Serious Deficiencies at US Sterile Manufacturer

The FDA has recently issued a Warning Letter as a result of an inspection conducted at a US-American manufacturer of sterile ophthalmic preparations, which revealed numerous serious deficiencies. These include environmental monitoring, lab data integrity, gowning procedures, media fill and maintenance/cleaning of production equipment.

Environmental Monitoring

In addition to serious violations of data integrity, the inspection also revealed specific deficiencies in environmental and personnel monitoring. For example, agar plates taken from ISO 5 areas which exceeded action limits did not trigger an investigation. In addition, one employee had given the result of this plate as "0". The discarded plate was retrieved that same day. The plate contained colonies too numerous to count. Furthermore, "post activity" personnel monitoring after an aseptic production activity was not carried out for more than one year.
However, the employees had always entered result "0" in the provided forms.

Laboratory Controls

Further cases of falsified laboratory results have been uncovered. For example, laboratory staff had evaluated or labelled sterility test media as "not turbid". During the inspection, however, it had been noticed that the media was probably turbid. However, the sterility of the products was never questioned by the manufacturer. Rather, the turbidity was described as 'inherent'. The FDA doubts this and states that in the case of an inherent turbidity of the media, it must be demonstrated that this inherent turbidity in no way masks a turbidity caused by microbial growth. According to the FDA, batches of a sterile ophthalmic product have been released to the market without demonstrating sterility.

Gowning Procedure

The inspectors had noticed improperly dressed employees in aseptic production. For example, sterile gloves are not individually wrapped and are retrieved by employees from a bulk container before entering the sterile area, which compromises the sterility of the gloves. Three operators observed during manufacturing had exposed skin, including foreheads, noses, and sides of faces due to ill-fitting hoods and goggles. The pharmaceutical manufacturer has indicated that new and better fitting protective clothing will be used. The manufacturer opened an investigation for the batch manufactured while ill-fitting protective clothing had been noticed, and reviewed personnel and environmental monitoring data. However, the FDA criticises the lack of evaluation for all other batches, which could have been negatively affected in quality by gowning practices.

Media Fill

The media fill was also criticised by the FDA. For example, no representative number of routine interventions was performed during a media fill. Also the type of procedure or the complexity of the procedure does not correspond to the routine and is therefore not representative either. Nor were any non-routine interventions performed during the media fill, such as adjustments to equipment. Also, the number of media fills required by the company SOP was not always adhered to. For example, no media fills were performed in two aseptic filling rooms for an entire year.

Maintenance & Cleaning

The maintenance and cleanability of the production equipment also gave rise to complaints. For example, aluminium foil and duct tape (!) had attracted attention at a filling line. According to the manufacturer, the aluminium foil serves to prevent the tops of bottles from falling from the hopper. In addition, dirt had been detected in the clean room and transport trolley.
Another serious problem is that similar GMP violations had already been described in inspections conducted in 2013, 2015 and 2017. The FDA strongly recommends engaging an external consultant to remedy the deficiencies.

Please also see the original FDA Warning Letter to Altaire Pharmaceuticals, Inc.