Poor Airflow Visualisation at European Manufacturer of Sterile Veterinary Medicinal Products

A European manufacturer of sterile veterinary medicinal products has received a Warning Letter following an inspection in April this year. Among other issues, airflow visualisation, aseptic behaviour and media fill (APS) were criticised.

Airflow issues

The FDA objects that the airflow visualisations (smoke studies) carried out for the filling line in Zone A do not demonstrate unidirectional airflow and show several deficiencies in the airflow patterns and their interaction with manual interventions. The FDA describes, for example, how air flowed from an operator - who was located in Zone B and leaning into the barrier - towards the critical area where uncovered sterile parts/components were present.

Further observations relate to airflow during interventions in the filling area: in the area where operators were connecting hose, air became partly stagnant; it also rose upwards there. The FDA also reports turbulent airflow during the transfer of stoppers from the stopper bowl to the stoppering station and above a conveyor belt transporting open vials. In the FDA's view, these airflow patterns are not isolated irregularities but indications that the protective effect of the Zone A airflow in aseptic work areas, and in particular during typical interventions, has not been adequately demonstrated.

A key criticism by the FDA, going beyond the individual observations, is that the company has not performed dynamic airflow visualisations during filling and stoppering operations. According to the FDA, the smoke studies reviewed during the inspection did not include airflow patterns under operating conditions during the filling of containers processed on the production line. The FDA considers this to represent an incomplete qualification of aseptic process conditions, as the airflow conditions during the actual critical process steps are not covered.

Poor aseptic practices

The FDA also describes poor aseptic practices during set-up and filling. The observations concern both the handling of materials, sterile components and equipment, and personnel behaviour in the Zone A environment. The FDA criticises, for example, that materials or components are introduced from less critical zones into critical areas without adequate disinfection. With regard to material handling, the FDA reports that an operator manually moved empty vials from Zone A into Zone B and later returned them to the critical area for filling without disinfecting them. The FDA further notes that an operator brought a bag into Zone A without disinfecting it and then repeatedly reached over unprotected sterile parts to make hose connections.

Regarding aseptic working practices, the FDA objects that personnel do not consistently follow the required practice of slow and controlled movements during aseptic operations and when making sterile connections. The FDA describes repeated reaching over sterilised equipment and positioning arms directly above sterile contact surfaces. Reaching into and over sterile components and equipment is also highlighted as a problem. In the FDA's view, it is not just individual procedures that are affected, but the fundamental principle of aseptic working practices.

Media Fills

Another point of criticism concerns media fills (APS). The FDA concludes that the media fills do not adequately simulate commercial manufacturing and therefore do not provide a reliable simulation of routine conditions. As a concrete example, the FDA states that inspectors observed significantly more interventions during aseptic filling operations than were documented in the corresponding media fill records. A review of batch records also revealed more interventions than would have been covered by the media fills. For the FDA, this indicates that the media fills do not represent a worst-case simulation, even though interventions into the Zone A area are among the most critical elements of aseptic processing.

Please see the FDA website for the full Warning Letter.