Back to Basics – The Risk Management Plan (RMP)

The Risk Management Plan (RMP) documents the risk management system considered necessary to identify, characterise and minimise a medicinal product’s important risks.

The RMP should be updated throughout the life cycle of the product, for example;

  • if there is a change in the list of the safety concerns
  • when there is a significant change in the existing additional pharmacovigilance activities
  • if an emerging safety issue is confirmed.

The RMP should be assigned a new RMP version number and a date each time it is updated and submitted for assessment.

An updated RMP can be submitted as a standalone [currently C.I.11] variation, when necessary, but it is most often submitted as a consequence of or part of another variation.

The format and content of the RMP should follow the RMP template; Guidance on the format of the risk management plan (RMP) in the EU – in integrated format which consists of seven parts.

For a generic medicinal product, hybrid products and/or fixed combination products with no new active substance the safety concerns should be aligned to those of the originator product that are available;

  • either from the originator’s approved RMP
  • or from the list of safety concerns of the substance published on the CMDh website.

RMPs are approved per each medicinal product, not per MAH, therefore only one RMP should be submitted for an MRP or DCP with different MAHs. The RMP must remain identical in RMS/all CMS throughout the product life cycle.

The RMP should be provided in eCTD section 1.8.2. To facilitate the assessment a ‘tracked changes’ version of the RMP, in Microsoft word, should also be provided in the ‘working-documents’ folder outside eCTD.

The QPPV’s actual signature or the evidence that the RMP was reviewed and approved by the QPPV should be included in the finalised approved version of the document; for eCTD submissions this would be the RMP submitted with the last eCTD sequence of the procedure (usually the closing sequence).

UK RMP: The MHRA states you can either submit a GB/UK RMP or use the approved EU RMP with the GB/UK specific annex attached. Further information of UK RMP can be found on the MHRA website and their Guidance note on good pharmacovigilance practices.

Feel free to contact us here at ERA to assist you with all things regulatory in Ireland, UK and across the EU.

We take the pain out of regulatory so that you can take your medicine to the next level.

Written by

Fiona Downey

Fiona Downey 1

Fiona Downey 1

Applying for Marketing Authorisation via national route or DCP procedure in Ireland – HPRA slot booking

The HPRA is now moving towards a system of slot allocation (expected submission dates) for new national product registration applications, in addition to the existing DCP slot requirement.

Upon request, applicants will be given a submission slot in an agreed month.

This will help capacity planning for timely assessment of applications and will help maintain access for products on the Irish and European markets.

Slot-booking for national product authorisation applications

Applicants should contact no later than two months before their preferred submission date to request their preferred slot. The email subject title should include ‘National MA submission’.

The following documents should be provided when requesting a slot.

  • A CMDh common request form for reference Member States (RMS) which is available on the CMDh website.
  • A justification of the relevance of the application to the Irish market.
    • This should make reference to the unmet medical need your product will address and you may be asked if you intend to market the product in Ireland as part of your justification for applying to HPRA.

It is important that dossiers are complete before making a request, as delayed submissions may result in the loss of a slot.

If your preferred slot is not available, the next available slot will be allocated within a six-month window. Applicants will receive an email confirmation of a successful slot booking. While the HPRA are adapting to this new process we will try to facilitate applications which require an earlier start date.

Slot-booking for DCP authorisations

If you would like the HPRA to function as an RMS, please contact at least three months before your preferred submission date to request your preferred slot. The email subject title should include ‘DCP submission’.

When requesting a DCP slot applicants should also provide the completed CMDh common request form for an RMS.

Again, It is important that dossiers are complete before making a request, as delayed submissions may result in the loss of a slot.

If your preferred slot is not available, the next available slot will be allocated, within a two-year window. Applicants will receive an email confirmation of a successful slot booking. The HPRA also operates a cancellation list for slots which become available at short notice.

Scientific advice

Due to the complexities of Article 10a applications, applicants should obtain national scientific advice before submitting requests for such new applications. Further information can be found on our national scientific and regulatory advice page.

Ireland as a CMS

Furthermore, IE routinely participates as a Concerned Member State (CMS) in standard DCP procedures. A zero-day procedure as a CMS may be possible for medicines where Ireland is experiencing a critical shortage of a particular medicine.

