A Long Time in the Works
by Barbara Unger, GMP Quality Expert, and GMP Regulatory Intelligence Editor-in-Chief
Implementation of the Mutual Recognition Agreement (MRA) for drug GMP inspections between the US FDA and the European Union (EU) inspectorates has been in the development since 1998 and was formalized this year. This agreement was driven by the reality of the changes in sites of drug manufacturing over the last decades. No longer is drug manufacturing primarily a ‘domestic’ function, either in the US or European countries. The current supply chains are global with significant proportions of manufacturing performed across the globe, most significantly in India and China. Both the FDA and EMA inspectorates have limited personnel and budgets and have been working to leverage their expertise and minimize where the two inspectorates visit facilities that their partner recently inspected, thus increasing their efficiency. This allows each inspectorate to take a more risk-based approach to inspections and concentrate on those facilities that are in developing regions and provide a large percentage of either APIs or finished products that are prescribed and sold in the US and EU.
The advantage for manufacturing sites located in the EU or the US is that they should see fewer duplicate inspections from the authorities. Thus, in general, a site will not be inspected by both the FDA and EU authorities, but rather the authorities will rely on each other’s inspection reports. When the FDA recognizes all EU Member state authorities, products will not need to be retested and released again upon import into the EU. This issue has been under discussion for as long as I can remember and will provide significant relief for US firms, including those that manufacture in third countries if they have been inspected by the partners.
The EU has MRAs in place with Australia (1999), Canada (2003), Israel (2013), Japan (2004), New Zealand (1999), Switzerland (2002), and now the US. Each agreement has slightly different features and product coverage in their agreements, but, in general, they allow the partners of the agreements to rely on their partner’s GMP inspection process, confidentially share information on inspections and drug defects, and waive batch testing of products, where it is required, that are imported from one partner area to another. The EMA website includes details on each of these agreements as they apply to human and veterinary products and includes links to additional documents.
Let’s focus on the specifics of the US and EU agreement. In the beginning, as this agreement was developed over the decades, each side expressed concerns. Among those concerns was the competence of each other’s inspectorates. For the FDA, this included concerns about the rigor and skills of the various European member states and inspectors, and, similarly, the EU was concerned about the various FDA district offices and the competence of those inspectors. This is a legitimate concern even within each of the regulatory authority inspection organizations. I’m sure we would all list a small handful of EU inspectorates that we personally consider the most rigorous in the region, and we can all name both FDA districts and individual inspectors who we feel are more rigorous than others. Personally, I think this is an issue that will always exist. The differences and similarities between inspectorates reviewing the same site have been covered in many articles including HERE and HERE. What we need to do is become ‘comfortable enough’ to rely on each other’s inspections; it will never be perfect.
The EU inspectorates also worked to ensure consistency in their interpretation and application of GMP standards, and frequently inspect in teams representing multiple member states. Further, the FDA developed a ‘capability assessment’ that they are applying to each of the member states to ensure the consistent application of cGMPs. Assessment of each other’s inspectorates began as early as 2001 but then languished until this recent focused activity.
The FD&C Act was amended in July 2012 to permit the FDA to make agreements with other inspectorates. This can be found in Title VII, section 712 (and HERE) of the Food and Drug Administration Safety and Innovation Act (FDASIA). Prior to this, the two authorities had agreements to share inspection information and perform joint inspections to increase the confidence in each other’s systems and processes. The consequences of these partnerships and sharing of information among the inspectorates have been felt for many years. In the past, if a firm had a problematic inspection or enforcement action, they dealt only with the single health authority that initiated the action. With the sharing of information that happened in the past 10+ years, firms with ‘problems’ received questions and requests for information from a variety of regulatory authorities which greatly complicated their response and remediation efforts.
In 2014, the US and EU developed a Mutual Reliance Initiative as part of a renewed effort to push forward to Mutual Recognition of GMP inspections. It included face-to-face negotiations and the development of details and timelines to achieve the end goal. The exchange of information continued during this period.
Most recently, the EU completed their assessment of the FDA in July 2017. By November 2017, the FDA will have completed assessments of eight Member State authorities and will complete assessments of all Member States by July 2019. While the recognition of inspections will be effective in November 2017, the agreement remains in transition until assessments of all EU Member States are completed in July 2019.
Additional details of the agreement are as follows:
- Products covered include human chemical pharmaceuticals; medical gasses; human biologicals; including immunologicals and biotherapeutics; human radiopharmaceuticals; homeopathic medicines classified as medicinal products; vitamins, minerals and herbal meds if they are classified as medicinal products; active pharmaceutical ingredients, intermediate products and bulk pharmaceuticals.
- Just as important are the products not covered, and these include: human blood and plasma; human tissue and organs, veterinary immunologicals; and advanced therapy medicinal products.
- The scope could be expanded to include veterinary products by July 2019, vaccines for human use and plasma-derived medicines by July 2022, and clinical trials products if they are inspected by FDA. Currently, clinical sites are generally only inspected ‘for cause’ and not as a part of routine GMP surveillance.
- “Territorial Applicability” includes products manufactured in the US and EU and manufacturers in third countries inspected by the authorities of either party.
- The two authorities will continue to exchange GMP documents and have a two-way alert system in place.
The MRA provides distinct advantages to both regulators and industry in each jurisdiction.
- Duplication of inspections should be substantially decreased. This permits regulators’ efforts to be focused on more high-risk product types and geographic areas that may not have a mature regulatory and GMP inspection program and processes. For industry, the resources, time, and effort previously devoted to redundant inspections can now be focused on new product development or process improvements.
- When the FDA completes its assessment of all member state authorities, products imported into the EU from sites inspected by the FDA will no longer need to repeat batch release testing. This has long been the goal of US firms and would be a significant change. Not having to identify a European lab, perform method transfers, and provide ongoing oversight for their operations will provide true regulatory relief.
- This agreement will also permit the authorities to leverage their limited inspection resources in third countries, particularly India and China, that have many pharma and API manufacturing sites. Each party can now rely on the other’s inspections and they can increase their overall inspection reach.
Regulators are already sharing GMP inspection information and will continue to do so during the transition period. It may take a while to be able to measure the decrease in duplicate inspections, though I would expect to see that decrease beginning in 2018 with more meaningful metrics awaiting 2019 and 2020. Both regulators and industry will be well served by this agreement.
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About the Author
Barbara W. Unger formed Unger Consulting, Inc. in December 2014 to provide GMP Quality consulting services to the pharmaceutical and biopharmaceutical industry. At Amgen, she led the segment of the Corporate GMP Audit group at Amgen focused on API manufacturers, Quality Systems and Computers. She developed, implemented and maintained the GMP Regulatory Intelligence program for 8 years at Amgen Inc. This included surveillance, analysis and communication of GMP related legislation, regulations, guidance and industry compliance enforcement trends. This was an essential service and tool within the Corporate Audit function.
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