Intas FDA 483 cites Manipulation of records

FDA published the USFDA483 issued to Intas site (FEI 3003157498) in Ahmedabad, India after inspection in May 2023 by Inspectors Rita Kabaso, Justin Boyd, Arsen Karapetyan. The 483 reports 16 observations including manipulated visual inspection reports; failure to characterise particles observed in injection vials; Inadequate validation, qualification, cleaning, maintenance of aseptic areas & processes; deficiencies in qualification and control of computer systems and electronic data, performance verification of equipment; lack of oversight by Quality unit over QC electronic data Read More..

1. Batch records do not include complete instructions and records
   • Manual visual inspection records of parental line manipulated to record values just below the limits for black particles, white particles, glass particles. Two pattern of manipulations – 1) removing the black, white, glass particles to other categories to avoid further investigation by crossing out originally recorded values and moving them to other categories 2) Identical visual inspection records by multiple operators where operators were grouping together and dividing what to record on reports.
   • Batch instructions, controls and records were inadequate, settings and changes to settings for tablet rejection limits during batch operation were not justified; operators could make changes during operation in PLCs which is not always recorded in electronic batch records and the change record of the PLC is not attached to the batch record (BMR) and inprocess controls are not always documented when changes are done.
2. Inadequate failure investigations
   • Failure to characterize the particles in reject injection in visual inspection and establish the root cause; Low Process Capability Index values (CpK, PpK) indicated process not capable, but not investigated. Excursion of Non viable particles in Grade A area during filling are not investigated and no procedure to remove vials, stoppers at the time of machine stoppage due to excursion; no measures to investigate and reduce recurrence of spore forming organisms in aseptic areas; for deviation of tablets with rough surfaces, impact on dissolution and homogeneity is not evaluated, when trend has started during a run, impact on previous and subsequent batches are not evaluated. Root cause for repeated complaints for odour in tablets is not established; retain samples not evaluated for a complaint; suitability failures in endotoxin testing are not investigated.
3. Inadequate design of production, process controls and process validation
   • No scientific justifications for sample size for evaluation of content uniformity of tablets, %RSD criteria for inter batch variability
   • For minimum and maximum in compression,  samples are not evaluated for Tablet weight, thickness, hardness, and content uniformity
   • Criteria are not established for evaluating inter batch (between batches) and intra batch (within the batch) variability for Impurities
   • Process validation for Ointment  did not consider variation in viscosity for evaluation for inter batch and intra batch variability.
   • Visual Inspection processes (manual and automated) are not adequately qualified with known particle sizes typically detected  during visual inspection
   • In Annual Product Quality Reviews (APQRs) outliers are not recognised and investigated
4. Inadequate validation of the aseptic and sterilization process
   • Inadequate sterilization verification of worst case locations like transfer ports, overlaps, folds in the filling line; media fill studies do not cover critical interventions, nature and frequency of interventions adequately; inadequate qualification of airflow pattern in mobile LAF
5. System for cleaning and disinfecting aseptic rooms are deficient
   • Process to qualify the application of sporicidal disinfectant and the machine in Grade B areas are qualified in a non representative room in Microbiology laboratory; blue wipes used to clean and disinfect equipment have loose fibers and fraying threads  
6. Deficiencies in monitoring of environmental conditions in aseptic processing areas, only non viable counts are verified in the RABS where sterile stopper bowl and stoppers are exposed
7. Deficiencies in qualification, validation and control of computer systems and electronic data of GMP related equipment such as Portable non viable particle monitoring equipment, Leak test equipment, Filter integrity test equipment, Titrator in laboratory. No interim controls are established after deficiencies identified in computerised systems during an assessment. Deficiencies include – electronic data are not backed up, reviewed, limited storage of electronic data after which the data is overwritten by new data, only print outs are taken and reviewed, lack of awareness of data storage capability of equipment, not storing the electronic data when the equipment has the capability.
8. Periodic performance qualification / verification / calibration of equipment are inadequate
   • No logical explanation for the parameters used for performance verification of automated visual inspection machine, like physical condition of machine, operational ranges and safety features are suitable for the purpose.
   • Tablet visual inspection machine verification failed to include assessment of rough surface, color and shape variation, thickness, printed tablets, the tablets passed by machine during challenge studies were not verified for removal of defects, periodic performance verification only involves checking the equipment and safety features, sample quantities are not based on historical trend data.
   • Tablet testers are moved around in different rooms, but installation, operation and performance qualification, calibration verification are not conducted after change in location. Calibration conducted is not equivalent to performance qualification.
9. Oversight of Quality unit over quality/production unit operations and laboratory electronic system and data is deficient as shown by several examples:
   • Multiple incidents of interruptions in HPLC / GC systems during testing, an instance where fresh sample solutions were prepared though initially prepared solution was within validity, lack of understanding of different types of communication errors and circumstances which may lead to interruptions
   • Lack of adequate control over issuance of work sheets and logbooks to manufacturing operations where Production personnel are responsible for storage, issuance and reconciliation of visual inspection forms.
   • In Chromleon system data is organised under an “FP” folder for sample sets sequentially without adequate organisation of data to different types of products, different types of tests making data review inefficient; It is a gap in the Firm’s Data Integrity Program
   • No electronic data is reviewed by the Quality Assurance unit for all chromatographic and non-chromatographic electronic data generated by the Quality Control Laboratory, only QC personnel perform review of electronic data.
   • Observation of an instance of inprocess test data for Compressed tablets not verified by Quality unit
   • Observation of an instance of “.pdf” report of inprocess tests of an entire batch attached to the electronic BMR not reviewed by Quality.
10. Inadequate maintenance of equipment and utensils
    • Inadequate sealing in the walls; air could be felt moving from Grade A area to Grade D area
    • Missing gaskets / Incompletely installed gaskets in a filling line
    • Gap in the cover intended to protect vials after vial washing
11. Aseptic filling rooms in parenteral filling line are not adequately designed to permit viewing of all aseptic operations, loading cannot be viewed.
12. APQR procedures are deficient
    • Statistical evaluation is conducted for assay, product weight but not for impurities and other parameters with no scientific justification for not evaluating the same.
    • Lack of understanding regarding application of statistical tools like Confidence Interval (CI).
13. Controls to prevent objectionable microorganisms in non sterile products are deficient
    • No routine / periodic identification of the microorganisms recovered from the purified water system to understand the microbial flora; no further investigation and identification after initial identification of Gram negative organisms when similar colony morphology is observed again
14. Status labels of Equipment and Utensils are deficient regarding obliteration of previous batch / activity identification. A container showed status as cleaned on 1 May 2023 with defined validity of cleaning, but had a whitish residue. The container was used for transferring material on 1 May 2023, but there is no usage log to establish traceability of materials stored in the container.
15. Environmental monitoring samples from aseptic area were not counted accurately. Counts recorded by analyst in interim reading report for different locations /samples were lower than what was observed by the inspectors in the plates.
16. Several test methods for raw materials were observed to be pending for validation / verification for approved / pending drug applications.