Brexit - is it still a concern for MA Holders?
Time is passing very fast, relentlessly, and while it may seem that Brexit happened only yesterday, it in fact has been a long time since the British voters passed the 2016 referendum and United Kingdom (UK) has formally left the European Union (EU). As a result, on 31 January 2020 UK became a third country to the EU. It’s been also quite a while since a transition period stated within Withdrawal Agreement, during which EU pharmaceutical law as laid out in the ‘Acquis Communautaire’ continued to be applicable to the UK, has ended (on 31 December 2020) .
Needless to say - Brexit itself was an event that cost entrepreneurs many sleepless nights due to the rather unpredictable course and tense negotiations between the EU and the UK. Most of people concerned, wondered if the EU and the UK would get along or not and which scenario will be implemented – “deal” or “no deal”. Ultimately, although Brexit means the exit of the entire UK from the EU, the matter isn’t that simple after all – Northern Ireland Protocol  needs to be taken into consideration. In short, while Northern Ireland (NI) is part of the UK, it remains under EU law in some aspects including regulatory of pharmaceutical industry such as Marketing Authorisation Holder (MAH) or batch release site localisation.
Brexit has touched practically every area of pharmaceutical industry, so describing the impact on each area would involve writing a lengthy essay. Therefore, this article will focus mainly on a selected regulatory aspects. At the beginning, let’s take a closer look on provisions of Brexit concerning MAH localisation and pharmacovigilance requirements.
MAH localisation – the original provisions
Quick regulatory background summary
For a better understanding of this article, let’s take a look at a brief summary on the UK status in Mutual Recognition Procedure / Decentralised Procedure (MRP/DCP) and central licenses. In case of MRP/DCP procedures MAH could choose the option to maintain a UK-wide marketing authorisation and retain the UK in respect of Northern Ireland (UK(NI)) as a Concerned Member State (CMS). In this case, the authorisation continued to be a UK-wide Marketing Authorisation (MA) with Northern Ireland as a CMS and Great Britain (GB) aligned with, but not part of, the MRP/DCP . In case of centralised procedures all existing Centrally Authorised Products (CAPs) MAs have been automatically converted into Great Britain MAs effective from 1 January 2021 in Great Britain only (England, Wales and Scotland) and have been issued with a Great Britain Product Licence (PLGB) MA number. These Great Britain MAs are referred to as “converted EU MAs”. As a result of the implementation of the Northern Ireland Protocol, existing CAPs remained valid for marketing products in Northern Ireland .
Brexit, Year 2020
It should be emphasized, that just like in any other relationship breakdown, we have two confronting sides which have different requirements and needs – in case of Brexit: EU (European Commission, EMA, CMDh and national Agencies) side and UK (MHRA) side.
From the European perspective, since from the Brexit date, UK has become a ‘third country’ (joining the group of China, India, Canada and other third countries) the EU requirement was that MAH for medicinal products authorised under EU laws has to be located in the EU/EEA region . Thus, at the end of the transition period, MAHs located in the United Kingdom had to have transferred its marketing authorisation to a holder located in the EU. Therefore, many pharmaceutical companies had to transfer MA holders localisation from UK to EU/EEA. A slight exception was allowed only for MAs in Northern Ireland (UK(NI)), where MAH could have been established in Northern Ireland, but not in Great Britain (UK(GB)) [6, 7].
From the UK-perspective, the marketing authorisation holder for a UK marketing authorisation must be established in the UK (Great Britain or Northern Ireland) or in the EU/EEA .
The question is: what in case of MRP/DCP procedures with UK-wide MA retaining UK(NI) as CMS? Where MAH can be located and where cannot be? Original guidelines tell us that for UK-wide MA (covering UK(NI) and (UK(GB)) MAH could not have been located in GB. It meant that although the MA covered whole UK, the MAH could not have been located at GB part of UK. Going forward, it meant that for medicinal products authorised in UK, by MHRA, MAH could not have been located in a large part of UK because part of UK(NI) remained to be part of MRP/DCP procedure. In order to comply with the guidelines, appropriate post-registration changes had to be submitted.
