The South Korean company Celltrion had received a so-called 483 FDA report as a result of inspections performed in May and June 2017. Deficiencies were mainly observed in the aseptic area. Due to the - in their opinion - insufficient answer to the 483 report, the FDA has now issued a Warning Letter.
The findings in the Warning Letter sound much more severe than those in the 483 document. The FDA criticises insufficient safety from microbial contamination, including the validation of all aseptic and sterilisation processes! In the 483 report, inadequate aseptic conduct of employees leaning over open vials was observed. The FDA criticised that there was no retrospective risk assessment for the product in question in Celltrion's reply. In addition to that, they will not accept contaminations and their removal by wiping with disinfectants (as described in a new SOP) instead of designing the processes in such a way that contamination of sterile surfaces is avoided.
The original 483 report also listed failures during media fill. For instance, more vials were removed (and therefore not tested) from the media fill run than it should have been the case according to the SOPs. These vials were intact and sealed and were removed from the run before a disruption (power failure) was simulated. In their reply, Celltrion had confirmed that they would review the media fill processes and perform an additional media fill. Here as well their reply was considered insufficient, as there was no retrospective evaluation performed either. The FDA had expected an evaluation of the preceding media fills and of the vials that were removed without justification, including a statement on the validity of the media fill concerned and a detailed evaluation of the complete media fill programme.
The visible particles already criticised in the Form 483 report also reappear in the Warning Letter. In spite of particle findings in the product, Celltrion had begun to examine these deviations very late and insufficiently. Particles found during visual inspection for instance were not examined and rejected vials were not considered in the test kits for training or qualification for visual inspection. Here as well, Celltrion wrote in their reply that they would improve the processes. However, the FDA disagreed again here, as a comprehensive evaluation was missing once again. The FDA would have expected a risk evaluation of other batches that might also have been affected by the particles detected or by other particles.
Because of the listed inspection findings, the FDA advised Celltrion in their Warning Letter to hire a GMP consultant. The consultant shall help Celltrion to fully correct the deficiencies and perform the retrospective evaluations requested.
More details can be found in the FDA Warning Letter to Celltrion Inc.