Process Validation in Bioprocessing
Dr Humberto Vega, Chemical Engineer and former Global Head of Technology Transfers & Validation at JnJ and Executive Director of Global MS&T, Bristol Myers Squibb
Dr. Bassem Gayed, Former Senior Director Cell Therapy Technical Operation, Bristol Myers Squibb
Process Validation spans Process Design, Qualification, and Continued Verification to ensure consistent product quality throughout the lifecycle. This paper reviews regulatory expectations, control strategies, and monitoring tools, emphasising that validation is a continuous, data-driven process, not a one-time event, essential for maintaining compliance, detecting variability, and ensuring patient safety.
Our Experience on Process Validation
Dr. Gayed and I had the experience of successfully transferring and validating drug products to commercial manufacturing facilities throughout our professional careers in biopharma. We have had the opportunity to shape the strategies leading to successful approval of the drug products. In this Expert Talk we provide the readers with a response to a few key questions commonly asked involving Process Validation as a continuous, data-driven process —not a one-time event—essential for maintaining compliance, detecting variability, and ensuring patient safety.
1. What is Process Validation?
Humberto: Process validation (PV) is a combination of activities resulting in a comprehensive consolidation of data supporting the design of the product and its manufacturing process, qualification of the manufacturing process, and continued monitoring of the manufacturing activities during the life of the product. In the past, PV was mainly used to highlight the execution of a validation protocol around the process. Later, the definition and scope of the term PV were expanded to capture three key stages that are now adopted across regulatory organisations and the industry:
Stage 1: Process Design, where process requirements, analytical methods, quality attributes, and process parameters are defined, leading to a comprehensive control strategy;
Stage 2: Process Qualification, where documented evidence that the process delivers product consistently meeting specifications via the process performance qualification (PPQ);
Stage 3: Continued Process Verification, where the validated process is closely monitored (e.g., CPV, APRs, lifecycle documents) to ensure no drifts or shifts affecting the quality of the product.
2. What are the key requirements to initiate PPQ activities?
Bassem: The initiation of PPQ requires the following: (1) Comprehensive validation master plan (e.g., contamination controls, cleaning, sterilization, filters, equipment qualifications, aseptic process simulations); (2) Complete knowledge transfer including process description and control strategy; (3) Approved procedures and batch records; (4) Approved and validated analytical methods; (5) Functional and qualified facility and equipment; (6) Fully trained and qualified personnel across all the functional groups (e.g., OPS, QA, Facilities, Technology); (7) Fully qualified suppliers and materials; (8) Functional quality management systems (e.g., deviations, change controls, LIMS); (9) Comprehensive risk assessments and validation protocols (e.g., defining number of lots, sampling plan, data analysis, management of deviations, acceptance criteria).
3. Are there differences between definitions of PV across Health Authorities (e.g., FDA and EU)?
Humberto: The basic concept of PV is similar across health authorities. Nevertheless, some specific terms may vary but the scope of the definitions are similar. For example, FDA defines PV as “the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products” while the EU GMP Annex 15 defines PV as “documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medical product meeting its predetermined specifications and quality attributes”. Additional terms that are used per PV stage include:
Stage 1: Process Design: Process Design vs. Pharmaceutical Development
Stage 2: Performance Qualification: Process Performance Qualification vs. Process Validation
Stage 3: Lifecycle: Continued Process Verification vs. On-going Process Verification
4. Can you use retrospective process validation?
Humberto: No. Retrospective validation is not an acceptable validation approach. The preferred approach is prospective validation (e.g., approved protocol defining validation expectations and acceptance criteria) followed by a full execution of validation studies or runs. A second option is concurrent validation, where a prospective validation protocol is in place, but validation runs are released to market as they are completed. The risk associated with concurrent validation must be evaluated and properly mitigated. A third option is a hybrid validation where the two approaches mentioned above can be used. A fourth validation element is the continuous process validation, where close monitoring of process and product performance is conducted to ensure the process remains under control after the regular PV runs.
5. How is the control strategy used during PV?
Humberto: The control strategy is the consolidation of the process and product knowledge defined during Stage 1 – Process Development. The CS defines the link between critical materials, process parameters, quality attributes, processing times, and hold times. This document is used to design the procedures and batch records as well as acceptance criteria for critical process parameters and critical quality attributes.
