Natco Pharma USFDA 483 Lists Eight Observations – Cites Deficient Cleaning, Data Integrity issues Read More

Natco Pharma (india) Kothur facility was inspected by USFDA in October 2023. The site (FEI 3004540906) was inspected by USFDA Inspectors Pratik S. Upadhyay and Saleem A. Akhtar and the USFDA 483 cited eight observations including Cleaning deficiencies of manufacturing equipment, data integrity issues with raw data sheets in scrapyard, deficiencies in aseptic area controls and gowning, alarm controls, user access controls of manufacturing equipment. Details of the observations are:

1. Deficiencies in cleaning and maintenance of non-dedicated equipment; can lead to potential cross contamination
   • Observed thick residues in parts of equipment not cleaded for several years since installation, swab results show active ingredients of previous products upto 800 times acceptance limit and several unknown peaks in chromatograms
   • Failure to perform impact assessment and risk assessment when new cleaning equipment introduced to improve cleaning
   • Swab sample analysis procedures are deficient – test procedures (STP) do not address swab blank solution, type of swab sticks, swab sample solution stability is not established. Adequate qualified swab sticks not maintained. Quality control is not aware of swab sample limits.
   • Inadequate maintenance of equipment – scratches, dents, missing pieces on equipment, coloured residue on gaskets
2. Lack of Quality oversight over control of GMP documents and data integrity – torn pieces of raw data sheets, balance print outs, batch record sheets in scrap yard; raw data recorded in uncontrolled white paper, tissue papers, gloves etc; Inadequate investigation into missing pages in batch records, QC testing documents. Training assessment recorded 100% scores to personnel but there were  no supporting assessment sheets, some assessments did not have relevant questions. Additional sheets were issued for missing pages in batch record, which was updated several days later including from and to Time records. In QC raw data sheets and balance print out were missing, but still analysis proceeded and results calculated and reported.
3. Inadequate contamination control procedures for preventing microbial contamination of aseptically manufactured sterile drug products. Space constrained in RABS and lapses in aseptic practices by operators. Inadequate oversight, monitoring and documentation of aseptic operations, as the view windows do not provide full view of the entire aseptic processing area; there are no video recording to review. Surface monitoring of the phone provided in aseptic area is performed only on the buttons and not on the receiver and mouthpiece.
4. Laboratory controls and investigation are deficient – Inadequate OOS investigation procedures – OOS samples are send to R&D for investigation, OOS procedure do not address involvement of R&D in OOS investigations, process and documentation for the same. Manufacturing date of products manufactured are given as date of issuance of (empty) batch record, but date of mixing of components happens with significant delay. Charging of batches for stability are delayed, root cause for stability OOS attributes delay in charging batch for stability.
5. Airflow visualisation studies in aseptic areas are deficient – significant smoke was seen being pushed from Grade B area into RABS; in the RABS dense smoke is seen only on one side (left) of filling area. Date and time of the smoke study are not captured in the videos.
6. Procedures for recording, reviewing and investigation of alarms from manufacturing equipment are deficient – Equipment do not have facility to store and print alarms; in the logbooks for recording alarms no alarms were recorded for the whole year 2022. During audit an equipment generated several alarms which were acknowledged by operator, but the whole of 2022 and 2023, no alarms have been recorded for the equipment.
7. User access controls are not exercised on manufacturing equipment – Fifteen operators access equipment, but operator access is not assigned to any one of them. No review of batch audit trail from equipment with shared user access.
8. Gowning procedures for aseptic area are deficient – no face / beard covers to tuck facial hair, only nose mask is used which is inadequate.

USFDA 483