FDA Form 483 due to Insufficient Investigations after OOS and OOT Results

Observations made by the inspector during an FDA inspection are listed on the FDA Form 483. The FDA regularly publishes some of these reports under "Frequently requested or proactively posted compliance records" on the FDA homepage.

On 15 May 2023, a new FDA Form 483 was published. The document dated 26 April 2023 refers to an inspection over several days in April 2023 at an Indian drug manufacturer.

Out-of-Specification (OOS) and Out-of-Trend (OOT) Results

The first observation addresses the investigation of OOS and OOT results for assay test by HPLC methods. The report describes several investigations in detail. According to the FDA, the company failed to follow its own SOPs. In particular, a complete investigation as established by the OOS and OOT procedures was not performed in several cases. Instead, the company invalidated OOS and OOT results by retesting the respective batches without a scientifically justified root cause.

Handling of Deviations

The second observation concerns the firm's deviation investigations and associated corrective and preventive actions (CAPAs). Similar to the OOS and OOT investigations, the own SOP was not followed. In particular, the FDA documented several examples where CAPAs were open for several months without justification for the long timeframe.

In another example, after an OOS for dissolution test, a human error as the root cause was identified. The company implemented a CAPA stating that the procedures should be updated and the analyst should be trained on the revised SOP. A few months later, another OOS for the same dissolution test was recorded. The FDA writes that the "firm again identified human error as the root cause, as the analyst did not ensure the tablet was placed in respective vessels 10 and 11. This is the same root cause that was identified earlier and CAPA was implemented, and procedures were updated. According to the investigation, the analyst was trained on the revised procedure. This confirmed that the CAPA and/ or training is not effective".

The full report, which also describes several other observations, is available as a PDF file on the FDA website.