FDA warning letters highlight data integrity issues

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Of the 70 Warning Letters issued by the US Food and Drug Administration (FDA) so far in 2024, three have identified data integrity issues at pharmaceutical manufacturing sites outside the US. Specifically, these recent warning letters describe microbiology and environmental monitoring related data integrity issues.

Data integrity violations in the microbiology lab

The first deviation – failure to follow and document laboratory controls at the time of performance, and failure to document and explain any departures from laboratory procedures – relates to the lack of data integrity within the microbiology laboratory.

In a letter issued to China-based Sichuan Deebio Pharmaceutical Co. Ltd on 5 February, the FDA’s Center for Drug Evaluation and Research (CDER) identified two significant deviations from current good manufacturing practice (cGMP) for active pharmaceutical ingredients (API), following a September 2023 inspection.

In the letter, FDA stated the company failed to ensure the integrity of data generated by the QC microbiology laboratory. Specifically, it highlighted that “investigators observed that numerous microbiological plates…were not read and recorded contemporaneously.”

“Non-contemporaneous documentation on laboratory worksheet records raises concerns about the validity and integrity of your firm’s laboratory testing records,” FDA added. The letter listed remediation activities, pointing to FDA guidance on Data Integrity and Compliance with Drug cGMP.

Environmental monitoring issues

A separate letter issued to Amman Pharmaceutical Industries of Jordan on 14 February detailed issues with environmental monitoring at their facility.

The company’s response indicated that it would perform a retrospective evaluation of “indicators of sterility assurance… with applicable product impact assessment.”

FDA deemed this response “inadequate” in part because it “failed to consider that persistently deficient environmental controls (eg, poor design of processing lines, lack of data integrity, and insufficient environmental monitoring) provide a fundamental lack of meaningful retrospective data to support daily sterility assurance.”

FDA asserted that laboratory data indicating the absence of microbial recovery “cannot be considered valid in light of the significant data integrity breaches that call into question the general reliability of your firm’s test results.”

FDA warning letters highlight CAPA concerns

Inadequate quality systems

The FDA also wrote to S & J International Enterprises Public Company Limited in January, stating that the company’s quality system “does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture.”

“Specifically, your QU did not implement adequate controls to prevent the alteration of production records, to ensure the complete documentation of laboratory preparation, and to ensure the review of raw analytical data.”

Based on its inspection findings, the FDA concluded that for instance, production staff could alter master batch records. These included “modifying batch formulations and other parameters or formulations before printing.”

Moreover, the company’s response was “inadequate” according to the FDA, due to not providing adequate detail or evidence of corrective actions to bring its operations into compliance with cGMP.

Data integrity has been highlighted as a key issue by the US FDA over recent years, being mentioned in 61 percent of warning issued in 2021.² Based on EPR analysis of the FDA letters,¹ issued as of 12 March 2024, the majority (33) were issued by the Center for Tobacco Products, with 19 issued by FDA’s CDER.

References

1. Warning Letters. [Internet} US FDA. [cited2024Mar]. Available from: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters
2. How to Avoid Warning Letters for Data Integrity Nonconformances. [Internet} MasterControl. [cited2024Mar]. Available from: https://www.mastercontrol.com/gxp-lifeline/data-integrity-trends/