6. Who is required for review, approval and execution of PV activities?
Bassem: The responsibility of Process Validation is not department-specific. It is a cross-functional activity where different groups contribute to the successful execution of the validation runs: (1) Manufacturing Science & Technology: Owns the technical knowledge of process and product, and guides how the process shall be executed according to the control strategy. The group also develop and implements the PV protocol; (2) Manufacturing Operations: Owns the procedures and batch records that define the production steps required for the process. Also, ensure the personnel are properly trained and qualified to execute the manufacturing operations; (3) Engineering & Facilities: Own the physical facility and equipment. Ensure the equipment and utilities are properly installed and qualified according to the process requirements; (4) Quality Assurance: Own the quality management systems utilised to demonstrate compliance with regulatory expectations; (5) Quality Control: Own the analytical methods and QC testing activities required to confirm satisfactory execution of the manufacturing process. All these groups are responsible for reviewing, approving and executing specific activities, as described above, linked to PV.
7. How are product and process variabilities incorporated into the PV studies?
Bassem: Incorporating variability into Process Validation is essential to building a robust understanding of how a process performs under real-world conditions. Product and process variability can originate from multiple sources—such as raw material attributes, operator technique, equipment performance, and environmental conditions. Rather than attempting to eliminate all variability, the goal of PV is to understand, quantify, and control it.
This begins in Stage 1 with risk assessments using tools like Failure Modes and Effects Analysis (FMEA), cause-and-effect (Ishikawa) diagrams, and multivariate data analysis to identify critical material attributes (CMAs), critical process parameters (CPPs), and critical quality attributes (CQAs). These assessments inform control strategies and determine which factors need enhanced monitoring.
During Process Performance Qualification (Stage 2), variability is addressed through appropriately designed sampling plans and the execution of multiple validation runs under normal operating conditions. Statistical tools such as Design of Experiments (DoE) and capability analysis may be applied to explore the range of acceptable variability, assess robustness, and establish process control limits.
Stage 3, Continued Process Verification (CPV), ensures that variability continues to be monitored across the product lifecycle using tools like control charts, process capability indices (Cp/Cpk), and trending dashboards. These tools help detect subtle process shifts early, enabling preventive actions to be taken before deviations occur.
By systematically incorporating and managing variability, manufacturers can ensure their processes are both capable and reliable—ultimately protecting product quality and patient safety.
8. How do you define the number of lots required for PV and the number of samples for the studies?
Bassem: Defining the number of lots and sampling plans for Process Validation is a risk-based decision guided by scientific rationale, regulatory expectations, and product complexity. Regulatory bodies such as the FDA typically expect a minimum of three consecutive commercial-scale PPQ batches produced under normal operating conditions to demonstrate process consistency and control.
However, the “three-lot rule” is not a regulatory requirement, and exceptions may be justified. For example, in cases where robust platform knowledge exists, a smaller number of lots may suffice if accompanied by strong supporting data. Conversely, for complex biologics—especially autologous or personalized therapies—additional lots may be needed due to inherent process variability and small batch sizes.
Sample size and sampling points are determined by factors such as:
· Process risk assessments, identifying critical steps
· Batch size and unit operation complexity
· Variability of the process and analytical methods
· Acceptance criteria for CPPs and CQAs
· Regulatory guidance and industry best practices
Ultimately, the number of PPQ runs and the extent of sampling must be scientifically justified, documented in the validation protocol, and agreed upon by all cross-functional stakeholders, including QA, MS&T, and regulatory affairs.
Final Remarks
Humberto & Bassem: Process Validation is no longer a one-time compliance task, it is a continuous, data-driven commitment to quality. As the pharmaceutical and biopharmaceutical industries evolve, driven by novel modalities and patient-centric therapies, PV must also evolve to keep pace.
Validation should be viewed not just as a regulatory requirement, but as a strategic tool to enhance operational excellence, build institutional knowledge, and reduce time to market. A well-executed PV program reduces the likelihood of batch failures, recalls, and costly remediation efforts. It also enables manufacturers to respond with agility to changes in scale, site, or supply chain, critical factors in today's globalised and dynamic environment.
The future of PV lies in its integration with digital technologies, real-time monitoring, and advanced analytics. This evolution enables a shift from reactive compliance to proactive assurance of quality, where variability is not feared but understood and managed.
By embracing PV as a lifecycle discipline, founded on science, rooted in cross-functional collaboration, and powered by data, we build the foundation for delivering safe, effective, and high-quality therapies to patients around the world.
Author Bio
Dr. Humberto Vega is a retired Chemical Engineer and former Global Head of Technology Transfers & Validation at Johnson & Johnson, as well as Executive Director of Global MS&T at Bristol Myers Squibb. He has more than 37 years of experience in the pharmaceutical and food industries. Dr. Vega holds professional memberships in PDA, IFT, and ISPE.
Dr. Bassem Gayed is a senior leader in the biopharma industry with deep expertise in cell therapy, advanced manufacturing, and regulatory engagement. Dr. Gayed bridges science and execution across the product lifecycle to make therapies more accessible and efficient. He holds a B.S. and PhD in Biomedical Engineering from UMDNJ/NJIT.
