After months of speculation, the first round of changes for pharmaceutical manufacturers arising from the planned withdrawal of the United Kingdom of Great Britain and Northern Ireland (UK) from the European Union (EU) have arrived. And the changes are major for companies based in the UK that currently market or plan to market centrally authorised products. As there is no precedent for a member state leaving the EU, for Brexit and EMA, this is new territory from a regulatory perspective.
2 May 2017 Notification
Britain notified the European Council of its intention to withdraw from the European Union (EU) on 29 March 2017. As a result of this notification, the European Commission (EC) and European Medicines Agency (EMA) issued a notice on 2 May 2017 to holders of marketing authorisations of centrally authorised medicinal products for human and veterinary use. The notification reminded marketing authorisation holders that:
- EU law requires their establishment in the EU and/or the European Economic Area (EEA), and
- Some activities related to pharmacovigilance, batch release etc., must be performed in the EU and/or the EEA.
The responsibility to prepare and proactively screen for, and implement these changes is placed on the marketing authorisation holders. Transfer and variation requests will need to be submitted with respect to procedural timelines, prior to the UK’s withdrawal from the EU. If this process is not undertaken, the threat of interruptions to marketing of authorised products was indicated as a possible outcome.
31 May 2017 Q&A Update
Further detail of the 2 May notification was provided in a Q&A document published last week (31 May 2017). This update clarified that companies established in the UK that are holders of marketing authorisations or orphan designations would need to transfer their central authorisation or designation to a holder in the EU/EEA, and submit the appropriate transfer documents if they plan to or wish to continue marketing in the EU. This means that if a UK-based Contract Research Organization (CRO) is acting as the Sponsor of a product on behalf of a company located outside of the EU/EEA, that company would need to switch to a CRO established in the EU/EEA.
For veterinary products, companies with Minor Use Minor Species/limited market (MUMS, or orphan designation for veterinary products) status would need to transfer their classification to an EU/EES-established company to retain their incentives.
Similarly, the Pharmacovigilance System Master File, and the residence and activities of the Qualified Person for Pharmacovigilance must be located in the EU/EEA.
Importantly, changes that will occur are not limited to regulatory compliance issues. If an active substance of a marketed product in the EU/EEA is manufactured in the UK, the active substance will be considered to be imported and must therefore be accompanied by a written confirmation from the exporting country that the manufacturing plant is in compliance with good manufacturing practice (GMP) and that controls of the plant are equivalent to those in the EU/EEA. As reported in the Pink Sheet, this requirement could be waived if the UK is included on the so-called “white list” of accredited companies with a GMP framework similar to the EU.
If a finished product is manufactured in the UK, the product will be considered an imported medicinal product in accordance with Articles 40(3) of Directive 2001/83/EC and Article 44(3) of Directive 2001/82/EC. The marketing authorisation holder will need to specify an authorised importer and a site of batch control in the EU/EEA where each production batch can undergo qualitative and quantitative analyses. The batch release site will also need to be in the EU/EEA. Further, the product must comply with the conditions listed in Articles 41 and 42 of Directive 2001/83/EC and Articles 45 and 46 of Directive 2001/82/EC, such as the availability of a qualified person within the Union (EEA), and GMP inspections. A variation application would need to be submitted and approved regarding these changes.
Small to medium enterprises (SMEs) will need to establish a legal entity in the EU to continue receiving financial and administrative incentives. This can also be done for non-EU/EEA companies via an EU/EEA-established CRO as long as both the CRO and company are SMEs.
All of these changes must occur prior to the planned departure of the UK from the EU on 30 March 2019. For the marketing authorisation holders of the 356 centrally authorised human medicines, this will undoubtedly require substantial efforts related to both relocation of manufacturing activities and regulatory submissions. The EMA advises Sponsors to identify the required changes, implement the change, and submit variation applications within time lines required for approval of the changes.
Camargo can advise on how these changes will affect your development program or marketing authorization. For strategies to remain in compliance with EU directives, contact us.
Authors: Angela Drew, PhD, Product Ideation Consultant, Camargo Pharmaceutical Services, and
Marc Wiles, PhD, Vice President of Scientific and Regulatory Affairs, Camargo Pharmaceutical Services