Haimen Pharma Inc. — EU GMP NCR (EudraGMDP) Findings

Four critical deficiencies were raised : 1) poor handling of deviations (3 recorded in 2022, 0 in 2023). However, inspectors noticed 7 incidents which should lead to deviations, such as rust on clean Posaconazole punches, inner of coating pan still wet 7 days after cleaning ; 2) high contamination risk in the cleanroom of the microbiological laboratory : 3 plastic boxes found filled with water and detergent (~40L). Boxes are used to clean the media reusable bottles. One box was full of glass bottles, water was turbid and there is no maximum duration for it to remain in the box. 3) high contamination risk in the microbial laboratory facilities : black filamentous traces observed on the wall above the autoclave. Also black and white traces found on empty reusable settle plates, packaged as ready to be sterilized. 4) poor management of API manufacturer : last audit of Posaconazole API manufacturer performed in April 2020 was not against EU GMP and findings included 2 criticals and 7 majors. Even if falsified sampling testing results were found during the audit, no follow up was done. Fourteen major deficiencies were also raised : 1) identification test performed only on composite sample for excipients ; 2) planned deviation allowed use of new Posaconazole API source on production lines even if the major change control, opened 7 days before, asked for several actions to be completed before ; 3) european GMP training not performed for employees ; 4) balances from the dispensing area moved without any restriction ; 5) deficient Posaconazole punches storage, maintenance and cleaning (rust, no protection against damage, cleaning method not validated) ; 6) coating pan in a bad state : still wet whereas cleaning done 7 days before, rust on the axis ; 7) data integrity issue with HPLC Empower software set up ; 8) microbiological laboratory incubators observed with settle plates inside closed plastic boxes ; 9) remaining raw material storage condition is not guaranteed after sampling, because commercial bags resealed with a machine found not qualified with black spots. 10) Neither checks performed for identity and conformity on packaging materials on delivery to the manual secondary packaging department before use, nor checks as IPC. 11) Microbiology not considered for equipments cleaning validation. Also the strategy applied for cleaning validation is based on an EHS approach, to define appropriated protection for workers according to hazard level of molecules. 12) The MAH did not carry out any audit on HAIMEN site before the EU regulatory dossier of Posaconazole tablet 100mg was submitted. 13) Poor handling of purified water production unit for workshop OSD 1 : water temperature in the loop above 33°C since several weeks, no internal specifications and no alarm set for temperature and water velocity, sanitization made every week without requirements in case of major incident, conductivity and TOC never tested in QC except during initial qualification, no trend analysis for using points results ; 14) Deficient traceability in the master batch record of Posaconazole 100mg, lot 106Z012326, manufactured on June 20th 2023 as equipments cleaning labels are not included, detergent used not registered, and names of the 10 workers needed to perform manual secondary packaging not recorded. Action taken/proposed by the NCA: Others Refusal of the national marketing authorization request of “POSACONAZOLE ELC 100 mg, comprimé gastro-résistant”. According to the information provided by the site, no EU customer was identified for any medicinal product manufactured at the site. Third countries national competent authorities should evaluate the criticality of products being supplied by this manufacturing site and enact measures to ensure continued supply where appropriate. *** UPDATE: ANSM received a comprehensive action plan that addresses the issues raised during the inspection. This action plan was reviewed and was found globally acceptable. However, due to the absence of any national product on the French market and the absence of any pending application involving this site, ANSM will not perform a follow-up inspection of this site to ensure the effective implementation of this action plan.