Final Guide on Investigating Out-of-spec Results
FDA has released a revised final guidance entitled “Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production.” The document discusses how to investigate OOS test results, including the roles/responsibilities of lab personnel, the lab phase of the investigation, additional testing that may be necessary, when to expand the investigation outside the laboratory, and the test results’ final evaluation.
Specifically, the revision updates terminology for consistency with current FDA guidance, and it clarifies concepts related to addressing outlier results, and practices related to the averaging of OOS results. The guidance stresses the importance of each step in the investigation being adequately documented. Lab managers should determine not only the reliability of the individual value obtained, but also the significance these OOS results represent to the lab quality assurance program.
Laboratory managers should also be cognizant of developing trends. “As part of an effective quality system, a firm’s upper management should appropriately monitor these trends and ensure that any problematic areas are addressed,” the guidance says. “Laboratory error should be relatively rare. Frequent errors suggest a problem that might be due to inadequate training of analysts, poorly maintained or improperly calibrated equipment, or careless work. Whenever laboratory error is identified, the firm should determine the source of that error and take corrective action to prevent recurrence. To ensure full compliance with the CGMP regulations, the manufacturer also should maintain adequate documentation of the corrective action.”
The agency says that when evidence of laboratory error remains unclear, a full-scale OOS investigation should be conducted by the manufacturing firm to determine what caused the unexpected results. “OOS test results should not be attributed to analytical error without completing an investigation that clearly establishes a laboratory root cause,” it says.
When an OOS investigation does not point to a laboratory error and testing results appear to be accurate, then a full-scale OOS investigation using a predefined procedure should be conducted, the guidance says. “A full-scale investigation should include a review of production and sampling procedures and will often include additional laboratory testing,” it says.