of the process under conditions representative of routine production. This means validating a statistically significant number of batches to demonstrate that the process is capable of consistently producing product that meets quality specifications.

In the context of transitioning from old validated methods to new approaches, PQ becomes especially important to ensure that changes do not negatively impact product quality or compliance with regulatory standards. A robust PQ process must incorporate a risk assessment framework, such as those mentioned in ICH Q9, to identify potential impacts on product quality.

Step 2: User Requirement Specification (URS) and Risk Assessment

The first stage in the PQ qualification process is to develop a User Requirement Specification (URS) that outlines the requirements for the manufacturing process, the environment, and the finished product. The URS should be clear, concise, and based on stakeholder input, including the Quality Assurance (QA), Quality Control (QC), and manufacturing teams.

A comprehensive URS will facilitate proper risk assessments, which are essential for identifying critical quality attributes (CQAs) and critical process parameters (CPPs). The URS should clearly define:

• The intended use of the product.
• Quality criteria based on regulatory requirements.
• Considerations for safety and efficacy.

Once the URS is defined, a formal risk assessment should be conducted. The risk assessment aims to evaluate the potential risks associated with the new manufacturing process compared to the established methods. This should involve a systematic examination using tools such as Failure Mode Effects Analysis (FMEA) or fault tree analysis. These methods help to prioritize risks based on their likelihood and potential impact on product quality.

According to ICH Q9, it is critical to document the risk assessment process, including the rationale for decisions made regarding risk levels and how they impact the PQ qualification strategy. The output should be a well-documented risk management plan that provides a roadmap for addressing identified risks during the execution of the qualification activities.

Step 3: Protocol Design for Process Performance Qualification

The next step in the PQ qualification process is the design of a comprehensive protocol that will guide how the qualification activities will be performed. The protocol should define the scope, objectives, procedures, and acceptance criteria for the PQ.

Key elements to include in the PQ protocol design are:

• Purpose and Objectives: Clearly state the objectives of the PQ, such as verifying that the new manufacturing process produces consistent product quality.
• Experimental Design: Define the protocols for planning the sampling strategy, including sample sizes and testing methods that align with predetermined specifications.
• Acceptance Criteria: Document the pass/fail criteria for each critical parameter, ensuring they are based on a thorough review of historical performance data from the existing validated methods.
• Collection of Data: Outline how data will be collected, analyzed, and documented, including details on equipment calibration and maintenance.

For a successful transition between methodologies, it is essential to collect data from both the old and new processes through bridging studies. This provides a basis for comparing variability, robustness, and reliability. The documentation generated from each qualification batch must conform to regulatory expectations as set forth in the FDA Process Validation Guidance.

Step 4: Execution of Process Performance Qualification (PPQ)

Executing the Process Performance Qualification involves carrying out the planned protocols in a controlled manner. During this phase, it is crucial to adhere closely to the established procedures to ensure that the results are reliable and defensible.

During execution, a series of representative production batches should be created under routine manufacturing conditions. Typically, this includes three consecutive production lots, although more may be required based on the risk assessment findings.

Process performance qualification should strictly adhere to the principles of Good Manufacturing Practices (GMP) as outlined in the EMA Guidelines for Analytical Method Validation. This includes:

• Documenting all activities, observations, and data collected during the qualification.
• Ensuring compliance with all applicable SOPs related to manufacturing and quality control.
• Using appropriate statistical methods to analyze the results, ensuring the integrity and reliability of the data collected.

It is also essential to ensure that deviations or nonconformances are appropriately addressed and documented. Any unexpected outcomes should be investigated, root causes identified, and corrective actions taken as part of the validation documentation. The completion report detailing the outcomes of the executed PPQ should conclude whether the process is capable of consistently producing acceptable product quality.

Step 5: Continuous Process Verification (CPV)

Upon successful completion of PQ, Continuous Process Verification (CPV) becomes a vital part of the validation lifecycle. CPV aims to provide a continuous assurance that the manufacturing process remains in a state of control over time. This step is essential, especially when transferring from old validated methods to new processes.

CPV focuses on the ongoing monitoring of key process parameters and quality attributes. By employing statistical process control (SPC) tools and techniques, organizations can monitor process performance and product quality continuously. An established CPV program must include:

• Data Collection: Regular collection and analysis of data from production batches post-validation.
• Key Performance Indicators (KPIs): Defining and monitoring KPIs that can indicate the health of the manufacturing process.
• Review Processes: Implementing a rigorous review process to analyze collected data, identify trends, and take preventive actions if parameters drift outside of established limits.

Engaging with stakeholders across the organization will be critical for ensuring that CPV data inform ongoing optimization opportunities and updating of quality systems. Documentation of all CPV activities must be thorough and readily accessible for audits and inspections by regulatory agencies.

Step 6: Revalidation and Periodic Review of the Process

Revalidation is an essential aspect of the validation lifecycle and should occur at planned intervals to ensure that the manufacturing process continues to meet its intended use and quality requirements. Revalidation may be prompted by significant changes to the process, equipment, or materials used, as well as during a scheduled review, as dictated by regulatory requirements.

Certain factors necessitating revalidation could include:

• Change in suppliers or raw materials.
• Modification of equipment or production methods.
• Annual or periodic review outcomes that indicate potential issues.

The revalidation process should follow similar steps as the initial PQ, including planning, execution of trials, data analysis, and reporting. It promotes continuous improvement and helps maintain a high compliance level with regulatory expectations as outlined in ICH Q10.

Stakeholders should be aware that while revalidation focuses on maintaining the status quo, it also offers an opportunity to adapt processes, integrate technological advancements, and further align with evolving regulatory expectations.

Conclusion

Bridging studies between old and new validated methods through a rigorous and compliant pq qualification approach is essential for ensuring that manufacturing processes deliver consistent, high-quality products to market. By understanding each step of the validation lifecycle, including URS, protocol design, execution of PPQ, CPV, and continuous improvement through revalidation, pharmaceutical professionals can mitigate risks and ensure compliance with regulatory standards. Ongoing collaboration between QA, QC, and production will further enhance the effectiveness of the validation process and contribute to overall product quality and safety.