Drugmakers receive FDA warning letter for cGMP violations, failure to obtain IND approval

The US Food and Drug Administration (FDA) has published several recent warning letters addressing current good manufacturing practice (cGMP) violations by drugmakers, as well as one warning letter sent to a company for conducting clinical trials without submitting an investigational new drug (IND) application.

On 11 February, FDA published warning letters to Wuhu Nuowei Chemistry and Chengdu Innovation Pharmaceutical in China and another letter to Texas-based Strukmyer Medical for failing to adhere to cGMP requirements. The agency also published a letter to ISOThrive warning the company for conducting two clinical trials of an investigational drug without first obtaining an IND.

FDA said it inspected ISOThrive under its Bioresearch Monitoring (BiMo) Program between 26 and 30 June 2023. While agency investigators notified the company that it was conducting clinical investigations of a drug without IND approval, the company argued that its drug qualified for an IND exemption.

More specifically, ISOThrive said that it qualifies for an exemption because the investigational drug is a commercially available dietary supplement, the endpoint of its studies was the tolerability of the product, and the clinical investigations were not designed to treat a disease. FDA, however, disagreed with its reasoning.

FDA said ISOThrive's product must first be lawfully marketed in the US as a drug to be exempt from an IND requirement.

"For the reasons described below, we conclude that the evidence collected during the inspection shows that [the product] was intended for use as a drug, not as a dietary supplement, in the two clinical investigations named above," said the agency. "Therefore, ISOThrive was required to submit an IND before conducting the clinical investigations."

ISOThrive had written to FDA stating that it would update its procedures to ensure that its decision-making to determine whether an IND is required is better aligned with the agency's requirements. Regulators noted that the company did not provide details on its corrective action plans to take such steps, and therefore, its response is inadequate.

FDA also sent warning letters to three drugmakers for failing to meet cGMP requirements.

In its letter to Wuhu Nuowei Chemistry, FDA inspectors said the company failed to ensure that its specifications and test procedures are appropriate to ensure that its active pharmaceutical ingredients (APIs) meet standards for quality and purity. The company's quality unit was also cited for failing to ensure that the API manufacturing procedures followed cGMP requirements and regulators said that the company failed to establish written procedures for cleaning equipment used to manufacture its API.

“Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP,” said FDA. “In addition to the lack of effective management oversight of your production and laboratory operations, we found your [quality unit] is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities.”

“Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to FDA requirements,” the agency added.

While Wuhu Nuowei Chemistry said it would stop producing all drugs meant for the US market and deregister its facility as a drug manufacturer, the FDA asked whether it plans to resume producing drugs for the US at the facility in the future and whether it would notify customers of its plans.

"If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations," said the agency. "If your firm intends to resume manufacturing drugs for the US market, you should engage a consultant qualified to evaluate your operations to assist your firm in meeting CGMP requirements."

In its warning letter to Chengdu Innovation, FDA said the company failed to test the identity of each lot of incoming production material, and its quality unit also failed in its duties. More specifically, the unit was warned for failing to establish a system to release or reject raw materials, intermediates, packaging, and labeling materials.

“The records and information you provided demonstrate that your quality unit (QU) did not effectively exercise its responsibilities to oversee the quality of your drug manufacturing operations,” said FDA. “Specifically, your QU did not establish an appropriate system to approve or reject incoming materials.”

“Based upon the nature of the deviations we identified at your firm, you should engage a consultant qualified to evaluate your operations and to assist your firm in meeting CGMP requirements,” the agency added. “The qualified consultant should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your corrective actions and preventive actions.”

Finally, FDA sent a warning letter to Strukmyer Medical, a company in Texas that produces products such as adhesive medical devices, collagen and other biological products. The company was cited for failing to adequately investigate unexplained discrepancies, batch failures or ensure that any batches of any of its products meet specifications.

"On over 60 occasions, your firm isolated objectionable microorganisms (e.g., Burkholderia, Pseudomonas, Staphylococcus, Bacillus, and Aspergillus species) from your [redacted] water system used as a component to manufacture over-the-counter (OTC) drug products intended for use in wounds and on burns between November 1, 2022 and July 10, 2024," said FDA.

"You failed to adequately investigate and implement corrective actions to determine root causes and prevent recurrence of these contamination incidents," the agency added. "We note that this drug product was previously the subject of a recall in 2020 for microbial contamination with Burkholderia cepacia."

Strukmyer was also cited for failing to adequately test components for identity and conformity and failing to properly validate and establish the reliability of its component supplier's test analyses. The company was also cited for failing to sanitize and sterilize equipment properly in its manufacturing process and for establishing a quality control unit empowered to approve and reject products or their components. The agency further recommended that the company consider engaging a qualified consultant.

Most companies were asked to respond to FDA’s warning letters within 15 working days stating their actions to ensure they complied with the agency’s regulatory requirements. Chengdu Innovation Pharmaceutical was given 30 working days to respond.

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Drugmakers receive FDA warning letter for cGMP violations, failure to obtain IND approval

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