assessment must capture failure modes, their consequences, likelihood, and detection measures. Regulatory frameworks such as ICH Q9 emphasize the importance of risk management in establishing a robust validation strategy.

Documentation of both the URS and the risk assessment must be thorough and clear, as they provide the rationale for the validation activities downstream. They must be maintained as part of the validation master plan and be available for audits.

Step 2: Qualification of the System

Qualification is the process of demonstrating that systems are designed and functioning as intended. The qualification phase can be structured into three stages: Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ).

• Installation Qualification (IQ): Confirming that the computerized system is installed correctly, according to supplier specifications, and is operational. Documentation should include installation reports and checks for hardware and software configurations.
• Operational Qualification (OQ): Addresses whether the system operates within predetermined limits under various conditions. It includes the execution of protocols to ensure that each function of the system meets the functional specifications as outlined in the URS.
• Performance Qualification (PQ): This phase validates the system’s functionality and performance during normal operations. Executing protocols under real operating conditions is crucial, especially for critical processes in blister packaging.

Validation documentation for all qualification stages should be meticulously compiled, as it is essential for confirming compliance with regulatory expectations, particularly from the FDA and EU guidelines. Each qualification stage should culminate in formal reports summarizing findings and any deviations encountered during testing.

Step 3: Process Performance Qualification (PPQ)

Process Performance Qualification (PPQ) is a critical step that validates the stability of the process under actual production conditions. This stage is often confused with PQ, but it specifically focuses on ensuring that the entire process works effectively across different production batches, demonstrating that the process consistently yields products meeting quality attributes.

The PPQ plan should involve defining the acceptance criteria, sample sizes, and the number of production lots needed for testing. Actual production runs should be conducted, and in-process controls monitored to determine adherence to predefined specifications and critical quality attributes (CQAs).

The data gathered during this phase must include measurements of process parameters like temperature, pressure, and humidity within the blister packaging environment. It’s crucial to document all findings systematically to understand the process capabilities and to establish a quality baseline for subsequent operations.

Step 4: Continued Process Verification (CPV)

Once the system and process have been validated, Continued Process Verification (CPV) becomes imperative. CPV involves ongoing monitoring of the manufacturing process and its controls to ensure sustained operational performance over time. It helps identify variations that could affect product quality, allowing for timely corrective actions.

Implementing a robust CPV plan will collect data during routine operations. This data can range from process parameters to product quality characteristics. Statistical process control (SPC) methods can be employed to detect trends and deviations that may signify potential quality issues.

Documentation and analysis from CPV activities are critical and must be periodically reviewed, allowing the organization to refine the process and the validity of the original user requirements. Such documentation is also essential for satisfying audit trails in accordance with EMA guidelines.

Step 5: Revalidation

Revalidation is essential in situations where there are significant changes in manufacturing processes, equipment, or product formulations. Regulatory authorities mandate revalidation to ensure that previously established controls remain effective. Regularly scheduled reviews may also warrant revalidation based on findings from CPV activities.

It is important for organizations to establish a revalidation strategy as part of their Quality Management System (QMS). Revalidation activities should involve re-assessment of the URS, risk analysis, and replication of qualification and performance evaluation protocols as necessary. An updated validation report should be generated after completing these activities, maintaining the integrity of the validation lifecycle.

The documentation surrounding revalidation activities should be structured and include a rationale for revalidation decisions, approaches used, and impact analysis to demonstrate compliance with both FDA and EU regulations as outlined in Annex 15 and related guidelines.

Conclusion

In summary, the implementation of a robust validation lifecycle for in-process controls on blister packaging lines is essential for ensuring product quality and regulatory compliance. From the initial URS and risk assessment through the qualification of systems and processes, to ongoing verification and revalidation, all steps must be meticulously documented and aligned with both domestic and international regulatory standards.

The successful execution of these steps ensures that the computerized systems in place support the production of pharmaceuticals that meet quality expectations, ultimately safeguarding public health and maintaining compliance with stringent regulations governing the pharmaceutical industry.