FDA 483 to Chinese API Manufacturer Sichuan Deebio cites Data Integrity issues

The USFDA 483 issued to Sichuan Deebio Pharmaceutical Co. Ltd cite critical data integrity observations of Microbiology plates discarded in waste bin without recording results and QC team leader not telling truth about the results; missing test data and repeat testing of samples till desired results are achieved.

Other lapses include inadequate failure investigations, failure to officially document deficiencies observed during customer audits and investigations through the Quality Management system. The API manufacturing site (FEI 3011139911) was inspected by UFSDA investigators Anders W. Evenson and Arsen Karapetyan in September 2023, resulting in USFDA 483 with six observations. The Firm is put under OAI classification by USFDA following the inspection.

USFDA 483

1. Laboratory records are not contemporaneous and not complete.
   • Microbiology test results for Water samples, QC Microbiology workbench monitoring, Biosafety cabinet monitoring were not recorded; Microbiology test plates were observed in waste bin. QC team leader claimed the plates were read and test work sheets are in QA, but later agreed she had not read the plates. QC team leader again changed the statement that the plates were read, but not recorded and she was not telling the truth about recording the results. The flipflop and misleading information delayed inspection with auditors spending more than 2 hours in the Microbiology lab.
   • Test results were not available for tests performed for process validation batches in the Multiparameter analyser equipment with SevenExcellence software, neither any print outs could be provided. It was claimed that the electronic data is lost due to inadequate data backup and print outs are not available since printer was not connected to the equipment during testing of the batches. Also electronic data review showed samples are tested till desired results are achieved.
2. Deficiencies in QC specifications, test methods, validations, controls,
   • There was no investigation to identify source of additional peaks observed during validation of Residual Solvent method
   • No procedure for controlling manual integration of GC, HPLC chromatograms
   • Drug substance not tested for impurities. There were no studies of impurity profile
3. Production and process control procedures are lacking
   • Blending process validation lacks in establishing blend uniformity, inprocess sampling, sample size and frequency, criteria for %RSD for intra batch variability, blending time. Customer complained batch result were OOS when sampled from top, middle and bottom
   • Multiple sublots are mixed for making one finished lot of APIs – But practice is not evaluated for impact on variation of assay content
   • No studies are conducted on effect of manufacturing process on microbiological and degradants control.
4. Failure investigations lack in conclusion and follow up
   • Investigation of complaints for OOS results for samples from top, middle and bottom of drug substance batch, microbial failures did not extend to other batches. Didi not evaluate critical piece of equipment or critical process parameters. No CAPAs are implemented following investigations
   • For deficiencies observed in customer audits – lack of electronic data controls, unreported test results etc – no official investigation, deviation, or CAPA was initiated and documented in order to have the ability to track and trend the deficiencies.
5. Inadequate procedures for cleaning and maintenance
   • Failure to develop validated cleaning and testing method for equipment to detect residues and residual solvents
   • Cleaning records are lacking, deviations in cleaning records are not documented and investigated
6. No official Transport Validation studies to provide assurance that drug substance stays within defined storage conditions for Temperature and %RH during transit.