Warning Letter to Indian Sterile Manufacturer due to egregious GMP Deficiencies

The nine-day FDA inspection of an Indian pharmaceutical manufacturer had already taken place in October 2023. Due to the numerous and, as the FDA itself writes, egregious GMP violations and the inadequate response to the list of deficiencies by the manufacturer, a Warning Letter has now been issued. 

Insanitary conditions

The FDA classifies the medicinal products manufactured by the Indian pharmaceutical manufacturer as contaminated because they were manufactured, packaged or stored under insanitary conditions. The FDA inspectors found the manufacturing facilities to be in a state of disrepair, inadequately cleaned and maintained. Among the findings mentioned were residues next to the HEPA filters in the ISO 5 area, several barefoot employees in an ISO 8 area and employees bringing materials into the ISO 7 area without the required protective clothing and gloves. Sterile filling takes place in a RABS, which was visibly dirty.

And even if these deficiencies would be enough, the FDA lists further critical GMP deficiencies in its Warning Letter.

Inadequate, aseptic working methods

The FDA describes deficiencies that were observed during the manufacture of sterile medicinal products: Employees used a cloth to wipe down parts of the filling line and conveyor belt in the ISO 5 areas. In addition, employees blocked the protective air flow by leaning over open product. Employees did not wear goggles and had exposed skin during line set-up and aseptic operations. In addition, the FDA criticised the lack of monitoring of aseptic behaviour and the effectiveness of employee training.

Deficiencies in the media fill

During the inspection, it was noted that the aseptic operations simulated during the media fill were not sufficiently representative of commercial aseptic manufacturing operations. As routine production staff do not record manual interventions in the batch documentation, the media fill programme lacks representative data to determine the number and duration of interventions to be simulated during the media fill. In addition, during the inspection, numerous procedures were performed during routine manufacturing that were not simulated in the media fill.

Inadequate smoke studies

The FDA also criticised the smoke studies conducted to show the flow in the aseptic processing areas. Several instances of turbulent airflow were noted in critical areas of the filling line, even directly above the filling line. In addition, the smoke study videos did not include the manual filling operations that simulate actual production. Also, not all parts of the line were assembled as used in routine production.

Deficiencies in environmental monitoring and data falsification

The FDA criticised the fact that the required number of samples for environmental and personnel monitoring were not collected in accordance with the manufacturer's procedures. Instead, interviews with employees and the management of the microbiology laboratory revealed that it is common practice to fabricate results for samples that were never taken. In addition, results were altered that would otherwise not fulfil the defined specifications. During the inspection, numerous limit violations were also found in environmental and personnel monitoring samples.

Ineffective quality system

According to the FDA, the manufacturer does not have an effective quality system in accordance with GMP. In addition to the lack of effective management oversight of its manufacturing and laboratory operations, the FDA found that the quality department was unable to exercise appropriate authority or had inadequately implemented its responsibilities. Company management should promptly and comprehensively evaluate the company's global manufacturing operations to ensure that systems, processes and products are in compliance with FDA requirements.

Delay in the recall of medicinal products

Due to the serious GMP violations and the associated patient risk, the FDA had already advised the manufacturer in a conference call on 25 October 2023 to recall medicinal products from the inspected facility. On 27 October, the FDA published its own announcement. Despite numerous attempts by the FDA to obtain a decision on a recall, the Indian manufacturer did not initiate the necessary recall until 15 November 2023, i.e. approximately three weeks after the initial discussion.

The Warning Letter with the (as the FDA itself writes) outrageous GMP violations can be found on the FDA's website.