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Plan to keep new methods adopted during COVID in place.
Although FDA announced in Februarythat it was resuming “normal, routine domestic surveillance” of drug and medical product manufacturing facilities, many of the innovations and modifications for site inspections adopted during the COVID-19 pandemic will continue to play a visible role in agency compliance and enforcement operations. FDA’s Office of Regulatory Affairs (ORA) delayed or cancelled most on-site inspections during the past two years due to travel restrictions and infection concerns, but now seeks to resume active inspections where needed and practical.1
This shift, however, does not signal an end to FDA’s wider use of paper document reviews and of virtual site visits, or remote interactive evaluations (RIEs), in ramping up oversight of biopharma manufacturing and research operations. These strategies notably reduced agency inspection costs, while enabling timely detection of compliance issues, and FDA sees value in continuing its expanded reliance on documents and records, on inspection reports from trusted regulatory authorities, and on wider use of remote real-time review of records and plant operations to provide assurance of proper manufacturing and clinical research operations.2
Judith McMeekin, associate commissioner for regulatory affairs, pointed out during a presentation sponsored by the Alliance for a Stronger FDA on April 6 that ORA saved nearly $40,000 in 2020 and 2021, providing resources to develop a foreign travel planning system, expand personnel training, enhance information systems, and upgrade labs. FDA analysts are comparing the benefits and shortcomings of onsite inspections vs. record requests in order to develop criteria for revising or continuing these alternative practices.
More flexible inspection programs could gain from legislation before Congress to reauthorize FDA user fees and update agency operations and policies. The bill includes a provision to clarify FDA’s authority for collecting manufacturing records from medical device makers in advance or in lieu of field inspections and also for clinical study sites under the agency’s bioresearch monitoring program (FDA already has such authority for drugs). The measure also clarifies agency use of inspection findings of trusted foreign regulatory authorities in determining the need for preapproval inspections (PAIs). The bills requires FDA to post more information on the findings from drug and device inspections, such as warning letters and import alerts. And to expand unannounced FDA inspections of foreign drug establishments, the legislators propose a new pilot to increase such site visits and to evaluate the impact on both domestic and foreign facilities.3
In response to these developments, FDA has worked to better explain its criteria for selecting and methods for conducting more remote and alternative facility assessments. At the recent FDA Generic Drugs Forum, staffers from the Office of Pharmaceutical Manufacturing Assessment (OPMA) in the Center for Drug Evaluation and Research (CDER)’s Office of Product Quality (OPQ) explained that FDA will weigh the need for an on-site inspection based on a risk-based assessment of product, process and facility risks.4 This involves scrutiny of records and other manufacturer information from trusted regulatory authorities.
Such information on a firm’s compliance history, process risks, manufacturing experience, and previous alerts, recalls, and complaints will help determine whether a PAI is needed or if FDA can assess the company’s capacity for risk mitigation and GMP compliance from company and regulator records. When FDA considers an RIE advisable, it will discuss the logistics, scope, and expectations with the manufacturer, request needed documents from the firm in advance, and outline its main questions or concerns and the logistics for conducting a remote facility tour. Such virtual site visits also can help all parties prepare for a future on-site inspection, if warranted, but do not qualify as formal inspections per se. They are voluntary for the company, but a refusal to cooperate with an RIE request can delay product approval.
OPMA Staff Fellow Alexander Gontcharov described an RIE for a foreign manufacturing facility utilizing a new unit of operation to produce delayed release tablets and capsules. This involved four three-hour sessions with a facility “walk-through” using a laptop on a cart with external cameras and microphones. Another RIE for a new unit producing new ointments and liquid products had three four-hour sessions that used a portable tablet PC with Wi-Fi connections. FDA investigators viewed warehouses, labs, and production areas, as well as document control systems. Inspection findings may be specified in a close-out memo, or FDA may later send a letter identifying difficulties found at the facility and if an on-site inspection is needed.
The shift to remote assessments is reflected in the rise of warning letters that involve alternative inspection tools, according to the 2021 annual report from CDER’s Office of Compliance (OC).5 While FDA exercised enforcement discretion in multiple cases to avoid shortages of critical medicines, OC reports a rise in drug adulteration warning letters based on sample testing and on information from records requests. In addition, OC conducted more than 45 remote regulatory assessments (RRAs) of clinical sites under the agency’s biomedical research compliance program. An FDA draft guidance published in April 2021 advises manufacturers on how the agency seeks to conduct this growing range of remote evaluations.6
Overall, FDA advises manufacturers to recognize the importance of RIEs and to query about any unclear agency information requests. While FDA recognizes that RIEs are not equivalent to full inspections and that the agency only can see what the firm makes available, these alternative tools have cut the need for on-site PAIs in half and helped the agency meet user fee approval goals for 90% of applications this past year.