(0.5 micrometers or larger) per cubic foot of air. This classification is less stringent compared to newer ISO standards.

ISO Class 7 is defined by ISO 14644-1. Here, the air quality is ensured to have no more than 352,000 particles (0.5 micrometers or larger) per cubic meter (approximately 100,000 particles per cubic foot). In practice, ISO Class 7 cleanrooms are capable of accommodating many vital manufacturing processes, including those for non-sterile drugs.

Grade C is defined under the EU’s GMP guidelines (Annex 1), which corresponds closely to ISO Class 7. However, it often emphasizes strict limits on both viable and non-viable particulate counts, aligning closely with the requirements of sterile production. Understanding the distinctions between these classifications is crucial for determining design and operational standards for cleanrooms.

2. User Requirement Specification (URS) & Risk Assessment

Establishing a robust User Requirement Specification (URS) is the first and foundational step in the validation lifecycle. The URS should clearly articulate the necessities and expectations for the cleanroom or HVAC system, which includes classification, operating conditions, equipment, and regulatory compliance metrics.

After the URS is established, conducting a thorough risk assessment is the next step. This analysis enables the QA team to identify potential risks associated with environmental contamination, equipment failure, and human error. Risk management is integral to the validation process, particularly through the adoption of ICH Q9 guidance, which focuses on quality risk management principles.

It is recommended that the URS incorporates parameters drawn from ISO 14644, which will serve as a baseline for testing and managing air quality. Document all identified risks, and establish mitigation strategies alongside acceptance criteria based on the validated classification of the environment.

• Define cleanroom classifications based on product requirements.
• Identify potential risks associated with identified classifications.
• Develop mitigation strategies to reduce risks to acceptable levels.

3. Protocol Design for Qualification

Equipped with a well-defined URS and risk assessment, the next step is the design of protocols for the qualification phases—Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ). Each qualification phase addresses specific aspects of the design and operational capabilities of the cleanrooms or HVAC systems.

The Installation Qualification involves verifying that all equipment and systems are installed correctly in accordance with the design specifications and URS. This includes checking the mechanical, electrical, and technical installation against manufacturer specifications.

Operational Qualification ensures that the systems perform as intended under simulated operational conditions. For cleanrooms, this means testing the HVAC system performance, including airflow patterns, differential pressure, and filtration efficiency. The results need to be documented thoroughly, with non-conformities addressed accordingly.

Performance Qualification is the final phase where the HVAC system and cleanroom go through their intended use under normal operational conditions to confirm that regulatory requirements are consistently met. Protocols should provide detailed instructions for environmental monitoring and sampling methodologies according to the previously established classifications.

4. Continued Process Verification (CPV)

Continued Process Verification (CPV) exemplifies the concept of ongoing quality assurance throughout the lifecycle of the cleanroom and manufacturing process. With CPV, organizations are encouraged to consistently gather and analyze data to ensure consistent process performance and product quality following the initial validation phases.

The critical focus of CPV is to establish a systematic approach where real-time data analysis, accompanied by risk assessment findings, drives continuous improvement. CPV can encompass environmental monitoring, equipment performance data, and product quality attributes. Monitoring temperature, humidity, air quality, and particulate counts in cleanrooms is essential.

CPV requirements must align with ISO 14644 standards as well as FDA and EU regulatory expectations. Documentation plays a crucial role in CPV; organizations must maintain comprehensive records of monitoring results which form the basis for informed decision-making. If deviations are noted, organizations should have defined protocols to investigate, report, and take corrective action.

5. Revalidation: When and Why?

Revalidation of cleanrooms and HVAC systems is essential in ensuring that systems remain capable of meeting required standards over time and across production volumes. It is triggered by significant changes in manufacturing processes, facility modifications, equipment upgrades, or changes in raw materials.

The two primary forms of revalidation are periodic and condition-based revalidation. Periodic revalidation is conducted at defined intervals, aligning with corporate policies and regulatory standards. Condition-based revalidation is initiated when production or operational conditions change significantly enough to warrant a reassessment of validated statuses.

Documentation and protocols for revalidation should reflect similar methodologies used in the initial qualification phases—IQ, OQ, and PQ. The revalidation process itself consists of reviewing the performance data accumulated during CPV, conducting an inward evaluation of potential risks, and facilitating a gap analysis to identify areas needing improvement or adjustment.

6. Documentation and Regulatory Expectations

The significance of thorough documentation throughout the validation lifecycle cannot be understated. FDA, EMA, and other regulatory guidelines (including ICH Q8-Q10) mandate that comprehensive records of validation efforts are maintained to demonstrate compliance and quality assurance. Key documentation should include the URS, risk assessments, qualification protocols, validation reports, and historical CPV data. Each document should articulate goals, methodologies, results, and corrective actions clearly.

In the US, adherence to 21 CFR Part 11 is crucial for systems that involve electronic records and signatures, ensuring that all electronic documentation within CPV processes remains trustworthy, reliable, and secure.

European regulations under the EU GMP also require rigorous documentation practices, ensuring traceability and review. Thorough documentation strengthens an organization’s position during regulatory inspections and audits and safeguards the integrity of the validation lifecycle.

Conclusion

In conclusion, understanding the differences between Class 100,000, ISO Class 7, and Grade C cleanrooms is imperative for pharmaceutical professionals involved in validation. From initial user requirements to continued process verification, every step must be performed with precision and adherence to regulatory standards. By embracing best practices in validation and maintaining thorough documentation, organizations will not only ensure compliance but also enhance product quality and efficacy.