The new veterinary regulation (Regulation 2019/6) and its implications on regulatory submissions for veterinary medicinal products

The new veterinary regulation (NVR), Regulation 2019/6 applied to all EU Member States from 28 January 2022. The new legislation represents a significant change in how veterinary medicinal products are authorised, monitored and controlled in the EU.

The Regulation was developed in order to implement a fit-for-purpose veterinary legislation which would no longer be based on the equivalent human medicines authorisation system.

The legislation repeals Directive 2001/82/EC.

The changes are intended to:

  • reduce the administrative burden on companies and regulatory authorities
  • enhance the availability of veterinary medicinal products
  • stimulate innovation of new and existing medicines
  • strengthen the EU response to fight antimicrobial resistance.

The new Regulation 2019/6 is broken down into the following chapters:

I. Subject matter, scope and definitions

II. Marketing authorisations

III. Procedures for marketing authorisations

IV. Post marketing authorisation measures

V. Homeopathic veterinary medicinal products

VI. Manufacturing, import and export

VII. Supply and use

VIII. Inspections and controls

IX. Restriction sand penalties

X. Regulatory network

XII. Common and procedural provisions

XII. Transitional and final provisions

Here is a summary of some of the noteworthy regulatory changes that have been introduced in chapters II, III & IV of the new veterinary regulation:

Chapter II – Marketing Authorisations:

An MA for a veterinary medicinal product shall be valid for an unlimited period of time. Hence, there is no longer a requirement for a renewal procedure or the sunset clause.

Chapter III – Procedures for marketing authorisations

  • Decentralised Procedure:
    • Scope and timelines remain unchanged
    • Responsibilities of RMS, CMS and applicant have changed at some steps of the procedure. For example,
      – CMSs will also provide comments directly to the applicant at Day 100 and Day 145 instead of to the RMS only (therefore, comments are no longer anonymised).
      – at Day 100-105 and Day 145-150, the applicant will now compile and circulate the LoQs.
      – at Day 210, RMS will now be required to circulate a Final Assessment Report (FAR).
    • Possibility now for re-examination request by applicant according to Article 50 of the NVR. For further information on this change, note that CMDv have published a Best Practice Guide for Re-examination of RMS assessment report procedure.
  • Mutal Recognition Procedure:
    • Scope remains the same. However, a minimum of six months is required between the decision granting the national MA and submission of an application for a MRP.
    • 90 day procedure length remains unchanged but there are changes to some of the time-points in the procedure.
    • Responsibilities of RMS, CMS and applicant have changed at some steps of the procedure, similar to those outlined above for the DCP.
  • Centralised Procedure:
    • Scope of the mandatory use of the procedure has been widened. Refer to Article 42 (point no. 4) for details.
  • National Procedure:
    • No significant changes.
  • Subsequent Recognition Procedure (SRP):
    • Previously known as the “Repeat Use Procedure” is now officially recognised under Article 53 of the NVR.
    • Timelines and other requirements have been changed.

Due to the changes caused by the new regulation, CMDv have published updated guidance for DCP, MRP and SRP procedures:

https://www.hma.eu/veterinary-medicines/cmdv/procedural-guidance/applications-for-marketing-authorisation/authorisation-procedures.html

Chapter IV: Post marketing authorisation measures (Variations)

In terms of variations to marketing authorisations, one of the main changes arising from Regulation EU 2019/6 is that instead of the previous categories of Type IA, IB and II variations there will now only be two categories of variations:

  • Variations Not Requiring Assessment = VNRA
  • Variations Requiring Assessment = VRA

 

 

 

VNRAs consist of all the previous type IA and some Type IB variation categories.

VRAs will consist of most of the previous Type IB and all of the Type II variation categories.

Commission Regulation 1234/2008 will now no longer apply to veterinary medicinal products due to the introduction of new veterinary regulation (2019/6).

 Variations Not Requiring Assessment (VNRA)

The Implementing Regulation (EU) 2021/17*, includes a list of all variations not requiring assessment along with any associated conditions and documentation requirements and is published in the EU Official Journal here.

The variations are classified as follows:

  1. Administrative changes
  2. Changes to the quality part of the dossier
  3. Changes to the safety, efficacy and pharmacovigilance part of the dossier
  4. Changes to the vaccine antigen master file (VAMF) part of the dossier

VNRAs will be processed as follows:

  • The MAH will:

– Record the change in the Product Union Database (UPD) within 30 days of implementation including required documents (no application form is necessary).
– Documents submitted directly to UPD. No CESP submission. Documents include those listed in the Implementing Act as well as SPC, package leaflet, labels.

