FDA End-of-Year Release of Warning Letters Impresses (or Depresses)

Primacy and recency are recognized psychological phenomena: people tend to remember the first thing they hear, and the last.   It’s why litigators concentrate on their opening statement to a jury, and their closing argument.

Maybe that’s also why FDA last week publicized the highest number of important Warning Letters of the year (compared with prior releases in 2023).  Perhaps FDA wanted us to remember 2023 as the year FDA succeeded in uncovering critical defects in drug and device manufacturing, and in clinical trials.  If FDA wanted to create that impression, it likely succeeded.

Warning Letters, generally made public in a batch each Tuesday, are FDA’s public sanction that is most widely used to bring pressure on manufacturers and clinical trial investigators.  They have great impact on most companies that receive them.  Excluding rashes of Warning Letters for things like hand sanitizer manufacturers not checking their ingredients properly, there are only a few each week, at most, that address drug or device manufacturing issues, and rarely is there a Warning Letter addressed to investigators in clinical trials.  In fact, a statistical analysis of such Warning Letters issued over 2023 shows that there were only an average of about 3 per week.  Last week, 11 such letters were posted in the Tuesday batch of posted Warning Letters.  Four of the letters addressed failure to comply with drug Current Good Manufacturing Practice regulations, four more stated that the recipients were distributing unapproved drug products, two alleged violations of the Quality System Regulation by medical device manufacturers, and one was addressed to a clinical investigator.

Summaries of the most striking recently released Warning Letters are included below.  We are unable to determine whether the number of such Warning Letters issued during the entire year represents a significant increase over 2022.  The FDA compliance data, sorted by category, shows there were 159 Warning Letters issued to drug manufacturers or sponsors during 2023, with 161 issued in calendar year 2022.  Overall, in 2023, about 30 of the Warning Letters were issued to manufacturers of hand sanitizer, and we are not sure how many of the letters issued in 2022 were addressed to manufacturers of hand sanitizer.

Here, then, are the critical findings in the recent raft of letters:

• Omeza LLC, an Over-the-Counter drug manufacturer in Sarasota, Florida, was advised in a Warning Letter to hire an independent expert on good manufacturing practices because FDA said it “observed mold-like substance on an air conditioning unit sleeve” located in a drug product manufacturing area and “insects both alive and dead, and other animal waste” in areas used to store bulk drug products and samples. The letter also stated that the company’s response to the inspection report was “inadequate because it did not include a review of environmental monitoring data in your manufacturing areas, an adequate risk analysis of previously manufactured drug product, or testing of reserve samples from impacted batches.”
• Dextrum Laboratories Inc. of Miami, Florida, a contract manufacturer of over-the-counter (OTC) drug products, including oral cough and cold drug products marketed for both adults and children, was also advised in a Warning Letter to retain an independent expert on good manufacturing practices. FDA stated that the firm failed to adequately test each shipment of glycerin for diethylene glycol (DEG) or ethylene glycol (EG) contamination, failed to adequately validate production and process controls, and failed to conduct a retrospective review to ensure materials previously used were suitable for their intended use.
• Patcos Cosmetics Pvt. Ltd. of Mumbai, India, was criticized for many of the same issues. According to FDA, the company failed to show that there was adequate testing for DEG and EG, and failed to have an efficient and adequate quality unit.
• Colonial Dames Company, Ltd. of Commerce, California, received a Warning Letter because FDA alleged that it failed to establish Standard Operating Procedures for production and process control to ensure its products met appropriate standards of identity, strength, quality, and purity; failed to appropriately clean, maintain cleaning records, and to sterilize equipment; failed to have an adequate and efficient quality unit; and failed to have adequate stability data.
• Four drug manufacturing companies received Warning Letters for manufacturing or distributing products that FDA said were unapproved drugs, including East Fork Cultivars of Takilma, Oregon (cannabidiol products; Warning Letter; Hua Da Trading, Inc. of Brooklyn, NY (sildenafil in a product marketed as a dietary supplement; https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/hua-da-trading-inc-664359-12202023); Botanical Be of El Paso, Texas (“Kuka Flex Forte” and “Reumo Flex,” marketed as dietary supplements, contain diclofenac; Warning Letter; and com, Inc., of Seattle, Washington (selling products marketed as “energy enhancing supplements or food” that contained sildenafil, tadalafil, or other drug active pharmaceutical ingredients; Warning Letter.
• Two device manufacturers received Warning Letters for QSR violations (QSR is FDA’s label for cGMP requirements applicable to medical device manufacturers). Terragene S.A., an Argentinian company that makes and sells Biological and Chemical Sterilization Process Indicator Systems, allegedly failed to show adequate procedures to handle complaints. FDA stated that the firm received 96 U.S. market complaints in 2021 through 2023 but could not provide documentation to demonstrate how the complaints were reviewed or evaluated.  FDA said that the firm also did not have an adequate procedure to determine whether Medical Device Reports (MDRs) needed to be filed with FDA, and was distributing a product that was required to be cleared in a new 510(k) submission, but had not been.  Swedish company Sonesta Medical AB was accused of several violations of medical device design requirements, failure to exercise appropriate control over contractors, and failure to adequately review complaints and determine whether MDRs needed to be filed with FDA.
• Finally, FDA said in a Warning Letter that a Clinical Investigator, Anish S. Shah, M.D., of Siyan Clinical Research in Santa Rosa, California, performed study-defined efficacy endpoints without being properly blinded as to blinded to certain safety assessments (“for example, clinical laboratory evaluations, vital signs, physical examinations, and adverse event assessments”).

*Legal Assistant