What is Process Validation?

Definition and Regulatory Background

In the “Guidelines on General Principles of Process Validation” issued in 1987, the United States Food and Drug Administration (FDA) defined validation in pharmaceuticals as follows: “Process validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.”

This foundational definition was significantly expanded and refined with the publication of FDA’s “Process Validation: General Principles and Practices” guidance in January 2011. This updated guidance replaced the 1987 guideline and introduced a comprehensive lifecycle approach that aligns with modern pharmaceutical quality systems. The 2011 guidance emphasizes that process validation should be viewed as a scientific endeavor rather than merely a documentation exercise, integrating seamlessly with International Council for Harmonisation (ICH) guidelines Q8(R2) on Pharmaceutical Development, Q9 on Quality Risk Management, and Q10 on Pharmaceutical Quality System.

The Challenge of Sampling Inspection in Pharmaceuticals

In the case of pharmaceutical products, unlike medical devices, the majority of product quality testing can only be conducted through destructive testing methods. Consequently, sampling inspection becomes inevitable rather than 100% inspection.

However, sampling inspection presents inherent limitations. For example, suppose a manufacturer produces one lot of 10,000 tablets. Even if 50 tablets are sampled and subjected to destructive testing to confirm the absence of foreign matter contamination, there remains a possibility that foreign matter could be present somewhere among the remaining 9,950 tablets. This fundamental limitation of sampling inspection creates uncertainty about the quality of untested units.

For this reason, regulatory authorities require pharmaceutical manufacturers to validate their processes in advance. The goal is to ensure that the manufacturing process itself is capable of consistently producing quality products, thereby providing assurance for all units in a batch, not just those that are sampled and tested.

Process Stability and Variability Control

Consider two contrasting process scenarios illustrated conceptually below. An “unstable process” exhibits quality variation from lot to lot, with variability potentially increasing over time. While such variability might be acceptable for products like bean-paste buns or jam-filled pastries, it is entirely unacceptable for pharmaceutical products. Depending on the type of medication, such variability could cause significant harm to patient health and safety.

Therefore, it is essential to stabilize the quality of each lot, achieving what is termed a “stable process.” However, in process industries such as pharmaceuticals (which are equipment-intensive manufacturing operations), quality can fluctuate due to various seasonal and environmental factors, including:

• Temperature, humidity, equipment housing conditions, and condensation
• Power supply fluctuations, vibration, and light exposure
• Environmental contamination, process water purity, and human factors
• Variations in raw material grades (for example, changes in raw material viscosity due to lot switchovers, which can impact product performance such as removal efficiency)

Unlike discrete manufacturing industries, process industries may experience situations where inputting one ton of raw materials results in 1.1 tons of product in one season and 0.9 tons in another season due to these environmental variables.

Additionally, deterioration of facilities and equipment over time can lead to degradation of product quality, further emphasizing the need for robust process control and ongoing monitoring.

Ensuring Consistent Product Quality Within Specifications

Process validation aims not only to stabilize the process but also to ensure that “a process consistently produces good products.” This means that all products within a lot must fall within specification limits (Spec Limits). In pharmaceutical manufacturing, when sampling inspection reveals an out-of-specification (OOS) result, the entire lot may need to be discarded depending on the circumstances and regulatory requirements.

The objective of process validation is to ensure that a process can consistently produce products that meet specifications under normal operating conditions. In other words, it guarantees process reproducibility (repeatability) and long-term process stability. During process validation, products are manufactured under established actual production conditions while simultaneously confirming various action levels and the content of standard operating procedures (SOPs). Through repeated challenge testing, the assurance level of the process is further enhanced.

Evolution of Batch Requirements: From Fixed Numbers to Science-Based Approaches

In 1987, the FDA required a minimum of three lots for process validation. The rationale for three lots was that two lots alone cannot demonstrate linearity or trending. Only by manufacturing three lots could linearity be properly assessed and process reproducibility be evaluated.

