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Both the European Union and United States are still ironing out issues such as confidentiality of information and recognition of competence of each party’s regulatory authorities in their agreement on GMP inspections.
The European Union-United States mutual recognition agreement (MRA) on GMP inspections, announced in early March 2017 (1), was a big step forward in the EU’s eagerness to play a key role in the achievement of uniform standards in pharmaceuticals across the world. This quest for leadership in harmonizing standards is being driven by the EU’s network of regulatory agencies headed by the European Medicines Agency (EMA), which operates a uniform set of cross-border standards within the Union.
The trans-Atlantic deal is by far the biggest of the MRAs on GMP inspections reached by the EU. But its complexity is likely to lead to a more gradual, incremental approach to MRAs by EMA. The agency is in no hurry to negotiate new MRAs. “At the moment, there are no plans for MRAs with other countries in the short term, [although] this is not to be excluded in the future,” an EMA spokesperson told Pharmaceutical Technology Europe.
The only MRA talks on the agenda is an extension of an existing 15-year-old MRA with Japan, which has restricted coverage of types of medicinal products (2). Both sides want to make it “fully operational” so that it applies to the manufacture of all or most medicines on the market.
The EU-US MRA has highlighted the difficulties of forming mutual GMP agreements among other non-EU countries. The agreement has taken approximately 20 years to set up, mainly because of the time needed to create trust between the two parties to the deal. It still will not come fully into force until 2019, while its scope in terms of types of medicines covered may not be finalized until July 2022 (3).
MRAs, which essentially enable the granting of GMP certificates by regulatory agencies in one country to be recognized in another country and vice versa, could be important for the future of the globalized pharmaceuticals market. They cover the production of finished medicines and APIs, and could in theory be extended to starting materials as well.
As pharmaceutical supply chains broaden across the world, the inspectorates of regulatory agencies are becoming severely stretched. MRAs are needed to make better use of limited resources, avoid repeated inspections of individual plants, encourage the exchange of information between agencies, and to disseminate best practices. “Mutual recognition agreements on GMP inspection have been important tools to reduce unnecessary, duplicative inspection of manufacturing sites,” says a spokesman for the European Federation of Pharmaceutical Industries and Associations (EFPIA), Brussels. MRAs also enable agencies to concentrate more of their inspection activities on higher-risk plants, particularly in developing countries.
The EU is a significant force in the international expansion of MRAs because its own pharmaceutical market of 28 member states-soon likely to be reduced to 27 by the exit of the United Kingdom-is based on mutual recognition, not only of GMP inspections but also drug marketing approvals. Outside of the Union, the EU also has MRAs on GMP inspections with Switzerland, Australia, New Zealand, Israel, Japan, Canada, and now the US. Only three of those MRAs-with Australia, New Zealand, and Switzerland-are currently categorized as being fully operational. Some of these MRAs stretch back to the turn of the century or earlier when there was a spurt of mutual recognition deals between the EU and other countries embracing a range of product categories including pharmaceuticals. But they had limited scope or failed to be fully implemented.
Most of the EU’s new MRAs in medicines have been reached through the framework of free-trade talks. The EU-US agreement was achieved during negotiations on the Transatlantic Trade and Investment Partnership (TTIP), an EU-US proposed pact on the removal of tariff and non-tariff barriers on which discussions are currently deadlocked. A new EU-Canada MRA was finalized in 2016 during negotiations on a Comprehensive Economic and Trade Agreement (CETA) between the two partners (4), which has taken seven years to complete. Now there should be opportunities for more MRAs being reached through bilateral or sectoral agreements, which are likely to replace multilateral deals as the main means of increasing trade by lifting obstacles like different regulations and standards.
The updated EU-US MRA has effectively become a separate sectoral deal while TTIP itself is on pause. The original agreement was reached in 1998 as part of a mutual recognition arrangement between the EU and US that also included telecommunications and electrical equipment (5). But the part on pharmaceuticals, which was limited in scope anyway, was never completely implemented. Among the main issues on both sides was to what extent the confidentiality of commercial information should be protected and above all, from the point of view of the US Food and Drug Administration (FDA), was the recognition of the competence of all national regulatory authorities in the EU. This became a critical matter after 10 new member states, most of them former communist Eastern European countries led by Poland, Hungary, Czech Republic, and Slovakia, joined the Union in 2004.