  • The relevant CA/RMS will

– Approve/reject the variation
– Inform MAH & CMS by recording decision in database and by e-mail

CMDv has written a Best Practice Guide for variations not requiring assessment in order to provide detailed guidance on the new process.

The EMA website includes a video tutorial showing how to submit a VNRA via the Union Product Database here.

Variations Requiring Assessment (VRA)

Every change not listed in the Implementing act mentioned above (2021/17)* will require a variation that needs to be assessed.

CMDv and EMA have written a new classification guideline for the VRAs:
Guidance on the details of the classification of variations requiring assessment according to Article 62 of Regulation (EMA/CMDv/7381/2021).

The format and categorisation is similar to the previous regulation which applied (Commission Regulation 1234/2008 ), however there are many differences.

The variations are divided into chapters as follows:

E. Administrative changes
F. Quality changes
G. Safety, Efficacy and Pharmacovigilance changes
H. VAMF or, PTMF changes
I. Changes of active substance(s), strength, pharmaceutical form, route of administration or food producing target species

Z-categories have also been included to address unlisted variations and VNRA, if requirements laid down in the Implementing Regulation are not met.

The timetable for VRAs is also outlined in the new guidance as follows:

  • a standard timetable, denoted by ‘S’ which will be 60 days
  • a reduced timetable, denoted by ‘R’ which will be 30 days
  • an extended timetable, denoted by ‘E’ which will be 90 days

For details on how to submit a VRA, CMDv have written a Best Practice Guide for Variations Requiring Assessment (EMA/CMDv/144277/2021). It has been prepared in order to facilitate the processing of VRAs for MRP/DCP products. The same general principles will apply to purely nationally authorised products.

Recommendation for the classification of variations not already listed

A procedure for requesting a recommendation for the classification of variations not already listed in either the above-mentioned Implementing Regulation or the EMA/CMDv Guidance on variations requiring assessment has also been established. This is similar to the previous CMDv recommendations for classification of unforeseen variations, according to Article 5 of Regulation 1234/2008.

Refer to CMDv new guideline for detailed advice this new process entitled: Procedural advice for requests for the classification of variations not already listed in Commission Implementing Regulation (EU) 2021/17 or EMA/CMDv Guidance on the details of the classification of variations requiring assessment according to Article 62 of Regulation 2019/6 (EMA/CMDv/144284/2021).

Worksharing and Grouping

Grouping and worksharing procedures do not apply to VNRA, they only apply to VRA.
As a consequence, no VNRAs can be included in a grouping or worksharing even if they are consequential or related to the VRAs included in the grouping or worksharing procedure.
However, the introduction section of CMDv Best Practice Guide for Variations Requiring Assessment (which also covers grouping), outlines the different approaches to follow when there is a need to co-ordinate changes that are related or consequential but are classified as VNRA and VRA.

The worksharing procedure is outlined in Article 65 of the NVR and it will be compulsory to follow this procedure, when the same change is being applied in different member states. Information related to worksharing is also mentioned in the CMDv BPG for Variations Requiring Assessment. However a specific guide on worksharing has also been written by CMDv: Best Practice Guide for Worksharing (EMA/CMDv/204024/2021).

Union Product Database

Due to the new regulation, the EMA has introduced new IT systems. The main one will be the Union Product Database (UPD).

It will contain information for all authorised veterinary medicines in the EU (including all nationally authorised products). For MAHs, it will provide self-service access for specific regulatory activities, including the management of variations that do not require assessment.

For more information on implementation, training, registration and access of the UPD, refer to the following link here on the EMA website.

The UPD will be linked to the other 3 other databases in the future. These databases are at different stages of development and introduction:

  • Union Pharmacovigilance Database

On 28 January 2022, the Union Pharmacovigilance Database (EVV) was successfully released. User guidance and the release notes are available here.

  • Manufacturing and Wholesale Distribution Database

The Manufacturers and Wholesale Distributors database (MWD) was released on 28 January 2022. The system is an enhanced and upgraded version of EudraGMDP, the EU database of manufacturing authorisations and certificates of good manufacturing practice, with changes affecting both the veterinary and the human domains. The MWD Project Group has also adopted requirements for aligning the GDP module with the change made to the system so far. Changes to the module will be delivered in a subsequent release scheduled for Q1 2022. In addition, enhanced search facilities on the GMP module will be delivered in the same release.

  • Database for the Collection of Data on Sales and Use of Antimicrobials in Animals.