Need support

Feel free to contact us here at ERA to assist you with all things regulatory in Ireland, UK and across the EU.

We take the pain out of regulatory so that you can take your medicine to the next level.

Written by

Alice D’Alton

Alice Dalton 1

Alice Dalton 1


UK Updates – Windsor Framework and Regulation (EU) 2023/1182 for Centralised Products

What it means for your company

  • Batches of medicinal product, authorised through the centralised procedure (CAP), that are currently lawfully on the market in Northern Ireland may remain so until their Expiry Date
    • However, these medicinal products cannot be moved from Northern Ireland to an EU/EEA Member State or be placed on the market in an EU/EEA Member State.
  • No new batches of authorised CAPs can be released on the market in Northern Ireland after Regulation (EU) 2023/1182 becomes applicable (01Jan2025)
    • Therefore the release of CAP medicinal product by your Qualified Person (QP) has to be planned accordingly and cannot be performed after this date.
  • It is recommended that companies and MAH’s anticipate any potential issues and resolve them in the next 8 months.
  • There is no possibility of multi-country packs for CAPs between Northern Ireland and any other EU/EEA member state after the regulation becomes applicable.
    • Any medicines placed on, or who are currently on the market before this happens may remain so until the expiry date is reached.
  • The product information (PI) of the CAPs will no longer require the mention of a local representative in Northern Ireland after the regulation becomes applicable.
    • The PI can be amended by way of an article 61(3) if no regulatory procedure is planned within 36 months.
    • This change should be made at the earliest opportunity.
    • The Q&As to stakeholders states ‘Additionally, it is also acceptable to request the deletion of the local representative for Northern Ireland in any regulatory procedure affecting the Annexes of the Marketing Authorisation submitted after 1 July 2024, provided that this change is only implemented after the date that Regulation (EU) 2023/1182 becomes applicable.’

Do you have a product that this may affect? There are lots of tasks that need to be done if so and these should begin this quarter!

The Legal Jargon behind it all

The Windsor Framework is a legal agreement between the European Union and the United Kingdom that was announced on February 27, 2023. It is a political declaration and a series of legal documents reached by the UK and EU in the Withdrawal Agreement Joint Committee. It covers topics such as trade, goods, services, sanitary and phytosanitary measures, and the democratic consent mechanism. The Framework was formally adopted by both parties on March 24, 2023, and came into effect on October 1, 2023.

Regulation (EU) 2023/1182 is a legal document that was passed by the European Parliament and the Council on June 14, 2023. It contains specific rules relating to medicinal products for human use intended to be placed on the market in Northern Ireland and amends Directive 2001/83/EC. The regulation is aimed at ensuring that medicinal products placed on the market in Northern Ireland comply with the provisions of Union law. This has resulted in increased costs and red tape for GB-based pharmaceutical manufacturers and suppliers who are required to meet EU testing and labelling requirements in addition to UK rules.

Regulation (EU) 2023/1182 came into force on June 20, 2023 1. However, it is not applicable until January 1, 2025, provided that the UK has provided the written guarantees referred to in Article 8 of that Regulation.

This can impact centralised procedures (CAPs) as medicines can now only be placed on the market in Northern Ireland if authorised by the UK authorities in accordance with the law of the United Kingdom and under the terms of the authorisation granted by them.

Pursuant to Article 13 of Regulation (EU) 2023/1182, Article 5a of Directive 2001/83/EC is deleted with effect from the date on which the Regulation becomes applicable (01Jan2025). Article 5a allowed for the medicinal products to be temporarily authorised to supply to in Northern Ireland of a medicinal product belonging to the categories referred to in Article 3(1) and (2) of Regulation (EC) No 726/2004 provided that certain conditions were fulfilled.

If you need assistance with any of the above, contact us.

Written by

Emily Fletcher

Emily Fletcher 1

Emily Fletcher 1

UK updates to your Medicine – Windsor Framework and Regulation (EU) 2023/1182

Initially this is what you need to know:

  • From the implementation of the Windsor Framework on 1 January 2025, the MHRA will regulate medicines across a UK-wide licensing regime.
  • Most new Marketing Authorisation Applications (MAAs) will be granted as PL licences covering the whole of the UK.
  • The MA number will have just a PL prefix (as it was before Brexit).

