Warning letters issued for cGMP violations, refusing entry, and falsifying documents

The US Food and Drug Administration has cited several companies for failing to meet its current good manufacturing practices (cGMP) requirements. One company was also cited for refusing to allow inspectors into its facility and another was found to be falsifying documents.

On 18 February, FDA published five new warning letters issued to four firms, including two over-the-counter (OTC) drug manufacturers, and a drug testing lab. The companies were primarily cited for failing to meet cGMP requirements and ensuring the final products met specifications and validation requirements.

Warning letters were sent to Indian drugmakers Tyche Industries and Jagsonpal Pharmaceuticals. In addition to the cGMP violations, the FDA noted that Jagsonpal initially refused to allow inspectors into its facility in Rajasthan, India on 15 March 2024. The company eventually allowed inspectors into the facility five days later, but they were given limited documentation.

While Jagsonpal lists itself as the manufacturer on import records, FDA noted that the company has delegated much of the work to a contract manufacturing organization (CMO) to perform manufacturing, processing, and packaging activities. The agency also said that it did not adequately ensure the CMO completed process validations, master production instructions, and other duties.

"FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer," said FDA. "You are responsible for the quality of your drugs regardless of agreements in place with your contract facility."

Tyche was also cited for several cGMP violations, including failing to keep a record of all quality-related activities when they were performed. FDA inspectors said that a company management team member disclosed that two of its operators admitted to falsifying temperature data for a drying oven, which later failed to meet manufacturing specifications.

“In addition, an Assistant Manager in Production, an Assistant Manager in Quality Assurance, and a Quality Control Manager admitted to participating in the preparation of a ‘backdated calculation sheet’ that was given to our investigator,” said FDA.

“You state that you removed some of the employees involved in these incidents from CGMP-related activities, but you do not explain what was done to prevent the other employees involved in these activities from further data integrity deviations,” the agency added. “Finally, you do not fully evaluate the scope of data integrity lapses at your firm, including by interviewing current and former employees and comprehensively reviewing data records.”

Tyche was also cited for failing to clean equipment and utensils used to manufacture their active pharmaceutical ingredients (API) and for testing the identity of each batch of incoming production material. The company was also told that its quality unit does not fully exercise its authority and responsibilities and should be given authority and resources to do its job.

Marshalls Traditional Healthcare in South Africa was issued a warning letter for failing to show proper conformance of its OTC drugs to the final specifications of those drugs and for failing to conduct appropriate laboratory testing to ensure they are free of objectionable microorganisms. It was also cited for failing to establish adequate written procedures for production and process controls to ensure the drugs meet identity, strength, quality, and purity specifications.

“You did not have data to demonstrate that you adequately validate your manufacturing processes used to manufacture your OTC drug products and demonstrate that your processes are reproducible and controlled to consistently yield drugs of uniform character and quality,” said FDA.

“Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle,” the agency added. “Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs.”

While Marshalls said it has delisted the OTC drug with the FDA, the agency said it should notify regulators if it plans to resume manufacturing operations and ensure it has first resolved all the issues inspectors have cited it for. The agency also recommended that the company engage a qualified consultant to help it comply with cGMP requirements.

“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 before you pursue resolution of your firm’s compliance status with FDA,” said FDA.

Another OTC drugmaker, Texas-based rapheGenerics Corp, which is owned by AmWiner & Raphe Holdings, was also warned for cGMP violations. It too was cited for failing to ensure its final products were in conformance with the drug specifications.

“Your firm manufactures topical over-the-counter (OTC) drug products, including drug products that contain the active ingredient minoxidil,” said FDA. “You failed to establish adequate release testing procedures or specifications for your OTC drug products, and accordingly released batches of drug products for distribution without conducting adequate testing to confirm critical quality attributes.”

The company was also cited for failing to complete equipment and process performance qualification (PPQ) before marketing its products. It was also warned for lacking appropriate documentation, qualification, maintenance, and monitoring of the purified water system used to make its drugs.

Finally, ABR Laboratory, a contract testing lab that analyzes drugs was cited for not using proper methods to test its clients’ OTC drug products.

“Your method was not verified to be equivalent or better than the United States Pharmacopeia (USP) method used to test multiple OTC drug products for potential microbial contamination,” said FDA.

“Method suitability testing ensures the method can reliably determine the presence of microbial growth in the drug product,” the agency added. “Without evaluating the validity of methods, you lack assurance that the data provided to customers was an accurate reflection of pharmaceutical drug product quality and safety.”

FDA said it considers contractors an extension of the manufacturer's own facility, and their failure to comply with cGMP requirements may affect the quality, safety, and efficacy of the drugs it is testing for its clients.

“It is essential that you understand your responsibility to operate in full compliance with CGMP, and that you inform all your customers of any out-of-specification (OOS) results or significant problems encountered during the testing of these drugs,” said the agency.

ABR Laboratory was also cited for failing to thoroughly investigate unexplained discrepancies or batch failures. The agency ultimately recommended that it engage a qualified consultant to help it come into conformance.

Warning letters

Warning letters issued for cGMP violations, refusing entry, and falsifying documents

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