IT development on the Collection of Antimicrobials Sales and Use Data (ASU) project started in January 2022. Information on the progress of this project will be published on the EMA website as this project develops.

Q&A on transitional arrangements

CMDv has prepared a Q&A document in order to assist both MAHs and NCAs in the management of the transition between the requirements of Directive 2001/82/EC and Regulation (EU) 2019/6. This Q&A document will be regularly updated and can be found under the following link.

This document includes an Annex which outlines how individual Member States will handle renewals of marketing authorisations after 28 January 2022.

Should you need any support with Veterinary Procedures feel free to contact us & the Ivowen team will be here to help.

Written by Claire Brown

When will DADI application forms replace the current eAFs?

The electronic application forms (eAFs) we are familiar with are in the process of being replaced later this year by a web based digital application form in a new eAF portal. The new eAF portal will look somewhat similar to the current IRIS portal.

This project, known as DADI (Digital Application Dataset Integration), is intended to be used for both CAP (Centrally Authorised Products) & NAP (Nationally Authorised Products) applications to make the future of form-filling and submission-handling more efficient at an EU level.

The Human medicinal product Variation application form will be the first to go live in DADI format. Every person involved in drafting an eAF will need to have an EMA account and user access. Companies who use consultants to prepare eAFs will need to make sure that they assign an EMA role to the consultant.

The next stages of DADI will cover the

  • Veterinary variation application form
  • Initial MAA form for Human and Veterinary products
  • Renewal form for Human and Veterinary products

 How will it work?

  1. The eAF will be filled in using the new eAF portal (via user interface).
  2. The user will then finalise the eAF by generating a PDF rendition
  3. This PDF version must still be included in the eCTD submission, as before.
  4. It will not be possible to submit the form directly from the eAF portal

 When will it happen?

As outlined in the EMA roadmap (link provided below) the two immediate key deliverables are as follows:

Key deliverables Go-Live Time Lines
Year Quarter
Launch of Human variations web-form (parallel use of old and new variation forms as part of a Transition period) 2022 Q4 (October)
Use of variation web form only 2023 Q2 (April)

It is important for all industry stake-holders to keep up to date with the development of these new web-based forms by consulting the EMA website for updates at the various launch stages.

Where can I find information?

  • DADI Network Project Webinar – 18/01/2022 – Live broadcast is available here.
  • The updated DADI roadmap, including key milestones, is available here.
  • The updated version of the DADI Questions and Answers documents is available here.
  • The “Common factors in the Fast Healthcare Interoperability Resources (FHIR) data standard for Art57(2) and eAF”documents are available in the following link.

The project will be implemented in phases, through a set of projects known as SPOR (Substances, Products, Organisations and Referentials) data management services for Human products. The Union Product Database will be the source of data for Veterinary products.

What is SPOR?

SPOR datasets Description of data types Status
Substance Management Services (SMS) Harmonised data and definitions to uniquely identify the ingredients and materials that constitute a medicinal product. Under Development
Product Management Services (PMS) Harmonised data and definitions to uniquely identify a medicinal product based on regulated information (e.g. marketing authorisation, packaging and medicinal information). Under Development
Organisations Management Services (OMS) Data comprising organisation name and location address, for organisations such as marketing authorisation holders, sponsors, regulatory authorities and manufacturers. Operational
Referentials Management Services (RMS) List of terms (controlled vocabularies) to describe attributes of products, e.g. lists of dosage forms, units of measurement and routes of administration. Operational

Once the above PMS and SMS are in place, pharmaceutical companies should start preparing to replace their current data submission format in Article 57 Database from the eXtended EudraVigilance Product Report Message (XEVPRM) format to the new ISO IDMP compatible format (HL7 FHIR). Webinars and training will be provided by EMA in due course.

 What do Marketing Authorisation Holders have to do at this stage?

  • Marketing authorisation holders need to check their data in SPOR (OMS) to ensure it is accurate and up to date. For CAPs the use of OMS data in the current eAF is already mandatory.
  • Marketing authorisation holders with authorised MA(s) need to check their data in Article 57 database (xEVMPD) to ensure it is accurate and up to date.

 Should you need any support at this stage in getting ready for the new Application Form format please feel free to contact us & the Ivowen team will be here to help.

