Published on 08/12/2025
What Is a Risk-Based Validation Approach?
Pharmaceutical process validation is essential to ensure that products are of the required quality, safety, and efficacy. The use of a risk-based validation approach aligns with regulatory expectations, such as those outlined in ISO 17665, EU GMP Annex 15, and the FDA’s Process Validation Guidance. In this article, we will provide a step-by-step tutorial on implementing a risk-based validation strategy, which includes the entire validation lifecycle from process design to revalidation.
Step 1: User Requirements Specification (URS) & Risk Assessment
The first step in the validation lifecycle is to develop a comprehensive User Requirements Specification (URS). The URS outlines the necessary requirements for the process to meet both regulatory and user needs. It serves as a baseline for both the design and validation of the system.
Once the URS is established, a risk assessment should be performed. This assessment should identify potential risks associated with the process and how these risks can affect product quality. Tools such as Failure Mode and Effects Analysis (FMEA) can be employed to evaluate and
In this phase, it is critical to collaborate with cross-functional teams, including Quality Assurance (QA), Quality Control (QC), manufacturing, and regulatory affairs, to ensure that all relevant risks are captured and properly mitigated. The harmonization of the URS with a risk management strategy aligns closely with the principles set forth in ICH Q9, which emphasizes risk-based quality management.
Step 2: Protocol Design and Justification
The next step in the validation lifecycle is to develop a detailed validation protocol. This document outlines the strategy to validate the manufacturing process and includes the objectives, scope, and responsibilities associated with the validation effort. According to ISO 14644-3, the protocol should include clear acceptance criteria.
The protocol design should be based on the findings from the URS and risk assessment. A risk-based approach helps identify critical process parameters (CPPs) and critical quality attributes (CQAs) that will drive the validation strategies. The protocol design must also include justification for the selected validation methods, sampling plans, and statistical criteria.
During the protocol review phase, ensure that there is alignment with regulatory expectations. Cross-reference the protocol with relevant guidelines, such as the FDA’s Process Validation Guidance and EMA’s guidelines on process validation. A clearly defined protocol that integrates regulatory compliance and process understanding reduces the likelihood of issues arising later in the validation lifecycle.
Step 3: Qualification of Equipment and Systems
With the protocol in place, the next step involves the qualification of equipment and systems used in the process. This includes Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ). Each qualification phase builds upon the previous one and must be documented meticulously.
Installation Qualification verifies that the equipment is installed correctly per the manufacturer’s specifications. Operational Qualification assesses if the equipment operates according to established limits and ranges. Performance Qualification ensures that the process consistently produces products that meet predetermined specifications and quality attributes.
The documentation from these activities serves as evidence that the equipment is fit for intended use. Consideration should also be given to maintaining compliance with ISO 17665, which details requirements for sterilization processes in health care. It is vital to maintain a clear record of all tests conducted and the results obtained, ensuring alignment with both FDA and EMA standards.
Step 4: Process Performance Qualification (PPQ)
Process Performance Qualification is the next stage in the validation lifecycle, where actual product is manufactured under normal operating conditions. During the PPQ, data collected should ideally mimic routine production conditions. This phase encompasses a predetermined number of batches to demonstrate that the manufacturing process is capable of delivering products that meet quality specifications consistently.
Sampling plans and product testing methodologies should comply with both regulatory expectations and scientific principles. The data collected during this phase should show that the manufacturing process operates within defined limits and controls while consistently producing products of acceptable quality.
In this step, it is critical to ensure that all actions are documented in accordance with FDA and EMA guidelines, which can provide insight into the reproducibility of the process under normal operating conditions. Regulatory agencies expect thorough documentation of the results and any deviations encountered during the PPQ phase, guiding future process improvements and ensuring compliance with ISO 17665 and ISO 14644-3 standards.
Step 5: Continued Process Verification (CPV)
After successful completion of PPQ, Continued Process Verification (CPV) must be established. CPV represents an ongoing commitment to quality by ensuring that the process remains in control over time. Data is continually collected post-validation through routine monitoring of the manufacturing process.
The establishment of a robust CPV program is essential for maintaining compliance with regulatory expectations and demonstrates the facility’s control over the manufacturing process. This involves regular data analysis and trend monitoring, which can identify deviations or shifts in the process that may affect product quality.
Documentation of CPV should include the review findings and any corrective actions taken to address the impacts of process deviations. This phase emphasizes that the validation process is not static; rather, it is a dynamic component that evolves as new data becomes available and as improvements are identified. Regulatory expectations under ICH Q8, Q9, and Q10 advocate for a life-cycle approach to process validation, reinforcing the importance of CPV as part of that lifecycle.
Step 6: Revalidation
The final step in the validation lifecycle is revalidation. Revalidation must occur periodically or whenever there are significant changes in the process, equipment, formulations, or regulatory requirements that may affect product quality. This ensures that the validation remains up-to-date and effective in reflecting the current state of the process.
During the revalidation process, a new risk assessment should be performed to identify any potential issues arising due to changes made since the last validation. The scope of revalidation should be clearly defined and documented, including timelines for periodic reviews based on regulatory guidelines and internal quality standards.
Documentation plays a vital role in demonstrating compliance during revalidation. Teams should keep records of any changes made, the rationale behind those changes, and their impact on process validation. Regular reviews and updates of the validation documentation also support ongoing compliance with ISO 17665, FDA, and EMA regulations, and strengthen the integrity of the overall validation effort.
In conclusion, a risk-based validation approach not only adheres to the regulatory landscape but also emphasizes the importance of understanding and controlling processes within pharmaceutical manufacturing. By following the steps outlined in this article, pharmaceutical organizations can establish a robust validation process, ultimately ensuring the quality and safety of their products.