MAH localisation requirements – further changes and current update
Changes in guidelines – Brexit, year 2021 and the present time
Therefore on 25 January 2021 Commission notice  has been published in order to reflect the actual (on that time) progress of the industry to implement the required changes and move relevant regulatory compliance functions to Northern Ireland or the EU in respect of nationally authorised products, as required by the Protocol. The Commission Notice of 25 January 2021 provided for a grace period of one year (until end-December 2021) for maintaining batch testing and manufacturing / logistics in parts of the United Kingdom other than Northern Ireland to ensure undisrupted supply of medicines to Northern Ireland, Cyprus, Ireland and Malta. It is worth noting that the commission notice from 25 January 2021 did not cover the question of localisation of Marketing Authorisation Holder - although such an issue existed.
More time passed and at the end of year 2021 pharma industry still had not adapted to post-Brexit requirements. The main reasons observed were the too high adjustment costs relative to the small size of the Northern Irish market and the complex logistics involved, for which no viable alternative logistical hubs in Northern Ireland have been identified . In order to address this situation, and with the aim of preventing shortages of medicines and ensuring a high level of public health protection, with regard to medicinal products for human use, the Commission on 17 December 2021 adopted legislative proposals amending relevant provisions of Directive 2001/83/EC, Directive 2001/20/EC and Regulation (EU) 536/2014, as well as a delegated regulation amending Commission Delegated Regulation (EU) 2016/161. As a result, another Commission Notice has been published on 29 December 2021 to explain how all the areas that didn’t comply will be managed until the date of entry into force of the amendments referred to above . Finally, Directive 2022/642 of the European Parliament and of the Council of 12 April 2022 amending Directives 2001/20/EC and 2001/83/EC came into force on the day of its publication which was 20 April 2022 . This Directive among the others allows exceptionally that marketing authorisation holder may be established in parts of the United Kingdom other than Northern Ireland – which means the Great Britain part.
Is the derogation for everyone?
It should to be noted the derogation concerns MRP/DCP procedures which include the MSs UK(NI), IE, CY or MT only. The issue how to handle UK(GB) sites in procedures without UK(NI), IE, CY and MT as CMS has been discussed in CMDh meeting on January 2022 and it was reminded that the UK(GB) sites (sites located in the UK e.g. MAH, batch control and batch release) should have been already deleted/changed. The CMDh agreed that MAHs that still have UK(GB) sites mentioned in the dossier in addition to EU sites, e.g. alternative batch release or batch control sites (except for procedures where IE, CY, MT and/or UK(NI) are CMS and have granted an exemption for their markets), should remove these alternative sites from the MA, using the respective variation procedure. The CMDh noted that this should be done immediately for all procedures not including IE, CY, MT and/or UK(NI) as CMS, as the timeframe for submission of these variations had already expired. The same concerns the MAH localisation change in MRP/DCP procedures without UK(NI), IE, CY and MT as CMS .
Pharmacovigilance Brexit requirements – variation reminder
When discussing adaptation of MAHs to Brexit requirements it is worth to remind about Pharmacovigilance area.
QPPV and PSMF localisation – EU perspective
From the EU perspective, in accordance with Article 104(3) of Directive 2001/83/EC, read in conjunction with the IE/NI Protocol, the qualified person responsible for pharmacovigilance (QPPV) must be established in and operate from the Union or Northern Ireland. In addition, in accordance with Article 7 of the Commission Implementing Regulation (EU) No 520/2012 (20) the pharmacovigilance system master file (PSMF) must be located either at the site in the Union where the main pharmacovigilance activities of the marketing authorisation holder are performed or at the site in the Union where the qualified person responsible for pharmacovigilance operates . The commission notice describing in detail the above, provides some derogation also in case of QPPV localisation. Literally: where the marketing authorisation is granted by the competent authority of the United Kingdom in respect of Northern Ireland, the qualified person responsible for pharmacovigilance, as well as the pharmacovigilance system master file, may exceptionally be allowed to be located and operate in parts of the United Kingdom other than Northern Ireland. This shall not apply to situations where the MAH already has at its disposal a QPPV established in the Union.
UK QPPV – UK requirements
Having UK MA (being or not part of DCP/MRP) it is worth to remember that UK Brexit requirements needs also to be fulfilled. According to MHRA guidance, for all UK MAs, the marketing authorisation holder (MAH) must have permanently and continuously at its disposal a QPPV who resides and operates anywhere in the UK or in the EU/EEA, and is responsible for the establishment and maintenance of the pharmacovigilance system (“the UK QPPV”). If the QPPV is not in the UK, there is a need for a national contact person for pharmacovigilance. MHRA gives a temporary exemption in place which MAHs do have 12 months (from 1 January 2021) to appoint a national contact person for pharmacovigilance that resides and operates in the UK. Once the national contact person for pharmacovigilance has been appointed, their details should be notified to the MHRA via the MHRA Submissions Portal .