Written by Marian Winder

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:

https://www.gov.uk/guidance/apply-for-a-licence-to-market-a-medicine-in-the-uk#national-procedure

https://www.gov.uk/guidance/guidance-note-on-new-assessment-routes

https://www.gov.uk/guidance/guidance-on-150-day-assessment-for-national-applications-for-medicines

https://services.intralinks.com/branding/3997623225/?clientID=3997623225

https://www.gov.uk/government/publications/mhra-fees

https://www.gov.uk/government/organisations/commission-on-human-medicines/about/membership

https://www.gov.uk/guidance/marketing-authorisation-application-submission-dates-for-150-days-national-and-european-commission-decision-reliance-procedures

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 ClinicalTrials.gov (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 CT.Submission@mhra.gov.uk once the result-related information has been uploaded to the public register and provide a link.

 

Pharmacovigilance

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: https://www.gov.uk/government/publications/guidance-on-pharmacovigilance-procedures-in-the-event-from-1-january-2021/updated-guidance-on-pharmacovigilance-procedures

 

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 https://www.gov.uk/government/publications/webinars-preparing-to-make-submissions-to-the-mhra-from-1-january-2021

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

  • Devices
  • Importing and Exporting
  • IT Systems
  • Paediatrics

IN DEPTH DETAILS ON THE NEW MHRA GUIDANCE CAN BE FOUND ON THE LINK BELOW:-

https://www.gov.uk/government/collections/mhra-post-transition-period-information

 

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

New pharmaceutical water quality guideline from February 2021

In 2018 the EMA had a public consultation (15th Nov 2018 – 15th May 2019) on draft guidance for industry on the pharmaceutical use of different grades of water in the manufacture of active substances and medicinal products. This consultation has resulted in an update to the old 2002 guidelines and the new guideline will come into effect from February 2021. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-water-pharmaceutical-use_en.pdf

Within the guideline, it is stated that the European Pharmacopoeia (Ph. Eur.) has set quality standards for three grades of water: water for injections (WFI), purified water and water for preparation of extracts. EMA also notes that potable water, while not covered by a pharmaceutical monograph, “is the prescribed source feed water for the production of pharmacopeial grade waters,” and must comply with the regulations on water intended for human consumption of a quality equivalent to that defined in Directive 98/83/EC or laid down by the competent authority.

The guideline itself provides recommendations for the minimum acceptable quality of water to be used for different uses and applications, including the manufacture of sterile and nonsterile medicinal products, active substances and water used for cleaning and rinsing equipment and container/closures for medicinal products.

The note for guidance has been updated to reflect the following changes in the European Pharmacopoeia:

  • revised monograph for Water for Injections (0169) allowing the possibility to use methods other than distillation for producing water of injectable quality (this change brings the Ph. Eur. more closely in line with the US Pharmacopeia and the Japanese Pharmacopoeia, allowing production of WFI by distillation or by a purification process proven “equivalent or superior to distillation”, and “by distillation or by reverse osmosis and/or ultrafiltration”, respectively);
  • new monograph for Water for preparation of extracts (2249);
  • suppression of the monograph for Water, highly purified (1927).

The guideline has also been updated to reflect current expectations for the minimum acceptable quality of water used in the manufacture of active substances and medicinal products for human and veterinary use.

The guideline can be read in conjunction with the questions and answers on production of water for injections by non-distillation methods – reverse osmosis and biofilms and control strategies https://www.ema.europa.eu/en/documents/other/questions-answers-production-water-injections-non-distillation-methods-reverse-osmosis-biofilms_en.pdf and the comments received on the draft guideline https://www.ema.europa.eu/en/documents/comments/overview-comments-received-draft-guideline-quality-water-pharmaceutical-use-ema/chmp/cvmp/qwp/496873/2018_en.pdf

Written by Emily Fletcher

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.

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.

Background:

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:

https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Advice_from_CMDh/CMDh_404_2019_Rev.0_2019_09_-_Nitrosamines_-_Information_on_nitrosamines_for_MAHs_.pdf

For Centrally Authorised Products refer to:

https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-information-nitrosamines-marketing-authorisation-holders_en.pdf

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:

https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-information-nitrosamines-marketing-authorisation_en.pdf

https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Advice_from_CMDh/CMDh_400_2019_Rev_1_09_2019_clean_-_Q_A_on_sartans_referral.pdf

For Centrally Authorised Products refer to:

https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-information-nitrosamines-marketing-authorisation_en.pdf

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.

Templates:

MAHs must test in accordance to

https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Advice_from_CMDh/Nitrosamins/CMDh_412_2019_Rev.2_2019_12_clean_-_PG_to_MAHs_on_nitrosamines.pdf and report the results to the relevant National Competent Authority using the Templates on:

https://www.hma.eu/226.html

https://www.ema.europa.eu/en/search/search?search_api_views_fulltext=nitrosamine

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

2019 – What a year

Ivowen attended the Medicines for Europe conference in January (Regulatory and Pharmacovigilance), the annual EuDRAcon conference in May, exhibited at TOPRA in October and joined our clients from around the world at CPhI in November.

