FDA Inspections Face Overhaul

As part of agency initiatives to strengthen its oversight of human food and food products, FDA is revising inspection and compliance programs for all regulated products, at home and abroad. While an overriding aim is to improve FDA’s capability for monitoring and curbing contamination issues involving foods, the changes also involve revised oversight and inspection programs for medicines and other regulated products. Some of these actions arise from FDA’s greater reliance on remote oversight activities advanced during the global COVID pandemic, which encouraged more cooperation with foreign inspection programs. Others have been advanced by FDA for years, such as encouraging modern manufacturing processes and attention to quality issues to ensure reliable supplies to prevent drug shortages.

For these purposes, FDA is in the process of restructuring its Office of Regulatory Affairs (ORA) to better monitor food safety issues and to schedule field inspections more efficiently. A prime aim is to prevent delayed responses to serious food contamination issues, as occurred with the baby-formula recall in 2022, which created a national crisis in formula shortages (1). FDA Commissioner Robert Califf announced in June 2023 a revised model for ORA to better align with a new unified Human Foods Program and to coordinate and respond expeditiously to public health issues (2). Califf further implemented these changes with the appointment of the first Deputy Commissioner for Human Foods on August 23, 2023 (3). This high-level official will oversee all human foods programs and work closely with a new associate commissioner for regulatory affairs who will head up revamped ORA operations.

As part of these changes, FDA said in its June 2023 announcement that it will shift certain enforcement functions currently managed within ORA to compliance offices in FDA centers. This move aims to “streamline operations and expedite decision-making” so that the agency can determine more quickly what sites to inspect and what compliance actions to take. ORA will focus more on conducting investigations, inspections, and oversight of imports, still operating through offices for medical devices, human & animal drugs, biologics, and bioresearch monitoring inspections (BIMO). More details on the plan are emerging and will involve Congressional review and more formal rulemaking, as well as agreement from FDA unions and staff.

More foreign inspections

Furthermore, ORA is taking steps to strengthen its oversight of domestic and foreign drug manufacturing activities. Alonza Cruse, director of ORA’s Office of Pharmaceutical Quality Program Operations, reported at the PDA/FDA joint regulatory conference in September 2023 that the agency has resumed foreign inspections,
including those in China, and is implementing pilot programs for unannounced inspections of manufacturing facilities in China and India. Cruse also noted an expansion in cooperative inspection activities with European and other regulatory authorities under enhanced mutual recognition agreements (MRAs).

These initiatives reflect recent Congressional directives. Under the Food and Drug Omnibus Reform Act (FDORA) enacted in late 2022, the legislators encouraged more unannounced FDA inspections of foreign drug establishments, shifting away from FDA’s usual practice of scheduling foreign site visits in advance to ensure access to the facility. At the same time, FDORA aimed to reduce unneeded foreign site visits by supporting expanded FDA use of MRAs with trusted foreign regulatory counterparts to obtain reports and information related to pre-approval inspections, as well as more routine manufacturing site visits. The legislation supports FDA recognition of inspections by foreign regulatory counterparts, such as the European Union, the United Kingdom, Switzerland, and other established agencies, in an ongoing effort to minimize duplicative site visits by all parties.

Similarly, the Center for Drug Evaluation and Research (CDER) is ramping up its compliance and inspection efforts to further encourage quality production operations and prevent drug shortages. CDER director Patrizia Cavazzoni emphasized at the PDA/FDA conference the importance of manufacturers maintaining proactive and prevention-focused quality systems to ensure “sustainable compliance” with current good manufacturing practice (CGMP). This involves ongoing oversight of facilities by senior management, effective systems for detecting emerging quality issues, and a structured approach to determine the root cause of such problems.

A prime objective of such efforts is to prevent and mitigate shortages in critical drugs. While economic issues underly production shortfalls for many medicines, Cavazzoni cited drug quality problems and manufacturing delays as responsible for nearly half of new shortages last year. Increased authority for FDA to require early notification can help reduce the severe impact of certain supply situations, but CDER seeks proactive and prevention-focused quality systems at facilities to ensure consistent compliance with manufacturing standards. This entails involvement of senior management to ensure adequate ongoing control and sufficient resources for the operation. Management should implement effective systems for detecting emerging issues and assess the root cause of any violations. Inspection reports and warning letters should be addressed with effective corrective actions procedures. A commitment to quality assurance by industry, Cavazzoni emphasized, is “essential for dependable drug supply.”

Quality clinical trial operations

FDA’s emphasis on considering risk factors in planning for medical
product oversight also applies to BIMO investigations, an effort also encouraged by a provision in FDORA that clarifies FDA’s authority to conduct BIMO inspections and which sites and facilities are subject to this oversight and required to provide records and other information. FDA issued a guidance in April 2023 that makes recommendations to industry on implementing a risk-based approach to monitor investigational studies on human drugs, biologics, medical devices and combination products (4).

This expands on a 2013 guidance on this subject, here providing additional recommendations for sponsors in planning and developing research monitoring plans and assessing results from such activities. The guidance emphasizes the importance of data integrity in clinical trial monitoring and the need to design research protocols that identify potential risks for data collections. Centralized monitoring, moreover, should be applied across multiple clinical sites so that sponsors may detect inconsistencies or omissions in data and determine which clinical sites need further review.

References

1. FDA. FDA Provides Update on Proposed Human Foods Program and Office of Regulatory Affairs Restructuring. Press Release. Feb. 28, 2023.
2. FDA. FDA Provides Update on Proposal for Unified Human Foods Program, including New Model for the Office of Regulatory Affairs. Press Release. June 27, 2023.
3. FDA. FDA Names First Deputy Commissioner for Proposed, Unified Human Foods Program. Press Release. Aug. 23, 2023.
4. FDA. A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers, Guidance for Industry. April 2023.

About the author

Jill Wechsler is Washington reporter for BioPharm International.

Inspections Face Overhaul. BioPharm International 2023 36 (10).