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FDA seeks to focus on problematic facilities and inform firms quickly about site problems.
To ensure the quality and safety of drugs, biologics, and medical products more efficiently and effectively, FDA is making significant changes in its plant inspection program, including more attention to imports and to foreign producers of drugs for American consumers. An aim is to target manufacturing oversight to more high-risk operations and free up resources for greater scrutiny of foreign facilities in the process. Agency officials also seek to better coordinate and clarify the roles of field investigators and staff from FDA’s Center for Drug Evaluation and Research (CDER) (as well as other agency review centers) in selecting sites, weighing compliance action, and communicating inspection findings to firms. And increased FDA collaboration with foreign regulatory inspectorates promises to reduce redundant site visits and increase oversight of violative situations.
After several years of planning, FDA’s Office of Regulatory Affairs (ORA), which manages the agency’s 5000 field inspectors, officially implemented its Program Alignment (PA) initiative in May 2017. This major reorganization shifts ORA from a geographically-based inspection operation to a program aligned by commodities and vertically integrated, with more specialized investigators able to identify and provide more timely information on critical manufacturing issues. Specialized inspection cadres for drugs, biologics, medical devices, food, bioresearch monitoring, and tobacco continue to operate out of ORA’s 20 district offices across the United States, with certain offices housing program managers that lead product inspection teams (1).
Drugs regulated by CDER and the Center for Veterinary Medicine (CVM), for example, are managed by the Office of Pharmaceutical Quality Operations (OPQO), directed by long-time ORA official Alonza Cruse. He oversees four divisions of pharmaceutical quality operations, each headed by a regional manager, plus a division for quality programs (for compounders and preapproval inspections) and a division for foreign inspections, Cruse explained at the PDA/FDA regulatory conference in September 2017. The aim is to achieve more consistent and timely inspections with reduced uncertainty for industry.
Similarly, ORA’s Office of Biological Products Operations, headed by Ginette Michaud, has two operating divisions to oversee the production of blood products, tissues, vaccines, and other products regulated by the Center for Biologics Evaluation and Research (CBER). The Office of Bioresearch Monitoring Operations under Chrissy Cochran also has two divisions, while the Office of Medical Devices and Radiological Health Operations has three divisions.
A key goal of the reorganization is to enhance communication and collaboration between field inspectors and center product specialists. This approach for drugs is spelled out in a “Concept of Operations” white paper released in August 2017 (2). The 20-page report maps out how ORA and CDER staffers will collaborate in the planning and conduct of inspections and the communication of findings to manufacturers, with decision trees for managing each of the four types of inspections. Increased integration of drug review and facility evaluations aims to achieve more consistency and certainty in regulatory decisions, commented FDA Commissioner Scott Gottlieb (3).
For preapproval inspections (PAIs), a CDER team, including staffers from the Office of Process and Facilities (OPF) in the Office of Product Quality (OPQ), prepares an integrated quality assessment. This assessment reviews information in an application on facilities, processes, and microbiology, plus past inspection reports, to determine whether a PAI is needed for each site listed in the submission. ORA leads any necessary inspection, with CDER participation, and communicates findings to the assessment team. A similar process is involved in planning for and conducting post-approval facility inspections, which may occur following manufacturing changes, particularly for a facility where a PAI has not taken place.
For GMP surveillance inspections, OPQ’s Office of Surveillance (OS) collaborates with ORA to determine the need, timing, and scope of site visits, based on a facility’s inspection history, type of products produced, and risks previously reported. ORA investigators generally conduct these inspections, informing CDER’s Office of Compliance (OC) if they observe questionable situations. ORA also leads for-cause inspections, interacting with CDER’s OPQ and OC.
To ensure timely inspections of facilities listed in new drug applications, FDA and industry agreed in the new prescription drug user fee program to delay application approval if a sponsor fails to identify all relevant sites in a submission. The aim is to provide complete facility information for ORA to have sufficient time to inspect and evaluate relevant production sites. The Generic Drug User Fee Amendments (GDUFA II) further establish a pre-submission correspondence process that requires manufacturers of critical drugs qualifying for priority approval to submit information on planned production facilities two months before filing the application-again, to support timely inspection of relevant production sites in tight timeframes.
A more efficient field inspection program also aims to communicate inspection findings to manufacturers more quickly. GDUFA II specifies that FDA will provide surveillance inspection findings to facility owners within 90 days of completing a site visit, beginning October 2018, and CDER officials expect to apply that goal to all drugs. The aim is for ORA to submit recommendations to CDER within 45 days of post-approval and surveillance inspections so that staff can follow up quickly with the manufacturer.
The need to oversee the growing number of overseas pharmaceutical manufacturers also is prompting US and European regulatory authorities to collaborate more on drug inspection activities. FDA and the European Medicines Agency (EMA) are moving forward with a Mutual Recognition Agreement (MRA) that will permit participants to rely more on each other’s inspection reports. By reducing the need to inspect all of more than 1000 registered drug production facilities in Europe, FDA would avoid duplicate site visits and free up resources to support greater oversight of firms in China, India, and other nations.
US and EU officials signed an agreement in March 2017 to extend and conclude the MRA negotiating process by July 2019 (4). The process involves FDA observing how EU member states inspect local facilities, and for EU officials to audit FDA’s inspection program. The two authorities also agreed in August 2017 to protect confidential information in inspection reports from public disclosure, which is important for sharing full inspection reports needed to decide whether or not to visit sites on each other’s inspection schedules. The EU completed its assessment of FDA inspection operations in July 2017, and FDA hopes to finish its audits of the 28 EU member states by mid-2019.
The current MRA initiative applies to GMP surveillance inspections for most drugs and biotech therapies, but could be extended to vaccines and veterinary products in the future. An important side-benefit of the final agreement may be to end EU batch inspection of US-made products shipped to Europe. In the future, pre-approval inspections might be covered in certain situations, prompting FDA and EU officials to examine how PAIs differ or are the same in the two regions. FDA’s need to complete such inspections in limited timeframes could lead to an agreement that permits FDA or EMA to request that a capable authority conduct a PAI by a certain date. More information on the MRA is available on FDA’s website (5, 6).
1. FDA, ORA Program Division Boundary Maps and Fact Sheets, FDA.gov.
2. FDA, Integration of FDA Facility Evaluation and Inspection Program for Human Drugs: A Concept of Operations, CDER, June 2, 2017.
3. S. Gottlieb, “New Steps to Strengthen FDA’s Inspection And Oversight Of Drug Manufacturing,” FDAVoice blog, FDA.gov.
4. FDA, “Mutual Recognition Promises New Framework for Pharmaceutical Inspections for United States and European Union,” News Release, March 2, 2017.
5. FDA, Frequently Asked Questions/The Mutual Recognition Agreement, March 2, 2017.
6. FDA, Office of Global Regulatory Operations and Policy (GO).
Volume 30, Number 11
When referring to this article, please cite it as J. Wechsler, “FDA Overhauls Inspection Process and Field Operations," BioPharm International 30 (11) 2017.