We all saw Brexit come and go, Twice !! We wait to see what lies in store for the next deadline in January 2020.

The FMD came into effect across Europe in February in most member states.

Bulgaria joined CESP, eCTD became mandatory for all human procedures, lots of new guidance was published (to keep us all on our toes) and Nitrosamines in medicinal products moved to the top of everyone’s agenda.

With the festive season now upon us and 2020 on the horizon, Ivowen are setting our sights on the year ahead.

We will be attending the Medicines for Europe conference in January 2020 (Regulatory and Pharmacovigilance) and we encourage you to contact us before mid-January with any specific questions you might like us to ‘ask the regulators’. This is a great opportunity to ask those difficult questions that you just could not get a straight answer to in 2019, on the ever present grey areas of Regulatory procedures.

To help you to plan ahead here are some helpful updates, in brief, as full articles will be posted in 2020:

Falsified Medicines Directive – Where we are now:

  • Implemented on 9th Feb 2019 in all MS except Greece, Italy and Belgium
  • The European Commission has produced a video to explain more about the safety features.
  • The HPRA have extended the use and learn period, initially to Sep 2019 and extended it again to end on a phased basis starting from 31st January 2020.
  • The MHRA is also taking a pragmatic, flexible approach to how they enforce the new legal requirements.

Nitrosamines

 

Ivowen are here to assist you in 2020 and will continue to provide the top quality service you have come to expect from us.

For more information on Ivowen’s services and how we can help you, contact us.

Written by Alice D’Alton.

Are you interested in online training??

In an ever changing and at times a fast paced environment the world of pharmaceuticals demands cohesion and understanding across the board, to allow growth and success in any business either directly or indirectly involved with it. With regulations and guidelines becoming more stringent and extensive along with constant revisions and updates of the same it can be hard to keep up. It is important that you and your colleagues have an understanding of these guidelines that relate to the work that you do to ensure safety of patients and company compliance.

In certain instances guidelines and recommendations are hundreds of pages long and differ between countries, this places huge time pressure on individuals and businesses to keep up to date and often a brief read over them leaves people feeling a little confused and sometimes without even a basic understanding as to what actually needs to be done.

IVOWEN are here to help you gain a better understanding of, and, confidence in, current guidelines and technical updates. Ivowen has always offered training in many areas of pharmaceuticals but are now looking at providing these training sessions online to help our clients to gain a higher level of expertise through easier access.

We would be very grateful if you could complete the online survey we have created to help us assess how the online training sector can benefit our clients.

It takes less than 3 minutes to complete and would help us immensely:

https://ivowen.typeform.com/to/drre5H

Thank you for your feedback.

Don’t get too busy to keep up to date!

 

“No company can afford not to move forward. It may be at the top of the heap today but at the bottom of the heap tomorrow, if it doesn’t.”

— James Cash Penney, founder, JC Penney

Written by Emily Fletcher

Ivowen attended TOPRA Symposium 2019

This year’s TOPRA Annual Symposium was held in Dublin in October. The Annual Symposium is an essential meeting for regulatory professionals to gain both an understanding of current and evolving regulatory requirements, as well as insights into future plans for regulations in the Human medicines, Veterinary medicines and Medical Device sectors.

Three members of our Team attended the Symposium this year, Majella Ryan, Alice D’Alton and Nanda Naik. This year was particularly satisfying for Ivowen as we had an exhibition stand at the three day event.

As well as exhibiting, Ivowen attended the sessions including ‘Life after Brexit’. This session was a live discussion of predictions and concerns about the possible outcome of ongoing negotiations with the EU.

Now that an extension has been granted, which will delay the UK exit until January 2020, we are left wondering if we will finally know the UK position when Ivowen attend the Medicines for Europe regulatory conference being held in Amsterdam on 29th – 31st January.

In the meantime, we await instruction from the regulators on whether UK will still be available on the CESP portal later this week. Ivowen is registered on the new MHRA submissions portal so either way we have you covered.

Ivowen will keep you up to date in the coming days and weeks

Please contact us, Ivowen are dedicated to keeping you up to date with the latest regulatory updates and innovations. We remain at your disposal to assist in all of your regulatory endeavours today and into the future.

Written by Alice D’Alton.