Problems in Clean Room at Contract Manufacturer of sterile Eye Preparations

A U.S. contract manufacturer of sterile over-the-counter and homeopathic ophthalmic products received a Warning Letter from the FDA due to, among other things, problems in aseptic manufacturing and facility conditions.

Premises

According to the FDA, the spatial conditions are not suitable for aseptic production. The aseptic production line is open to the room environment and is not protected by a barrier. The only protection is a HEPA-filtered air flow coming from the side. The structural design of the production line also requires intensive manual activities during set-up and routine production. In addition, the FDA criticizes unsuitable construction materials in the cleanroom, which are not smooth and therefore not easy to clean. For example, the FDA describes chipboard between the surfaces of the HEPA filters and the housing, rust on the frames of the HEPA filters, peeling paint and rust on the aseptic line and power cables attached to the ceiling above the line. Other negative details include damaged chairs with exposed seat cushions, discolored and poorly maintained rigid doors, and gaps in the cleanroom ceiling.

In addition to the poor design of the production line, the FDA writes of deficiencies in the layout of the cleanroom and the maintenance of the equipment. The ventilation concept does not ensure separation from adjacent rooms with lower air quality.

According to the FDA, the qualification of the ventilation or airflow in critical areas is also inadequate to minimize the risk of contamination. For example, the manufacturer has not conducted adequate dynamic or static flow studies to demonstrate unidirectional airflow. In addition, the HEPA certification record shows that the flow velocities at each of the HEPA filters installed in the room wall were inadequate and uneven across the panels.

Environmental monitoring

The FDA also criticized the environmental monitoring of the aseptic manufacturing areas. The FDA found the frequency, sampling points, incubation parameters and action levels of the monitoring to be inadequate. No monitoring was established in the rooms adjacent to the manufacturing area. Of particular concern to the FDA is the fact that fungi and bacteria were repeatedly found in the critical areas (e.g. ISO-5) from 2021-2023. According to the FDA, the shortened incubation period and the temperatures used for the samples are moreover not sufficient to consistently and reliably detect fungi.

Deficiencies in media fill (aseptic process simulation (APS))

The FDA also describes deficiencies in media fill (aseptic process simulation (APS)). According to the FDA, media fills were not performed with sufficient frequency. For example, products declared as sterile were last distributed in November 2023, but the last media fill had already taken place in October 2021. Moreover the time covered by the APS was significantly shorter than the actual filling time, which can be 10-13 hours. 

Inadequate aseptic, poor behavior in the cleanroom

The employees in the aseptic area were not trained or qualified in the correct use of protective clothing. Employees were observed with incomplete protective clothing and exposed facial skin.

The FDA also criticized the inadequate sterilization of device surfaces that come into contact with the sterile goods. For example, sterilized connecting tubes were stored in an unclassified room in an unsealed container, and the tubes were also discolored. The sterilization of numerous items of equipment, such as sterile product transfer tubing, was not documented.

Lack of validation

The FDA also criticized the issue of validation. According to the FDA, the manufacturer failed to adequately validate the manufacturing processes for the production of the sterile ophthalmic drug product. No process performance qualification (PPQ) and no proper qualification of the equipment was carried out. This also included the supply equipment.
The water system that produces the water used for the formulation was also not validated. The manufacturer has therefore not ensured that the water used in production is suitable for the intended use in sterile ophthalmic medicinal products.

You can find the Warning Letter to the US manufacturer on the FDA website.