Two OTC manufacturers warned for inadequate investigations, lax testing and validation practices
Two domestic drug manufacturers were criticized in warning letters recently sent by the US Food and Drug Administration (FDA) for similar good manufacturing practice (GMP) violations tied to poor failure investigations, and slipshod programs for testing incoming ingredients, including proper screening for ethanol. Other issues stemmed from inadequate validation of manufacturing processes, and both firms were cited for repeat violations.The warning letters, which were posted on 12 April, targeted Fresno, CA, based firm Generitech Corporation, a manufacturer of a topical hydroquinone cream, and Yusef Manufacturing Laboratories, a maker of sunscreens and hand sanitizers based in Clearfield, Utah.
Investigators cited Generitech for four GMP deficiencies, including a failure to perform identity tests for salicylic acid active pharmaceutical ingredients (APIs) used to formulate its drug product. FDA said, “without adequate testing, you do not have scientific evidence that your raw materials conform to appropriate specifications before use in the manufacture of drug products.”
For several batches, assay results for the salicylic acid exceeded specifications, yet failures were not adequately investigated.
The firm also failed to validate manufacturing processes and did not adequately qualify equipment used to manufacture products. The warning letter states, “You have not completed the appropriate process performance qualification (PPQ) studies for multiple topical OTC drug products, and you do not have a rigorous ongoing program to monitor process control to ensure stable manufacing operations and consistent drug quality.”
“Without appropriately validating your processes and qualifying our equipment, you cannot demonstrate that your manufacturing process can consistently manufacturing drug products that meet predetermined quality attributes,” said FDA.
The company also failed to keep equipment clean; such equipment was used to manufacture both topical OTC drug and cosmetic products.
FDA said that “inadequate removal of active ingredients and residues from manufacturing equipment during cleaning can result in cross-contamination of your drug products.”
Similar GMP problems were observed in an April 2014 warning letter. “Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate,” said FDA.
Yusef did not test ethanol API
Similar GMP problems were observed by investigators after a September 2021 inspection of Yusef Manufacturing Laboratories. For instance, the company was lambasted for not testing ethanol API from its supplier.
FDA reminded the company that “the use of ethanol contaminated with methanol has resulted in various lethal poisoning incidents in human worldwide.” The agency advised the company to consult its January 2021 guidance Policy for Testing of Alcohol (Ethanol) and Isopropyl Alcohol for Methanol, Including During the Public Health Emergency (COVID-19).
The warning letter also offers insights on how not to conduct a failure investigation. For example, a failed assay result was generated through testing one batch of SPF30 Lip Balm Sunscreen. Instead of conducting a thorough investigation of the failed batch, the firm collected fresh samples from the top, middle and bottom of three boxes of unlabeled finished product and obtained passing results, instead of reporting the average of the passing results.
The firm was also criticized for not adequately validating manufacturing processes to demonstrate that the processes are reproducible and controlled. “Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw materials inputs, in-process material and finished drugs,” FDA said, further noting that “successful process qualification studies are necessary before commercial distribution.”
The firm also failed to support the product’s three-year expiration date with adequate stability studies.
Like the Generitech warning letter, the firm was also criticized for not learning from past mistakes. Similar violations were observed in a 2017 warning letter, as well as during previous inspections conducted in September 2007, February 2011, May 2016, February 2018 and September 2019.
FDA warning letter to Generitech
FDA warning letter to Yusef Manufacturing
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