Remote inspections prompt drop in data integrity citations in FY2021

The inability to conduct onsite inspections impeded investigators’ ability to uncover data integrity issues at manufacturing sites in drug warning letters in FY2021, underscoring the importance of onsite inspections, said US Food and Drug Administration (FDA) consumer safety officer Maan Abduldayem.

Abduldayem provided an update on enforcement actions taken by the Center for Drug Evaluation and Research’s Office of Manufacturing Quality at the 46^th annual International GMP conference in Athens, GA. The meeting, held virtually on 8 March, was co-sponsored by the University of Georgia College of Pharmacy and FDA. He also addressed which countries are being targeted in warning letters and some top deficiencies cited in the letters.

FDA’s inability to conduct boots-on-the-grounds inspections has not significantly impeded the issuance of warning letters, according to Abduldayem’s presentation released at the meeting. FDA issued 82 drug GMP warning letters in FY2021 and 81 letters in FY2020. In FY2019, before the pandemic took hold, 99 warning letters were issued. These numbers exclude warning letters sent to compounding pharmacies.

Citing declining COVID-19 cases, FDA resumed its domestic surveillance inspections in February 2022. (RELATED: FDA to resume routine domestic surveillance inspections next week, Regulatory Focus 4 February 2022)

During much of the COVID-19 pandemic, FDA relied on the use of alternative tools, such as remote records requests and sampling in lieu of conducting onsite inspections.

Significant drop in onsite inspections

Abduldayem reiterated an earlier observation by FDA that a growing number of enforcement actions stem from inspection alternatives, such as sampling products and reviewing companies’ written responses to record requests, rather than from traditional onsite inspections. (RELATED: FDA official: Growing number of enforcement actions stem from inspection alternatives, Regulatory Focus 1 November 2021)

Final numbers for FY2021 show 58.5% of the warning letters were based on testing samples, 26.8% were based on inspections, 12.2% stemmed from records requests and 2.4% followed a manufacturer’s refusal to comply with a records request.

This stands in marked contrast with FY2020, when an overwhelming majority of warning letters, 97.5%, were based on onsite inspections and only 2.5% were based on testing samples.

Data integrity violations dropped

Abduldayem said the drop in onsite inspections translated into a marked decrease in data integrity violations found at firms. In FY2021, investigators noted data integrity lapses in five warning letters, dropping from 32 such violations found in FY2019 and 24 in FY2020.

"There has been some decrease in the number of cases involving data integrity ... this highlights the importance of physical inspection of sites," Abduldayem said.

Examples of data integrity violations include destroying retain samples and batch records that are missing, problems that were noted in a February warning letter to Indian drug maker Indiana Chem-Port. (RELATED: Indian firm warned for litany of violations related to API manufacturing, Regulatory Focus 16 February 2022.

Shift in countries receiving warning letters

Another trend is a noticeable shift in countries where warning letters are going; companies in Mexico received significantly more letters than past year, while Indian firms received fewer.

The number of warning letters going to sites in Mexico jumped from three in FY2020 to 43 in FY2021, as due to FDA’s crackdown on adulterated hand sanitizers.

US companies received the second highest number of warning letters at 21, a decrease from the 35 in FY2020. Sites in the rest of the world, which includes Europe, received nine, decreasing from 18 letters sent in FY2020.

The number of warning letters sent to sites in India dropped from 16 to two, while letters to Chinese manufacturers increased slightly -- from seven in FY2020 to nine in FY2021.

In other areas, Abduldayem said the top GMP deficiency found in warning letters in FY2021 were inadequate failure investigations under 21 CFR 211.192 as well as inadequate written procedures under 211.100(a); these two violations were found in 61 warning letters. The next top deficiency was inadequate stability testing procedures, a violation under 211.166(a) found in 46 letters.

He said that some of the “themes” observed in recent warning letters are inadequate process validation or low process capability; deficient investigation of laboratory processes; “excessive” variably in the quality of components; chemical or microbial contamination of drug products; deficient facilities or equipment; and quality unit failures.

International GMP meeting

Remote inspections prompt drop in data integrity citations in FY2021

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