Case of non-compliant eye drops: investigation on non visible particles

Introduction
Since January 2022, the European Pharmacopoeia (EP) has mandated the control of non-visible particles in non-injectable liquid preparations, including ophthalmic preparations such as eye drops. The implementation of this control was executed for the purpose of regulating a recently manufactured insulin eye drop. One of the batches produced did not meet the specifications required by the EP. The objective of this study was to ascertain the origin of this non-conformity.

Material and method
To determine the causes of non-conformity, the 5M method was used (method, material, medium, material and labor). The search for non-visible particles was carried out using the light-blocking method with the HIAC 9703+ particle counter (Beckman - Coulter). The non-visible particle sizes that were examined in this study are 10 and 25 µm. Each bottle of eye drops that was subjected to testing (n = 3) underwent four particle counts on a volume of 5 milliliters. A negative control was performed with water for injections. The raw materials used in the formulation of the eye drops (insulin and artificial tears) were examined, as well as the sterile single-use equipment employed for preparation. Four kinds of syringes, each with a distinct volume and provided by disparate laboratories, were subjected to rigorous evaluation in a controlled experimental setting (n=5).

Results
The 5M analysis revealed a deviation in the "method": 20-mL syringes were used to produce the non-compliant batch of eye drops, instead of the 30-mL syringes that have been planned. The "manpower" is qualified, and the "environment" is a closed system; therefore, these parameters are considered not to be at fault. The results for raw materials demonstrate compliance with established standards. An analysis of the number of non-visible particles for syringes supplied by Laboratory A (10 mL, 30 mL, 60 mL) was conducted to ascertain compliance with EP specifications. In contrast, the 20-mL syringes provided by laboratory B contain a concentration of non-visible particles that exceeds the EP specifications for particles measuring at least 10 µm (2,312 ± 393 particles/mL).

Discussion - Conclusion
Subsequent to the acquisition of these results, a materiovigilance procedure was executed with laboratory B. The supplier determined that the quantification of non-visible particles utilizing the light-blocking method was compromised by the presence of silicone oil (employed due to its lubricating properties). He advises the implementation of the "microscopic particle counting test," though this approach is not currently viable. This interference, which is not observed in other syringes, prompts further investigation. Despite the regulatory oversight of silicone oil by the EP, numerous research studies have demonstrated its propensity to induce protein and monoclonal antibody aggregation. At present, an alternative supplier is being sought.

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