FDA warning letters address CGMP, clinical study plan failures

Intas Pharmaceuticals was again in hot water with the US Food and Drug Administration (FDA) for a host of current good manufacturing practice (CGMP) violations, including manipulating particle counts and defect quantities to keep products within rejection limits and failing to validate its manufacturing processes to ensure a state of control.

The problems were detailed in a 28 November warning letter and come on the heels of a May inspection at the company’s site in Ahmedabad, India. FDA also chastised Intas for not learning from its past mistakes and cited similar violations in a July 2023 warning letter (RELATED: FDA warns Intas, Centaur and Baxter over GMP violations at Indian facilities, Regulatory Focus 2 August 2023).

Since 2021, visual inspectors “manipulated particle and other defect counts on manual visual inspection records in many instances, in order to keep the finished product batches within rejection limits,” FDA wrote in the most recent warning letter to Intas. More specifically, the investigation found that operators manipulated the defect quantities to keep rejections within limits to avoid a deviation and investigation. This practice occurred in “at least” nine manual visual inspections.

Intas also failed to investigate “significant deviations” of its aseptic processing manufacturing operations involving visual inspection failures for non-viable particulates (NVP) that exceeded action levels. When conducted, investigations were often “insufficient and lacked scientifically supported” root causes.

The firm also failed to provide challenge test vials to ensure that operators could perform adequate visual inspection of drug products. Additionally, the company failed to maintain a defect library for training purposes.

FDA also scolded the drugmaker for failing to validate manufacturing process by not assessing inter- and intra-batch variability. In the absence of such evaluations, processing times were left to the operators’ discretion.

“Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. 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,” FDA wrote.  

The firm also failed to conduct smoke studies to evaluate whether laminar air flow (LAF) “can provide appropriate unidirectional air during dynamic activities.”

On 14 November, FDA placed the company’s products on an import alert. FDA told the company to schedule a regulatory meeting within five days and to respond to the violations within 15 working days.

Investigator didn’t follow plan

FDA also warned a clinical investigator for failing to adhere to a clinical study investigation plan in a 22 November warning letter. The agency told clinical investigator Melanie Hoppers of Physicians Quality Care in Jackson, TN, that it found “objectionable conditions” during a mid-December 2022 inspection, which was conducted under the agency’s Bioresearch Monitoring Program.

FDA objected to Hoppers’ handling of a Phase 3b multicenter trial evaluating the efficacy of Genentech’s Xofluza (baloxavir marboxil). The drug aims to reduce flu transmission from otherwise healthy patients to household members.

In at least six cases, patients were assigned to the study and dispensed the investigational drug without a laboratory-confirmed randomization, according to FDA.

“We emphasize that as the clinical investigator, you were ultimately responsible to ensure that your clinical study was conducted properly and in compliance with FDA regulations, both to protect the rights, safety, and welfare of study subjects and to ensure the integrity of study data. Your failure to ensure that subjects met protocol-required inclusion criteria, and your lack of oversight and supervision of the clinical study, raise significant concerns about the safety of study subjects enrolled at your site, and about the integrity of the data generated at your site,” FDA wrote in the warning letter.

Intas Warning Letter

Hoppers Warning Letter