Amneal Warning Letter Cites Fibers in PP Bags of Injectable Product, Lapses in BET testing

The USFDA issued a Warning letter to Amneal Pharmaceuticals following critical deviations observed during an inspection in March 2025 at its Gujarat facility (FEI 3018907202). The Warning letter issued on August 27, 2025 highlights serious deficiencies in the investigation of fibrous particulate contamination in polypropylene (PP) bags used for injectable products and Bacterial Endotoxin Testing (BET) practices. FDA also noted that Amneal’s Quality Unit (QU) was not fully exercising its responsibilities and called for a comprehensive overhaul of its investigation systems, laboratory controls, and to provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities.

Fibrous Particles in Polypropylene (PP) Bags

• Amneal’s investigations into observation of fibrous particles in polypropylene bags of Ropivacaine hydrochloride injection (in 2024) were deficient. Two batches of the drug product exceeded the acceptance criteria for fibrous particles during visual inspection. Amneal performed a risk assessment and released the batches without adequate evaluation of impact of particulates on patient safety and route of administration. Amneal also relaxed the specifications for major defects to enable use of unsuitable polypropylene bags, even while it was aware of risk of particulate contamination from the polypropylene bags purchased from its vendor. Ropivacaine hydrochloride injection is administered epidurally, for local or regional anaesthesia for surgery and for acute pain management. FDA Warning letter highlighted that particulate matter in the epidural space may cause an epidural inflammatory process or permanent nerve injury. After the FDA observations, Amneal recalled the batches and responded that it also proposed to revise the limits for major defect and total defect for polypropylene bag visual inspection. But FDA contended that these levels are still unacceptably high and Amneal’s health hazard assessment minimized the severity of risks associated with particle contamination in sterile injectable drug products. FDA has asked Amneal for comprehensive assessment of system for investigation of deviations, independent review of the material system and a third party review of its defect categorisation in visual inspection program.

Deficiencies in Bacterial Endotoxin Testing (BET)

• FDA investigators observed the Bacterial Endotoxin Testing activity and identified numerous deficiencies – Failure to completely discharge the micropipette solution, Improper gel-clot inspection technique to check the firmness of the gel for endotoxin detection, second analyst failing to adequately verify the analysis, non- contemporaneous documentation and premature result recording. FDA has asked Amneal to comprehensively assess and remediate its laboratory practices, procedures, methods.

Key takeaways

In injectable products, it is critical to define and follow appropriate Acceptable Quality Level (AQL) criteria for particulates in visual inspection as it can lead to serious consequences for patient safety. The 100% visual inspection will reject defective units (any particulate or fibrous material result in immediate rejection of the vial). Apart from that robust AQL limits for individual and total defects for batches also should also be defined in line with the USFDA draft guidance for Inspection of Injectable Products for Visible Particulates. For example an AQL level of 0.65% as per ANSI/ASQ Z1.4 (USP 790) or ASTM E2234 or a more stringent AQL level considering historical trend, nature of drug product, route of administration etc. Failure of a batch to meet these criteria indicates underlying issues; there could be vials with particles of size approaching visible detection limits which still pose a patient safety risk.  This require deeper investigation to identify and eliminate root causes with appropriate CAPA.

Quality Units should exercise its responsibilities to ensure quality and integrity of the product and patient safety. Another key takeaway is the proper training and imparting of skill sets to analysts. It should include practical training and demonstration of the analysis process. Analyst qualification should also address each unit task in the analytical process rather than only matching results of qualification sample.

• USFDA Warning Letter Amneal (August 2025)
• USFDA Guidance: Inspection of Injectable Products for Visible Particulates