FDA warns OTC maker over testing program, clinical investigator for failing to adhere to study plan

The US Food and Drug Administration (FDA) recently warned an over-the-counter (OTC) drugmaker citing the failures to conduct raw materials and release testing for its fluoride toothpaste tablets. In a separate compliance action, the agency warned a clinical investigator for failing to ensure that study drugs were administered to pediatric patients according to the clinical investigation plan. Both warning letters were posted to FDA’s website on 3 September.

OTC drugmaker Kaylaan LLC received a warning letter following a two-week inspection last spring. FDA said the company manufactured batches of its Kaylaan Toothpaste Tablets with Fluoride since 2021 without conducting release testing. FDA told the firm that “because you lack adequate testing of each batch of your drug product, it is unknown whether they conform to all appropriate finished product specifications and are suitable for release and distribution.”

Kaylaan also failed to test incoming raw materials to confirm their identity, and instead relied on the supplier’s certificate of analysis (COA) in lieu of conducting its own testing.

FDA said the company also failed to validate its processes and qualify equipment used to manufacture its OTC drug product. Company officials told FDA that even though the formula has changed since 2021, the manufacturing process has stayed the same. As such, formula changes were made “without adequate change control evaluation to assess the impact on finished product quality.”

Furthermore, the inspection noted numerous product quality defects such as chipping and sticking tablets.

FDA also faulted the company for keeping the facility in a poor state of repair. “Our investigator observed paint peeling from the floor, and windows that were cracked and repaired with tape. In addition, vents and light fixtures above tablet presses were covered in white powder,” said the warning letter. “It is essential your facility is in a good state of repair, and sanitary conditions are maintained to ensure ongoing suitability for drug manufacturing.

FDA told the company to hire a good manufacturing practice consultant to help resolve these issues and perform a comprehensive six-system audit of its entire operation.

The company has 15 days to resolve the issues identified in the warning letter.

Clinical Integrative Research Center cited for BIMO violations

A Center for Drug Evaluation and Research (CDER) investigator found “objectionable conditions” related to clinical investigator Julio Flamini’s oversight of patients participating in clinical investigations, according to a warning letter dated 20 August. The agency said that Flamini, a clinical investigator at the Clinical Integrative Research Center of Atlanta, did not adhere to an investigational plan, which resulted in the accidental overdosing of a subjects.

The trial protocol required the investigational drug be administered based on the patients’ weight over a 20-week titration phase. The protocol’s titration schedule dictated that subjects, who ranged in age from 12 to 18 years, were to receive a percentage of the daily dose of 0.2 mg/kg, not to exceed 12.5 mg per day. Yet a 15-year-old female, who weighed 59.1 kg (130 lbs), who should have received a dose of 1.2 mL, received 10 times the maximum daily dose for a total dose of 120 mg per day for 7 days, exceeding the weight-based dose.

The patient “was exposed to an increased risk of adverse events, such as Drug Reaction with Eosinophilia and Systemic Symptoms syndrome.” While no adverse events were reported, and the site reported that immediate action was taken to address safety concerns.

At the time of the occurrence, Flamini said that “no electronic dose calculator was provided by the sponsor, and the electronic dispensing algorithm lacked safety guards to prevent errors.”

To remediate this failing, the trial site established a standard operating procedure to address medication dispensation procedures and to “enhance the accuracy and integrity of medication dispensation process, to reduce the risk of dosage effects.”

Yet FDA said the response lacked details regarding the prevention of similar such violations in the future.

“We emphasize that as the clinical investigator, it is your responsibility to ensure that studies are conducted in accordance with the investigational plan, to protect the rights, safety, and welfare of subjects and to ensure the integrity of study data. Your failure to conduct the clinical study in accordance with the protocol resulted in an overdose of [redacted] to a pediatric subject. This conduct raises significant concerns about your protection of the study subjects enrolled at your site, and also raises concerns about the validity and integrity of the data collected at your site.”

The site has 15 days to correct the deficiencies identified in the warning letter.

Warning Letters: Julio R. Flamini, Kaylaan LLC

FDA warns OTC maker over testing program, clinical investigator for failing to adhere to study plan

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