Zydus Vadodara USFDA 483 cites Contamination, DI issues

USFDA inspection of Zydus Life sciences, Vadodara facility resulted in USFDA 483 with 10 observations. The facility (FEI 3013712903) was inspected by USFDA investigators Justin A Boyd and Anastasia M Shields in April 2024. Major deficiencies observed were pertaining to Inadequate failure investigation of batches and impact evaluation, Data integrity issues involving creation of sampling records for samples not collected, Lapses in aseptic area and aseptic practices, Lapses in cleaning, maintenance and cleaning validation. Other deficiencies included deficient process validation failing to evaluate intra and intrabatch variability, inadequate control over computerised systems and inadequate training and evaluation of operators involved in manual visual inspection:

Zydus Vadodara USFDA 483 – April 2024

1. Batch failure Investigations are not thorough to identify all root causes, evaluate other impacted batches; Actions taken on potentially impacted batches are inadequate.
   • Batches were rejected for unspecified impurities out of specification (OOS/OOT) due to cross contamination. But other batches with similar impurities within limits for unspecified impurities were not evaluated and released.
   • Higher glass particulates in injection vials were attributed to drug-vial interaction and incompatibility of the glass vial. However, batches released to market with same type of vials were allowed to remain in market.
2. Data Integrity lapses in creating sampling records, not following sampling plans, inadequate documentation
   • Samples for microbiology analysis and BET were collected from same point for multiple sampling points, records created for samples not collected. Samples were collected by employees not qualified for sampling.
   • Different processing methods for chromatographic integration were used within same sequence without adequate documentation.
3. Inadequate validation of aseptic area – Failure to demonstrate unidirectional airflow in the RABS under dynamic conditions during interventions
4. Procedures to prevent microbiological contamination of sterile products and aseptic behaviour are not followed. Not ensured sterile components are only contacted with sterile forceps and manipulations within aseptic area are performed from the side without disrupting laminar air flow.
5. Failure to establish adequate production and process controls:
   • Process validations are inadequate; Did not evaluate inter and intra batch variability and no acceptance criteria are defined.
6. Aseptic areas are deficient in system for monitoring of environmental conditions.
   • Frequent communication errors in NVPC continuous monitoring system, alarms are not acknowledged timely
7. Lapses in cleaning and maintenance with scratches, rough surfaces on equipment, residue observed inside of RABS during aseptic filling of a batch.
8. Training is deficient. Operators involved in manual visual inspection of injection vials for identification of glass particles are not challenged sufficiently.
9. Procedure for cleaning and Cleaning validation document were deficient – the hardest to clean / most toxic API was incorrectly identified. The cleaning validation did not assess the full range of equipment surfaces for cleanability
10. Control over computer system are deficient.
    • MODA system for microbiology documentation allowed to override bar code scanners for sampling entries, did not have autosave function and allowed manually saving data without audit trial of changes.