An eleven-day FDA inspection in early 2023 of a contract manufacturer of homeopathic and over-the-counter (OTC) drug products, including those intended for infants and children, revealed serious lapses in the firm’s manufacturing, deviation, laboratory, and complaint investigation systems. This is an analysis of that Denison Pharmaceuticals 483, which turned into a Warning Letter.
The FDA found that customer complaints about product odor and adverse event reports for products labeled “safe for newborn” were not appropriately investigated, resulting in potentially harmful children’s products remaining on the market.
At the 48th annual International GMP Conference held in early March 2024 at the University of Georgia in Athens, Georgia, FDA national expert pharmaceutical investigator Simone Pitts reviewed some of the deficiencies documented in the warning letter issued to the firm – Lincoln, Rhode Island-based Denison Pharmaceuticals – on July 26, 2023.
“If you know anything about the agency,” she commented, “everything stops, and it’s all hands on deck when it comes to products involving babies. We have to take care of them and have to make sure they’re okay.” Based on the inspection findings, “there is no way that this was safe for infants and children.”
Pitts explained, “If you are a CMO, a contract manufacturer, you are held to the same regulations as if you were an original or an application holder. You are not off the hook. You are still liable. If you use a CMO, they are an extension of your company.”
Machine Lubricant in Product
The company was manufacturing products using an equipment lubricant that ended up in the product. It was not a food-grade lubricant, i.e., it was unacceptable for use in pharmaceutical manufacturing.
According to the warning letter, “your investigation into the contamination of (b)(4) with (b)(4) lubricant, a non-food grade lubricant not intended for ingestion, concluded that only Lot (b)(4) was impacted and was rejected. However, your investigation did not consider other potentially affected drug products manufactured in the same mixing tank and indicated that no corrective action and preventive action (CAPA) was required.”
Pitts pointed to the Code of Federal Regulations (CFR) section the agency cited in the letter, 21 CFR 211.192, that states in part, “Any unexplained discrepancy…or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy.”
She emphasized that “in the current thinking of the agency, you need to determine a root cause. You need to find out the issue, identify a root cause, and put in an effective CAPA. A CAPA is a corrective and preventive action to make sure that the issue that caused the failure in the very beginning will not happen again. The lubricant was used for manufacturing equipment over several months, and several batches were manufactured during this timeframe, including the products that were made for infants.”
The safety data sheet (SDS) from the lubricant manufacturer lists health hazards such as skin and respiratory irritation, genetic defects, and cancer, “which never should have made it into the finished product.”
In the firm’s March 2, 2023, response to the 483, it indicated it was conducting an investigation and considering recalling drug products. In a follow-up teleconference on April 19, 2023, the agency recommended the removal of “all batches of drug products currently in distribution from the U.S. market that were manufactured between April 2020, and December 2020, when the non-food grade lubricant was used in the mixing vessel.” On May 3, 2023, Denison issued a voluntary nationwide recall of the suspect products.
At the end of her presentation of this case study, Pitts offered this insight and advice: “For most of our inspections, we are only there for a small period of time, so a snapshot in time. So how we assess you is to make sure that you have all the bells and whistles in place. Most importantly, we are making sure that you have a quality unit – a quality unit that is present, and that is effective, and has the authority to do things like quality oversight, to make sure that they approve procedures, analytical methods, process validation. We are looking to make sure there is a robust quality management system in place.”
Analysis of the 483
Denison Pharmaceuticals 483 – February 2023 – Redica Systems
The 15-page, nine-observation FDA Form 483 (see it on Redica Systems here and here) was issued to Denison on February 17, 2023, by the FDA Investigators listed below. The Redica Systems FDA investigator profiles for each show inspection history and focus areas, the percent of time each investigator’s inspections results in a 483, and the % of the time those 483s result in a warning letter:
The Redica Systems Quality System Labeling (QSL) model is an algorithm designed and trained by industry experts to analyze the text in form 483s and warning letters and label the deficiencies by quality system and more granular subtopics under each system. In addition, the text is mapped to the CFR and the QSL lists the CFR the inspection deficiency most closely matches (“inferred CFR”).
Below is a list of the unique deficiencies noted by the QSL in the Denison 483 dated February 17, 2023. Some were found multiple times, but each is listed only once. Those that were specifically cited in the warning letter are noted with an *, including both those Pitts mentioned in her overview and those she did not.
Summary
The citations in the Denison warning letter focused on three areas:
● deviation investigations (21 CFR 211.192, the Quality Unit)
● laboratory identity testing (21 CFR 211.84(d)(1), the Materials System), and
● the accuracy, sensitivity, specificity, and reproducibility of test methods (21 CFR 211.165(e), the Laboratory system).
Examples of inspection findings under each of the three areas specifically cited also mention deficiencies in the company’s complaint procedures and the water systems it used in manufacturing.
Analysis of the 483 that led to the warning letter shows deficiencies in each of the six quality systems (Quality Unit, Facilities and Equipment, Production, Laboratory, Materials, and Packaging and Labeling), some of them multiple times. The range of deficiencies in the aggregate shows a contract manufacturer with critical issues, so it is not surprising that a warning letter resulted from the inspection.
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