FDA warns Intas, Centaur and Baxter over GMP violations at Indian facilities

The US Food and Drug Administration (FDA) on 1 August posted warning letters it recently delivered to three drugmakers, Intas Pharmaceuticals Limited, Centaur Pharmaceuticals Private Limited and Baxter Healthcare Corporation for good manufacturing practices (GMPs) violations at their facilities in India.

The agency’s warning letter to Intas followed an inspection of its Sanand, India facility in November and December 2022 cited the firm for “significant” GMP violations, including data integrity lapses, such as the unauthorized destruction of records, and other problems found in the production and laboratory areas.

FDA said the firm “failed to ensure reliability of data relating to the quality of medicines produced at your facility.”

FDA investigators found plastic bags “filled with torn and discarded original CGMP documents” in multiple places at the facility; in its quality control (QC) scrap area, in the parenteral scrap room and on a truck outside the facility. Among the discarded documents were engineering checklists associated with the Environmental Monitoring System (EMS), torn Karl Fischer (KF) analytical test reports, auto titration curves and analytical balance weight slips.

In another case, inspectors found that an analyst “destroyed CGMP records by pouring acetic acid in a trash bin containing analytical balance slips.” A quality control unit employee had observed the same analyst destroying records and reported the incident to quality control laboratory management. Yet the company waited six days to launch an investigation.

FDA inspectors also found that an analyst weighed out the same samples of amitriptyline hydrochloride tablets USP 100 mg batches multiple times, yet did not report all the test results, and in some cases, discarded balance printouts in the trash. In addition, the time stamps on the analytical balance and printouts did not match its Laboratory Information Management System (LIMS) records.

The firm also failed to exercise appropriate controls over its computer systems by allowing manual changes to be made in the electronic batch record entries prior to saving. In another case, the inspector observed a production employee “manually alter the reported time that an operation was performed.”

Other problems were found in the laboratory; the agency found that colony forming units (CFU) were not accurately measured in the lab’s environmental monitoring (EM) data. “Our investigators observed colony counts shortly after being read by your analyst for environmental and personnel monitoring that did not match your official records,” FDA wrote.

The firm also had lax procedures for controlling the manufacturing process by not evaluating both inter-batch as well as intra-batch variability.

The agency recommended the company hire a consultant and the firm was placed on an import alert.

The warning letter follows a Form 483 citing data integrity violations, such as altering and manipulating visual inspection records and using these deficient records to release products, at another Intas facility in Gujarat, India. (RELATED: This Week at FDA: Leqembi fully approved, Senators at odds over PAHPA, and more, Regulatory Focus 7 July 2023)

Baxter reprimanded for multitude of GMP violations

Baxter Healthcare’s sterile drug manufacturing facility in Ahmedabad, India was also targeted in a warning letter posted on 1 August for a multitude of GMP violations, including a failure to conduct adequate investigations, such as endotoxin testing and 100% automated visual inspections of sterile products.

Baxter also failed to keep its equipment clean and in good working order; investigators found white spots on the bottom of a bulk holding tank despite the vessel being documented as clean.

In addition, FDA investigators found equipment had damaged metal and plastic parts, and open vials were exposed to worn bolt threading. In addition, the process flow “required employees to duck underneath the sterile processing line conveyer in order to perform interventions near open vials.”

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

FDA advised Baxter to hire a GMP consultant and to respond within 15 days to the warning letter.

Centaur had not cleaned sections of equipment in 14 years

FDA found similar equipment cleaning lapses during its inspection of Centaur Pharmaceuticals in Maharashtra, India, where the firm makes alprazolam and clobazam tablets. Agency inspectors found residues of possibly different products on direct and indirect product surfaces.

In response, the firm acknowledged that the “sections” of the equipment had not been cleaned since being installed 14 years ago.

FDA said that “dirty surfaces can facilitate contamination of the drug.”

FDA also criticized the firm for failing to adequately investigate extraneous peaks observed in long-term stability samples tested for dissolution by high-performance liquid chromatography (HPLC).

The firm investigated and attributed the peaks to “interference from excipients used during manufacturing” and concluded that the peaks do not impact product quality. Yet the firm was unable to provide a scientific explanation for this conclusion.

This is the second warning letter the company has received in 30 days. Intas’ active pharmaceutical ingredient (API) site in Mumbai was chastised in an earlier warning letter for failure to maintain adequate oversight of its paper and electronic records, including the shredding of GMP documents without adequate justification. (RELATED: FDA warns API manufacturer, OTC maker for sloppy GMP oversight, Regulatory Focus, 21 July 2023)

Intas, Baxter, Centaur

FDA warns Intas, Centaur and Baxter over GMP violations at Indian facilities

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