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With the cancellation of most field site visits last year due to the coronovirus pandemic, FDA now faces a serous backlog in inspections both in the US and abroad.
For years now, Congressional leaders and policy watchdogs have urged FDA to bolster its oversight of foreign drug manufacturing facilities to better ensure the quality and safety of the growing volume of medicines and ingredients imported to the US. With the cancellation of most field site visits last year due to the coronavirus pandemic, FDA now faces a serous backlog in inspections both in the US and abroad, raising the risk of shortages in vital medicines as well as access to needed treatments to counter new variants to the COVID-19 virus. Greater scrutiny of the vulnerability in the biopharmaceutical supply chain, moreover, as more drug manufacturing has shifted overseas, has increased pressure on FDA to renew site visits of facilities at home and around the world.Even before the COVID-19 pandemic, FDA faced significant challenges in conducting timely inspections of foreign facilities, namely a shortage of trained investigators, the need to pre-announce facility inspections, and language barriers that made site assessments more difficult and less reliable. The pandemic has made the situation even worse, according to the latest report from the Government Accountability Office (GAO), which finds that FDA failed to complete more than 1000 of planned surveillance inspections in 2020 due to travel restrictions and safety concerns imposed by the pandemic. FDA conducted just three foreign mission critical inspections and 52 domestic inspections between March and October 2020, compared to more than 600 foreign inspections during the same period in 2019.1 FDA’s China office resumed some preapproval inspections in October 2020, but plans for surveillance inspections remain uncertain.
GAO predicts that continued postponement of planned surveillance inspections to ensure compliance with good manufacturing practices (GMPs) will greatly increase the number of facilities in high-risk categories—i.e., those never inspected or not visited for five years or previously cited for infractions. Such developments could undermine FDA’s risk-based inspection program, which aims to better target agency resources to operations most likely to raise pharmaceutical quality and safety issues.
This serious drop-off in manufacturing inspections comes after years of complaints from GAO and other analysts about inadequate FDA oversight of the growing number of foreign firms producing drugs and active pharmaceutical ingredients (APIs) for the US. At a hearing this week before the House Appropriations subcommittee that handles FDA funding, GAO health care director Mary Denigan-Macauley expressed fears that the mounting inspection backlog could take years to address.2
As in several past reports, GAO criticizes certain FDA inspection practices as limiting the effectiveness of foreign site visits. A main target is the agency’s practice of providing up to 12 weeks advance notice of its plan to inspect a foreign facility, a timeframe FDA officials claim is necessary to ensure that a plant is open and operating before making costly arrangements to send an inspector. Greater use of FDA staff posted in China or India can reduce the pre-announcement timeframe to a few days, but these operations are limited. The practice of relying on foreign companies to select translators for inspections is also noted by GAO, which proposes that FDA adopt the European Union policy of providing a manufacturer with a list of approved translators for the company to select one and pay for the service. More product sampling and testing at US borders led to FDA put 54 foreign manufacturers on “import alert,” but that addresses only a fraction of potential problems and is “not a substitute for an inspection,” according to the GAO analysts.
FDA’s field inspection program continues to have difficulties in hiring and training investigators, particularly those able and willing to travel overseas. The legislators noted that Congress provided additional funds last year to address problems with the foreign inspection program, but that the resources were used primarily to update and correct FDA’s inventory of active manufacturing sites to better identify those overseas facilities actually subject to inspection. It remains to be seen if FDA is able to address some of these issues with a portion of the $500 million in additional funding provided to bolster agency programs and initiatives to combat COVID-19.
Some manufacturers and agency critics maintain that inspections should resume, with investigators being vaccinated and provided protective gear. This raises the issue of whether inspections of pharmaceutical producers and research sites are considered “essential” under current guidelines and therefore should override travel restrictions and other limitations on federal agency programs. Although there has been much talk about expanded use of alternative methods to check that a facility meets good manufacturing practices (GMP) standards, FDA has appeared reluctant to consider scrutiny of paper records and of inspection reports from European inspectorates sufficient in many cases. FDA says it continues to assess the viability of making greater use of alternative inspection methods, such as virtual inspections using remote video viewing systems.
In addition to the cancellation of most GMP inspections, GAO also notes a sharp decline in preapproval inspections usually conducted to support market approval of a new therapy. While this change did not delay approval of most new applications for much of last year, as many facilities had been assessed prior to the inspection shut-down, months of inactivity now appear to be taking a toll on the agency’s ability to confirm the capabilities of a facility not inspected in recent years.3
Although many of the 1000 postponed surveillance inspections may not cause immediate damage, continued delays may have lasting repercussions on FDA’s reputation for providing a global standard for effective oversight of medicines and medical products. Members of Congress charged with approving FDA’s annual budget aim to further address these issues in the coming months. Proposals on the table may seek to encourage more biopharmaceutical production in the U.S. by authorizing “country of origin” labeling or public disclosure of a manufacturer’s compliance status, along with added FDA support for modern manufacturing systems that can better ensure product quality with less oversight.