Serious GMP Violations in the Aseptic Area

The FDA uncovered serious deficiencies in the aseptic area during an inspection of a US manufacturer. Deficiencies in smoke studies, media fills, pressure monitoring and cleaning validation are listed.

Smoke studies / Smoke studies

According to the FDA, the smoke studies were not conducted under conditions that adequately simulate actual manufacturing. For example, the smoke study conducted in 2018 did not reflect routine manufacturing conditions at the aseptic filling line. According to the manufacturer, this was the only smoke study conducted at the filling line in question. The manufacturer began commercial manufacturing of medicinal products on this line in 2020 without adequate smoke studies. According to the FDA, without adequate smoke studies, it is not possible to ensure that the unidirectional airflow according to ISO 5 actually protects the medicinal product from contamination.

Media Fills

There were further complaints at the Media Fills. Since 2020, there have been several positive results in the Media Fills affecting both of the company's filling lines. The manufacturer did not complete investigations of two 2020 cases and did not adequately address the cause of another case in 2021. Instead, the media fill was invalidated without adequate scientific justification.

Pressure monitoring of the premises

According to the FDA, the manufacturer does not have an adequate building management system (BMS) to monitor and record differential pressures in the aseptic manufacturing areas. The manufacturer records differential pressures by having employees look at photoelectric gauges with upper and lower limits and record readings. This frequency is not sufficient to detect pressure deviations (e.g. reversals) that could ultimately affect aseptic conditions and thus endanger the product.

Cleaning validation

The FDA was also not satisfied with the cleaning validation. The authority writes in the Warning Letter that the cleaning validation for the aseptic filling line for ophthalmic medicinal products was not completed. For the preparation container and the transfer line used for formulation and filling, there were no recovery studies or detection limits in the analytics of the cleaning validation. In addition, only the viscosity of the various ophthalmic drugs was considered when determining the conditions under which the cleaning validation should be performed, and other factors that may complicate the cleaning of certain formulations were disregarded. The FDA lacks documented, scientific evidence that viscosity is the determining factor in determining which product surface is most difficult to clean.


In conclusion, the FDA considers the US manufacturer's quality unit to be inadequate. In addition to the lack of effective oversight of manufacturing operations to ensure reliable facilities and equipment, the FDA writes that the quality unit is unable to exercise adequate authority and its responsibilities are inadequately implemented. The company's global manufacturing operations should be promptly and comprehensively assessed to ensure that systems, processes and manufactured products meet FDA requirements.

For more detailed information please see the FDA Warning Letter issued to K.C. Pharmaceuticals Inc.

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