FDA criticises Root Cause Analysis and CAPA in a Warning Letter

In a Warning Letter to the company Abraxis (USA), the US regulatory authority FDA criticises Failure Investigation and Root Cause Analysis in relation to deviations in various media fills. What is interesting here is the procedure for conducting the failure investigations".

The Allegation

According to the Warning Letter, the company failed to effectively implement appropriate corrective and preventive actions (CAPA) and return the aseptic processing line to a controlled state. It also found fault with investigations, assessments and corrective actions.

What happened?

Between April and November 2021, deviations occurred during the simulation of aseptic processing operations (media fill) on a filling line, all of which were assigned different causes:

During a media fill in April, a very high number of contaminated units was detected. Ten different microbes were identified in the samples of contaminated units, including spore-forming, vegetative, gram-negative and gram-positive microbes. The investigation carried out traced the cause to problems with a filling manifold.

Then in July 2021, contaminated units were found again during a media fill. The cause was now traced back to the staff's work clothes, inadequate disinfection of the internal RABS (Restricted Access Barrier System) and contaminated forceps.

A media fill in October 2021 was stopped but still found to have a high number of contaminated units. Here, sampling was determined to be the cause.

In November of the same year, a "turby vial" was discovered. The postulated cause was now insufficient disinfection of the area below the work surface, which could have contaminated the RABS gloves.

What is the FDA criticising?

The FDA finds the investigations generally inadequate. For example, the robustness of single-use systems was not adequately assessed or other potential contaminations were not considered. Also, derived CAPA measures did not go far enough for the FDA, as other processes and systems were not sufficiently assessed.

Ultimately, the FDA does not consider the aseptic manufacturing processes to be under control. Without a comprehensive assessment of contamination risks and sufficient CAPAs, there is no assurance that a recurrence of sterility problems can be prevented.