product performance. For example, in sterile drug manufacturing, the sterility assurance level (SAL) is a CQA defined under ISO 11135.

Subsequently, a risk assessment should be conducted using methodologies detailed in ICH Q9. The aim is to identify potential risks associated with each parameter listed in the URS. Utilizing tools like Failure Mode Effects Analysis (FMEA) can aid teams in this task. By mapping out the impact and likelihood of identified risks, professionals can prioritize what CQAs and CPPs need the most attention during the validation lifecycle.

• URS Components:Overview of product specifications, performance criteria, regulatory requirements.
• Risk Assessment:Documentation of potential risks, evaluation of risk control measures.

It is critical that the URS and risk assessment documentation are reviewed and approved by relevant stakeholders to ensure alignment with regulatory expectations, particularly those outlined in FDA Guidance for Industry and EU GMP Annex 15.

Step 2: Developing Protocol Design for Process Validation

Once the URS and risk assessments are finalized, the next step is to design the validation protocols. This involves creating detailed documents that outline how validation activities will be conducted to ensure they conform to the requirements set out in the URS.

The validation protocol should be comprehensive, including methodologies for qualifying equipment, executing process performance qualifications (PPQ), and capturing all necessary data. Key elements to include are:

• Objective: Clear goals that the validation aims to achieve.
• Methods: Detailed step-by-step methods aligned with regulatory guidance (e.g., ICH Q8-Q10).
• Acceptance Criteria: Specific, measurable criteria based on CQAs and CPPs that must be met to confirm process validation.
• Documentation Requirements: Planning for all relevant documentation must be made, to ensure a clear audit trail.

The creation of a sampling plan is also imperative at this stage. Statistic-based sampling plans as per ICH Q2 can validate any material processed and assure that quality attributes are consistently met across full batch sizes.

Step 3: Equipment and Facility Qualification

The qualification of equipment and facilities is vital, as they must operate according to the requirements set forth in the URS. This involves three key stages: Design Qualification (DQ), Installation Qualification (IQ), and Operational Qualification (OQ).

Design Qualification (DQ) assesses whether the design of facilities, systems, and equipment complies with the URS and is suitable for the intended operations. This documentation must demonstrate that the design will meet the critical quality and regulatory standards.

Installation Qualification (IQ) verifies that equipment is installed correctly according to specifications. Documentation collected here should include calibration records, and manufacturer’s recommendations must also be adhered to.

Operational Qualification (OQ) is crucial as it confirms that equipment functions as intended across operational ranges. Here, CPPs are thoroughly examined to demonstrate that they are capable of generating the desired CQAs. For example, for sterilizing equipment, factors like temperature, pressure, and exposure time must be evaluated based on CQAs.

This stage is in line with WHO guidelines on validation regarding the need for documented evidence that systems meet operational requirements.

Step 4: Execution of Process Performance Qualification (PPQ)

The Process Performance Qualification (PPQ) stage involves statistical and empirical evaluations of the process under actual manufacturing conditions. The objective here is to verify that the process consistently produces quality products meeting all defined CQAs.

During PPQ, manufacturers should run multiple batches to establish a representative range of operating conditions and variations. It’s critical to follow proper sampling methods, ensuring that the samples chosen reflect potential variations in input materials, equipment performance, and processing conditions.

• Data Collection: Begin by documenting quantitative and qualitative data for each batch during the qualification runs.
• Statistical Analysis: Employ appropriate statistical methods, as described in ICH Q8, to analyze the data. This includes applying control charts and capability indices to assess stability and process consistency.
• Autogenous Process Variability: Assess variability’s impact on CQAs, using targeted tests throughout each batch.

In addition, a continuous monitoring plan should be integrated into PPQ efforts to assure ongoing compliance with process capabilities, ensuring that the specified criteria remain valid.

Step 5: Implementing Continued Process Verification (CPV)

After successful PPQ completion, Continued Process Verification (CPV) is implemented. This ongoing validation assesses processes with statistical methods to monitor process performance continuously. CPV is crucial for maintaining compliance with ISO 14644, focusing on cleanroom classification and assurance levels.

The CPV program should clearly define the data collection methods for critical parameters, draw from both real-time data and historical data, and link findings back to CQAs and CPPs. Statistical Process Control (SPC) techniques can provide insights. This includes calculating process capability indices (Cp, Cpk) to ensure that processes remain within control limits.

• Data Review: Regularly review collected data against established variations and determine when adjustments are necessary.
• Reporting Mechanisms: Reporting should be clearly defined, establishing who receives timely updates on process variations, deviations, and trends.
• Continuous Improvement: The insights gathered from CPV should guide improvement initiatives, involving regular updates to risk assessments and URS documentation as needed.

All CPV activities must adhere to guidelines established in ICH Q10, focusing on lifecycle management, which emphasizes the importance of maintaining consistent product quality post-commercialization.

Step 6: Establishing a Revalidation Schedule

Revalidation plays a fundamental role in maintaining process validation through the lifecycle of the product, particularly under changing circumstances that could impact product quality. Regulatory bodies necessitate a rigorous, risk-based approach to determine when revalidation is warranted. Factors influencing the need for revalidation include:

• Significant changes to processes, equipment, or formulations.
• Process deviations or trends that are adverse or non-conforming.
• External environmental changes that may impact quality.

The revalidation process should mirror prior validation phases, where URS updates, risk assessment updates, and reinvocation of protocols will take place. The revalidation plan should specify the criteria for reevaluation, such as acceptance limits based on discussed statistical criteria.

It is beneficial to incorporate ongoing training and support for staff involved in the revalidation process. Well-documented processes help ensure that standards of compliance, as specified in regulations like FDA’s Guidance for Industry and the FDA’s Process Validation Guidance, are consistently met throughout the validation lifecycle.

In conclusion, understanding how to identify Critical Quality Attributes (CQAs) and Critical Process Parameters (CPPs) is vital in achieving compliance with industry standards like ISO 11135 and maintaining quality assurance in the manufacturing process. By following each of the outlined steps and maintaining rigorous documentation and statistical evaluations, pharmaceutical companies can ensure the integrity of their processes while safeguarding product quality.