Procedures designed to prevent microbial contamination of sterile products are not followed. Observed poor operator practices in the aseptic filling line like operators leaning over and hand, forearm, head directly above the open sterile vials, stopper bowls. During different interventions like adjusting the tubing, removing broken vials, installing the stopper bowl, removing stopper jams etc various deficiencies were observed. Lapses observed include Operators not sanitising hands, not sanitising tools, wipes which were moved from Grade B to Grade Area, while removing broken vials in vial filling line not removing surrounding vials to prevent glass particulates contamination, leaving the barrier open, touching the inside of sterile bowls, not attending to liquid spills promptly. Several interventions were also not recorded or under recorded.
Test records not complete, do not record all data, updated without performing tests: Vial integrity test records were updated for passing results without actually performing the tests. Same vials were repeatedly tested assigning different identifications (IDs) to generate passing results as otherwise some vials may fail the test. Only passing integrity test results were printed, if there are failures, leaks, interrupted tests, alarms results are not printed. For environmental monitoring in Grade A area, not all samples which were documented were actually taken. Unexposed swabs, Microbiology media plates were delivered to Microbiology QC which obviously reported no growth. Media plates for surface monitoring never touched the surfaces or much smaller areas were sampled from surfaces than defined. Non Viable Particle Count (NVPC) monitoring samples were not collected from designated Grade A, Grade B aseptic processing areas; but samples were collected from aseptic area corridor after operations. The time and date in the NVPC instrument prints were changed to match sample time. The practices have been ongoing as some of the samples can fail the tests. In chromatography tests, when processing chromatograms, only final version after performing manual integration are saved.
Production controls are lacking, records are not complete, updated without performing tasks: In aseptic vial filling lines Checklist for verification of contact parts documented removing, washing, sterilisation of stopper bowl, cap bowl in between batches. But the CCTV records showed these were never removed during disassembling step. The e-logs documented cleaning, mopping, disinfection, rinse, sanitisation of the areas, vial filling machines, stoppering, sealing machines; But the CCTV records show most of the cleaning activities were not performed. Not all interventions in aseptic lines are recorded, Interventions are under recorded, non-conformance investigations are not performed when the interventions exceed the maximum permitted levels. There is no alternate person to record interventions when the assigned person moves from the area for taking weights, going to washrooms etc.
Validation of aseptic processes, area are inadequate: Chemical Indicators (CI) and Biological Indicators (BI) are not placed at worst case locations during requalification. Smoke studies are not conducted and airflow not assessed under dynamic conditions, did not assess ingress of air from Grade C to Grade Areas. Simulations studies did not cover all operator interventions, interventions causing obstruction and turbulence of airflow.
Failure investigations are inadequate, fails to establish root cause and CAPAs:
An investigation into exceeding vial rejection rates; decided to monitor, next 30 batches. During monitoring of 30 batches additional batches were found to exceed rejection rates, but no root cause or CAPA was identified.
Root cause for an impurity OOS during long term stability studies was attributed to exposure of sample during sample preparation and OOS was invalidated. But The investigation did not assess exposure of open vials before capping in manufacturing line. Other stability data on the product showed increasing trend of impurity.
No OOT investigation was initiated when test for assay did not follow the expected trend in comparison to previous stability studies
In an OOS incident and investigation one of the duplicate tests was OOS multiple times. However the test results were averaged to obtain passing result. No procedure in place for averaging of results.
An OOS investigation into unknown individual impurity exceeding the limit identified root cause as prolonged exposure of dispensed API to room temperature before compounding, while there are other batches with similar time of exposure. Investigations did not demonstrate this is the root cause; neither any time limit was established for exposure in batch records.
In a test for Osmolality OOS is attributed to dirty sample vial, while no OOS with 30 other samples tested on same day.
In a test of Particulate matter by light obscuration OOS result was attributed to wet measuring cylinder, though in hypothesis testing the sample was still complying, but with a higher result.
Process performance studies did not evaluate inter batch and intra batch variability, acceptance criteria is not defined for variability, sources of variability not evaluated. Allowable time limit for line stoppage during vial filling is not validated
Controls over computer or related systems are inadequate. Operators are able to change date and time on Cimet Non Viable Particle Count (NVPC) equipment; Oxi Dissolved Oxygen Meter. The equipment are capable of storing and backing up of electronic data; but the capabilities are not used.
Changes to procedures are not adequately reviewed: Through change controls requirement to review CCTV footings of aseptic manufacturing operations before batch release was removed; The time for which CCTV footings were saved and preserved was reduced with justification for “better compliance”. The changes lack rationale and justification.
Laboratory controls, Test methods for sterility do not include the establishment of scientifically sound and appropriate test procedures
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