Brexit took place at 11pm on 31 Jan 2020 as the UK departed from the European Union. A transition period of 11 months began on 01 Feb 2020 until 31 Dec 2020. This transition period allowed for the UK to continue to follow EU rules while both sides worked out what the future EU/UK relationship would look like. As a consequence of this effort to avoid a hard border on the island of Ireland/ NIP, Northern Ireland remains tied with EU rules for goods and there is free movement between NI and Ireland. This is different for which is now considered to be a ‘third country’. The MHRA (Medicines and Healthcare products Regulatory Agency) and the VMD (Veterinary Medicines Directorate) remain the national competent authorities for the entire UK while EU rules apply to Northern Ireland.

So how has Brexit impacted the pharmaceutical world? It has certainly made it more complicated and to answer that question, several areas need to be considered in what is an ever-evolving situation. Back in Oct 2020, the HPRA issued a guidance for stakeholders for human and veterinary medicines due to its widely publicised priority to ensure continuity in the supply of health products.

HPRA has continuously liaised with the UK’s regulatory body MHRA and the VMD to ensure the ongoing supply of products within the Irish market.

The guidance explains the type of support offered by the HPRA to manage any problems such as pathways for critical products, developing multi-lingual packs/joint labelling and transfer of authorisations to reduce pressure on supply. The guidance also provided direction on other aspects such as Post Brexit Licensing scenarios for Marketing Authorisation Holders (MAHs).

Marketing authorisation applicants who wish to obtain a marketing authorisation for the United Kingdom in respect of Northern Ireland must include Northern Ireland in the scope of their marketing authorisation application in the decentralised procedure (DCP) or the mutual recognition procedure (MRP). In accordance with Directives 2001/82/EC and 2001/83/EC, the marketing authorisation holder (MAH) must be located within the EU/EEA (apart from the specific situation of medicines authorised by UK in respect of Northern Ireland, where an MAH in NI could be established as outlined in the notice to stakeholders). In addition, for marketing authorisations issued through the mutual recognition procedure (MRP) or decentralised procedure (DCP), the Reference Member State (RMS) must be based in the EU/EEA. Procedures for MAHs to change RMS and to transfer MAHs to EU/EEA based MAHs are explained.

Guidance has been developed also for managing specific scenarios such as Licencing of product under development, authorised generic medicinal products, Medical Devices with ancillary medicinal substances and parallel product authorisations.

Clinical trial for human medicines is also covered in the guidance. The European Clinical Trial Regulation EU No. 536/2014 which came into effect 31 Jan 2022.

The key features of the new Clinical Trial Regulation include:

  • Identical rules for conducting clinical trials throughout the European Union (EU)
  • Increase in the efficiency in approval process for clinical trials
  • Single submission and approval of multinational clinical trial applications through an EU ‘Clinical Trial portal and database’ (known as the Clinical Trial Information System (CTIS);
  • A harmonised procedure for assessment by member states, divided in two parts
  • Strictly defined deadlines for assessment
  • Involvement of the ethics committees in the assessment procedure

In the new clinical trial regulation (article 74, paragraph 1), where the sponsor of a clinical trial is not established in the EU, that sponsor is required to ensure that a natural or legal person is established in the EU as its legal representative. Member States may choose not to implement paragraph 1 for clinical trials to be conducted solely on their territory or on another territory once certain conditions are met.

Other examples of changes due to Brexit are:

The Qualified Person Pharmacovigilance (QPPV) and Pharmacovigilance System Master File (PSMF) must be located in the EU/EEA for human and veterinary medicines.

Changes to import and export requirements e.g. all products that originate in the UK or are imported via UK need to be imported by the holder of an MIA (Manufacturer’s and Importer’s ) located in the EU/EEA and certified by a QP in the EEA.

For product going to the UK from Ireland, the need for the Irish wholesaler to update its authorisation to change the activity to include ‘Export’ to allow this and to comply with UK regulations.

Numerous documents have been issued by the various regulatory agencies to provide guidance on the particular areas of interest e.g. Reference medicinal products (updated CMDH guidance May 2021), time limited conditional exemptions for supply to Irish market post Brexit (Jan 2021), Importing medicines and medical devices into Ireland from GB (Jan 2021) to name but a few.