No action is necessary for this conversion for Marketing Authorisation Holders who only hold a PLGB licence for a particular product.

  • If a MAH currently holds both a PLNI and a PLGB for the same product and wishes to retain UK-wide authorisation, the PLNI will need to be cancelled in order for the existing PLGB to be converted to a PL.

Where an MAH only holds a PLNI and subsequently seeks authorisation for the whole of the UK, the PLNI will need to be cancelled prior to the granting of the PL.

MAHs involved in EU procedures, with NI included as a CMS, will need to notify the RMS to withdraw NI as a CMS from the procedure. This must occur before the cancellation of the PLNI and the granting of the new PL.

  • UK Only’ is required to be printed on the UK packaging from 01Jan2025, a sticker is allowed to be placed on packaging for a period of 6 months (until 30June2025) but this must be replaced with direct printing on the packaging after this.
  • And from 1 January 2025, the EU Falsified Medicines Directive (FMD) will no longer apply in Northern Ireland.
  • From 1 January features included for the purposes of compliance with EU FMD requirements may be removed or covered.

MHRA Overview:

Current position From 1 January 2025 Action required from MAHs
New MAA for product in scope of the Centrally Authorised Procedure GB: national applications, reliance/recognition applications, PL

EC no longer able to authorise for NI.

For products entering the market from 1 January 2025, MAHs may apply for PL licences only. Must comply with labelling and packaging requirements.
New MAA for product in scope of the Centrally Authorised Procedure NI: EC authorisation.
Supply of GB authorised products may be permitted through routes, e.g., NIMAR, Reg 174, Reg 167.

EC no longer able to authorise for NI.

For products entering the market from 1 January 2025, MAHs may apply for PL licences only. Must comply with labelling and packaging requirements.
New MAA for Non-CAP product authorisations UK-wide authorisation or option to apply for PLGB or PLNI PL


PLNI through the MRP/DCP

For products entering the market from 1 January 2025, MAHs may apply for PL licences or PLNI only if using the MRP/DCP. Must comply with labelling and packaging requirements.
Products with existing authorisations granted before 1 January 2025. UK-wide licence PL Must comply with labelling and packaging requirements.
Products with existing authorisations granted before 1 January 2025. Separate PLGB and PLNI for the same product. Option A:

PL only

By 30 September 2024 the MAH should request that the MHRA cancel the PLNI, effective on 31 December 2024. PLGB licences will convert to PL by 1 January 2025.

Must comply with labelling and packaging requirements.

Products with existing authorisations granted before 1 January 2025. Separate PLGB and PLNI for the same product. Option B:

Retain NI only through the MRP/DCP.

No action required from MAH.

PLGB will be cancelled by the MHRA on 31 December 2024 as cannot hold a PL and PLNI simultaneously for the same product.

Must comply with labelling and packaging requirements.

Products with existing authorisations granted before 1 January 2025. PLNI through the MRP/DCP, with no PLGB for the same product. PLNI through the MRP/DCP only. Where a MAH subsequently applies for a PL, the PLNI will need to be cancelled prior to the granting of the PL. The MAH should inform the RMS of its intention to withdraw NI as a CMS from the MRP/DCP.

Must comply with labelling and packaging requirements.

Products with existing authorisations granted before 1 January 2025. PLGB only PL only No action required from MAH.

PLGBs will be converted to PL by 1 Jan 2025.

Must comply with labelling and packaging requirements.

CAP Bridging Mechanism Permits supply of GB-licensed product in NI for up to 6 months if no equivalent available. Not applicable as the MHRA will license novel/CAP medicines in NI through a UK-wide licensing route. Not applicable.
Existing Stock in Existing Packaging on the market Continues as currently. Can continue to be supplied to patients until the product’s date of expiry in the territory for which the product was valid for supply prior to 1 Jan 2025. Not applicable.

More on Windsor Framework in the weeks to come……

If you need any help to navigate this new min field of UK updates, don’t hesitate to contact us for support.

