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Warning letters, 483s, Recalls, Import Alerts, Audit observations
Warning letters, 483s, Recalls, Import Alerts, Audit observations
FDA has published the USFDA Form 483 issued to sterile drug manufacturing facility of Fareva Amboise (FEI 3000234005) at Poce Sur Cisse in France. The site was inspected by FDA inspectors Vivin George, Justin A Boyd, Karen A Briggs from 8-16 September, 2025. Major deficiencies observed include inadequate control of aseptic processes, aseptic practices, validation of aseptic processes raising concerns of procedures to control microbial contamination of sterile drug products. Other major deviations include lapses over computer system controls and data integrity, document control, deficient equipment cleaning and disinfection practices.
Quality unit approved qualification of the Grade A filling line, though smoke studies show turbulent and stagnant air and airflow was not functioning properly. Deficiencies observed during smoke studies include observation of smoke flow from operator in Grade B area along the arm to Grade A area; smoke flow over operators hand towards conveyor line having open vials while contact plate surface monitoring during filling operations. Operators did not follow slow and controlled movement during aseptic operations. During installation of stopper bowl and further intervention to remove sterile stoppers operator was reaching over sterile surfaces and stopper bowl. Materials were observed to be transferred from Grade C to Grade B and from Grade B to Grade A area without disinfection. Biological indicator placement strategy in Grade A area for evaluating cycle effectiveness lacked scientific justification.
Media fill studies did not simulate commercial batch conditions. There were no requirements of minimum number of times an intervention must occur during media fills. Number of interventions in commercial batches were also not trended. During media fill studies after stoppages filled vials were rejected, however there was no procedure defining requirement to reject vials during stoppages in commercial batches. No documentation was required for rejected vials during each interventions in commercial batches.
More observations of deficient aseptic technique and lack of adherence to sterile behavior protocols were made during set up and aseptic filling operations. During interventions like weight checks, clearing jammed stoppers, surface monitoring with contact plates operators were seen leaning over sterile surfaces. These personnel were held to Grade B area requirements upon exit. An incident of Corynebacterium tuberculostearicum recovered on forearm of personnel involved in filling was not investigated. Contact plates were used for surfaces which are not flat like scissors and forceps.
Operators reached under barriers, transferred materials to Grade A area without disinfection. Operator was observed to remove protective covers from the sterilized stopper bowl in the Grade B area before transferring it into the Grade A area and installing it on the filling line. During tubing connections an operator was observed to be removing a gasket placing it in the Grade A and putting it back placing it back on the pipe. Non-viable particle count, active air samples are taken in aseptic area only after aseptic connection is completed. For a Terminally Sterilised (TS) product, operator placed a phone, used cleaning wipe, extra gaskets etc onto base of filling machine inside Grade A barrier. However, procedure to perform the connections is same for aseptic products as well.
Equipment cleaning was found to be not effective with residues observed on “cleaned” equipment on gasket and inside of equipment. Analysis of the residue showed presence of an API used in a product several months back. Many other products have been manufactured hence in the equipment and distributed. Cleaning validation did not cover all hardest-to-clean areas in equipment. Also, operators performing cleaning verification on equipment did not have access to all parts.
There was no routine use of sporicidal agent on equipment surfaces in Grade A area and no disinfection efficacy studies were performed on all equipment surfaces in Grade A filling area. Also operators did not use a unidirectional wiping technique or sequentially clean and disinfect the area in the direction of product flow, during cleaning and disinfection of filling line after aseptic filling of batches.
Damages were observed on aseptic filling and capping lines that make them prone to particle generation and also difficult to clean. Also observed several areas of fraying, several gouges and scratches on equipment which were clean and ready to use. Preventive maintenance checks on this equipment noted no deficiencies, also frequency of preventive maintenance lacked scientific justification.
Challenge test kits to qualify visual inspectors were inadequate to thoroughly challenge the visual inspectors and tests did not represent routine production. The vials with unknown sizes of particles did not ensure all defect types are covered, did not have sufficient vials and did not represent the largest vial size used. There was no process in place to routinely identify particles, presence of any new particles and their source, no defect library was established. The qualification process and acceptance criteria was inadequate, no limits for individual or total rejects established and even when inspectors missed major visible defects they still passed qualification.
No process validation data is established for compression machine settings and process parameters like filling depth, displacement value used to accept or reject batches. Operators are able to change filling depth, percent variation for rejects.
Data integrity assessments are not completed for many equipment / instruments like non-viable particle counter (NVPC), tablet press, hardness tester. User can change time, date, clear stored data on non-viable particle counter (NVPC). Electronic data on NVPC were not reviewed and documented, only paper copies are reviewed. The electronic data showed, several failing particle count results in Grade A areas. In an instance a non-confirming particle count result in Grade A area not recorded, NVPC was taken to Grade B area, brought back to Grade A area and retested and the confirming result only was included in the media fill batch record. In the tablet press user is able to change parameters like filling depth, displacement value, and there is no audit trail to track, alarms are not reviewed. For Tablet hardness tester, user is able to change date and time, does not store electronic data and only generates printouts. There was no reconciliation of printouts, and a copy was found in trash can.
There was no process to reconcile the GMP forms printed from Master Control to determine whether all issued original GMP forms are used or returned to QA. Employees are permitted to print excess copies of GMP forms and destroy unused forms and there is no assurance forms with original GMP data are not similarly destroyed. Employees have uncontrolled access to paper shredders located in the production and laboratory areas.
Batch records were also found to be deficient in that for interventions during sterile operations, type, frequency and time of interventions were not routinely documented. Also identify of person performing the inspection was not recorded in visual inspection records.
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