FDA reprimands two OTC drugmakers for inadequate screening for contaminants

The US Food and Drug Administration (FDA) has recently warned two manufacturers of over-the-counter (OTC) drugs for failing to test their products for the presence of contaminants. Specifically, the agency warned one company for making hand sanitizers contaminated with either methanol or benzene and another company for failing to test cough and cold products for diethylene glycol (DEG) and ehylene glycol (EG).

The warning letters were issued in mid to late December and highlight priorities and concerns that have been high on the agency’s radar this past year. Last year, an FDA compliance official told a meeting that said benzene contamination is a “hot topic” that is causing “a lot of issues” in the quality space, and also expressed concerns about the growing number of contaminated products containing DEG or EG, which are some of the “scariest things” his office is seeing (RELATED: FDA official cites concerns with benzene and DEG contamination, Regulatory Focus, 8 May 2023).

Firm taken to task for not screening for methanol and benzene

Following a summer inspection, FDA sent a warning letter to Inopak, Ltd., of Ringwood, NJ, for failing to test its hand sanitizers for benzene and methanol, two contaminants. The warning letter was issued on 15 December and posted on 2 January.

The firm used a contract manufacturing organization (CMO) to manufacture its SaniGuard SF foam hand sanitizer alcohol 70%. While using a CMO, however, the firm ignored its responsibilities stated in the quality agreement stipulating its responsibilities for reviewing formulations, specifications, laboratory results, batch records, and certificates of analysis (COAs), according to FDA.

Specifically, the firm’s quality unit (QU) failed to adequately review this documentation attesting that that required testing was conducted for methanol before accepting the component for use in drug manufacture. The firm failed to ensure that ethanol used in the product had acceptable levels of known impurities such as benzene, acetaldehyde, and acetal.

FDA has issued a plethora of warning letters and public health advisories over the past two years to firms making adulterated hand sanitizers contaminated with either methanol or benzene. In some cases, these firms have refused FDA’s request for records (RELATED: FDA issues blitz of warning letters over testing violations and refusing records requests, Regulatory Focus 9 August 2023).

The firm also failed to adequately investigate the leaking drug product received from its CMO. FDA said the firm “segregated and labeled the product as rejected as established in your procedures. However, your procedures do not adequately establish a requirement to investigate or communicate to your CMO to investigate non-conformances such as leaking drug products.”

The firm also failed to maintain an ongoing stability testing program to support the expiration date of distributed drug products. The firm is no longer manufacturing drugs at the facility.

Dextrum lambasted for not screening ingredients for DEG

Dextrum Laboratories of Miami, FL, a contract manufacturer of OTC drugs, including oral cough and cold drug products marketed for adults and children, was warned for failing to test the active pharmaceutical ingredient dextromethorphan for diethylene glycol (DEG) or ethylene glycol (EG) contamination.

The agency reminded the firm that “identity testing for this and certain other high-risk drug components include a limit test in the United States Pharmacopeia (USP) to ensure that the component meets the relevant safety limits for levels of DEG or EG. Because you did not perform identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in manufacture of your drug products.”

FDA also told the firm that “the use of ingredients contaminated with DEG or EG has resulted in various lethal poisoning incidents in humans worldwide.”

The firm was also lambasted for failing to adequately monitor the microbiological quality of the water used to manufacture their aqueous-based OTC drug products. FDA told the company that “water for pharmaceutical must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes.”

The firm was advised to correct these deficiencies within 15 days, and failure to address the violations may result in regulatory or legal action, including seizure or an injunction.

Clinical investigator did not adhere to clinical study plan

FDA also warned a clinical investigator for failing to follow a clinical investigational plan for testing a drug to treat depression. The inspection was conducted under the agency’s Bioresearch Monitoring Program (BIMO).

Contrary to the clinical study plan, which stated that the safety assessments had to be completed by a blinded assessor, the clinical investigator Dr. Anish Shah, director of Siyan Clinical Research in Santa Rosa, CA, was not blinded. The blinded assessor was responsible for administering efficacy assessments, including the Montgomery-Asberg Depression Rating Scale (MADRS) assessments, that were required to be completed during all study visits from Visit 2 until Visit 8 or early termination.

The warning letter states that “specifically, as a designated blinded rater, you conducted a total of 16 MADRS assessments for all three subjects enrolled at your site…. However, you were not blinded to certain safety assessments.” These safety assessments included vital sign measurements, including blood pressure, heart rate, and body temperature.

Despite the protocol stating that the blinded assessor would not have access to the ClinTrak Electronic Data Capture system and not have access to subject source data, Shah “failed to adhere to this requirement.”

FDA told Shah that “your administration of at least five of the seven required MADRS assessments for each enrolled subject as an unblinded assessor, as well as your failure to ensure that protocol-required blinding procedures were followed, raises significant concerns about the reliability and integrity of the data collected at your site.”

Shah has 15 days to notify FDA of any actions taken to resolve the deficiencies resolved in the warning letter.

Inopak warning letter; Dextrum warning letter; Shah warning letter

FDA reprimands two OTC drugmakers for inadequate screening for contaminants

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