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MAGYAR

CMDh practical guidance for Marketing Authorisation Holders of nationally authorised products (incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamines

With regard to the Art. 5(3) referral, MAHs are requested to evaluate the risk of the presence of nitrosamine impurities in their human medicinal products containing chemically synthesized active pharmaceutical ingredients (Information on nitrosamines for marketing authorisation holders”). This evaluation should be performed in 3 sequential steps:

Step 1 – Risk evaluation

Step 2 – Confirmatory testing

Step 3 – Changes to the marketing authorization

This practical guidance is prepared in order to explain the necessary steps for fulfilling the requested risk assessment. Q/As are enclosed for each of the three steps. Further details on how to proceed with the confirmatory testing and necessary changes of the marketing authorization will later be added to this living document. Furthermore, questions from MAHs/API manufacturers might also be included in this document at a later stage if regarded necessary.

1. Step 1 – Risk evaluation

MAH should perform risk evaluation of their medicinal products containing chemically synthesized API. The risk evaluations should be prioritized according to the published “Questions and answers on “Information on nitrosamines for marketing authorisation holders” and the outcome templates should be submitted per product as soon as available. MAHs are obliged to submit the conclusions of the risk evaluations for all of their products until 30.09.2020 as outlined below.

1.1. How should I submit the outcome of the risk evaluation to the competent authorities?

Two templates have been prepared (https://www.hma.eu/226.html) for the outcomes “no risk identified” and “risk identified”. The relevant template for each medicinal product has to be sent to all national competent authorities where the respective product is authorized as soon as the individual risk evaluation is finalized:

· By attaching it to an email (see Annex below);

Specific for Hungary:

Please send the outcome to the Hungarian Authority using nitrozamin@ogyei.gov.hu email address.

· The heading should include “Outcome of risk assessment nitrosamines - Step 1”, “no risk” or “potential risk” and in case of MRP/DCP the EU procedure number; Guidance given by authorities on national websites also has to be regarded (see Annex below).

The risk assessment documents do not have to be submitted to the authorities at this moment, but should be available upon request.

The Excel sheet (https://www.hma.eu/226.html) does not have to be submitted with each notification email but might be submitted at the end of the risk evaluation for all products of a MAH or on request of the member states. Note that member states may require the submission of the excel sheet with the relevant notification as part of national guidance.

Specific for Hungary:

Please send the outcome to the Hungarian Authority using nitrozamin@ogyei.gov.hu email address.

1.2. Can we combine several MAs in one template of the risk evaluation step 1 outcome?

Yes, you can combine several products on one template (when the outcome is identical) but you should consider national requirements as mentioned in the practical guidance. These national requirements may not be overruled by the general possibility as given by CMDh.

In case several MRP/DCP are included in one template, the email header should just read “Outcome of risk assessment nitrosamines – Step 1” and “no risk” or “potential risk” without mentioning any MRP/DCP number. In the template itself it is mandatory to mention the marketing authorisation number AND the MPR/DCP number for each product included.

1.3. Is the risk evaluation also required for products that are currently not marketed or is it sufficient to give a commitment that the risk evaluation will be performed before placing the product on the market?

The risk evaluation has to be performed for ALL products covered by the “Information on nitrosamines for MAHs”, independent from their marketing status.

1.4. Are radiopharmaceuticals excluded from the risk evaluation?

No, the risk evaluation has to be performed also for radiopharmaceuticals.

1.5. Are homeopathics and traditional herbal medicinal products excluded from the risk evaluation? 

The risk evaluation of homeopathics and traditional herbal medicinal products is currently not required but it might be considered at a later point in time, depending on the experience gained.

1.6. What is the approach for new and ongoing marketing authorisation applications (MAA)?

The potential presence of nitrosamines will be evaluated as part of the marketing authorisation application as follows:

· At the submission stage:

- Applicants are required to submit as part of their MAA a risk evaluation –including the relevant documentation - as per principles outlined in step 1 of the Information on nitrosamines for marketing authorisation holders. 

- If at this stage the risk of presence of nitrosamines in the medicinal product is already identified, the applicants are required to provide the risk assessment outlining the impact on the benefit-risk balance of the product and a risk mitigating strategy. Applicants should also submit confirmatory testing plans or confirmatory testing data as mentioned in the step 2 of the “Information on nitrosamines for marketing authorisation holders”.

- In case applicants have not submitted a sufficient risk evaluation, risk assessment if applicable, including confirmatory testing results or testing plans with their MAA, these should be submitted during the marketing authorisation review procedure.

