Ensuring Patient Safety and Drug Manufacturing Quality Through Partnership with European Union Regulators
By: Anna K. Abram, Deputy Commissioner for Policy, Legislation and International Affairs, and Mark Abdoo, Associate Commissioner for Global Policy and Strategy
As drug manufacturing has globalized, ensuring that companies meet the U.S. Food and Drug Administration’s (FDA) strict standards for producing safe, effective and high-quality medicines has become increasingly challenging. One way the FDA has addressed this challenge is through the Mutual Recognition Agreement (MRA) with the European Union (EU), which allows us to more effectively deploy our inspectional resources across the globe.
Pharmaceutical establishments that make active pharmaceutical ingredients and finished drug products used by U.S. patients are subject to routine inspections by the FDA to determine if they are in compliance with Current Good Manufacturing Practices (CGMP). The FDA prioritizes and schedules these inspections, which we call surveillance inspections, based on a risk-based site selection model. During an inspection, FDA investigators focus on whether the facility is adequately controlling its manufacturing operations. This includes establishing strong quality managements systems, obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations and maintaining reliable testing laboratories. With 4,600-plus registered establishments subject to surveillance inspections, three-fifths on foreign soil, routine surveillance is a large-scale endeavor for the FDA.
The MRA is designed to ease part of this burden and minimize resource-intensive duplicative inspectional efforts by the U.S. and the EU. The EU conducts similar inspections of establishments that manufacture medicines to be used in the EU, so under the MRA, the FDA may rely on the inspectional findings of EU member states in a European facility that will export to the U.S., and an EU nation may accept the FDA’s inspectional findings at a U.S. facility that exports to a nation in the EU.
The MRA has been two decades in the making. In 1998, the United States and the European Community, which in 2009 was absorbed into the wider framework of the European Union, signed a broad Mutual Recognition Agreement. This Agreement included, among other things, a Pharmaceutical Annex (Annex) providing for anticipated and limited reliance on each other’s CGMP inspections. However, this Agreement was never fully implemented. The Food and Drug Administration Safety and Innovation Act (FDASIA), which was signed into law in 2012, revived the concept, giving the FDA the authority to enter into agreements to recognize drug inspections conducted by foreign regulatory authorities if the FDA determined those authorities are capable of conducting inspections that met U.S. requirements.
Following FDASIA, the FDA and the EU began talks to revise the Annex so that it could be implemented, finalizing it in 2017. They also began the process of evaluating how each party inspected drug manufacturers. For the FDA, it meant observing the EU’s Joint Assessment Process (JAP) of the inspectorates for each EU member state. The EU’s internal audits are based on the 78 indicators in the Compliance Assessment Program. These indicators are common standards established by the Pharmaceutical Inspection Cooperation Scheme (PIC/S) – a cooperative arrangement among 53 regulatory authorities, including the FDA. The U.S. investigators also observed each of the member state inspectorates as they inspected a drug manufacturing facility.
This enabled the FDA to ensure that EU member state inspectorates were meeting the requirements of the Compliance Assessment Program. A complicating factor in the FDA’s extensive efforts to determine if each inspectorate had the capability, capacity and procedures in place to carry out CGMP inspections at a level equivalent to the U.S. was that each of the EU member state inspectorates differ in organization and governance.
After five years of close FDA-EU cooperation, today we’re pleased to announce that the FDA has completed capability assessments of 28 EU member states. The 28 regulatory authorities found to be capable are those located in: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Greece, Germany, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, and the United Kingdom. Meanwhile, the EU made the same determination about the FDA in June 2017.
We see evidence that the MRA is creating important efficiencies. Before the MRA was implemented, the EU and the FDA sometimes would inspect the same facilities in the same year, even if the facility had a strong record of compliance. We expect the MRA will reduce this duplication, allowing the FDA and the EU to reallocate their resources towards inspection of drug manufacturing facilities that have potentially higher public health risks. In addition, information from EU inspection reports will help to inform our risk-based site selection model for inspections, ensuring that our resources are allocated in the most efficient and appropriate manner, while considering risks in the product and manufacturing process that could cause potential harm to patients. Prioritizing inspections in this way will allow us to identify drug supply issues more quickly and to prevent poor quality drugs from entering our drug supply chain from higher risk facilities.
Currently, the MRA is being applied to surveillance inspections conducted only within our respective borders. However, the U.S. and the EU have the option of relying on inspection reports for manufacturing facilities located outside each other’s territories. And while the MRA is now limited to inspections of facilities manufacturing human drug products, we’re evaluating the possibility of including other regulated products, such as veterinary products, human vaccines, and plasma-derived drugs, in the future.
At a time when medical product manufacturing is a global enterprise, there is much to be gained by partnering with regulatory counterparts to reduce duplicative efforts and maximize global resources in order to better fulfill our public health mission. The FDA will continue to work with our global counterparts to address the challenges posed by a global drug supply chain to ensure safe, quality drug products for U.S. consumers.