.

Should any products be missing from the list, please add them to the list which is to be submitted.

List of nationally authorised MP (chemically synthetised API) for the identification of the risk of nitrosamines 15.4.2021.xlsx, soubor typu xlsx, (177.44 kB)

List of nationally authorised MP (biological API) for the identification of the risk of nitrosamines 15.4.2021.xlsx, soubor typu xlsx, (21.56 kB)

 

For more details, please refer to documents published on EMA and CMDh websites:
 
EMA: Article 5(3) opinions: Nitrosamine impurities in human medicinal products (Updated 9 July 2020): https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/article-53-opinions#nitrosamine-impurities-in-human-medicinal-products-(updated-18/02/2021)-section

EMA: Nitrosamine impurities: https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/nitrosamine-impurities

EMA and CMDh: 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: https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-marketing-authorisation-holders/applicants-chmp-opinion-article-53-regulation-ec-no-726/2004-referral-nitrosamine-impurities-human-medicinal-products_en.pdf

CMDh: Information on nitrosamines for Marketing Authorisation Holders: https://www.hma.eu/620.html

CMDh: CMDh practical guidance for Marketing Authorisation Holders of nationally authorised products (incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamines: https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Advice_from_CMDh/Nitrosamins/CMDh_412_2019_Rev.10_2021_02_clean_-_PG_to_MAHs_on_nitrosamines_rev_02_Feb_2021_clean.pdf 

Initial article: 29 November 2019


Update of 07 January 2020: On 03 January 2020 was updated list of nationally autohorised medicinal products for the identification of the risk of nitrosamines including radipharmaceuticlas, which are also concerned.

Update of 6 April 2020: added information about the extension of the risk evaluation deadline (step 1) and clarified the information when and how this risk assessment should be sent; update of Q&A on EMA and CMDh websites.

Update of 18 August 2020: deadline for Medicinal Products containing chemically synthetised active substances moved to 31 March 2021. Added requirement for risk assessment also for medicinal products containing biological active substances (with deadlines of Step 1: 01 July 2021 and Step 3: 01 July 2023). Also updated links to EMA and CMDh documents.

Update of 08 September 2020: updated lists of nationally authorised medicinal products with chemically synthesised active substances and biological active substances.

 

Update of 30. 6. 2021: new cover letters and response templates were added.  Also the list of medicinal products with chemically synthetized active substances and biological active substances were updated. In addition , the links to EMA and CMDh documents were updated.

 

Marketing Authorisation Section