Written by

Emily Fletcher

Emily Fletcher 1

Emily Fletcher 1

New UK National Procedure – Expedited 150 day procedure

There are now several routes to obtain a marketing authorisation in the United Kingdom (UK), Great Britain (England, Scotland and Wales) or Northern Ireland. The options available will be determined by the intended market and the type of application. In this article we will discuss the purely National procedure.

To help you to decide what type of license you will require, here is a brief explanation of the new types of MA you can obtain:

MA prefix for UK Possible MA types Territory Leg & Guidance
PL UK wide Authorised for use in United Kingdom (Great Britain & Northern Ireland) EU & MHRA rules apply
PLGB GB Authorised for use in Great Britain only (England, Scotland and Wales only) MHRA rules apply
PLNI NI Authorised for use in Northern Ireland only EU rules apply

One option you can pursue is the National procedure (a 150-day procedure) to obtain a marketing authorisation (MA) in the UK, Great Britain or/in Northern Ireland. The MHRA has introduced this accelerated procedure aimed at expediting the availability of medicines for patients in the UK and proposes to reach its opinion on marketing authorisation applications (MAAs) within 150 days of filing an application (excluding the time taken to provide further information or data required).

Applications should be submitted via the MHRA Submission Portal, and the appropriate national fee will apply.

The accelerated assessment is available for all high-quality new MAAs for both new, and existing active substances, as well as orphan designations. Interested applicants should contact the MHRA in advance of submitting the application.

For medicines containing new active substances or biosimilar products, the MHRA encourages applicants to provide a summary of the dossier to share their intentions and to verify the new active substance status.

The pre-submission meeting offers the opportunity to discuss the arrangements for the UK Compliance Check (CC) on Paediatric Investigation Plans (PIPs). Additionally, it also offers the opportunity to enhance joint discussion with National Institute for Health and Care Excellence (NICE) Health Technology Assessment (HTA) evaluation process.

The MHRA will operate a ‘fixed submission date’ system to facilitate consultation with the Commission on Human Medicines (CHM) and will publish a set of dates to facilitate planning the submissions to coordinate with appropriate meeting dates of CHM. The submission slots will be linked to the dates of CHM meetings.

The assessment timetable will begin after the validation of the application. The assessment process will run in two phases totalling 150 days like so:

  • Phase I: completed 80 days after the clock starts. Issues that arose or requiring clarification from the initial assessment will be raised with the applicant and should be addressed within the clock off period of 60 days.
  • Phase II: commence on receipt of the applicant’s responses. The MHRA will provide a decision on the acceptability of the product by day 150.

If the MHRA refuses to grant the MA-based on advice from CHM, there is an opportunity for the applicant to request a review of the decision.

The conclusion of the assessment will lead to the publication of a UK Public Assessment Report for the product.

Here are some useful links to obtain further information:

If you need any clarification or support to help you to navigate the new post Brexit procedures, please contact us and Ivowen will gladly assist you in a timely manner.

BREXIT – MHRA post-transition period information

The UK has left the EU and the transition period after Brexit comes to an end this year.

The MHRA have issued new guidance for industry and organisations effective from 01st January 2021.  From this date the MHRA will be the UK’s standalone medicines and medical devices regulator.

Areas covered in the new guidance include:

Clinical Trials

From 1 January 2021, for registering clinical trials, existing and established international registers will still be used, such as ISRCTN registry (UK), or (USA), to ensure the public is aware of your trial. For trials involving both UK and EU sites a record in the EU Clinical Trials Register will exist (other than adult Phase 1 studies).  In the UK, any favourable opinion given by a research ethics committee is subject to the condition that the clinical trial is registered on a publicly accessible database. The time frame for publishing the summary of results is within 6 months of the end of trial for paediatric clinical trials or within one year of the end of trial for non-paediatric clinical trials. You do not need to submit this clinical trial summary report to the MHRA as well; however, you must send a short confirmatory email to once the result-related information has been uploaded to the public register and provide a link.



