FDA Warning Letter: OOS Handling and HPLC Method Validation

At the beginning of January 2026, the U.S. Food and Drug Administration (FDA) published a Warning Letter dated 23 December 2025, citing significant current good manufacturing practice (CGMP) violations, with a particular focus on out-of-specification (OOS) investigations and HPLC-based analytical controls. The Warning Letter refers to an inspection conducted in July 2025 at a manufacturer of over-the-counter (OTC) drug products in Michigan, as well as to the company’s response to the Form FDA 483 issued at the conclusion of the inspection.

Investigation of OOS Laboratory Results

The FDA criticized the company for repeatedly failing to conduct scientifically sound and conclusive investigations into several out-of-specification (OOS) assay and stability results for OTC products. Multiple failing stability time points were retested without identifying robust root causes, no effective corrective and preventive actions (CAPAs) were implemented, and customers were not informed about distributed lots with failing results.

Of particular concern to the agency was the continued reliance on “packaging defects” as a presumed root cause, without providing data to demonstrate how such defects could impact assay results. Similar observations had already been raised during a previous FDA inspection, highlighting a recurring deficiency.

HPLC Analysis

In parallel, the FDA identified major deficiencies in laboratory controls, specifically related to sample preparation procedures used for HPLC analysis. The applied preparation techniques were not adequately validated and may themselves have contributed to inaccurate or OOS results.

Although the firm acknowledged gaps in method validation, it failed to assess the full impact on historical test data and did not establish adequate interim controls while revalidation activities are ongoing.

Conclusion

As corrective action, the FDA is requesting a comprehensive, independent retrospective review of all invalidated OOS results for products currently on the U.S. market, full remediation of the OOS investigation and CAPA systems, strengthened quality unit oversight, and a thorough reassessment and revalidation of analytical methods and overall laboratory practices.

This case once again underlines that weak OOS investigations and poorly justified HPLC methodologies are not isolated findings, but indicators of systemic quality failures, with direct consequences for product compliance, market access, and regulatory confidence.

For further information, please refer to the Warning Letter issued to Tower Laboratories Ltd. on the FDA's website.