FDA Warning Letter: Deviation from USP Compendial Methods

The U.S. Food and Drug Administration (FDA) has published a Warning Letter dated April 14, 2022. This Warning Letter goes back to an inspection from September 20 to September 24, 2021. The firm's response to the FDA 483 issued after the inspection was considered inadequate by the FDA "because it did not provide sufficient detail or evidence of corrective actions to bring [the] operations into compliance with CGMP."

The product in focus is Mint Gel Topical Anesthetic, a United States Pharmacopeia (USP) article manufactured by Cetylite Industries, Inc., an American firm located in New Jersey.

Deviation from USP Compendial Method

The core problem was that the company deviated from the USP for analytical testing, but could not adequately demonstrate that the method is equivalent or better than the current USP compendial method.

More concretely, it was about the fact that the company utilized a compendial method for the aerosol form instead of using the compendial method for Benzocaine, Butamben, and Tetracaine Hydrochloride Gel to analyze the drug product. However, the company had not appropriately validated that the aerosol method was suitable for testing the gel form. On the contrary, the data provided by the company in response to the Form FDA 483 showed differing results from the company's test methods versus the USP compendial method for the gel product.

The FDA now expects that only current USP compendial methods are used until alternative methods have been demonstrated to be equivalent or better than the USP methods. Furthermore, all reserve samples for all drugs released to the U.S. market within expiry must be tested using a validated method.

Inadequate Investigate of an out of specification (OOS) test result

The second aspect of the Warning Letter concerns an OOS investigation.

After an OOS for tetracaine HCl for potency was observed, the company retested using the corresponding USP compendial method, which also resulted in an OOS. After that, the laboratory retested the sample using two additional methods, which finally led to passing results. The batch was then released without further investigations.

This practice is, of course, not GMP-compliant. Therefore, it is even more surprising that the company itself considers the approach to be in line with the regulations, even in retrospect. In the Warning Letter, the FDA writes in this regard: "In your response you stated that you believe that your OOS investigation was a thorough investigation that supported the quality unit’s decision to release the lot. Your response is inadequate, you repeatedly tested the sample until you achieved a passing result without establishing a scientifically sound justification for the repeated tests including an OOS when you used the compendial method."

The complete Warning Letter to Cetylite Industries, Inc. can be found on the FDA website.