Guidance on qualified person responsible for pharmacovigilance (QPPV) including pharmacovigilance system master files (PSMF) from 1 January 2021

From 1 January 2021, the following legal obligations will apply to holders of UK marketing authorisations (MA). These include those that cover the whole of the UK, or are specific to Northern Ireland or to Great Britain (England, Wales and Scotland):

  • To operate a pharmacovigilance system for UK authorised products.
  • To have an appropriately qualified person responsible for pharmacovigilance (QPPV) that resides and operates in the EU or the UK and is responsible for the establishment and maintenance of the pharmacovigilance system for UK authorised products.
  • To maintain and make available upon request a pharmacovigilance system master file (PSMF) that describes the pharmacovigilance system for UK authorised products. The PSMF must be accessible electronically or physically from the UK at the same site at which reports of suspected adverse reaction may be accessed.

Statutory guidance concerning the QPPV for UK authorised products is described in the Good Pharmacovigilance Practices (GVP) Module I. This guidance will be supplemented by the ‘Exceptions and modifications to the EU guidance on good pharmacovigilance practices that apply to UK marketing authorisation holders’, which will be published in due course.

Updated guidance on pharmacovigilance procedures

Detailed guidance on pharmacovigilance procedures from 1 January 2021 is published on the MHRA website:


Marketing Authorisations

New guidelines have been outlined for Marketing Authorisations, to include Conditional MAs, registering new packaging information, guidance on the handling of applications for Centrally Authorised Products (CAPs),  Article 29 applications, converting parallel distribution notices to UK parallel import licences, handling of ASMFs and CoS from January 2021, reference medicinal products, converting CAPs to UK MAs, guidance on licencing biosimilars, bioequivalence/therapeutic equivalence studies and renewing marketing authorisations.

 New Submission Registrations

For planned applications for submission to the UK (for example, a Marketing Authorisation for the UK market), you will need to submit the information through the MHRA national portals.

All current Eudravigilance Gateway users who wish to gain access to the new MHRA Gateway will need to first gain access to MHRA Submissions. The steps for gaining MHRA Gateway access are contained within MHRA Submissions.  MHRA Submissions will not be used to send or receive ICSRs.

A useful webinar on how to gain access to MHRA submissions portal is available on the MHRA website at the following link

Within the recent MHRA guidelines, the following areas are also covered:

  • Devices
  • Importing and Exporting
  • IT Systems
  • Paediatrics



If you need any clarification or support to help you to navigate the end of transition period please contact us and Ivowen will gladly assist you in a timely manner.


Written by Mary Canning


BREXIT – No extension to the transition period

It seems that Brexit is on course for 1st January 2021….

The 30th June 2020 came and the legal deadline for agreeing to an extension of the transition period has passed with no request from the UK. Therefore the Brexit trade deal transition phase will come to an end on the 31st December 2020. At this stage there will be one of two possible outcomes: Brexit image 22 07 20 3 The next important dates are the 15-16th October (European Council Meeting) and 26th November (penultimate plenary session of 2020. European lawmakers have stated that a trade deal must be negotiated, checked, translated and presented to the European Parliament by this date if the transition period is to end by 31 December 2020). If the UK exits without a trade deal, trade between the UK and EU will change immediately on the 1st January 2021 (i.e. Hard Brexit).

The European Commission (EC), European Medicines Agency (EMA) and Heads of Medicines Agencies (HMA) have recently reminded clinical trial sponsors that they must comply with EU clinical trial rules following the Brexit transition period that expires on 31 December 2020

The UK Government launched a major new public information campaign to give everyone the facts that they will need to be ready for 1 January 2021. A straightforward checker tool at will help identify some of the specific steps any business or individual needs to take to be ready, and will allow companies to sign up for bespoke updates.

To keep up to date with all EMA advice on Brexit please refer to the following:

For more detailed information about how 2020 currently looks with regard to Brexit please see:

If you require any assistance for UK products please contact us:

Written by Emily Fletcher

Emily Fletcher

Emily Flecther


European Procedural Guidance during COVID-19 Pandemic

In response to the significant impact the COVID-19 pandemic is having on European regulatory activity, the European Commission, the European Medicines Agency and the Heads of Medicines Agencies network (EC, EMA and HMA, respectively) have approved a number of measures to help the management of marketing authorisations for human medicinal products considered crucial during the pandemic period.

