Process Validation Lifecycle: Risk-Based Approach

Stage 1 – Process Design

The manufacturing process is developed and designed in this stage based on scientific principles and quality risk management. It involves identifying critical process parameters and their acceptable ranges and establishing control strategies.

Building and Capturing Process Knowledge and Understanding

At the initial stages of process design in pharmaceutical development, it is not required to adhere to the cGMP conditions that are required for later stages, such as process qualification (Stage 2) and continued process verification (Stage 3). While exempt from cGMP, these early experiments should still follow scientific methods and principles to ensure reliability and validity. Good documentation practices are emphasized to record and track the experiments and their outcomes accurately.

The guidance for conducting early process design experiments in a scientifically sound manner aligns with the ICH Q10 Pharmaceutical Quality System, which outlines a comprehensive model for quality management throughout the lifecycle of a pharmaceutical product.

The information gathered during product development, including the dosage form, product quality attributes, and an overview of the manufacturing process, is crucial for the process design stage.

When designing the process, it’s important to consider the functionality and limitations of commercial-scale manufacturing equipment and factors that could introduce variability into the production process. These include differences in raw material lots, operator performance, environmental conditions, and measurement systems.

Laboratory or pilot-scale models can be employed to anticipate variability in the commercial manufacturing process. These models help estimate and understand the potential variability in the production process.

DOE (Design of Experiment) studies help understand the process by identifying how different variables affect the process outcomes. These studies can reveal complex interactions between variables and help optimize the process design.

Establishing a Strategy for Process Control

The main goal of process control strategies is to manage and reduce variability in the manufacturing process. This variability can come from different sources (like raw materials or the manufacturing process itself), and it can negatively affect the quality of the final product. Process controls are implemented to ensure the product meets the desired quality standards.

Types of Process Controls:

• Reducing Input Variation: This strategy involves decreasing the variability of input materials or conditions before the manufacturing process.
• Adjusting for Input Variation: This approach accepts that there will be some variation in inputs and focuses on adjusting the manufacturing process in real time to compensate for this variation, thus minimizing its impact on the final product.
• Combination of Both: Often, the most effective process control strategies use a mix of both approaches to tackle input variation from multiple angles.

More sophisticated process control strategies might employ Process Analytical Technology (PAT), which allows for the real-time analysis and adjustment of processing conditions. Using PAT, manufacturers can ensure that despite variations in inputs or process conditions, the output remains consistent in quality.

Stage 2 – Process Qualification

Process Qualification (PQ) is an essential stage within the broader framework of process validation, which is a critical aspect of quality assurance in cGMP. 

Process validation ensures that manufacturing processes can consistently produce a product that meets predetermined quality criteria. The PQ stage, in particular, focuses on evaluating and verifying that the process design is theoretically sound and practically capable of reproducible commercial manufacturing. This evaluation is split into two main elements: the facility’s design and the equipment and utilities qualification and process performance qualification (PPQ). 

Successful completion of Stage 2 is a prerequisite for moving forward to commercial distribution. If they meet the established quality criteria, products manufactured during this stage can be released for distribution. This allows for the transition from validation to actual production, where the processes and systems validated during PQ are put into regular operation, with ongoing quality monitoring to ensure continued compliance with all necessary standards and regulations.

Design of a Facility and Qualification of Utilities and Equipment

Proper design of the manufacturing facility is mandated to ensure that the environment is conducive to producing high-quality products. This includes considerations for layout, material flow, and environmental conditions (e.g., temperature, humidity) to minimize the risk of contamination, cross-contamination, and errors.

Before proceeding to Process Performance Qualification (PPQ), the facility and its systems (utilities, equipment) must be commissioned and qualified. This means ensuring they are correctly installed, operate as intended, and suit their intended use.

The Quality Control (QC) or Quality Assurance (QA) unit within the organization plays a crucial role in reviewing and approving both the qualification plan and the final qualification report. This ensures that all qualification activities meet the established standards and regulatory requirements.

Process Performance Qualification

Process Performance Qualification (PPQ) is a blend of various elements—qualified facilities, utilities, equipment, and trained personnel—alongside the actual manufacturing process, control procedures, and components to produce commercial batches of a product.

PPQ integrates all critical components—qualified facilities, utilities, equipment, and trained personnel—with the commercial manufacturing process. This integration aims to produce commercial batches of a product, ensuring that the entire system functions cohesively and effectively at a commercial scale.

Successful completion of the PPQ is mandatory before a manufacturer can begin distributing the drug product commercially. This requirement ensures that the product manufactured at a commercial scale meets all quality standards and regulations.

The approach to conducting a PPQ is grounded in solid scientific principles. It requires a comprehensive understanding of the product and process, ensuring that every aspect of the manufacturing is under control. 

The conditions under which the PPQ is conducted are based on cumulative data from various studies, including designed experiments and batches produced at different scales. This data helps in fine-tuning the manufacturing conditions to optimize product quality.

Factors such as production volume, process complexity, and understanding of the process influence the duration of enhanced monitoring and testing. Experience with similar products and processes also plays a crucial role in determining this period.

