All you need to know about the EU & USA MRA
March 2017 was a historical month for the pharmaceutical industry and for EU and US. The amended mutual recognition agreement (MRA) on “Pharmaceutical Good Manufacturing Practices” between the EU and the US was signed. Best case scenario, it could lead to significantly reduced inspection pressure of the FDA EU inspectorates and we might be done with re-testing of imported batches and batch certification. So let’s hope this amended MRA will actually be implemented and history doesn’t repeat itself.
Mutual Recognition Agreement
In the broadest sense of the word, a mutual recognition agreement is a bilateral trading agreement to facilitate trading between nations or regions. It facilitates market access while safeguarding consumer health, mutual acceptance of reports, and certificates, exchange of information, and encourages harmonization. An MRA covers various economic sectors including Pharmaceutical Good Manufacturing Practices. The sectoral annex of “Pharmaceutical good manufacturing practices” mentions for instance; recognition of GMP regulation, exchange of reports of inspections of manufacturers, and the possibility to rely on foreign test results for batch release, the so-called re-testing. The EU has MRAs with several countries; Australia, Canada, Japan, New Zealand, Israel, Switzerland and the US and all with different terms and conditions. All these MRAs are in force, except the one with the US. Which was first drafted in 1998, but was never actually implemented. So, what happened?
History of MRA events so far (link)
- In 1994, MRA negotiations began between the EU and the US.
- After numerous difficulties, (disclosure of inspection reports to the public and differing opinions on how to focus on post approval inspections or on post- and preapproval inspections) the negotiations finally resulted in an MRA in 1998, which already contained a “Pharmaceutical good manufacturing practices” annex.
- Apart from the usual 18 months, the implementation period was extended to 3 years. In this period, it was recognized that legislation and implementation of this legislation were too different, to be able to mutually accept GMP inspection information at that moment. The MRA came a bit too soon. Hence, it was never implemented.
- Despite the apparent failure of the MRA, it was recognized something should be done. The FDA expanded its reach beyond US borders by opening offices in Europe, China, India, and Latin America and conducted significantly more foreign inspections to gain more insight into the GMP compliance level of foreign companies.
- Together with the Food and Drug Administration Safety and Innovation Act. In 2012 (FDASIA), stating that FDA cannot and should not monitor the world’s drug inventory by itself, this resulted in 2014 in Mutual Reliance Initiative (MRI). Which aims to increase strategic collaboration between the FDA and EU member states through the exchange of information.
- Additionally, in September 2014, the FDA was invited to observe the EU’s Joint Audit Program, in which two EU nations audit the inspectorate – the regulatory authority – of another EU country.
- These combined initiatives eventually resulted in an amended MRA on a sectoral annex of “Pharmaceutical good manufacturing practices” in March 2017.
Amended MRA EU and US 2017
The signed amended MRA is a major achievement, but euphoria should be tempered. Although this MRA could probably significantly cut costs for (bio) pharmaceutical companies enormously, it still contains a lot of terms and conditions. Aspects like an FDA assessment of the EU member states, an EU assessment of the FDA, and not all products are included in the annex. Depending on all these terms and conditions and assessment outcomes, parts of the MRA will come into force in time.
EU assessment of FDA
The EU’s assessment of the FDA started in September 2015. EU officials visited three FDA district offices, FDA headquarters complex, and an FDA laboratory. The EU team inspected with the same criteria that apply within EU. In late 2016, EU also observed FDA conducting an inspection as part of its evaluation. The progress in collaboration, negotiations, and assessments was found positive and finalization of the assessment in 2017 should be achievable.
FDA assessment of EU member states
- FDA assessment started a year earlier in September 2014 with their presence at the Joint Audit Program of EU.
- However, this is just a small part of the full capability assessment that the FDA will perform in all member states. In 2017, the FDA had already attended 14 audits of different EU member states and expects to be present at the remaining 14 before the end of 2017.
- For this full capability assessment, the FDA requires each member state to provide a capability assessment package to FDA containing e.g. a finalized Joint audit program audit report, completed conflicts of interest questionnaire, four inspection reports including the report from the inspections observed during the Joint Audit Program audit, standard operating procedures (report finalization, training and inspector qualification, etc.) and an inventory of manufacturing facilities.
- Eight of these packages should be assessed by FDA, before the MRA comes into force on 1 November 2017. Subsequently, the FDA and EU can and will rely on each other’s GMP inspections.
- FDA intends to complete all of the 28 (27 after March 2019 depending on Brexit negotiations) full assessments by 15th of July 2019. After completion of all assessments, re-testing of imported batches and batch certification is no longer required. Until that moment, each imported batch and each batch to be certified is to be re-tested. The fact that delivery of capability assessment packages and their assessments are already planned and documented in the MRA, provides confidence that these milestones will be achieved.
NOTE: Not all Pharmaceutical products are included!
A wide variety of the pharmaceutical products are included in the amended MRA, but medicines derived from blood or blood plasma, human tissues and organs, immunologicals, and veterinary products are not. for now, Medicinal products for veterinary use are expected to be included in July 2019 and Vaccines and plasma derived medicinal products in July 2022.
The signed amended MRA is an important step forward. Nonetheless, it contains a significant number of terms and conditions, but it does provide a roadmap. If a positive attitude is maintained and the challenging timelines are respected, both parties will mutually accept GMP inspection information from 1 November 2017 onwards and omit the further need for import testing and batch certification after 15th of July 2019.
Until then, it is business as usual.
Blog by: Jeroen Ottens MSc, PharmD - Consultant