The objective of these measures agreed at European level is to promote regulatory flexibility, facilitate, simplify and accelerate the administrative procedures, as far as possible, in order to respond more efficiently to emerging needs during this period.

As a result, the EC recently published questions and answers on regulatory expectations for medicinal products for human use during the COVID-19 pandemic:

Questions and Answers on Regulatory Expectations for Medicinal Products for Human Use during the COVID-19 Pandemic

This Q & A document which provides guidance to marketing authorisation holders (MAH) includes the following topics:

  • renewal applications
  • sunset clause
  • an exceptional change management process (ECMP) for crucial medicines for use in COVID-19 patients
  • circumstances under which the validity GMP certificates and authorisations to manufacture/import can be extended
  • circumstances under which the validity GDP certificates and wholesale authorisations can be extended
  • adaptions to the work of a Qualified Person (QP)
  • the possibility of adapting quality requirements for medicines intended to be used for the treatment of COVID-19 patients
  • the impact on reporting into EudraVigilance of Individual Case Safety Reports (ICSRs)
  • flexibility in the labelling and packaging requirements to facilitate the movement of medicinal products within the EU

Further to the European Commission’s Q&A document, the CMDh has agreed additional questions and answers that provide practical information on how to specifically address and apply the provisions determined by the European Commission for MR/DC procedures:

Practical Guidance of the CMDh for facilitating the Handling of Processes during the COVID-19 Crisis

The CMDh document addresses issues such as the impact of COVID-19 on assessment timelines, how to use the ECMP procedure (which is only applicable for products that are crucial for the treatment of COVID-19 patients) and QP declarations based on a desktop audits. It also includes a useful annex that details Member States’ email addresses and links to relevant published guidance on MS websites.

Both documents will be updated and supplemented with additional information, as appropriate during the pandemic.

Everyone at Ivowen is working tirelessly to keep our clients applications on track. We are liaising with the National Competent Authorities all the time to ensure we avoid delays and get the best results possible in these unprecedented times.

If you need any assistance in this regard please don’t hesitate to contact us.








Written by Claire Brown.

How to get an Assessor’s opinion before you contact the Competent Authorities

Firstly, in this very unusual time for us all I want to let you know that our dedicated team are all healthy, safe and working from home, business as usual, to ensure that we continue to provide you with the high quality and efficient service you have come to expect from Ivowen.

Have you ever wished you could get the opinion of an Assessor before you go to the National Competent Authorities with your queries? 

Well, I am delighted to introduce you to to our newest team member Claire Brown.

Claire has come directly to Ivowen from the Health Products Regulatory Authority (HPRA) and brings with her a wealth of experience as a pharmaceutical assessor of human medicinal products. Claire has been part of the team here in Ivowen since 2019 and has more than 12 years experience working in the HPRA. She started there as a Scientific Officer working mostly on veterinary medicinal products and was promoted to Pharmaceutical Assessor after 3 years.

Claire completed her undergraduate work in Chemistry and her postgraduate work in Neuropharmacology and Industrial Pharmaceutical Science.

Claire adds her extensive experience to our knowledgeable team so that we can enhance the services we provide to you and continue to give you an ‘Assessor’s eye’ opinion on your applications before you submit them.

I invite you to visit our updated Meet the Team page to see all the talented people who enable us to guide you through all aspects of regulatory strategy, dossier preparation, MA submissions through to national phase, post-approval variations, product development, quality overviews, medical devices and much much more.

If you could use some assistance to navigate the complex world of regulatory, please feel free to contact us for further information.

Written by Alice D’Alton.

Alice Dalton

Nitrosamines and responsibilities of MAHs – Deadline is approaching

As an MAH, do any of your authorised human medicinal products contain chemically synthesised active substances? If so, read the following to identify what your responsibilities are with regard to reporting results of risk analysis to the appropriate Competent Authorities by 26 March 2020 deadline.

On 20th December 2019, the EMA published a Q & A on the document entitled ‘Information on nitrosamines for MAHs’ which includes new and updated information. This Q & A document should be read in conjunction with the document Information on nitrosamines for marketing authorisation holders (dated Sept 2019).