With all of the necessary changes, there is a cohesive willingness by the authorities to address the potential medicines shortages in countries that are typically dependent on the UK. The publication of a notice by the European Commission in Jan 2021 on the application of the EU pharmaceutical acquis in these markets demonstrates this. Commission proposals from Oct 2021 (Medicines non-paper) provide possible permanent and extended temporary derogations such as GB location of MAHs for UK MAs. For a NI, GB or UK Marketing Authorization, the MAH must be located in UK or EU and transfer must be completed by 01 Jan 2023.

The EU and UK Trade and Co-operation Agreement (TCA) was published on 24 Dec 2020. There is a dedicated annex (TBT-2: Medicinal Products) for human and veterinary GMP inspections between the regulatory bodies in the UK and the EU. The annex mainly refers to cooperation, the recognition of inspections, the exchange and recognition of official GMP documents and the establishment of a working group. A key point is that the UK and the EU will mutually recognise GMP inspections for all product types. It also covers conditions around requests for GMP documentation, the rights to carry out inspections and to reject GMP documents under certain circumstances. The timelines for notification of changes to GMP regulations and guidelines between parties are also included. UK GMP is still considered equal to EU GMP. It should however be noted that there is no waiver on the EU part for import testing. UK law, on the other hand, has no testing requirements for imports from EU/EEA.

There is a UK roll-over of EU Mutual Recognition Agreements (MRAs) for Australia, Canada, Israel, Japan, New Zealand, Switzerland and the USA. The validity of existing MAs needs to be considered also e.g. a Centrally Authorized Procedure (CAP) is unchanged in NI but needs to be converted to a GB MA for GB.

With regard to imports into NI from GB, this is still permitted via a wholesaler provided the batch has been tested and QP certified. Product moving from GB to NI will have regulatory checks and customs control. EU safety features are still required in NI but the NI importer is not required to re-affix them for imports from EU via GB. Unique identifier codes are not mandatory in GB but the MHRA recommends retention of tamper evident features for the GB market. EU regulation 2016/161 has been amended so that exports from EU to GB do not require decommissioning. Similar easements have been introduced for Cyprus, Malta and Republic of Ireland.

The Brexit impact on QP certification of marketed products is:

For imports to GB from EU/EEA, a new type of Wholesale Distribution Authorization (WDA) requires a Responsible Person (Import) and this RP(I) must verify QP certification has happened in EU/EEA. If this is not available, an MIA is required for import.

Approved country batch testing is recognized until at least 01 Jan 2023.

For IMPs imported to GB from EU/EEA, a MIA (IMP) is required but the QP is not required to re-certify imports if already QP certified in an approved country. A QP resident in EU/EEA is acceptable on a UK MIA (IMP).

An additional dimension is the nuanced interpretations that are arising at an EU Member State level of the licenses required by individual parties to conduct various activities across the supply chain, for example importation from the UK into the EU and whether or not the product is passing through a Member State or is destined for the market in that Member State.

The future is still uncertain due to an ever-changing political situation and the NIP dispute could escalate. Continuation depends on democratic consent by NI Assemble in 2024.

MIAS Pharma provides batch certification and associated supply chain services. We have experience and expertise in regulatory requirements and regulatory compliance for the supply chain. We are well positioned to support you in navigating the ever-increasing levels of complexity to ensure that you are meeting current regulatory requirements for compliant operation of your supply chain.

References:

  1. Brexit Guidance for Stakeholders Human and Veterinary Medicines issued by HPRA Oct 2020
  2. HPRA website – Brexit and the Regulation of Health Products – Latest Information (18 Feb 2022) http://www.hpra.ie/homepage/about-us/stakeholders/brexit/brexit—latest-information
  3. UK Exit from EU by David Cockburn, EQPA QP Forum December 2021
  4. Brexit Agreement – what now? ECA website (13 Jan 2021): https://www.gmp-compliance.org/gmp-news/brexit-agreement-what-now

If you would like to get in touch with MIAS Pharma, please email info@miaspharma.com or call us on +353 (1) 846 3605.