Accuracy, Specificity and Reproducibility of Analytical Test Methods in the Focus of a FDA Warning Letter

The U.S. Food and Drug Administration (FDA) has issued a warning letter dated April 12, 2022, to an American manufacturer of over-the-counter (OTC) drug products.

During an inspection from August 30 to September 14, 2021, the FDA investigators observed significant violations of current Good Manufacturing Practice (cGMP) regulations for finished pharmaceuticals. Among others, the analytical test methods had not been validated for accuracy, specificity, and reproducibility. Further violations concern the process validation and OOS investigations.

Accuracy, Specificity and Reproducibility of Analytical Test Methods

The firm released OTC drug products based on release testing performed by a third-party contract testing laboratory. However, the analytical test methods had not been validated for accuracy, specificity, and reproducibility.

The FDA describes an example. Thus, a zinc oxide release test method was used in the contract testing laboratory, although this method was only validated for another customer’s zinc-based products. In addition, this unvalidated test method lacked scientific evidence to demonstrate that it is stability-indicating for the firm's specific formulations.

It should be noted that the problem had already been known for a long time. In the warning letter, the FDA writes: "FDA initially made you aware of your lack of method validation over two years ago during your previous inspection and since then, you manufactured, released, and distributed numerous batches from multiple product codes without having adequate release and stability method validation data. This is a repeat violation."

Process and Cleaning Validation

According to the FDA, the company distributed various OTC drug products with at least 23 unique drug product item codes, but failed to adequately validate the drug manufacturing processes and lacked adequate process validation studies for these products. Furthermore, there appear to be significant gaps with regard to cleaning validation.

Both seem to be problems that have already existed for a longer period of time. The company had committed to performing process and cleaning validation for the products in response to the previous inspection and at a regulatory meeting held with FDA at the end of 2019. However, only PPQ studies for one product were performed, and no validation report had been completed.

OOS Investigations and Ineffective CAPA

Another issue concerns inadequate OOS investigations and ineffective corrective actions and preventive actions (CAPA). According to the FDA, the company repeatedly obtained OOS viscosity and high water activity results during an approximately two-year time period. The company's approach was that if the water activity exceeded the specifications, the batch would then be tested for bioburden. The FDA notes that several of these high water activity batches were also OOS for bioburden and failed release. In addition, the company received multiple complaints regarding product consistency and regarding lack of effect.

The FDA is very concerned and writes in this regard: "You rejected this lot, but your investigation did not determine the root cause of the microbial failure or extend the investigation to determine if any additional lots may have been affected. It is also concerning that you obtained OOS results for high water activity and failing results for bioburden in a product that does not appear to contain water as a component."

Further Procedure

The list of measures and documents required by the FDA on all three sets of issues is very long. Based upon the nature of the violations, the FDA strongly recommends engaging a consultant to assist the company in meeting cGMP requirements. Failure to promptly and adequately address the points mentioned may result in regulatory or legal action.

For further information, please see the complete FDA Warning Letter to The W.S. Badger Company, Inc.