About the Form 483

FDA inspected a Telangana-based Sterile Facility in February 2024 and issued 7 observations relating to contamination control, environmental monitoring, and Root Cause analysis among others. The inspection was conducted from February 19, 2024, to February 29, 2024. 

The Form 483, which was 9 pages long, indicates significant violations of aseptic processing and quality control practices, risking product sterility and patient safety. According to the form, immediate corrective actions are necessary to prevent potential harm to consumers and ensure compliance with FDA regulations.

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Detailed analysis of procedures impacted

The following is the summary of each of 8 procedures impacted, along with observations, Potential Root Cause and suggested CAPAs.

Environment Monitoring:  

Key Observation: Procedures designed to prevent microbiological contamination not followed, leading to inadequate aseptic process simulations and personnel monitoring post-interventions.

Possible Route Cause: Inadequate adherence to environment monitoring SOPs and failure to perform necessary aseptic process simulations fully reflective of operational conditions may stem from a lack of understanding amongst the staff regarding the criticality of these processes or insufficient training on the procedures.

Suggested CAPA: Revise and re-enforce training on environment monitoring SOPs, emphasizing the significance of these processes. Implement a regular review and testing schedule for aseptic process simulations to ensure all potential interventions are accurately replicated.

Contamination Control: 

Key Observation: Lack of disinfectant efficacy study for tubing used during vial filling, with no sterilization prior to installation in the filling assembly.

Possible Route Cause: The absence of disinfectant efficacy studies and lack of sterilization for tubing prior to installation indicates a critical oversight in the validation process for aseptic filling equipment, potentially due to an underestimation of contamination risk or gaps in validation protocols.

Suggested CAPA:  Conduct a full review of equipment validation processes with a focus on sterilization and disinfection effectiveness. Initiate efficacy studies for all critical equipment used in aseptic processing, particularly tubing, and ensure results are documented and actions taken as appropriate.

Root Cause Analysis:

Key Observation: Written records not always made of investigations into unexplained discrepancies and out-of-specification results, missing confirmations of probable causes.

Possible Route Cause: The lack of thorough investigations and written records for unexplained discrepancies or out-of-specification results suggests gaps in the systematic problem-solving procedures or possibly insufficient resources dedicated to thorough analysis.

Suggested CAPA: Enhance the potential root cause analysis process by adopting a more systematic approach, such as the Fishbone or Five Whys methods, and ensure sufficient resources and training are provided to staff involved in these investigations.

Corrective and Preventive Actions (CAPAs): 

Key Observation: Investigations not leading to definitive potential root cause identification or effective corrective measures, allowing continuation of identified issues.

Possible Route Cause: Recurrent issues without definitive potential root cause identification or effective subsequent corrective actions point towards a weakness in the CAPA process, likely due to a lack of robustness in the investigation methods or inadequate training on CAPA procedures.

Suggested CAPA: Strengthen the CAPA process by incorporating more rigorous investigation methodologies, ensuring comprehensive training for involved personnel, and implementing a follow-up mechanism to verify the effectiveness of corrective actions.

‍Audit management: 

Key Observation: Failures in following standard operating procedures for microbial colony enumeration and lack of action when discrepancies identified.

Possible Route Cause: Failures in following SOPs for microbial colony enumeration and responding appropriately to discrepancies suggest an inadequate audit trail and quality control checking process, alongside a possible lack of awareness around the importance of accurate record-keeping and compliance.

Suggested CAPA:  Implement a more robust audit and quality control review process, including retraining staff on the significance of following SOPs accurately and maintaining a proper audit trail for all quality-related activities.

Data Backup and Recovery:

Key Observation: Failure to maintain backup files of data and lack of audit trail functionality for Nonviable Particle Counters, compromising data verification.

Possible Route Cause: The failure to maintain backup files of data and lack of audit trail functionality for nonviable particle counters may indicate inadequate IT infrastructure or awareness regarding the necessity for data integrity and traceability within manufacturing environments.

Suggested CAPA:  Upgrade IT infrastructure to include audit trail functionality for all critical equipment and ensure that data backup processes are established and regularly tested for efficacy to safeguard against data loss.

Facility Management: 

Key Observation: Critical equipment not suitably located to facilitate operations, impacting the integrity of the aseptic processing environment.

Possible Route Cause:  Misplacement of critical equipment, undermining the aseptic processing conditions, could be traced back to insufficient planning in the layout design or a lack of proper validation and verification processes for equipment placement.

Suggested CAPA:  Review and redo the facility layout design with a focus on optimal placement of equipment to support aseptic processing. Conduct thorough validation and verification processes to ensure all equipment placement aligns with best practices for aseptic environments.

Employee Training: 

Key Observation: Employees engaged in manufacturing lack necessary training for their roles, affecting the ability to identify and rectify defects efficiently.

Possible Route Cause:  Employees lacking necessary training for their roles demonstrates gaps in the training program, possibly due to insufficiently robust training materials, infrequent training sessions, or a lack of comprehensive assessment and verification of employee competencies.

Suggested CAPA: Overhaul the training program to include comprehensive materials, regular and frequent training sessions, and robust competency assessments to ensure all employees are fully equipped to perform their roles effectively.

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Investigator Insight

The investigators of this Form 483 were Ashar P Parikh and Marcellinus D Dordunoo.

Ashar P Parikh is a thorough and meticulous FDA auditor with a keen focus on the importance of quality control, employee training, and maintaining aseptic conditions. Parikh emphasizes adherence to established procedures and regulations with greater emphasis on proper documentation and execution of processes. Parikh demonstrates a critical eye for detail, especially when it comes to cleanliness and employee competence in their roles. He has issued 7 Form 483s since 2018.

Marcellinus D. Dordunoo is a methodical investigator, focusing heavily on compliance with procedures, data integrity, sample handling, and the training of employees. His observational history indicates a high regard for thoroughness, accuracy, and adherence to regulations. His assessments tend to uncover procedural gaps, inadequate staff training, and concerns regarding contamination prevention and data protection. Dordunoo places a strong emphasis on procedural adherence, data integrity, and staff training. His inspections often uncover undetected gaps in these areas. 

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