Aseptic Process Simulation/Media Fill also under Scrutiny during European GMP Inspections

The ECA regularly publishes deficiencies identified by the US FDA during its inspections and subsequently published in Warning Letters. The European Union equivalent is the so-called "STATEMENTS OF NON-COMPLIANCE WITH GMP", also known as Non-Compliance Reports, which are published via the EudraGMDP database. A recent statement by the French supervisory authority describes deficiencies at a Chinese manufacturer of biosimilars. What did the French authority find?

The inspection focused on aseptically manufactured small-volume parenteral products produced using biotechnological processes (biosimilars). Four product batches were involved, marketed as vials and pre-filled syringes. Overall, the inspection identified one critical deficiency and eight major deficiencies.

Inspection findings

• Deviations in the aseptic process simulation (APS, also known as a Media Fill) and inadequate assessment of their impact on the products, as well as observations relating to environmental monitoring in Grade A/B cleanroom areas.
• A lack of effective cleaning and disinfection practices in the cleanrooms, including microbiologically inadequate transfer processes into Grade A/B areas.
• Deficiencies in the visual inspection of filled units, including non-compliance with pharmacopoeial requirements (Ph. Eur.) and qualification data.
• Deficiencies in the requalification of the cleanroom in which the pre-filled syringes are filled, in accordance with Annex 1 of the EU GMP Guide.
• Failure to implement a comprehensive environmental monitoring programme in the cleanroom in accordance with Annex 1 of the EU GMP Guide.
• Deficiencies in the handling of particulate contamination in 200-litre single-use bags, including the introduction of an additional 3 µm filter downstream of the final 0.22 µm sterilising-grade filter.
• Deficiencies in defining interventions as part of personnel requalification during APS, as well as in establishing acceptance criteria for Quality Control personnel involved in the initial qualification for APS evaluation.
• Deficiencies in the management of computerised systems in the Quality Control laboratory with regard to Annex 11 of the EU GMP Guide.
• Failure to establish approved quality agreements with marketing authorisation holders and importers.

The first item listed describes the critical deficiency; the remaining items describe the major deficiencies.

Consequences of the inspection

The consequences of the inspection were the withdrawal of the GMP certificate and a ban on supplying the inspected batches to the EU. In addition, a further GMP inspection has been announced to verify whether the CAPA plan has been fully implemented.

Interestingly, the European authorities allow a somewhat longer period for responding to the Statement than the FDA does: 20 working days, compared with the 15 working days expected by the FDA in response to a Warning Letter.

Conclusion

Aseptic process simulation is also subject to close scrutiny in the EU, as is generally the case in sterile manufacturing.

The Non-Compliance Records can be found on the EudraGMDP website.