Good x Practice (GxP) inspections are critical to ensuring that life science companies comply with industry benchmarks for safety, data quality and product efficacy. Cleanrooms are often the focus of these types of reviews due to their role in ensuring patient safety. They need to prove that they are consistently cleaned and sterilised to reduce the risk of harmful bacteria and viruses.
This level of cleanliness is outlined in numerous global regulations, including those of the Medicines and Healthcare products Regulatory Agency (MHRA) and the Food and Drug Administration (FDA). Regulations require manufacturers to demonstrate and certify that they are conducting environmental monitoring and providing risk-based contamination control strategies.
To continue operations, it is essential that the cleanrooms pass inspection, thereby ensuring they meet regulatory requirements. It is essential to understand what to expect during a GxP inspection, including the observation of operational documentation, real-time cleanroom performance, environmental monitoring (EM) data, and trace material and personnel flows. Procedures and evaluated practices must align to avoid failing the inspection.
Additionally, there are ten areas that pharmaceutical companies should keep in mind, ranging from conducting a risk assessment to verifying materials and workflows, which will help them pass their FDA, MHRA and EU Annex 1 inspections, including:
Tip 1: Self-review and risk assessment
Teams can prepare for their GxP inspection by conducting a mock regulatory audit. They should conduct a full cleanroom walk-through, ask operators to explain their aseptic behaviours, and verify that flows and practices align with SOPs. The walk-through should include key test areas, including HVAC performance, Contamination Control Strategy (CCS) implementation, EM data integrity and cleaning routines.
Tools like ICH Q9 can aid in this preparation by identifying vulnerabilities that need to be fixed before the real inspection. Additionally, account for the different regulations depending on where they operate. For the FDA and MHRA, teams should be ready to proactively identify contamination risks and common GMP deficiencies.
Tip 2: Data integrity and security
Data Integrity is imperative, regardless of what a company is or what industry it operates in. Cleanroom monitoring generates records, including viable and non-viable particle counts, equipment qualification data, environmental monitoring (EM) results, and pressure differentials.
Regulators will review records for compliance both digitally and on paper to ALCOA+ (Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, and Available).
Plan to provide trend reports and raw data during the inspection. Additionally, teams should ensure that computer access is restricted by role and that critical systems are audited, as this is imperative for data security. All team members must be trained and able to effectively explain data for a successful audit.
Tip 3: CCS and environmental monitoring programme
While not mandated by the FDA, it is essential to have a robust CSS, as the EU Annex 1 requires it. This Annex includes viable and non-viable monitoring of ≥5.0 µm particles during routine operations for Grades A-D. CCS should be maintained so they are current in conjunction with EM and septic controls. Note that the FDA will focus on the EM and aseptic controls only for control particles ≥ 0.5 µm.
Tip 4: Cleanroom classification and HVAC performance
Cleanrooms are expected to remain in a validated state of control. This includes documented classification and qualification, along with HVAC monitoring. Teams need to be ready to provide validated smoke studies, differential pressure monitoring results and HEPA filter integrity tests. All gauges must be in stable control and calibrated.
The FDA will require ISO classification and a validated HVAC, while the MHRA will evaluate the pressure differentials, airflow and segregation. Annex 1 has stricter Grade A-D limits, monitoring ≥5.0 µm particles during HEPA filter operation.
Tip 5: Personnel gowning and aseptic practices
Cleanroom staff present the highest contamination risk to operations. This results in inspectors observing gowning and aseptic manipulations during the audit. Teams should be ready to demonstrate their media fill, gowning and aseptic practices. Additionally, gowning qualification records and training may be reviewed, so be sure to reinforce controlled movement and aseptic rigour with teams.
Tip 6: Cleaning, disinfection and sterilisation practices
Contamination control is crucial for maintaining the integrity of pharmaceutical cleanrooms. During the inspection, auditors will verify cleaning validation, the use of disinfectants, rotation, residue management and sterilisation cycle qualification to ensure they meet regulatory requirements.
Teams should be equipped with disinfectant efficacy reports, residue studies, and cleaning logs and procedures. Additionally, they may be asked to confirm disinfectant in-use dating and rotation schedules. Inspectors often check stock solutions and expiry labelling on the floor.
Tip 7: Equipment and utility qualification maintenance
Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ) reports should be updated and complete with concise qualification summaries to be ready for inspection. HVAC, autoclaves and cleanroom reports may also be reviewed during the GxP inspection to ensure the equipment is aligned with the intended use and validates the equipment use is proportional to risk.
Tip 8: Material and personnel flows verification
Flows are crucial for reducing the risk of cross-contamination in a pharmaceutical cleanroom. During the inspection, inspectors will walk the staff and material routes to ensure separation. This is required by the FDA. The MHRA will evaluate pressure differentials and airlocks, while Annex 1 will ensure risk-based flow assessments are integrated into CCS.
To prepare for the inspection, ensure that the flow diagrams accurately reflect the practices being implemented. Additionally, growing and material transfer procedures may be asked to be demonstrated to ensure there are no shortcuts.
Tip 9: Cleanroom deviations, Corrective and Preventive Actions (CAPAs) and change controls management
Investigation reports for EM excursions and gowning failures should be readily available in case they are requested during their inspection. Root-cause analysis, risk-based CAPAs and evidence of effectiveness verification may also be requested. These are all important demonstrations of pharmaceutical cleanroom handling deviations and the management of contamination risks.
The FDA will complete investigations under 21 CFR 211.192, the MHRA will focus on CAPA effectiveness checks and Annex 1 will assess systemic contamination risks.
Tip 10: Inspection readiness and cleanroom culture
Beyond preparing for a GxP inspection, it is essential that these procedures are integrated into the organisation’s culture. Culture is imperative to ensuring compliance beyond an audit, and inspectors will often assess quality culture by observing behaviours, asking operators about their roles and testing transparency.
The FDA, MHRA and Annex 1 will all emphasise leadership accountability and cultural maturity during their assessments.
Teams can prepare for this by conducting mock cleanroom inspections and empowering staff to answer questions confidently and consistently. Additionally, senior management should demonstrate oversight of cleanroom operations and effective governance of contamination control.
Preparation is key
Organisations that focus on these 10 areas before conducting their GxP inspection will be better aligned with regulations, including those of the FDA, MHRA and Annex 1 requirements. Getting past the cleanroom inspection is instrumental in demonstrating strong CSS, EM, gowning, cleaning, HVAC qualification and robust deviation management practices.
The regulations outline specific requirements that help reduce contamination risks and validate controls. This ultimately helps reinforce cleanliness and increases patient safety. Through complying to regulatory requirements, organisations can continue operations and increase patient confidence.