However, the regulatory landscape has evolved significantly since then. The 2011 FDA guidance deliberately moved away from prescriptive batch number requirements. Instead, it adopts a risk-based, science-driven approach that requires manufacturers to justify the number of batches needed based on:

• The level of product and process understanding gained during development
• The complexity and novelty of the manufacturing process
• Prior experience with similar products and processes
• Results of process characterization studies and designed experiments
• The robustness of the process control strategy

This means that depending on the scientific understanding and risk assessment, the number of validation batches required may be fewer than three for well-understood processes with robust control strategies, or significantly more than three for complex or novel processes. The key principle is that manufacturers must provide scientific justification for their approach and demonstrate that they have achieved a high degree of assurance that the process will consistently produce quality product.

Understanding the Distinction: Validation versus Verification

The difference between validation and verification is fundamental to understanding pharmaceutical quality assurance. Validation refers to “establishing in advance assurance that products can be manufactured according to defined quality and specifications,” whereas verification means “confirming that products were manufactured according to defined quality and specifications.”

In other words, validation is prospective (forward-looking), while verification is retrospective (backward-looking). Validation establishes confidence before routine production begins, while verification confirms that established processes continue to perform as expected during routine manufacturing.

The Modern Era: From Traditional Validation to Quality by Design

The pharmaceutical industry has evolved from the traditional approach of “validation plus sampling inspection” to an era where Quality by Design (QbD) principles enable continuous verification throughout the product lifecycle. However, to replace traditional validation with continuous verification approaches, pharmaceutical development must be conducted using QbD principles from the outset, and manufacturing approval must be obtained based on QbD methodologies when seeking new drug approval.

The Three-Stage Lifecycle Approach

The 2011 FDA guidance introduced a comprehensive three-stage approach to process validation:

Stage 1: Process Design – During this stage, the commercial manufacturing process is defined based on knowledge acquired through development and scale-up activities. This includes establishing a control strategy that ensures the process is capable of consistently delivering quality products. Key activities include:

• Defining the target product profile and critical quality attributes (CQAs)
• Identifying critical process parameters (CPPs) and critical material attributes (CMAs)
• Establishing the design space through systematic experimentation
• Developing a comprehensive control strategy
• Applying risk management principles (ICH Q9)

Stage 2: Process Qualification – This stage confirms that the process design is capable of reproducible commercial manufacturing. It consists of two elements:

• Design qualification: Verification that facility and equipment design is suitable for intended use
• Process Performance Qualification (PPQ): Demonstrating that the commercial manufacturing process performs as expected under routine conditions

The number of PPQ batches is determined based on process understanding, complexity, and risk assessment, not on an arbitrary fixed number.

Stage 3: Continued Process Verification – This stage provides ongoing assurance that the process remains in a state of control during commercial manufacturing. It involves:

• Systematic collection and evaluation of process and product data
• Trending and analysis to detect unplanned departures from the process
• Statistical process control methods
• Periodic requalification activities as appropriate
• Management of process changes and continuous improvement initiatives

Integration with ICH Quality Guidelines

The modern approach to process validation is closely integrated with ICH quality guidelines:

ICH Q8(R2) – Pharmaceutical Development introduces the concept of Quality by Design, which emphasizes building quality into the product through systematic understanding of how formulation and manufacturing variables affect product quality. Key concepts include:

• Quality Target Product Profile (QTPP): Defines the desired product characteristics
• Design Space: The multidimensional combination of input variables and process parameters that have been demonstrated to provide assurance of quality
• Control Strategy: A planned set of controls derived from product and process understanding

ICH Q9 – Quality Risk Management provides a systematic approach to quality risk management that can be applied throughout the product lifecycle. It offers various tools and methodologies such as Failure Mode and Effects Analysis (FMEA), Hazard Analysis and Critical Control Points (HACCP), and others to assess, control, communicate, and review risks to quality.

ICH Q10 – Pharmaceutical Quality System describes a comprehensive model for an effective pharmaceutical quality system that is based on International Organization for Standardization (ISO) quality concepts and includes applicable Good Manufacturing Practice (GMP) regulations. It facilitates continual improvement and enables innovation in pharmaceutical development and manufacturing.

