Eugia Bhiwadi Facility Classified OAI: What Leads to OAI Classifications

The Eugia facility in Bhiwadi, Rajasthan, India (FEI 3009883410) was recently classified as OAI (Official Action Indicated) by the USFDA following an inspection in April-May 2024. Investigators Anastasia M. Shields, Justin A. Boyd, and Vaishali J. Patel conducted the inspection, resulting in the issuance of a USFDA Form 483 with seven observations. It’s important to note that not all Form 483 observations lead to an OAI classification or regulatory actions such as warning letters or import alerts. So, what led this facility to be classified as OAI?

Aseptic Processing Lapses: A Major Concern

One of the critical issues identified during the inspection was related to aseptic operations. The inspectors observed several lapses that could compromise the sterility of the products:

• Airflow Obstructions: Operators were found obstructing laminar airflow during interventions on the aseptic processing line, potentially leading to contamination.
• Inadequate Airflow Demonstration: Airflow visualization studies in Grade A areas did not demonstrate adequate airflow during commercial operations.
• Delayed Surface Monitoring: Surface monitoring of the filling and stoppering machine was not performed in a timely manner following the completion of aseptic filling operations. In some cases, surface monitoring was conducted the next day, raising concerns that the data might not accurately reflect the environmental conditions at the time of filling.
• Contaminant-Risk Cleaning Materials: The cleaning wipes used in aseptic areas were observed to have loose threads and fibers, posing a contamination risk.

Such lapses in aseptic practices can severely compromise product sterility and safety. Moreover, the facility’s aseptic process simulation studies had failures, with root causes attributed to non-routine operator interventions. However, the investigations were deemed inadequate as they failed to assess other interventions and did not evaluate the impact on commercial products.

Containment Control Issues

The inspection also uncovered significant deficiencies in the facility’s containment control systems:

• Unrestricted Movement: There were no adequate restrictions on personnel movement between different manufacturing blocks. Personnel interacted in shared spaces such as common areas and canteens, increasing the risk of cross-contamination. Maintenance tools were also were not dedicated for different manufacturing blocks and maintenance personnel working in the area where tools are stored were not restricted from entering the production buildings
• Shared Facilities and Documents: The QC and Microbiology facilities were shared among different manufacturing blocks and people from different manufacturing blocks access the shared QC and Microbiology facilities. Additionally, documents such as batch records and environmental monitoring records moved between blocks and administrative areas and new documents were issued to different manufacturing blocks from this shared document control area, further heightening contamination risks. The administration building personnel were also not restricted from access to production areas, raising further concerns.

The facility lacked programs, procedures, or test methods to detect contamination and had no established protocols for deactivating agents to address contamination incidents when new products were introduced.

How an inspection becomes classified as Official Action Indicated (OAI) 

According to Carmelo Rosa, Director of the USFDA CDER Office of Manufacturing and Product Quality Division, the decision to classify a firm as OAI is based on several factors: – “Form 483 observations, evidence from the inspection, content of the 483 response, history of the firm, the risk to patients from the deficiencies found, and whether the observations include repeats from previous inspections of the facility or another facility in the same company”. Serious deficiencies, such as inadequate control over aseptic operations and containment controls, especially when multiple related observations point to product safety concerns, is a sure recipe for an OAI classification.

Compliance and Control Measures

Strengthen Aseptic Processes Aseptic process involves numerous processes, conditions and factors with potential for contamination from many sources. Operator interventions during aseptic process is a key source of microbiological contamination. Periodic training and requalification of the operators as well as Quality personnel assigned to monitor the aseptic operations are essential. Ensure individual operators demonstrate proficiency in aseptic operations including gowning and process interventions. Post batch review of deviations and routine and nonroutine interventions in the batch along with operators can be very useful in identifying non routine interventions promptly. Batch release decision in case of deviations should be well justified on why such interventions will not impact sterility of the product. Evaluate reasons for such interventions, corrective measures, and include such interventions in future media fill studies.

Enhance Containment Controls: In facilities handling high-potency drugs, stringent containment control measures are critical to avoid cross-contamination. The acceptable carry over limits for high potent drugs could be very low or even nil in case of highly sensitising substances like penicillin and lactams. Ensuring containment control measures are only practical solution for avoiding contamination in such cases. Conduct comprehensive risk assessments to identify all potential contamination sources. The Quality Risk Assessment (QRM) should consider all possible mechanisms of cross contamination – Surface to Surface, Airborne to Air / Surface, Direct or Indirect contamination from Process and / or Equipment failure, Originating from movement of Personnel, materials, equipment or equipment parts. For example (but not limited to) – equipment, gowning and laundry, exhausts, effluents and backflows, spillages and leaks, equipment failures, common entry / exit to production areas or blocks, common areas like canteen, wash rooms, transportation, shared facilities like QC, QA, Engineering & Maintenance, Document storage and archival, Administrative office areas, Training rooms all should be included in the risk assessment, evaluated for potential contamination and carry over of drug residues and control measures implemented. Implement and validate containment measures by sampling and monitoring areas for contaminants. Consider dedicating certain facilities like QC, Microbiology, and in-process QA within specific production blocks to minimize cross-contamination risks.

Serious deficiencies with potential product safety concerns should be addressed comprehensively to ensure safety and integrity of products and prevent regulatory interventions and official actions.

Additional Reads & References:

• Qvents News: Eugia USFDA 483 Cites Inadequate Containment Controls, Aseptic Practices
• PIC/S Aide-Memoire Cross-Contamination In Shared Facilities
• The requirements for manufacturing highly active or sensitising drugs comparing Good Manufacturing Practices (Petrelli F, Caraffa A, Scuri S, Grappasonni I, Magrini E, Cocchini A. Acta Biomed. 2019 May 23;
• Who Decides if my FDA Inspection is Classified OAI? By Jerry Chapman, Redica Blogs