Earlier this month the FDA recognized the drug inspectorates of Ireland and Lithuania for purposes of the Mutual Recognition Agreement (MRA), and in March of this year, the agency recognized the drug inspectorates of Greece, Hungary, the Czech Republic and Romania.
Indeed, it was last October 2017, that FDA made its long anticipated announcement recognizing the first European drug regulatory authorities capable of conducting inspections of manufacturing facilities that meet FDA requirements, namely, those in Austria, Croatia, France, Italy, Malta, Spain, Sweden, and the UK. We have previously blogged about the MRA here, here, and here.
But where, oh where, is Germany? No offense to such national pharmaceutical behemoths as Malta, Croatia and Lithuania, but Germany is the fourth largest pharmaceutical market in the world and is, by far, the largest in Europe. It is also home to dozens of pharmaceutical and biologics manufacturing facilities, and yet it is nowhere to be found on this list.
We have no way of knowing with certainty why Germany is not on the list as yet because the FDA does not publicly disclose the results of its evaluation process. Nevertheless, the agency has outlined the general process by which it certifies that an EU country’s drug inspectorate can be recognized by FDA, and therein could lie the reason why Germany has not yet made the list.
Each of the 28 countries that make up the EU has its own inspectorate, and FDA has stated that it intends to audit, or perform a capability assessment on, each one by July 2019. It is certainly possible that one has not yet been performed on the German inspectorate, but this is unlikely, given the international significance of the German pharmaceutical market.
According to FDA, although the overall legal requirements and guidelines for drug inspectorates are located at the EU level, some discretion is left to the individual countries to implement the EU requirements in ways the member states see fit for their constituencies.
FDA has summarized its assessment of the adequacy of EU member state inspectorates as a two-step process: First, FDA observes the EU’s internal audit of an EU member country to ensure that the inspectorate is functioning properly and does not deviate in any significant way from EU law and guidance. These audits include observations of drug manufacturing facility inspections conducted by the audited inspectorates and utilize numerous indicators based on the Pharmaceutical Inspection Co-operation Scheme (PIC/S) compliance assessment program.
We understand, through the grapevine, that FDA has already observed the EU’s internal audit of Germany’s inspectorate, though we don’t know whether FDA had any significant problems with it. If there were problems this could have delayed FDA from adding Germany to the list of approved MRA countries.
Subsequently, FDA conducts an independent and comprehensive assessment of the inspectorate. This assessment includes a review of the country’s conflict-of-interest policies, their legislation related to good manufacturing practices, samples of inspection reports, inspector training records, inventory of drug manufacturing facilities, surveillance program, and standard operating procedures. It is certainly possible that Germany passed the internal audit but that FDA’s independent assessment raised certain concerns that would need to be resolved before the country can be added to the MRA list.
We look forward to seeing which countries are added to the list in the next MRA update and will blog about it, as warranted.