Identity Testing of Glycerin in Focus of an FDA Warning Letter

Recommendation

10-12 October 2023
Barcelona, Spain

Validation of Analytical Test Procedures & Measurement Uncertainty
Qualification and Validation in an uncertain analytical world – a holistic approach

On 01 August 2023, the U.S. Food and Drug Administration (FDA) has published a new Warning Letter. The document dated 18 July 2023 goes back to an inspection in January 2023 at a drug manufacturing facility in Illinois. The FDA considers the firm's response to the inspection findings, which preceded the Warning Letter, as "inadequate because it did not provide sufficient detail or evidence of corrective actions to bring [the] operations into compliance with CGMP."

As in several cases in recent months, it is again about a US manufacturer who failed to conduct proper identity testing of glycerin and other high-risk components.

Identity Testing of Glycerin

According to the FDA, the firm failed to test the incoming components for identity prior to manufacturing the over-the-counter (OTC) drug products. In addition, the company "relied on certificates of analysis (COAs) from unqualified suppliers for specifications such as purity, strength, and quality." Therefore, it was not ensured that the incoming components met the appropriate specifications.

The FDA points out that glycerin is an example of a component with higher risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination. The use of glycerin contaminated with DEG has resulted in various lethal poisoning incidents in humans worldwide. For this reason, according to the United States Pharmacopeia (USP), the identity testing of glycerin and other high-risk components such as propylene glycol includes a limit test to ensure that the component meets the relevant safety limits for the levels of DEG or EG.

In this context, the FDA once again expressly draws attention to its guidance document "Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol".

The FDA now expects test results for DEG and EG in retain samples to be made available retrospectively. In addition, a risk assessment for drug products within expiry which contain any ingredient at risk for DEG or EG contamination is expected.

Further CGMP Violations

In addition to the above-mentioned glycerin testing, a number of other CGMP violations are documented in the Warning Letter:

• Process validation: No data to demonstrate that the manufacturing processes were adequately validated could be provided.
• Cleaning validation: The company used the same equipment for drug products and nonpharmaceutical products such as cosmetics. However, no evidence that cleaning validation for the equipment used to manufacture the OTC drug products could be provided.
• Water system: Although the firm uses water as a component to manufacture the OTC drug products, no documentation that a qualification of the water system was performed was available. In addition, the firm failed to show that the water system is monitored adequately.
• Quality unit (QU): During the inspection, it came out that multiple documents related to CGMP activities had not been completed. This includes SOPs, validation plans, the stability program, CAPAs and CGMP training.

For further information and a complete list of all the actions the FDA expects the company to take, please see the Warning Letter to Avlon Industries, Inc. on the FDA website.

Further Warning Letters related to Glycerin

As mentioned above, one of the main findings was that the glycerin was not checked for the presence of diethylene glycol (DEG) or ethylene glycol (EG). This aspect has been criticized by the FDA several times in recent months. However, the problem seems to have been around for years, as shown by the two examples from 2020 and 2018, respectively, in the following table: