The US Food and Drug Administration (FDA) has a backlog of almost 500 domestic pharma inspections, having performed only a third of its usual number last year because of the Covid-19 pandemic. Our analysis of inspection data shows that the FDA would need to complete at least an extra 457 inspections in the US to account for the shortfall between 2019 (692 inspections) and last year (235 inspections).
Acting FDA Commissioner Janet Woodcock stated in a press release this month that the pandemic had “significantly impacted” inspections. At the onset of the pandemic, the FDA reserved US inspections for ‘mission-critical’ issues, temporarily postponing all routine domestic inspections on 17 March 2020 and abroad on 10 March. As the pandemic continued, the FDA launched Covid-19 Advisory Rating Levels to resume prioritised domestic inspections.
Mission-critical inspections involve products that have received breakthrough therapy or regenerative medicine advanced therapy (RMAT) designation, are otherwise the only drug for a serious disease, or are for Covid-19. They may also involve a product that requires surveillance due to recall, or that is linked to serious adverse events. According to a ‘Roadmap’ document issued by the FDA this month, the agency will continue to prioritise ‘mission-critical’ inspections throughout the rest of the pandemic. Routine surveillance inspections will also take place, but at longer intervals than under normal circumstances.
Since last March, the FDA has carried out 106 domestic inspections for non-biologic drugs and 53 for biologics. The FDA increased its use of remote assessments during the pandemic. Recent guidance states that the agency may use teleconference, livestream video and/or pre-recorded video, and screen sharing of data and documents during remote inspections (B/POR, April 2021).
Regulators accept that virtual and desktop inspections are now the standard until the Covid-19 emergency has ended. Despite this, health officials at the 2021 ISPE Global Pharmaceutical Regulatory Summit webinar on 28 April stated that onsite inspections were much better at uncovering violations of good manufacturing practice (GMP) and that they were keen to resume them.
Carmelo Rosa, the director of drug quality at the FDA’s Centre for Drug Evaluation and Research, was asked during the ISPE webinar how to prepare for a desktop audit. He responded that “[the FDA is] asking for the same information multiple times.” This includes reports on out of specification results, validation reports and information from previous inspections. He said that submitting this information “would really help in [the FDA’s] request for records.”
Alonza Cruse, the director of pharmaceutical quality operations at the FDA’s Office of Regulatory Affairs, added that “Good communication is important. Start getting introductory questions, maybe do a test of the technology [used for the audit].” Cruse added that it is important to have a “good point of contact or a translator to help us understand what is going on.”
Inspection failures increase as FDA directs attention to problem sites
There are three outcomes to an FDA inspection. The most serious outcome is Official Action Indicated (OAI). An OAI is issued after a Form 483, which must be answered within 15 days and can lead to serious regulatory consequences and the potential for a Warning Letter. Voluntary Action Indicated (VAI) means that problems were found but the FDA is not prepared to take regulatory action. No Action Indicated (NAI) means no objectionable conditions were found during the inspection.
Inspection outcomes for facilities in the US are better than for India and China (E/MOR, March 2021). In 2019, the last year in which inspections were carried out normally, OAIs were given after 11% of inspections in the US, 14% of inspections in India, and 16% in China. Voluntary Action Indicated (VAI), meaning problems were found but the FDA was not prepared to take regulatory action, was given after 49% of inspections in the US, 52% of inspections in India, and 63% in China. Since 2011, the Pfizer subsidiary Meridian Medical Technologies (Columbia, MD, US), and PharMedium Services (Lake Forest, IL, US) have received the highest number of US facility OAIs, with nine each.
An excess capacity manufacturer of drug delivery devices, Meridian markets its own auto-injectors filled with poison antidotes and for the treatment of convulsions and pain. It markets these products to the US armed forces, US emergency medical personnel, the North Atlantic Treaty Organisation (NATO) and other armed forces. Most of its OAIs occurred in 2013–2014, with one of the violations including not following procedures designed to prevent microbiological contamination of sterile products. In 2017, the FDA found significant GMP violations in epinephrine auto-injectors, including Mylan’s EpiPen and EpiPen Jr, during an inspection of Meridian’s plant in Missouri.
PharMedium Services was a compounder owned by Amerisource Bergen. It operated four facilities in Tennessee, Mississippi, Texas and New Jersey before it closed last year. In May 2019, a US District Judge entered a consent decree of permanent injunction prohibiting the company from manufacturing drugs at its Tennessee facility. Despite previous warnings from the FDA, PharMedium had manufactured adulterated oxytocin and morphine sulfate in insanitary conditions (B/POR, June 2019). AmerisourceBergen announced PharMedium’s closure last year.
The importance of inspections and maintaining drug quality (and of contract manufacturing organisation relationships) was brought into sharp focus by the pandemic. Emergent BioSolutions (Gaithersburg, MD, US) recently had disasters at its plant in Baltimore, Maryland, where the company allegedly ruined up to 30 million doses of Covid-19 vaccine.
In March, Emergent contaminated 15 million doses of Johnson and Johnson’s (J&J) (New Brunswick, NJ, US) Covid-19 vaccine by mixing up ingredients with AstraZeneca’s (Cambridge, UK) vaccine. In a separate incident, the facility discarded up to a further 15 million doses of J&J’s Covid-19 vaccine between last October and this January because of suspected contamination, the New York Times has reported. Following an FDA inspection of the facility on 12 April that discovered multiple serious problems, Emergent was forced to stop manufacturing any new material at the site and to quarantine existing doses (B/POR, March 2021).
FDA cuts 60% of inspections over decade
Figure 1 shows that the number of FDA GMP inspections in the US was already declining between 2011 and 2019 before the outbreak began. There were 1,681 inspections in 2011 compared to just 692 inspections in 2019, representing a fall of 59%. The passage of the FDA Safety and Innovation Act (FDASIA) ratified the FDA’s move to a risk-based approach and removed the requirement to inspect domestic facilities on a fixed biennial schedule.
Since 2012, the FDA has directed more frequent inspections to higher-risk facilities. The FDA uncovered more deficiencies, particularly in foreign facilities that had not been inspected as frequently as domestic ones prior to the inception of FDASIA and the Generic Drug User Fee Act (GDUFA). The FDA’s drug inspection program shifted from one focused heavily on US-based facilities through the early 2000s to a programme that, since 2015, has conducted more foreign than domestic drug inspections.
In a previous article, entitled FDA Faces Backlog of Hundreds of China and India Facilities as it Restarts Inspections, we found that the number of FDA inspections in both China and India had increased over the same decade (EMOR, March 2021). This has accompanied a rise in offshoring of manufacturing by US pharma companies for profitability, especially the relocation of active pharmaceutical ingredient (API) manufacture to India and China.
Despite this, when measured against the number of facilities, US inspection rates are higher than those in Asia. In 2019, there were around 71 inspections for every 100 FDA-registered facilities in the US (according to facility numbers as of 17 May 2021 in the GlobalData Contract Service Providers database), whereas there were 28 inspections for every 100 FDA-registered facilities in China and 33 inspections for every 100 facilities in India (EMOR, March 2021).