Warning Letter: Microbiological OOS and Inadequate Microbiological Method Validation

From 22 to 24 April 2025, the FDA inspected the Absolutely Natural pharmaceutical manufacturing facility in Melbourne, a manufacturer of OTC products, and found significant violations of current good manufacturing practice (CGMP), which led to a Warning Letter in December 2025..

1. Inadequate OOS investigations

The company failed to thoroughly investigate microbiological deviations (OOS). A batch rejected in July 2024 due to elevated total bacterial count and detection of Pseudomonas aeruginosa was not sufficiently investigated for the cause of contamination, and potential impact on other batches was not assessed. The FDA is demanding a comprehensive, scientifically sound and documented root cause analysis, a retrospective review of all invalid OOS results for products still on the market, and an effective CAPA plan. The measures taken to date have been deemed insufficient.

The FDA therefore requires a retrospective, independent review of all invalid OOS results (including in-process and release/stability tests) for US products currently on the US market and not yet expired at the time of this letter, as well as a report summarising the results of the analysis, including the following information for each OOS:

• Evaluate whether the scientific rationale and evidence for the invalid OOS result conclusively or inconclusively demonstrate a causal laboratory error.
• For investigations that conclusively demonstrate the laboratory cause, provide a rationale and ensure that all other laboratory methods susceptible to the same or similar cause are also identified.
• For all OOS results where retrospective review has determined that no conclusive cause or no cause could be identified in the laboratory, a thorough review of production must be conducted and a summary of potential causes in manufacturing for each investigation and any improvements to manufacturing processes must be provided.
• A comprehensive review and corrective action plan for your systems for investigating OOS results.

The CAPA should include, among other things, the following points:

• Monitoring of laboratory investigations by the quality department
• Identification of unfavourable control trends in the laboratory 
• Elimination of causes of laboratory deviations
• Initiation of thorough investigations of possible causes in manufacturing if a cause cannot be clearly identified in the laboratory
• Appropriate scope of each investigation and its CAPA
• Revised OOS investigation procedures with these and other corrective actions

In addition, the FDA also criticised the following points:

2. Inadequate validation of microbiological test methods

The alternative rapid microbiological testing methods used have not been sufficiently validated and their equivalence or superiority to USP methods has not been demonstrated. The methods only provide qualitative pass/fail results and do not allow for reliable quantitative statements or trend analyses. Furthermore, their suitability for detecting Burkholderia cepacia complex (BCC) has not been proven. The FDA requires an independent assessment of laboratory practices, a complete re-evaluation and validation of all microbiological methods, and the establishment of appropriate specifications and testing strategies, particularly with regard to BCC.

3. Lack of identity checks for components

The company did not perform adequate identity checks on each incoming batch of components, particularly for high-risk substances. The required USP limit tests to detect hazardous contaminants were not performed consistently. Since contaminated components have led to fatal poisonings worldwide (e.g. ethylene glycol, diethylene glycol and other critical substances), the FDA considers this deficiency to be particularly critical. The announced corrective measures were deemed insufficient, as no retroactive testing of components already in use was performed.

Overall, the FDA sees significant systemic deficiencies in the areas of OOS investigations, laboratory methods, CAPA management and incoming goods inspections, and is calling for comprehensive, independent assessments and sustainable corrective measures. Further details can be found directly in the published Warning Letter.