The momentum toward an updated MRA started to gather pace from 2014 when FDA began to send its inspection teams to observe EMA’s regular audits of the efficiency of the GMP inspections of EU national regulatory agencies. In the period between 2014 to 2016, FDA has observed 12 of these audits of which five were of Eastern European agencies. A further 12, with FDA acting as observers, have been scheduled to take place this year.
Under the EU-US MRA agreement, both parties are given time to complete final assessments of the competence of the other party’s regulatory authorities with regard to GMP inspections. For EMA, it just has to evaluate FDA’s efficiency in this area. But FDA has to assess the regulatory authorities in 28 countries.
Over the past seven years, EMA and FDA have been collaborating in GMP inspection activities to help forge trust. In addition to FDA observing EMA’s audit of national agencies, there have been a joint GMP inspection pilot programme, work sharing on inspections, and regular meetings on inspection plans and outcomes. The text of the agreement states that by November 2017, FDA must have assessed authorities in eight EU countries to trigger the start of the implementation of the MRA (3). FDA’s assessment of the other 20 national authorities must be completed by 15 July 2019 (3). The EU has made clear that the MRA covers all EU member states so that if FDA has not completed its assessment of all of the EU’s national agencies by the 2019 deadline, the deal will be terminated (3).
The EU is also taking a relatively tough line on the issue of the confidentiality of data generated by GMP inspections, such as proprietary information on manufacturing processes and other commercial secrets. “The foundation of this MRA is the ability to share information,” explained EMA’s spokesperson. “EMA and a majority of the EU countries can provide FDA with unredacted inspection reports as part of existing confidentiality arrangements. By contrast, currently, FDA is only able to exchange confidential information that is not classified as trade secrets in the US with EU authorities. FDA, therefore, redacts confidential information classified as trade secret information from inspection reports that it gives to the EU.”
EMA argues that the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA) (6) allows FDA to share trade secrets with other regulators. “In the context of the MRA discussions, FDA has assessed and certified that all EU member states have the authority and can demonstrate the ability to protect trade secret information,” said the spokesperson. “This is an important step towards signing confidentiality arrangements with all EU member states in the future, which would enable FDA to share unredacted inspection reports with the EU member states.”
The EU is currently negotiating approximately a dozen free-trade agreements (FTAs), the majority with countries in the Asia Pacific region. But with the exception of a proposed FTA with Japan, none currently include talks on MRAs on GMP inspections. One FTA under discussion is with New Zealand with which the EU already has a fully operational MRA on GMP inspections. EMA sees MRAs as being types of formalized mutual reliance that require a lengthy assessment of the each of the partners GMP inspection systems. “In the long-term, more MRAs with trusted international partners should be pursued as far as possible,” said the EMA spokesperson.
In the meantime, other kinds of cooperation can be encouraged. Data from GMP inspections can be shared by agencies so that certain sites can be categorized as being low risk, and therefore, allow inspection resources to be reallocated to other sites more at risk, according to the agency. These collaborative schemes can provide the groundwork for the eventual achievement of MRAs. But the reaching of these mutual agreements will take a long time.
1. EMA, “European and US Regulators Agree on Mutual Recognition of Inspections of Medicines Manufacturers,” Press Release, 2 Mar. 2017.
2. European Union, “Agreement on Mutual Recognition Between the European Community and Japan,” Official Journal of European Union 22001A1029(01) (Brussels, October 2001).
3. European Commission, Decision on the Agreement on Mutual Recognition Between the European Community and the United States in order to Amend the Sectoral Annex on Pharmaceutical Good Manufacturing Practices (GMPs), C(2017) 1323, Annex 1 (Brussels, March 2017).
4. European Union, Comprehensive Economic and Trade Agreement Between Canada and the European Union-Protocol on the Mutual Recognition of the Compliance and Enforcement Programme regarding Good Manufacturing Practices for Pharmaceutical Products, COM(2016) 444, Annex 7 (Strasbourg, July 2016).
5. European Community, “Agreement on Mutual Recognition Between the European Community and the United States of America,” Official Journal of the European Communities L 31/3 (Brussels, February 1999).
6. US Congress, Food and Drug Administration Safety and Innovation Act, Public Law No: 112-144 (Washington DC, July 2012).
Pharmaceutical Technology Europe
Vol. 29, No. 4
When referring to this article, please cite it as S. Milmo, "EU–US Mutual Recognition Agreement on GMP Inspections," Pharmaceutical Technology Europe 29 (4) 2017.