Process Analytical Technology (PAT): Real-Time Quality Assurance

The FDA published its guidance on “PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance” in September 2004. PAT represents a paradigm shift from traditional quality control approaches.

PAT is defined as “a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.”

The term “analytical” in PAT is viewed broadly to include:

• Chemical analysis
• Physical analysis
• Microbiological analysis
• Mathematical and statistical analysis
• Risk analysis conducted in an integrated manner

Key benefits of PAT implementation include:

• Real-time or near-real-time monitoring of critical quality attributes
• Enhanced process understanding through continuous data collection
• Ability to detect and correct deviations promptly
• Reduced reliance on end-product testing
• Potential for real-time release testing (RTRT)
• Support for continuous manufacturing processes
• Improved process efficiency and consistency

PAT tools may include process analyzers, process control tools, multivariate data acquisition and analysis tools, and continuous improvement and knowledge management tools. These technologies enable manufacturers to move from a reactive “test quality in” approach to a proactive “build quality in” philosophy.

Continuous Verification and Real-Time Release

When manufacturers develop products using QbD principles and implement robust PAT systems, they may qualify for enhanced regulatory flexibility. This can include:

Continuous Process Verification: Rather than relying solely on initial validation batches, manufacturers establish ongoing programs that continuously verify process performance throughout commercial manufacturing. This approach generates a continuous stream of data that provides greater assurance of process capability than periodic revalidation.

Real-Time Release Testing (RTRT): When sufficient process understanding has been established and demonstrated through PAT, manufacturers may be able to release batches based on in-process measurements rather than waiting for end-product testing results. This requires:

• Demonstrated process understanding and control
• Validated mathematical relationships between in-process measurements and final product quality attributes
• Robust process control systems
• Appropriate risk management
• Regulatory approval of the RTRT approach

Process Capability and Statistical Considerations

Modern process validation emphasizes the use of quantitative, statistical methods to assess process capability and establish appropriate control limits. Key statistical concepts include:

Process Capability Indices (Cpk): These measure how well a process meets specifications relative to its inherent variability. A capable process typically has a Cpk of 1.0 or greater, though higher values (1.33 or above) are often targeted to provide additional assurance.

Statistical Process Control (SPC): Control charts and other SPC tools are used during continued process verification to:

• Monitor process performance over time
• Detect trends and shifts in process behavior
• Distinguish between common cause and special cause variation
• Trigger appropriate investigations and corrective actions

Design of Experiments (DoE): Systematic experimental approaches are used during process design to:

• Identify critical process parameters
• Understand interactions between variables
• Establish the design space
• Optimize process conditions

Looking Forward: The Future of Process Validation

The pharmaceutical industry continues to evolve toward more sophisticated approaches to ensuring product quality. Emerging trends include:

• Advanced Analytics and Artificial Intelligence: Machine learning and advanced data analytics are being explored to enhance process understanding, predict quality outcomes, and optimize manufacturing operations.
• Continuous Manufacturing: Moving from batch production to continuous processing presents both challenges and opportunities for process validation, with PAT playing a crucial role in ensuring quality.
• Digital Transformation: Electronic batch records, digital twins, and integrated manufacturing execution systems are enabling more sophisticated approaches to process monitoring and control.
• Regulatory Convergence: International harmonization efforts continue to align expectations across regulatory authorities, facilitating global pharmaceutical development and manufacturing.

The evolution from the simple three-batch rule of 1987 to today’s sophisticated, science-based lifecycle approach reflects the pharmaceutical industry’s growing maturity and commitment to ensuring that patients receive consistently high-quality medicines. While this evolution has increased the complexity of validation activities, it has also provided manufacturers with greater flexibility and the opportunity to leverage scientific understanding for continuous improvement in product quality and patient safety.

For those seeking to deepen their understanding of these topics, numerous educational resources are available, including professional training courses on GMP, validation, QbD, PAT, and related subjects offered by industry organizations, regulatory agencies, and academic institutions worldwide.