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Volume 31, Issue 10
FDA is revising its inspection process and seeks harmonization of standards for US and foreign regulatory oversight to ensure the safety of medicines.
In the name of enhancing transparency in agency decisions and compliance actions, FDA is publishing updated information on how it selects and schedules pharmaceutical plant inspections around the world and the process for disclosing the findings of those oversight actions. The increasingly global nature of the biopharmaceutical supply chain has prompted FDA to revise its inspection process and to seek harmonization in standards for United States and foreign regulatory oversight to further ensure the safety and quality of medicines in the US and around the world.
This approach is highlighted in a September 5thstatement by FDA Commissioner Scott Gottlieb outlining a series of actions FDA is taking to ensure drug quality by all producers (1). Gottlieb noted that FDA moved to modernize its field inspection program through a recent reorganization of its Office of Regional Affairs (ORA) to better align staff expertise with inspection priorities and to expand oversight of foreign manufacturers.
It’s no coincidence that the FDA commissioner is emphasizing the agency’s more extensive scrutiny of foreign manufacturers in the wake of uncovering potentially harmful impurities in a widely used API produced in China. FDA and other regulatory authorities have launched massive recalls of valsartan, a common generic-drug treatment for high blood pressure, after multiple drug manufacturers detected a possible cancer-causing chemical known as N-nitrosodimethylamine in the Chinese API (2). Continued FDA testing of these drugs has uncovered an additional impurity-N-Nitrosodiethylamine (NDEA)-in valsartan drug products (3). The problem evidently arose when Zhejiang Huahai Pharmaceutical made a change in its manufacturing process four years ago.
One response from FDA is to emphasize how its pharmaceutical inspection program is designed to focus on more problematic production sites, including the rising number of overseas firms providing pharmaceuticals for the US. In 2017, FDA conducted 1453 surveillance inspections, including 762 on foreign soil, to ensure that firms were following good manufacturing practices (GMPs) and maintaining high quality standards.
To this end, FDA has implemented a risk-based program for scheduling both foreign and domestic GMP surveillance inspections, as outlined in an updated manual of policies and procedures (MAPP) document from the Center for Drug Evaluation and Research (CDER). This inspection model is structured so that inspection frequency for all facilities relates to operations that pose the greatest potential risk for problems-regardless of where the facility is located. Priority factors considered in scheduling inspection visits include the facility’s compliance history, recall trends, time since last inspection, inherent risk of product being produced, and processing complexity. These criteria are similar to those initially proposed by CDER in 2005 and then codified in legislation in 2012. CDER notes that its Office of Surveillance (OS) in the Office of Pharmaceutical Quality maintains oversight of more than 5000 drug manufacturing facilities around the world, including 3000 outside the US. The agency taps risk information on these sites from the OS database to produce an annual Site Surveillance Inspection List that sets priorities for surveillance inspections.
FDA also is expanding its capacity for monitoring foreign manufacturers through expanded collaboration with European and other capable regulators. An FDA Mutual Recognition Agreement (MRA) with the European Union has been established to recognize drug inspections conducted by participating parties. The aim is to avoid duplicate inspections of facilities that demonstrate good compliance with standards and rules in order to focus resources on more high-risk and non-compliant operations.
In addition to targeting inspections to more problematic firms, Gottlieb discusses how FDA is making inspection results more visible to the public (5). The aim is to be more transparent about inspection outcomes and compliance issues, particularly where the agency uncovers violative conditions that may warrant further regulatory action. FDA recently updated its inspections classifications database to provide more recent information on the outcomes of GMP surveillance visits (6). This supports the EU MRA through the addition of inspection reports from European and other recognized regulatory authorities. Access to more current inspection reports aims to enable FDA and other regulators to issue import alerts, warning letters, and recalls more efficiently to prevent repeat violations.
FDA also is working to speed up the process for communicating inspection findings to facility owners to facilitate fast resolution of any quality failings. Agency officials now aim to provide inspection classification information to companies within 90 days of the close of a surveillance inspection, which is much faster than in the past. FDA similarly seeks to notify firms seeking approval of new drugs and generics when issues are identified during premarket inspections that could block application approval. While the agency recognizes that the majority of firms in the US and overseas meet quality standards, the aim is to prevent problems that can delay efforts to provide quality products efficiently to patients.
1. FDA, “Statement from FDA Commissioner Scott Gottlieb, M.D., on the Agency’s Global Efforts to Help Assure Product Quality and Transparency at Foreign Drug Manufacturing Facilities,” Press Release, Sept. 5, 2018, www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm619435.htm.
2. FDA, FDA Updates on Valsartan Recalls, FDA.gov, ww.fda.gov/drugs/drugsafety/ucm613916.htmValsartan.
3. FDA, “FDA provides update on its ongoing investigation into valsartan products; and reports on the finding of an additional impurity identified in one firm’s already recalled products,” Press Release, Sept. 13, 2018, www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm620499.htm
4. FDA, MAPP 5014.1 Understanding CDER’s Risk-Based Site Selection Model (CDER, OPQ, Sept. 26, 2018), www.fda.gov/downloads/AboutFDA/CentersOff ices/Off iceofMedical-ProductsandTobacco/CDER/ManualofPoliciesProcedures/UCM619302.pdf.
5. FDA, Mutual Recognition Agreement, FDA.gov, www.fda.gov/InternationalPrograms/Agreements/ucm598735.htm.
6. FDA, Inspection Classification Database, FDA.gov, www.fda.gov/ICECI/Inspections/ucm222557.htm.
Vol. 31, No. 10
When referring to this article, please cite it as J. Wechsler, “FDA Clarifies Worldwide Inspection Policies," BioPharm International 31 (9) 2018.