into the validation process to ensure that the identified risks are adequately mitigated. A thorough risk assessment may utilize tools like Failure Mode and Effects Analysis (FMEA) to prioritize risks based on their severity and likelihood of occurrence.

• Define tooling functions: Determine what processes the tooling must facilitate, including cutting, forming, and sealing.
• Engage stakeholders: Collect input from manufacturing, quality assurance, and regulatory affairs to refine URS.
• Implement FMEA: Identify potential failure modes and assess their impact on product integrity.

Documenting the URS and risk assessment outcomes is critical for compliance with regulatory standards, particularly relevant for FDA guidance on process validation, where the quality of the output is directly linked to manufacturing processes.

Step 2: Process Design and Validation Protocol Development

Following the completion of the URS and risk assessment, the next step is process design, which consolidates the intended use and design input into a workable manufacturing process. This stage includes selecting the appropriate tooling materials, configurations, and operational parameters. The main goal is to design a robust process that consistently produces acceptable quality products.

To assure the design aligns with URS requirements, Development and Validation protocols must be established. This documentation should include:

• Validation Scope: Define what will be validated, including tooling types and processes involved in blister production.
• Validation Strategy: Outline the approach to be taken—will it be a full verification of the tooling components or a risk-based approach?
• Acceptance Criteria: Establish measurable criteria that the tooling must meet, which should be derived from the URS.

Effective protocol development is crucial for ensuring regulatory compliance associated with manufacturing processes as outlined in EMA guidelines for process validation.

Step 3: Qualification Phases (DQ, IQ, OQ, PQ)

Once the validation protocol has been established, the qualification of the tooling is performed in phases: Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ). Each phase has specific deliverables and responsibilities linked to validation efforts.

3.1 Design Qualification (DQ)

The DQ phase involves confirming that the design specifications of the tooling are appropriate for the intended use and adhere to regulatory requirements. Documents such as design documents and risk assessment reports are evaluated to ensure compliance.

3.2 Installation Qualification (IQ)

The IQ process verifies that the tooling has been correctly installed and that it matches the documented specifications in the URS and design documentation. This validation phase typically includes:

• Verification: Check installation against Manufacturer’s specifications.
• Documentation: Ensure all required installation protocols and manuals are available and adhered to.

3.3 Operational Qualification (OQ)

OQ assesses whether the tooling operates consistently and reliably throughout the specified operational range. Key activities include:

• Execution of predefined tests: Verify tooling’s operational parameters in accordance with the validation protocol.
• Monitoring: Evaluate response to critical parameters like temperature, pressure, and time.

3.4 Performance Qualification (PQ)

PQ finalizes the qualification process by demonstrating that the equipment performs intended functions consistently and produces the desired product quality across intended use scenarios. It is generally performed using a series of production runs conducted under defined parameters.

All qualification stages need comprehensive documentation that aligns with FDA’s validation expectations. Regulations under ICH Q8-10 detail specific requirements for establishing product quality through validated processes.

Step 4: Process Performance Qualification (PPQ)

PPQ is an extended qualification activity that bridges the transition from validation to routine manufacturing. It is essential for ensuring the tooling consistently produces products that meet quality specifications under normal operating conditions. This phase typically involves running multiple batches of product using the qualified tooling in a controlled environment.

Key documentation for PPQ includes:

• Batch Records: Documentation of all production batches including material, equipment use, and environmental conditions.
• Test Results: Collecting and analyzing data to confirm if the output meets established specifications.
• Variability Analysis: Using statistical tools to assess process capability using the obtained data.

In accordance with FDA’s Process Validation Guidance, it’s imperative that PPQ data is complete, reviewed, and presented for regulatory submissions if required. The performance qualification serves as a critical element in the validation lifecycle, ensuring robust control over product quality moving forward.

Step 5: Continued Process Verification (CPV)

Post-PPQ, continued process verification (CPV) is essential for maintaining process quality over time. Regulations require ongoing monitoring of critical process parameters (CPPs) and critical quality attributes (CQAs) to assure product quality. This ongoing verification is a continuous part of the quality system that actively confirms that the validation remains in a state of control throughout the commercial lifecycle.

CPV methods can include:

• Statistical Process Control (SPC): Utilizing control charts to monitor variation.
• Change Control Processes: Ensuring any changes in the process, equipment, or materials undergo a thorough evaluation.
• Periodic Review Process: Regularly review process performance and product quality data.

Documentation and tracking during CPV are vital for identifying variation and trends, enhancing decision-making and additional actions needed. Regulatory frameworks, including ICH guidelines, emphasize the importance of continual verification as a means of sustaining output quality and ensuring compliance with evolving standards.

Step 6: Revalidation and Change Control

As the production scale or market demands evolve, revalidation is necessary to ensure that tooling remains effective and compliant. Revalidation should be triggered by several factors such as changes in raw material, equipment modifications or upgrades, significant deviations from established process controls, or a change in manufacturing location.

Two core aspects are critical during the revalidation process:

• Scope of Revalidation: Determine which aspects of the previously validated process need to be reassessed—complete requalification or partial validation based on the change.
• Documentation Review: Ensure all historical documentation is thoroughly reviewed for process changes before resuming normal operations.

Effective change control is essential to manage, evaluate, and implement changes across the validation lifecycle. Keeping strict adherence to GAMP 5 guidelines helps in assessing the impact of changes to computerized systems, ensuring that compliance is maintained across all phases of process operations.

This article consolidated pivotal processes and best practice approaches in tooling qualification for blister machines while ensuring alignment with regulatory expectations. Continuous engagement with regulatory updates and guidelines is a core function throughout all stages of validation, thereby ensuring that processes remain compliant, efficient, and capable of delivering high-quality products to the market.