Warning Letter due to Particles in Infusion Bags

During an inspection at the Indian production site of an American sterile manufacturer, the FDA found numerous GMP deficiencies. The contamination of sterile infusions bags by particulates was a serious problem.

The FDA cited violations of 21 CFR 211.192 because the company failed to thoroughly investigate unexplained deviations and specification violations in batches or components, regardless of whether the affected batch had already been released and was on the market.

Recurring problems with visible particle contamination

The focus was on recurring problems with visible particle contamination. In 2024, the company launched an investigation after two batches of ropivacaine hydrochloride in polypropylene infusion bags exceeded the acceptance criteria for particulate matter in visual inspection. The cause was identified as the packaging material: the polypropylene bags, in which predominantly white fibres were detected. Although additional visual inspections and a risk assessment were carried out, the manufacturer ultimately released the batches. The FDA criticises that the risk assessment was inadequate as it significantly underestimated the severity of particle contamination in a sterile injection product for epidural use. In particular, the route of administration and the specific patient population were not sufficiently taken into account.

The FDA points out that visible particles in epidurally administered injectables pose significant risks: they can lead to epidural inflammation, abscesses or meningitis and, depending on the injection site, even cause spinal cord infarcts or permanent nerve damage. The company was already aware of the problem, as several batches had been discarded at the end of 2022 and beginning of 2023 due to the discovery of particles. At that time, the polypropylene bags were also identified as the source of the white fibres, and it was found that these particles were difficult to detect by visual inspection. Despite these findings, the company continued to use the bags and did not implement appropriate CAPA measures to prevent a recurrence.

Acceptance criteria for major defects and overall rejection rate unacceptable

In addition, the company relaxed the acceptance criteria for major defects and the overall rejection rate in a manner that was unacceptable to the FDA. This was justified by the high particle rates in the bag batches from an unreliable supplier. However, from the FDA's point of view, it is not permissible to raise specifications to such an extent as to allow the use of unsuitable packaging components. Only after the FDA had identified the deficiencies during the ongoing inspection the company did take appropriate action. On 26 March 2025, a field alert report was submitted for two batches of ropivacaine hydrochloride injection, and on 18 April 2025, these two batches were recalled, as announced by the FDA on its website. At the same time, the company announced that it would readjust the defect limits for visual inspection. However, the FDA continued to consider the proposed new limits to be insufficient. The assessment of patient risk was also criticised, as the severity of the risks associated with epidural injectables continued to be downplayed.

The FDA required that, in addition to maintaining a 100% visual final inspection, supplementary visual inspection methods be used for particles. A final inspection programme must reliably detect not only particles, but also other critical defects, including container or closure defects, cracks, volume deviations, crimping problems, discolouration, bubbles or other appearance defects. As a general rule, visible particles in injectables must be prevented by appropriate preventive measures in the process design and by strict production controls.

Comprehensive explanation for improvement of systems for deviation and error investigations required

The manufacturer must now provide a comprehensive explanation of how it intends to improve its systems for deviation and error investigations. This includes root cause analyses, CAPA effectiveness and quality oversight. An independent review of material management is also required, including all suppliers of components, containers and closures, an assessment of material quality and retest data, and an evaluation of the entire supplier qualification programme. On this basis, a systemic CAPA programme must be developed that will prevent the use of unsuitable materials in the future.

In addition, the FDA expects the manufacturer to commit to an external review of the defect categorisation in the visual inspection programme and a comprehensive assessment of the role of the Quality Unit. It must be ensured that the Quality Unit is equipped with sufficient authority and resources and that it fully inspects all batches prior to release and monitors all investigations. The company must also demonstrate how top management actively supports quality assurance, in particular through the timely provision of resources. Finally, the FDA is calling for the introduction of interim measures to ensure that all batches intended for the US market are essentially free of visible particles. In addition, risk assessment procedures must be revised to fully cover the potential impact on patients, including the route of administration, patient population and particle characteristics. All affected employees must be trained in the revised procedures and guidelines.

Deficiency in endotoxin testing and documentation

The FDA found another serious deficiency in the testing for endotoxins and its documentation. This included incorrect pipetting technique, inadequate evaluation of gel formation, and incomplete or retrospective documentation. Despite individual corrections such as SOP adjustments, training, retests and the purchase of new equipment, the company's response remained inadequate as no comprehensive system evaluation of laboratory activities was carried out.

The detailed Warning Letter can be found on the FDA website.