Bio-Thera Solutions Ltd. — EU GMP NCR (EudraGMDP) Findings

This NCR is limited to the drug product manufacturing activities related to the 4 products: - Usymro® (Ustekinumab) 45 mg and 90 mg, solution for injection and Usymro® (Ustekinumab) 130 mg, concentrate for solution for infusion (vial and pre-filled syringe presentations); - Avzivi® (Bevacizumab) 25 mg/mL concentrate for solution for infusion (vial presentation); - Tofidence® (Tocilizumab) 20 mg/mL concentrate for solution for infusion (vial presentation); - Gotenfia® (Golimumab) 50 mg and 100 mg solution for injection (pre-filled syringe presentation). The inspection raised 33 deficiencies including 1 critical deficiency and 8 major deficiencies related to drug product manufacturing activities. One critical deficiency was raised: 1) Failure to investigate and assess product impact in the deviations including deviations related to Aseptic Process Simulation (APS) failure and environmental monitoring excursions in grade A/B cleanrooms. Eight major deficiencies were raised: 1) Failure to have efficient cleaning and disinfection practices of cleanrooms, as well as material transfer processes to grade A/B areas, by using practices that were not conducive to minimizing microbial contamination; 2) Failure to have suitable manual visual inspection process of filled units by deviating from Eur. Pharmacopeia requirements and from qualification data of manual inspection tables; 3) Failure to requalify cleanroom for the prefilled syringe filling room in accordance with Annex 1 of EU GMP; 4) Failure to implement cleanroom environmental monitoring program fully in accordance with Annex 1 of EU GMP; 5) Failure to adequately manage particle contamination on 200 L single-use storage bags (used during vial filling of Avzivi® and Tofidence®) by modifying the manufacturing process to include a 3 µm filter after the final sterilizing filtration 0,22 µm; 6) Failure to adequately define the aseptic interventions for the annual requalification of operators of filling lines as well as acceptance criteria during the initial qualification of the QC employees for APS reading; 7) Failure to manage computerized systems in the QC lab in accordance with Annex 11 of EU GMPs requirements; 8) Failure to establish approved quality agreements with Marketing Authorization Holders and Importers. Action taken/proposed by the NCA: Withdrawal, of current valid GMP certificate No. 2024_HPF_PT_003_NA / Prohibition of supply No batch of the 4 products manufactured prior to the issuance of this NCR and manufactured while this NCR is in force should be supplied to Europe.