Table of Contents
Introduction
Risk-based commissioning, qualification, and validation (CQV) approaches offer streamlined, science-driven processes to ensure systems and equipment meet stringent compliance and quality standards. Designed to focus resources on high-risk areas, this approach is increasingly popular in regulated industries like pharmaceuticals and biotechnology. However, risk-based CQV frameworks can sometimes be seen as "too risky" in high-stakes environments. In these cases, regulatory bodies, while supportive of risk-based methods, emphasize limits on how extensively risk-based CQV should replace traditional, comprehensive protocols.
This post will explore when risk-based CQV might be deemed too risky, how regulatory bodies perceive the approach, and the critical steps that make a risk-based CQV approach effective and compliant.
Overview of Risk-Based CQV
The risk-based CQV model aligns with frameworks like ASTM E2500 and ISPE’s Baseline Guide Vol. 5, which emphasize a science-based approach that assesses potential risks to product quality and patient safety. This method leverages systematic risk assessment to determine which systems, processes, and equipment demand the highest scrutiny and control during qualification. With guidance from regulatory bodies such as the FDA, EMA, and PIC/S, the risk-based CQV approach allocates resources based on the criticality of each component in maintaining product quality and safety.
Regulatory Emphasis on Risk Management in CQV
Global regulatory bodies acknowledge and support risk-based CQV approaches, yet they highlight the importance of appropriate application and safeguards:
- FDA Process Validation Guidance: The FDA advocates a lifecycle approach to validation that relies on process understanding and risk management.
- EMA's Annex 15 on Qualification and Validation: Emphasizes that risk-based strategies should incorporate robust controls for high-risk areas, such as sterile production, where contamination risks are elevated.
- EU GMP Annex 20: Broadly applies Quality Risk Management (QRM) principles to pharmaceutical manufacturing operations, advising that risk-based approaches should augment—rather than replace—monitoring and qualification activities in high-stakes systems.
When is Risk-Based CQV Considered Too Risky?
The appropriateness of a risk-based CQV approach may vary depending on the level of risk posed by the system, equipment, or process in question. Here are specific conditions under which risk-based CQV might be considered too risky:
- High Impact on Patient Safety: When equipment failures or process deviations directly impact patient health, such as in the manufacture of sterile or biopharmaceutical products, regulatory bodies recommend rigorous, traditional CQV over streamlined risk-based approaches.
- Limited Data to Inform Risk Assessments: Risk-based CQV depends on robust historical data to accurately evaluate and mitigate risks. If data is insufficient, the resulting risk assessment may overlook critical risk factors.
- Complex or Automated Systems: Computerized and automated systems, especially in regulated environments, require full validation, even when risk-based CQV is applied.
- Reliance on Vendor Documentation: Vendor-supplied data alone may not always satisfy regulatory requirements. It should be verified against specific quality criteria to avoid compliance gaps.
Steps for a Successful Risk-Based Approach
A successful risk-based CQV approach requires systematic planning, risk assessment, documentation, and alignment with regulatory expectations. Key steps include:
1. Define Objectives and Scope
Clearly define CQV goals, establish scope, and involve stakeholders to align expectations.
2. Perform a Comprehensive Risk Assessment
Use tools like FMEA and HACCP, engage SMEs, and document assumptions for a thorough risk assessment.
3. Classify Systems and Components Based on Risk
Classify systems as high, medium, or low risk to allocate resources effectively, following guidance from ASTM E2500 and ISPE’s Baseline Guide.
4. Design and Document Control Strategies
Define control measures, automate monitoring for high-risk areas, and document all controls thoroughly for regulatory review.
5. Plan Validation and Verification Activities
Set acceptance criteria, establish testing protocols, and streamline documentation for low-risk elements.
6. Implement Robust Documentation Practices
Maintain detailed risk assessment documentation, real-time records of testing, and a traceability matrix linking risk controls to regulatory requirements.
7. Continuous Monitoring and Periodic Review
Implement automated monitoring for immediate alerts, schedule periodic reviews, and update documentation based on findings.
8. Train Personnel on Risk-Based Principles and Practices
Provide QRM and protocol-specific training to ensure personnel understand and follow the risk-based approach.
9. Perform Internal Audits and Quality Checks
Conduct audits to validate risk-based CQV effectiveness, assess control strategies, and use findings to refine protocols and training.
Regulatory Perceptions on Over-Reliance on Risk-Based CQV
Regulatory bodies generally support risk-based CQV but recommend caution in high-risk areas:
- FDA: Supports risk-based CQV but suggests that over-reliance may trigger scrutiny if compliance appears compromised.
- EMA: Advocates risk-based approaches but emphasizes full validation for critical areas like sterile production.
- ISPE Baseline Guide: Notes that while risk-based CQV can drive efficiency, deviations must be justified to avoid compliance issues.
- Swissmedic: Thus far Swissmedic has taken a cautious approach to risk based qualification approaches, with few projects implementing the approach based on prior feedback from site and facility audits.
Conclusion
A risk-based CQV approach, when applied thoughtfully, enhances efficiency while ensuring compliance and quality. By following a structured process, assessing risks, classifying systems, and maintaining robust documentation and monitoring, organizations can balance efficiency with patient safety and regulatory expectations. Blending traditional and risk-based CQV practices can further ensure that all high-impact areas meet compliance, supporting both operational goals and regulatory approval.
