The Brexit1 deadline has been extended once again, now to January 31, 2020, and the status of the Brexit deal will depend on the outcome of an upcoming election scheduled for December 12. Regardless of the outcome, drug manufacturers and contract test laboratories need to be proactive and understand the potential regulatory considerations relating to commercial drug product release testing and Brexit.
This article provides a brief overview of the EU-U.S. Mutual Recognition Agreement (MRA) and discusses considerations for implementing viable alternatives for testing to support EU, U.K. and U.S. drug product releases if and when Brexit moves ahead.
Recognizing areas to reduce the burden of regulatory inspection
In the past, drug manufacturing facilities – even those with a long history of compliance – were often inspected by both the EU authorities and the U.S. Food and Drug Administration, sometimes within the same year. Recognizing that these replicated efforts use resources that could be reallocated toward drug manufacturing facilities with higher public health risks, the EU and FDA agreed to rely on each other’s inspection reports (following a program of joint inspections) and encourage greater international harmonization of compliance standards while still protecting consumer safety.
This decision was formalized over the last two years in a Mutual Recognition Agreement (MRA), which is defined as an agreement between two or more countries to recognize a specific process or procedure of the other country (see the FDA FAQs). The MRA includes marketed, finished pharmaceuticals and biological products for human use, intermediates and active pharmaceutical ingredients but currently excludes some products such as vaccines and advanced therapy medicinal products (ATMPs).
The MRA between the EU and U.S. allows the FDA and EU inspectorates to use inspection reports and other related information obtained during drug manufacturing facility inspections to determine if a facility is manufacturing high quality drugs. These inspections can be conducted by an EU inspectorate or by the FDA; both entities still reserve the right to inspect each other at any time and in any country.
The benefits of a Mutual Recognition Agreement in terms of Brexit
Currently, with the EU-U.S. MRA in place, EU authorities can rely on FDA inspections of U.S. facilities – and vice versa – and waive retesting of U.S. products upon importation into the EU, provided that Qualified Persons verify controls have been carried out in the U.S. The U.K. follows EU Good Manufacturing Practice (GMP) regulations, and, in the current pre-Brexit state, also operates under the U.S.-EU MRA.
If the Brexit withdrawal agreement is signed off, the current arrangements will apply through the transition period. Marketing authorization holders will be able to continue to rely on QC testing conducted in the U.K., where Covance has sites in Harrogate, York and Huntingdon. We believe that during this potential transition period it is likely that a similar MRA will be formed between the EU and U.K. Both parties have followed the same GMP regulations over the last 40+ years and have strong ethical motivations to continue the freedom of movement of medicines.
In the unlikely scenario of a delayed agreement between the U.K. and EU post-Brexit, Covance has set up a mitigation strategy where the U.S.-based Covance site in Greenfield, Indiana can take on product release testing for the EU market operating under the current EU-U.S. MRA. The Greenfield site has a strong history of successful GMP regulatory inspections with no 483s or major/critical findings reported since 2011. This includes the MHRA (U.K.) in March 2017; FDA (U.S.) – Jan 2016; FDA (U.S.) – Nov 2013; and Health Canada – May 2012.
Positioning for a smooth transition while facing the unknown
Sponsors with global product releases need a partner that can provide access to many facilities worldwide and offer guidance on how to best meet global regulations. Our CMC teams at Covance are confident that our global release strategy will help reduce the risk of any drug product-related delays associated with the uncertainty surrounding Brexit. Prepare for the unknown and ensure your programs and processes are best positioned for a smooth transition.
1 Brexit is shorthand for “British exit” – the United Kingdom’s vote in a June 23, 2016, referendum to leave the European Union.