The ultimate objective of PPQ and process validation is to establish scientific evidence that the manufacturing process is reproducible and can consistently produce quality products. This evidence forms the basis for confidence in the process’s capability to meet quality standards on an ongoing basis.

The goal of validating any manufacturing process is to establish scientific evidence that the process is reproducible and will consistently deliver quality products.

PPQ Protocol

The PPQ (Process Performance Qualification) protocol is a detailed document crucial for the second stage of process validation in pharmaceutical manufacturing. This protocol ensures that the manufacturing process is designed correctly and can consistently produce high-quality products under commercial production conditions. 

Some of the key elements that should be included in the PPQ protocol are:

1. Manufacturing Conditions

• Operating Parameters and Processing Limits (conditions under which the manufacturing process operates, including temperatures, pressures, times, and other critical parameters that influence product quality)
• Component Inputs (raw materials used, including specifications and handling requirements).

2. Data Collection and Evaluation

This includes process monitoring data, quality control results, and any other relevant information that can influence the assessment of the process’s capability.

3. Testing and Acceptance Criteria

• Tests to be Performed (in-process, release, and characterization tests)
• Acceptance Criteria

4. Sampling Plan

Detailed strategy for taking samples throughout the manufacturing process, specifying sampling points, the number of samples, and the sampling frequency.

5. Criteria and Process Performance Indicators

Establishes the benchmarks and performance indicators used to make a science- and risk-based decision on the process’s capability to produce quality products consistently. This section should include:

• Statistical Methods – Description of the statistical analyses to be applied to the collected data, focusing on intra-batch and inter-batch variability

• Deviation Management

6. Facility and Equipment Design

If not already addressed in previous stages, the protocol should cover the design of the manufacturing facilities, the qualification of utilities and equipment, and personnel training. Verification of material sources, including components and container/closures, should also be included to ensure all elements meet quality standards.

7. Validation of Analytical Methods

Confirms the status of analytical method validation, ensuring that the methods used for process monitoring, in-process materials, and the final product are accurate, reliable, and validated.

8. Review and Approval

The protocol requires a thorough review and approval by relevant departments, including the quality unit, to ensure it meets all regulatory standards and internal quality assurance requirements.

PPQ Protocol Execution and Report

The execution and reporting of the Process Performance Qualification (PPQ) protocol are vital steps in the process validation framework. These steps ensure the manufacturing process can consistently produce products that meet quality specifications and regulatory standards. 

PPQ Protocol Execution

• Review and Approval: Before starting the PPQ protocol execution, it must be thoroughly reviewed and approved by all relevant departments, including the quality unit, to ensure it meets all regulatory requirements and internal standards.
• Adherence to Established Procedures: Any deviations from the established protocol must follow predefined procedures or allowances within the protocol itself. 
• Commercial Manufacturing Conditions: The PPQ protocol must be executed under the commercial manufacturing process and routine procedures. 
• Normal Operating Conditions: The execution should involve the personnel who routinely perform the manufacturing process using the standard utility systems, materials, environment, and procedures. 

PPQ Report Preparation

After completing the PPQ protocol execution, a comprehensive report is prepared, covering several key areas:

• Protocol Adherence: The report discusses and references all aspects of the PPQ protocol, ensuring that the execution was aligned with the planned activities and conditions.
• Data Summary and Analysis: It summarizes and analyzes the data collected during the PPQ execution, as specified by the protocol. This analysis is crucial for understanding the process’s performance and identifying any areas of concern.
• Unexpected Observations: The report evaluates any unexpected observations and additional data not specified in the protocol.
• Manufacturing Nonconformances: Any deviations, unexpected test results, or other relevant information affecting the process’s validity are summarized and discussed. This includes a detailed description of any corrective actions or changes recommended for existing procedures and controls.
• Conclusions and Justifications: A clear conclusion is provided, stating whether the process met the conditions established in the protocol and is considered to be in control. If the conclusion is negative, the report specifies what needs to be addressed before reaching a positive conclusion. 
• Review and Approval: The report includes reviews and approvals from all appropriate departments and the quality unit, ensuring it meets the required standards and regulatory compliance.

The execution and reporting of the PPQ protocol are critical for confirming that a pharmaceutical manufacturing process is under control and capable of consistently producing products that meet all quality requirements. This process validates the manufacturing process and provides a documented basis for making informed decisions about the process’s readiness for commercial production.

Stage 3 – Continued Process Verification

The final stage of process validation is continued process verification, which ensures that the process remains controlled during commercial manufacturing. It involves implementing a system or systems to detect deviations from the process as designed and monitoring process performance to identify variability and opportunities for improvement.

Data should be collected and analyzed during continued verification to evaluate process stability and capability. The data should include trends in process parameters and quality attributes and be statistically trended and reviewed by trained personnel. The quality unit should periodically review the data and assess process stability and capability. Any deviations, out-of-specification results, or process yield variations should be investigated, and corrective actions should be taken as necessary.

The continued process verification program should include monitoring and sampling process parameters and quality attributes to ensure the process remains in control. The monitoring and sampling should be adjusted based on the variability estimates obtained during the process qualification stage. Any proposed changes to the process should be documented, justified, and approved by the quality unit before implementation.