 

· During the MA evaluation procedure:

- If the risk evaluation was not submitted as part of the MAA, it will be requested during the MA review process as a major objection. Where a risk of the presence of nitrosamine has been identified in the risk evaluation, a risk assessment will have to be provided, adequately documented and supported by confirmatory testing in case a possible risk of presence of nitrosamines has been identified and should be submitted as part of the Day 106 responses to the list of questions.

- If the applicant is not able to provide satisfactory information and justification on the benefit-risk profile of the product until Day 106, the procedure will remain in clock stop until the necessary data is provided.

- Any outstanding issues would have to be addressed before Day 210;

- If concerns on quality of the products are still not sufficiently addressed at Day 210, considerations on the impact of the risk evaluation/ assessment on the presence of nitrosamines in the product will be made and final decision on granting the MA will be made by the RMS in liaison with CMS.

 

Note: for the purpose of this Q&A please see below definition:

Risk evaluation: all activities in step 1.

Risk assessment: all activities in step 2 and 3.

1.7. How to deal with pending or newly submitted MRPs or RUPs or line extensions?

No risk assessment is generally necessary before submitting a RUP or MRP or a line extension. Instead, the MAH has to submit the outcome of the risk evaluation to all member states in which the MA is already approved within the deadline as mentioned in the “Information on nitrosamines for marketing authorisation holders”. However, in some cases depending on the product a risk assessment might be requested by the RMS or CMS during the procedure.

1.8. Where should I place the outcome of the risk evaluation and risk assessment in the dossier?

The risk evaluation should be submitted as an attachment to Module 1, corresponding reference can be made in Module 3, section 3.2.P.5.6 Justification of specification. The risk assessment should be included in Module 3.2.

1.9. When in the step 1 template a potential risk for nitrosamines is identified as not all relevant data were available and later on it is clarified that there is actually no risk, may I submit updated templates, i.e. replace the “risk identified” template by a “no risk identified” template?

No, the submission of the risk evaluation template as outcome of step 1 can take place only once. If the template is completed with a potential risk identified than the confirmatory testing has to be started immediately. This has to be confirmed anyway, including the relevant performance dates, in the template submitted as step 1 outcome.

2. Step 2 – confirmatory testing for approved products

2.1. When should I perform confirmatory testing for nitrosamines?

Confirmatory timely testing should be performed as soon as the risk assessment indicates a potential risk for the formation of, or contamination with nitrosamines. In case a high risk is identified the confirmatory testing should be initiated immediately. Member states should be informed as soon as possible. All confirmatory testing should be finalized until 26.09.2022 at the latest (see Q/A 7 in “Questions and answers on “Information on nitrosamines for marketing authorisation holders”).

MAHs are reminded that all activities related to confirmatory testing (step 2) and related investigations in case of confirmed presence of nitrosamines (e.g. risk assessment on root causes and establishment of CAPAs) should be performed timely in order to ensure that any required variations will be submitted within the 3-year timeframe, i.e. not later than September 30, 2022.

2.2. To whom should the outcome of the testing be sent when nitrosamines are actually detected?

The outcome of the confirmatory testing should include the results and an investigation report detailing the risk assessment and proposed CAPAs.

Please send these documents immediately after detection to the email addresses (as given below to) to the concerned national competent authorities in case of purely national MAs, to the RMS in case of MRP/DCP products (copying the CMS’s) or to the EMA in case of CAPs including “Outcome of confirmatory testing nitrosamines - Step 2” in the heading. For MRP/DCP products the EU procedure number should be added as well. Please also regard guidance given by national competent authorities in this respect. The RMS will evaluate the results and then inform the CMSs about the outcome of their evaluation, so that the CMSs are aware that the MAH has performed and finalised Step 2. Necessary measures will then be decided on by the authorities.

As the outcome of step 2 an individual template has to be completed for each single product, it will NOT be allowed to combine several products on one template.

Specific for Hungary:

Please send the outcome to the Hungarian Authority using nitrozamin@ogyei.gov.hu email address.

Furthermore, please also take into account guidance from national competent authorities given below for submission details (see Annex) as well as regarding the notification of product defects and recalls.

3. Step 3 Changes to the marketing authorization

3.1. When should any necessary variations be submitted?

The necessary variations for amendment of the quality dossier should also be submitted within 3 years (26.09.2022) to the RMS according to the usual channels (see Q/A 8 in “Questions and answers on “Information on nitrosamines for marketing authorisation holders”). Worksharing is highly recommended in all cases where the same variation applies to several national or MRP/DCP products.

 

Last updated: 2020.04.03 17:54