Further information for companies in relation to centrally and non-centrally authorised medicines is available from the EMA website and CMDh website.


In June 2018, authorities in the EU became aware of the presence of a nitrosamine, N-nitrosodimethylamine (NDMA), in valsartan from one manufacturer of active pharmaceutical ingredients (APIs). Subsequently another nitrosamine, N-nitrosodiethylamine (NDEA), was detected and other sartans from more API manufacturers were later implicated.

NDMA and NDEA are classified as probable human carcinogens (substances that could cause cancer) and their presence in sartans was, at the time, unexpected.

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 Article 31 review of sartans identified a number of root causes of nitrosamine formation and contamination.

A review was performed which indicated 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.

While 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, it is now known that these impurities can form during production under certain conditions and when certain solvents, reagents and other raw materials are used. In addition, impurities can be carried over during the manufacturing process when using already-contaminated equipment or reagents.

Responsibilities of MAH: 

Despite the low risk of nitrosamines being present, Marketing Authorisation Holders (MAHs) are asked to take precautionary measures to mitigate the risk of nitrosamine formation or presence during the manufacture of ALL authorised human medicinal products containing chemically synthesised APIs  including generics and over-the counter (OTC) products. However, in view of the large number of authorised products, MAHs should use a risk-based approach and prioritize their evaluations and confirmatory testing.

The EMA’s human medicines committee (CHMP) requested in September 2019 that MAHs for human medicines containing chemically synthesised active substances, review their medicines for the possible presence of nitrosamines and test all products at risk.

It is the responsibility of MAHs to work closely with the manufacturers of APIs and finished products to perform risk evaluation and report this to the Competent Authorities where the products are authorised within 6 months of the guideline on “Information on nitrosamines for marketing authorisation holders”. This guideline was published on 26 September 2019, thus MAHs should supply complete risk evaluations to the respective Competent Authorities by 26 March 2020.

In summary MAHs must perform the following steps:

Step 1: Risk Evaluation

MAH’s should perform risk analysis of their medicinal products containing chemically synthesised API. The MAHs should prioritise products in order to establish the sequence in which their products are to be evaluated. The factors to be taken into account are outlined in the dedicated Q&A document on the EMA & CMDh websites. For products of high priority the risk evaluation should be done immediately. The risk evaluation of all products should be concluded at the latest with 6 months of the publication of Information on Nitrosamines for Marketing Authorisation Holders.

If a risk of presence of nitrosamine is identified as a result of the evaluation, the MAH should proceed to step 2 below.

After the individual risk evaluation is finished send the appropriate template for the outcomes of “no risk identified” or “risk identified” including the required email headings and details. The guidance given by the relevant national competent authorities’ website also has to be regarded, refer to Annex 1 in CMDh practical guidance for MAH of nationally authorised products (including MRP/DCP in relation to Art. 5 (3) Referral for Nitrosamines.

For MRP/DCP Products refer to:

For Centrally Authorised Products refer to:

It is also very useful to refer to the Question & Answer Documents and the templates on the following links:

For MRP/DCP Products refer to:

For Centrally Authorised Products refer to:

Step 2: Conformity Testing

If the presence of nitrosamine is identified as a result of the risk evaluation, confirmatory testing should be carried out using appropriately validated and sensitive methods. 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 Marketing Authorisations should be concluded within 3 years (by 26/02/2022) of the publication of Information on Nitrosamines for Marketing Authorisation Holders or at an earlier time if otherwise justified.

MAHs should inform the relevant Competent Authorities immediately if tests confirm the presence of nitrosamines impurity irrespective of the amount detected.


MAHs must test in accordance to and report the results to the relevant National Competent Authority using the Templates on:

Step 3: Changes to the Marketing Authorisation

MAHs should apply for a variation in a timely manner to introduce any required changes, such as amendment to the manufacturing process or changes to product specifications.

Refer to Templates on the EMA and CMDh websites to report results to the relevant Competent Authorities. It is also advised to view the relevant Competent Authorities websites to view national requirements on submitting this information.

If you need any clarification or support to help implement the responsibilities of a MAH with regard to Nitrosamines reporting contact us and we will gladly assist you in a timely manner.

Written by