Data Integrity issues, Delayed records: Jiangsu Hengrui site in China classified OAI

USFDA had inspected the Jiangsu Hengrui Pharma’s Huanghe road site in January 2024. The site was inspected by investigators Arsen Karapetyan and Qiao Y Bobo and the Firm was issued USFDA 483 with 8 observations. Following the inspection, the site (FEI 3007373503 ) is classified OAI (Official Action Indicated). Earlier the site had positive inspections with classification VAI (Voluntary Action Indicated) in 2018 and 2016) and NAI (No Action Indicated) 2012 and 2014).

Critical Data Integrity issues were observed during the inspection with original GxP documents found in the Waste bin and production persons able to duplicate batch records. There were no Data Integrity program for reviewing of the electronic data from QC instruments by Quality Assurance unit; instruments for Particle Monitoring and Integrity testing were not 21 CFR Part 11 compliant. Other issues observed include inadequate validation of procedures for control of microbial contamination of sterile products, inadequate cleaning validation studies, and poor facility maintenance. The site was seen to be causing delays in inspection by not making records and information readily available.

Jiangsu Hengrui has several approved injection products in the US. An OAI classification normally implies that the USFDA may put all new approvals from the facility on hold till all corrective actions are completed. An OAI classification may also be followed by further regulatory actions like Warning letter or Import Alerts by the agency.

Observations

1. Validation of procedures and processes to prevent microbial contamination of sterile products are inadequate
   • Airflow visualisation study did not include transitions between Grade A and Grade B areas
   • The duration of Interventions and frequency of interventions studied in Media Fill studies are not representative of commercial manufacturing
   • Procedures for requalification of operators for sterile operations are inadequate. Operators who performed bulk of the interventions and operators who performed no interventions were all considered requalified based on their participation in Media fill studies.
2. Container Closure Integrity studies were inadequate. Empty vials were used for the studies and not filled vials, and there were no positive controls. The Dye Integrity test was performed manually with human eye detection, with no limit of detection specified.
3. Cleaning Validation studies were inadequate:
   • Worst case contaminant determination did not include concentrations of contaminants in all equipment
   • Swab sampling did not cover all hard to clean / worse case areas, for e.g. tank outlet pipes
   • Cleaning Validation test results were reported as not detected but limit of detection not provided.
4. Quality Unit oversight and control is inadequate with lapses in Document control, review of audit trails, no adequate data integrity program
   • Original GxP document including pages of Batch records, validation reports, change control documents were observed in waste bin. There were corresponding archived documents but information did not match with documents observed in waste bin.
   • Production personnel are able to duplicate batch records issued through a DMS software using a QR code
   • The designated area for storing products awaiting destruction was not secure, with open doors, no personnel present, and alarm system not functioning
   • The facility lacked a proper data integrity program, including procedures for Quality Assurance (QA) to review electronic data from lab instruments.
   • Eye inspection reports of Visual Inspectors were not reviewed by QA.
5. Records for inspection were not readily made available causing delay in inspection
   • The USFDA auditors were diverted from a shorter path and routed on a longer path to reach the office waste disposal area, causing delays.
   • Personnel were observed placing documents in waste bins, and a stack of documents under a vehicle, which included original pages of Batch records, Validation protocols and reports, standard operating procedures, change control documents
6. Computerised systems and equipment in manufacturing areas were not 21 CFR Part 11 compliant with no timestamp audit trail, data archival & retrieval, alarm management. Instrument are not qualified.
   • Portable Non Viable Particle (NVP) monitoring instrument for environmental monitoring in Grade B & Grade C areas
   • Integrity test equipment
7. Buildings used for holding finished drug products are not maintained and are not in good state of repair.
   • Pools of water was observed on the warehouse floor with pallets containing finished parenteral drug product stored directly above the water.
   • Black mold like growth near stored finished drug products in warehouse.
   • Observed corroded pipes of air condenser leaking water, rusted metallic beams of pallet racks in warehouse.
8. Washing and toilet facilities lack hot and cold water.

Jiangsu Hengrui Pharmaceuticals USFDA 483 (January 2024)