The European Medicines Agency (“EMA”) has released a Practical Guidance concerning the steps that centralised Market Authorisation Holders (“MAH”) will be required to take should the United Kingdom (“UK”) become a third country to the EU on 29 March 2019. The Practical Guidance also makes reference to a list of Questions and Answers drafted by the EMA jointly with the European Commission which is intended to help better understand the necessary changes that MAHs may need to make.
The Practical Guidance responds to a number of detailed procedural issues in a series of nine questions and provides directions that MAHs will need to follow to make preparations for Brexit. The Practical Guidance provides some clarity concerning procedural questions such as in relation to transfers of marketing authorisations, transfer of sponsors, and changes to the Qualified person for Pharmacovigilance (“QPPV”) and the Pharmacovigilance System Master File (“PSMF”).
Subject to the outcome of the Brexit negotiations, preparations and changes will need to be fully implemented and completed before 29 March 2019, the anticipated date for Brexit.
Transfer of marketing authorisation
Article 2 of Regulation (EC) No 726/2004 on medicinal products provides that the MAH must be “established in the Union”. If Brexit occurs on 29 March 2019, the UK will no longer be a part of the European Economic Area (the “EEA”). MAHs established in the UK will no longer have valid EU marketing authorisations. Prior to this date, they will, consequently, be required to either, apply for a transfer of their existing marketing authorisation to an establishment in one of the remaining countries of the EEA or, license the product to a third party established in one of the remaining countries of the EEA.
New MAHs within the EEA will be required to provide proof of establishment. This proof must be issued in accordance with the national provisions of the EEA country in which they are established. The transfer of the marketing authorisation must be fully completed and implemented before 29 March 2019.
A single transfer application in relation to several UK marketing authorisations will not be possible. A separate transfer application must be submitted for each marketing authorisation. This will be the case even where the transfer is from the UK MAH to an entity that the UK MAH has itself established in an EEA country and which will become the MAH for the medicinal product.
Where the existing name of a medicinal product is constructed as [international non-proprietary name (INN) / common name + name of the MAH], the name of the medicinal product may need to be changed to reflect the name of the new MAH. In such circumstances, a Type IA variation must be submitted before the transfer application.
The Practical Guidance provides further important details:
- For on-going regulatory procedures, it is advised that MAHs contact the Agency when these procedures run in parallel with the transfer application;
- For related orphan designations, the EMA recommends submitting the application for a transfer of orphan designation before or at the latest in parallel with the application for the transfer of marketing authorisation.
The Practical Guidance includes one element of simplification in favour of UK MAHs. This is the transfer of all of their marketing authorisations to the same legal entity in EEA. Although a single transfer application will not be available, it will be possible for MAHs to create a combined version of each required supportive document. The exception to this possibility will relate to documents concerning product information and mock-ups for all the products transferred.
As regards mock-ups, the Practical Guidance highlights that Regulation (EC) No 2141/96 provides that mock-ups should be submitted as part of the marketing authorisation application. As an exception to this approach, where the only change to the artworks of a product that is subject to a transfer obligation is the name and/or address of the MAH, a written confirmation may be accepted by the EMA that mock-ups remain unchanged.
The Practical Guidance provides that Brexit-related variations may, in certain circumstances, be grouped together. Such grouping must not delay the implementation of changes that must be in place by the time of UK’s withdrawal from the EU.
MAHs are reminded by the Practical Guidance that a work-sharing application is at their disposal. This application can be used where identical changes apply to several products held by the same MAH.
MAHs are advised that, before the submission of variations, they should cooperate with the EMA Procedure Manager responsible for their medicinal product.
Changes to the manufacture of the active substance or finished product
After UK’s withdrawal from the EU, active substances and medicinal products manufactured in the UK will be considered as imported active substances from a third country when imported into the EU.
The Practical Guideline provides, however, that submissions concerning new manufacturing sites in the EEA for active substances or finished products may be undertaken as a Type II variation. However, individual variations will be required for the active substance and for the finished product. If there is a change in the UK release site a related Type IA variation will also be required.
Changes impacting on the manufacturing activities
The batch release site for medicinal products placed on the market in the EEA must be located in the EEA.
The Practical Guidance provides that for medicinal products in relation to which batch release and quality control testing sites for finished products are only based in the UK, MAHs will be required to establish new batch release and testing sites in the EEA. Where the MAH has established new batch release and testing sites within the EEA, the MAH has the option to delete reference to the UK site or replace the UK site with a site in the EEA.
The Practical Guidance also requires that an import site must be established within EEA for finished products manufactured in the UK.
The Practical Guidance provides a non-exhaustive list of scenarios that could apply should the MAH decide to separate activities concerning manufacturing, testing, importation and/or batch release of a medicinal product across UK and EEA sites.
Sponsors of Orphan Medicinal Products
Sponsors must be established within the EEA.
In preparation for the UK’s withdrawal from the EU, the name and address of the sponsor of an orphan drug designation currently established in the UK must be replaced by those of a sponsor established within the EEA. If this involves a change in the legal entity of the sponsor, this will result in a transfer of the orphan medicinal product designation.
The transfer to an EEA sponsor or change in name/address of the sponsor must take place at the latest by the date on which the UK leaves the EU. Proof of the new sponsor’s establishment in the EEA must be submitted by this date. Such proof can take form of a certificate of registration in the register of legal entities, a certificate of incorporation or, in case of an individual, a copy of passport or ID card.
According to the Practical Guidance, transfers of orphan designations are free of charge.
QPPVs and PSMF
EU rules require that the Qualified Person for Pharmacovigilance (“QPPV”) should reside and carry out his/her tasks in one of the EEA countries. Where the QPPV for a MAH is currently established in the UK, they will be required to transfer their place of residence and to carry out their tasks in the EEA. Alternatively, a new QPPV must be appointed. The PSMF should also be located within the EEA.
A MAH will not be required to notify the EMA of changes to the location of the QPPV or PSMF within the EEA by submitting a variation unless a new QPPV is appointed, in which case a Type I Variation must be submitted. Changes related to QPPVs and the PSMF must instead be notified to the authorities through the Article 57 database.
Person responsible of scientific services and person responsible for batch recall and quality defects
Changes concerning the person responsible of scientific services and the person responsible for batch recall and quality defects must be notified exclusively in writing using the template provided in Question 8 of the Practical Guidance.