Natco Pharma USFDA 483 Flags Deficiencies in Aseptic Areas, Validation

1. Discrepancies in Non Viable Particle (NVP) monitoring in aseptic areas & Data Integrity concerns

• The Quality Unit did not review the electronic data from the non-viable particle (NVP) monitoring equipment, only print outs were documented. Discrepancies were found between the electronic data and the hardcopy reports, with results altered from over the action limit to below action limit.
• It was observed same locations were sampled repeatedly until a passing result was obtained for non viable particle count and no incident reports or investigations were initiated as required by the Site SOPs
• Operators failed to print and document all environmental monitoring data during aseptic operations; also over 300 data reports for environmental monitoring from the change room were not documented.

2. Deficiencies in Equipment and Facility Maintenance in Aseptic areas

• Auditors observed damages on the wall above and below the clean room phone panel in the Grade A extended laminar airflow (LAF) area, exposed bolt threads, gaps and rough edges, rough sealant surfaces in the Grade A area LAF, LAF frame

3. Inadequate Validation of Aseptic Processes – gaps in smoke studies, media fill studies

• In the videos of the dynamic airflow visualisation studies only limited portions of the RABS visible at a time due to the camera angle, smoke generation device not visible in many videos, inadequate smoke to visualise the airflow pattern which all prevented adequate assessment of the airflow pattern
• The airflow visualisation study reports were signed off despite many comments for reshoot of certain videos due to narrow camera view or lack of smoke, and recording turbulent air during interventions
• Gaps were also observed in the media fill studies, the firm did not incubate all the integral vials from the studies

4. Failure to thoroughly investigate deviations

• Disinfectant efficacy study did not cover all new microorganisms identified during an OOS investigation of environmental monitoring
• In the non-viable particle monitoring, failing results were not investigated adequately.
• Interruptions in chromatographic analysis sequences – Project integrity failures in Empower 3 – were not thoroughly reviewed or evaluated by the Quality Unit. Instances were observed where samples solutions were injected with principal peak elution, but results were not evaluated for compliance with specifications.

5. Lapses in Personnel Qualification and Training

• All employees performing visual inspection of sterile drug products were not qualified after revising the procedure for Qualification of Visual Inspectors, which was effective from January 2025

6. Facility Deficiencies

• The aseptic processing area’s viewing windows did not allow for adequate observation of critical operations, such as filling, stoppering, and sealing and interventions.

7. Quality Unit gaps in following GMP practices, document review, awareness of instruments and systems

• Quality Unit lacked understanding of various communication errors and circumstances that can lead to aborted, interrupted or incomplete sequences in Empower 3.
• Failure to complete assessment of all batches and analytical data of a retrospective review for extraneous peaks in the chromatograms, which was a response to previous inspection deficiencies
• Investigations are not properly documented and retained. The paper waste shredder log indicated shredding of draft investigation reports. But the contents of these draft reports were not available for review along with the final reports.
• Gaps observed in documentation and review of environmental monitoring records.

What it should address:

When observations in the USFDA Form 483 point to gaps in Quality oversight, lack of depth and thoroughness in following GMP practices, review of documents and gap in awareness of the Firm’s own systems and instruments, the corrective actions (CAPA) should comprehensively address the issues to prevent any recurrence. Apart from addressing the specific issues cited, the CAPA plan should be addressing system improvements:

• Issue of inadequate electronic data review and control should look at all other areas in production where similar situation might exist – e.g. (but not limited to) manufacturing equipment like compression machine, critical utilities like water, air, HVAC systems, monitoring and control systems for Temperature, Humidity.
• When there are multiple observations of deficiencies in aseptic areas and validations, put together they raises concerns of sterility of drug products and microbiological contamination. This will require a thorough review of all distributed batches within valid expiry for allaying concerns of sterility assurance. All relevant supporting data – environmental monitoring records, raw data and electronic records, aseptic practices and procedures, history of past incidents and failures, complaints will need to be reviewed, retest of samples performed where required and accordingly actions initiated.
• In Media fill studies it is not acceptable to skip incubation of all integral vials; seal integrity check is a physical check and not a substitute for the incubation of all media fill units. All breaches in a vial like small, transient breaches which can allow microorganisms to enter may not get detected by physical leak tests
• Observations pointing to lack of full understanding of instruments and systems should trigger a review of all analytical systems and adequacy of current controls and awareness of the systems and actions to improve procedures and awareness of the systems.
• Training systems must be reviewed for controls to ensure completion of training before new SOPs or changes in SOPs are made effective and actions taken to expeditiously complete all pending trainings.
• Observation of shredding and discarding of draft investigation reports raises a new concern. Companies should have adequate controls to prevent unwanted printing and discarding of records. Such observations also call for a thorough review of shredder logs, identify instances of destruction of GMP documents and an impact assessment. Particular attention should be given to those investigations where root causes are not established, deviations or failures (like OOS, complaints) are invalidated.
• Observation of deficiencies in facilities and facility maintenance should trigger a thorough review of all production buildings and facilities, equipment to identify quality impacting gaps, and enhancement of procedures to identify such gaps promptly and corrective actions.
• The procedures for reporting quality events, incidents and investigation also will require a thorough review. Measures will need to be taken for enhancing the cGMP understanding, awareness of systems and procedures, and competencies of personnel involved in activities impacting quality and safety of products.