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Industry should be seeking more information from FDA on how it will restart its current inspection program.
FDA announced in July that it plans to resume inspections of some US-regulated facilities this week, but it’s not clear how it will decide which sites to visit and what alternative oversight strategies will apply where on-site inspections are difficult. Yet, the resurgence in COVID-19 cases in the United States looks to limit actual inspections and require FDA to rely more on “virtual” inspections or “paper reviews.” The prospect of further delays in initiating foreign inspections, moreover, raises a host of questions about assuring access to the growing volume of drugs and active ingredients produced overseas and may boost collaboration with foreign inspectorates to vet their local facilities. Overriding all these planning efforts, however, is the expectation that multiple new COVID-19 vaccines and therapeutics will seek regulatory approval in the coming months and will require full FDA vetting of production facilities, operations, and records to allay consumer fears about product safety and quality.
In March 2020, FDA halted most foreign and then domestic field inspections, citing the need to protect staff overseas and the agency’s ability to block the import of any unsafe products at the borders. FDA officials emphasized that inspections are just one part of FDA’s program for assuring product quality and safety, and that manufacturers ultimately are responsible for ensuring compliance with standards. Although FDA initially indicated that inspections would halt for only a month or so, in May Commissioner Stephen Hahn acknowledged the need to further delay “routine surveillance inspections” as the pandemic continued.
During this inspection hiatus, FDA has conducted some “mission critical” site visits but has not provided details as to where such oversight has been warranted and how it was carried out. FDA inspections are particularly important for companies looking to resolve earlier Official Action Indicated (OAI) citations that prevent the filing of new applications and limit business opportunities. And manufacturers looking to bring new drugs to market usually require a pre-approval inspection (PAI) for final approval. But as the recent surge in COVID-19 cases in the US further delays state and local reopening, FDA is under pressure to devise new strategies for meeting application review deadlines set by user fees that increasingly involve drugs and medical products from facilities that were not inspected prior to the pandemic.
FDA now says it will resume “prioritized” domestic inspections in local areas able to reduce new COVID-19 cases and hospitalizations. Based on a state’s phase of reopening and local trend and intensity of infection, the plan is to determine where the agency can resume mission-critical inspections only, all inspections with measures to protect staff, or all regulatory activities. This approach has raised questions about which localities will qualify for site visits and what fits “mission critical” or “priority” categories: A new drug nearing its approval deadline? A site able to produce medicines in shortage? Or a firm looking to demonstrate that it has fixed earlier quality problems and wants to resume all operations?
One surprise is that FDA stated it will pre-announce all prioritized inspections, an approach that is routine overseas, but not at home. The agency explains that providing time to plan for site visits in advance will enhance the safety of both the inspectors and of company staff and also ensure that appropriate personnel are on-site when needed.
All these challenges raise the prospect that FDA may be conducting fewer on-site inspections in the coming months and will look to tap policies and programs that provide alternative oversight approaches. FDA gained more explicit authority under the FDA Safety and Innovation Act (FDASIA) of 2012 to use new methods to track manufacturing operations in the US and abroad, initially to reduce drug shortages linked to an increasingly global pharmaceutical supply chain. The legislation established a risk-based approach for determining inspection frequency, strengthened FDA’s authority to take action against manufacturers that refuse or delay an inspection, and authorized the agency to request and access manufacturer records “in lieu of or in advance” of an inspection.
This “in lieu of” provision for obtaining manufacturing records is considered key to providing a framework for more virtual or “records-only” inspections, according to experts participating in a recent webinar hosted by the Food and Drug Law Institute (FDLI). So far, FDA has been reluctant to conduct full remote inspections, but has accessed records for less formal “assessments” to help determine the need for and timing of a site visit. FDA guidance issued in October 2014 outlines procedures for the agency to request and obtain plant operating records for such purposes. With these provisions in mind, manufacturers should be establishing policies and systems able to evaluate and comply with FDA requests for production records, e-data bases, and relevant documents. At the same time, industry should be seeking more information from FDA on how it will restart its current inspection program, including the time frame for advance notices of planned inspections, how the agency is prioritizing inspections, and how a remote inspection would be conducted.