designed and maintained to prevent contamination.

EU GMP Annex 1 (2022): Emphasizes contamination control strategy across the entire facility, not just cleanrooms.

WHO GMP: States that even non-classified areas must be kept clean and free from microbial growth.

PIC/S PI 032: Highlights the importance of monitoring and maintaining facility areas outside classified zones.

These requirements establish that non-classified zones cannot be ignored in contamination control programs.

Audit Findings Related to Fungal Contamination

Examples of real regulatory findings include:

• FDA 483: Visible mold growth observed in a non-classified corridor adjacent to sterile manufacturing.
• EMA Observation: Facility lacked a cleaning SOP for warehouse areas, resulting in fungal contamination.
• WHO Audit: No routine inspection of HVAC ducts serving non-classified spaces, allowing fungal buildup.
• PIC/S Finding: Inadequate pest control in unclassified zones leading to fungal introduction.

These findings illustrate the regulatory expectation that the entire facility—not only classified areas—supports GMP compliance.

Root Causes of Fungal Contamination

Root cause investigations revealed several contributing factors:

• Poor Facility Design: Non-classified zones lacked adequate ventilation and humidity control.
• Inadequate Cleaning SOPs: No defined cleaning frequency or disinfectant use in unclassified areas.
• Neglected Maintenance: Leaks and condensation left unaddressed, creating fungal growth conditions.
• HVAC Oversight Gaps: No monitoring of air handling units serving non-classified areas.
• Weak QA Oversight: QA focused only on classified zones, neglecting facility-wide contamination control.

These systemic weaknesses contributed to contamination spread into GMP manufacturing zones.

Corrective and Preventive Actions (CAPA)

The facility implemented a multi-tier CAPA plan to address fungal contamination:

1. Immediate Actions: Quarantine affected products and disinfect contaminated surfaces with sporicidal agents.
2. Root Cause Analysis: Identify moisture sources and HVAC deficiencies contributing to fungal growth.
3. SOP Revisions: Update cleaning procedures to include non-classified zones with defined frequencies.
4. HVAC Maintenance: Inspect and clean ducts, install HEPA pre-filters, and establish monitoring for humidity.
5. Facility Repairs: Eliminate leaks, improve drainage, and resurface walls to resist fungal growth.
6. QA Oversight Expansion: Extend QA monitoring and internal audits to include non-classified areas.
7. Preventive Training: Train staff on contamination risks originating in non-classified spaces.

This CAPA framework addressed immediate risks and established long-term preventive measures.

Best Practices to Prevent Fungal Contamination

To prevent similar issues, facilities should implement the following best practices:

• Maintain facility-wide cleaning schedules covering both classified and unclassified areas.
• Monitor environmental conditions (temperature, RH) even in non-classified spaces.
• Perform periodic facility inspections for leaks, condensation, or visible fungal growth.
• Integrate non-classified zone oversight into the Contamination Control Strategy (CCS).
• Ensure pest control programs extend to warehouses and storage areas.
• Trend EM data across the facility to detect early warning signals.
• Incorporate non-classified zones into internal audit schedules.

These practices strengthen contamination control and align with regulatory expectations.

Checklist for Internal Compliance Readiness

• Facility-wide cleaning SOPs include non-classified areas
• Routine inspections conducted for walls, ceilings, and storage zones
• Humidity and ventilation controls in place across facility
• QA oversight documented for both classified and non-classified areas
• CAPA implemented for identified fungal risks
• Training logs confirm staff awareness of fungal risks
• HVAC ducts monitored and maintained regularly
• Deviations linked to CAPA with effectiveness checks
• Internal audits simulate regulatory focus on facility-wide contamination control
• Management reviews monitor fungal risk controls

This checklist ensures facilities remain regulator-ready by addressing contamination risks in all zones.

Conclusion: Controlling Risks Beyond Classified Cleanrooms

The case study of fungal contamination in non-classified zones demonstrates that contamination risks are not limited to controlled cleanrooms. Regulators expect facilities to implement holistic contamination control strategies that include warehouses, corridors, and other ancillary spaces. By strengthening cleaning SOPs, HVAC oversight, QA monitoring, and CAPA implementation, companies can prevent contamination migration, maintain GMP compliance, and protect patient safety.

Abbreviations

• GMP – Good Manufacturing Practice
• FDA – Food and Drug Administration
• EMA – European Medicines Agency
• WHO – World Health Organization
• PIC/S – Pharmaceutical Inspection Co-operation Scheme
• CAPA – Corrective and Preventive Action
• SOP – Standard Operating Procedure
• QMS – Quality Management System
• HVAC – Heating, Ventilation, and Air Conditioning
• EM – Environmental Monitoring
• QA – Quality Assurance
• CCS – Contamination Control Strategy
• RH – Relative Humidity

References

• FDA 21 CFR Part 211
• EU GMP Guidelines (EudraLex Volume 4)
• WHO GMP Guidelines
• PIC/S Publications