For all UK national MAs, including those that cover the whole of the UK or are specific to Northern Ireland or to Great Britain, the MAH must maintain, and make available (electronic access) upon request of the MHRA, a PSMF that describes the pharmacovigilance system for UK authorised products (‘the UK PSMF’). The UK PSMF should be an accurate representation of the pharmacovigilance system that has been established and MAH must make sure that every pharmacovigilance system covering UK authorised products has been assigned a unique PSMF number by the MHRA (so called UK PSMF number). A UK PSMF number can be requested via the MHRA Submissions Portal. Similarly to EU case, having UK PSMF there should be also a summary of Pharmacovigilance systems called in UK guidance as “SPS” .
Variation reminder – final call
In case of UK MAs granted before Brexit (either in MRP/DCP or central), when all steps concerning QPPV or UK PSMF are done, Type IAIN variations related to the SPS should be submitted to the MHRA. All applications to update the SPS are required to be submitted via the MHRA Submissions Portal. MHRA has published “overview of managing updates” for UK licences granted via MRP/DCP since in such case there will be action needed concerning both:
- UK MA via described IAIN variation;
- and EU part of MA (UK(NI)) via XEVMPD database (without any variation).
MHRA has published also a variation timeframe according to which, in case there is no changes made by MAH regarding QPPV details from those entered in XEVMPD by 13 December 2020, then these details for the QPPV, together with the UK location of PSMF and UK PSMF number, should be submitted by deadline set as 30 June 2022 . Therefore it is kind of “final call” to all MAHs who have not submitted this notification yet.
To the end
Although Brexit happened years ago, the adaptation to Brexit requirements for both sides EU and UK is quite challenging. Fortunately, both sides are taking appropriate steps to meet the realities of the pharmaceutical industry and working on adjusting the guidelines in order to prevent shortages of medicines and ensure adequate level of public health protection. On the other hand, constantly changing requirements make it difficult to keep up with the most up to date regulations at the moment and what the requirements will look like in the future. It is very challenging for MAHs indeed.
It is also worth to remember that some post-Brexit actions had dates set far in the future which are getting closer now – such as the variation concerning Notification of QPPV and PSMF details to the MHRA.
One thing is sure, the story of Brexit is not over yet and probably won't be any time soon. Therefore, wanting to meet the Brexit requirements it is highly recommended to follow changes in Directives and guidelines on an ongoing basis.
- Walker N. House of Commons Library, Briefing Paper, Number 7960, 6 January 2021. Brexit timeline: events leading to the UK’s exit from the European Union.
- Agreement on the withdrawal of the United Kingdom of Great Britain and Northern Ireland from the European Union and the European Atomic Energy Community.
- MHRA Guidance on handling of Decentralised and Mutual Recognition Procedures which are approved or pending.
- MHRA Great Britain Marketing Authorisations (MAs) for Centrally Authorised Products (CAPs)
- Directive 2001/83 EC, Article 8(2).
- Commission Notice – Application of the Union’s pharmaceutical acquis in markets historically dependent on medicines supply from or through Great Britain after the end of the transition period, 13 March 2020.
- CMDh/426/2020, December 2020, Practical guidance on the implementation of the Protocol on Ireland/Northern Ireland for medicinal products for human use approved via MRP/DCP.
- MHRA Guidance on MAH and QPPV location
- Commission Notice – Application of the Union’s pharmaceutical acquis in markets historically dependent on medicines supply from or through Great Britain after the end of the transition period (2021/C 27/08)
- Proposal for a Directive of the European Parliament and of the Council amending Directives 2001/20/EC and 2001/83/EC as regards derogations from certain obligations concerning certain medicinal products for human use made available in the United Kingdom in respect of Northern Ireland, as well as in Cyprus, Ireland and Malta. COM(2021) 997 final
- Commission Notice – Application of the Union’s pharmaceutical acquis in markets historically dependent on medicines supply from or through parts of the United Kingdom other than Northern Ireland (2021/C 524/02)
- Directive (EU) 2022/642 of the European Parliament and of the Council of 12 April 2022
- Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) Draft minutes for the meeting on 25-27 January 2022
- MHRA Guidance on qualified person responsible for pharmacovigilance (QPPV) including pharmacovigilance system master files (PSMF)
If you have any questions regarding the Brexit requirements for the pharmaceutical industry, please do not hesitate to contact us.