FDA official: Most drug GMP warning letters in FY2022 stemmed from onsite inspections

A US Food and Drug Administration (FDA) official said that most warning letters issued for drug good manufacturing practice (GMP) issues in fiscal year 2022 were the result of onsite inspections, reversing a pandemic-era trend of enforcement actions triggered by the use of alternative tools.

Yet the agency faces “incredible challenges” going forward, as it tackles a backlog of inspections that were put on hold during the pandemic, asserted Jeffrey Meng, program division director, Division of Pharmaceutical Quality Operations III, Office of Regulatory Affairs, who provided an update on compliance activities at the PharmaLink conference hosted by the Regulatory Affairs Professionals Society (RAPS) and the Association of Food and Drug Officials (AFDO).

Meng also offered insights on what the agency will be looking for in inspections going forward.

Onsite inspections: The gold standard

In FY 2022, FDA issued 62 warning letters and 23 import alerts related to drugs, excluding compound related actions. The number of warning letters prompted by onsite inspections increased dramatically in FY 2022; 42 (67.7%) of the warning letters followed onsite inspections, while 16 (25.8%) resulted from inspecting samples and four (6.5%) were the result of a records request.

In FY 2021, fewer warning letters followed onsite inspections, as the pandemic halted many inspections, except for those deemed mission critical. In FY 2021, 21 (25.3%) of such warning letters followed onsite inspections. The remainder stemmed from alternative tools: 59% were from testing samples, and 13.3% emanated from a records request, while 2.4% were from a refusal of a section 704 records request. (RELATED: FDA Officials: Growing number of enforcement actions stem from inspection alternatives, Regulatory Focus 1 November 2021)

Meng told attendees that onsite inspections are the “gold standard, because it allows a more holistic snapshot of a firm’s operations,” while alternative methods only allow FDA to see “a fraction of the firm’s operations.”

Challenge going forward

The agency faces a daunting challenge in addressing the backlog of foreign and domestic onsite inspections for sites considered high priority but were not deemed mission critical.

“Looking forward to 2023 and beyond, we have resumed all routine domestic operations and are currently resuming normal foreign inspections. This opening of worldwide operations for FDA will be and is an incredible challenge.”

He said that the FDA has already made “incredible headway” in addressing the domestic backlog.

Firms should exercise appropriate controls

Meng said that to avoid enforcement action, companies should exercise appropriate controls and oversight of their products. He illustrated two warning letters showing what can happen when these controls are not exercised.

The first example was Pharmatech LLC, a drug and dietary supplement manufacturer that operated in Florida, and manufactured and distributed Diocto Liquid, a drug used to treat constipation. In July 2016, FDA conducted an inspection following an outbreak of Burkholdria cepacia infections tied to use of the product. FDA found that the water sample taken from the firm’s water system had tested positive for the presence of the bacteria and issued a warning letter. (RELATED: s FDA Warns of Bacterial Contamination in Pharmatech Liquid Drugs, Regulatory Focus, 9 August 2017)

The firm told FDA that the company fixed its water system yet failed to do so.

In June 2022 the CEO, Raidel Figueroa, pled guilty to “conspiring to defraud FDA, falsifying records in an FDA investigation, obstructing proceeding from the FDA, and distributing adulterated drugs,” according to a statement from the Department of Justice. The contamination resulted in multiple adverse events, including deaths; there are several pending wrongful death lawsuits pending.

Another case involved Illinois-based Dental Technologies. Investigators found that a sample of the firm’s Paroex 0.12% chlorhexidine oral rinse contained Burkholderia cepacia complex in quantities too numerous to count on an aerobic plate during an inspection that followed a mass recall of the drug in October 2020. (RELATED: This week at FDA; Medtronic MiniMed problems; Device Classification Flurry, Regulatory Focus 17 December 2021)

“I bring these examples to your attention because I firmly believe that in 2022, we should not be experiencing deaths tied to liquid product ADEs [adverse drug event] in drugs,” said Meng. “Make sure that you have appropriate controls and oversight” over your product.

FDA will be relying on new CPGs

Looking ahead, Meng said FDA will be taking a hard look at management responsibility and risk management in upcoming inspections, as per the agency’s recently updated compliance policy guideline on good manufacturing practice (GMP) preapproval and post-approval surveillance inspections. (RELATED: FDA addresses alternative inspecting tools, expectations for nitrosamine assessments in updated CPGs, Regulatory Focus 17 October 2022).

Meng said the CPGs are “critical” and are the agency’s’ “bread and butter for inspections going forward.”

“We are using a risk-based model to decide on which firms to inspect next and for industry side we expect formal implementation of risk management programs so that we can have better assurance over the quality system of the product being manufactured.”

AFDO/RAPS PharmaLink meeting

FDA official: Most drug GMP warning letters in FY2022 stemmed from onsite inspections

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