Why Three Lots Are Required: Understanding Process Validation Requirements

Historical Context and Statistical Foundation

The FDA’s “Guideline on General Principles of Process Validation,” issued in May 1987, established fundamental principles for validation in pharmaceutical manufacturing processes. This guideline specifically requires “three or more consecutive lots” for process validation implementation. The requirement for validating three lots is based on the following rationale.

Key Points of the 1987 Guideline

1. Ensuring Statistical Reliability

The validation of three lots is considered the minimum number necessary to determine whether a process is stable. Through three consecutive implementations, if consistent results are obtained, the process’s consistency and reproducibility can be confirmed to a reasonable degree, thereby increasing the reliability of validation. From a statistical perspective, three data points represent the minimum sample size required to begin assessing trends and variability. While this may seem modest by modern standards, it was established as a practical baseline that balances scientific rigor with manufacturing feasibility.

2. Confirmation of Reproducibility

With only one or two lots, there is a possibility that favorable results were obtained by chance, making it difficult to properly evaluate the process performance. An important consideration is that with data from only two lots, a straight line can always be drawn between two points, making it challenging to determine whether the process is truly stable. By adding a third lot, it becomes possible to more accurately assess whether the data align linearly—in other words, whether the process maintains consistency. This approach enables more reliable confirmation of process stability and reproducibility. The third data point serves as a critical validation checkpoint, revealing whether the apparent relationship between the first two lots represents a genuine process characteristic or merely coincidental alignment.

3. Capturing Process Variability

Manufacturing processes involve numerous factors, and adequate lot numbers are necessary to evaluate the impact of these factors on product quality. Three lots are considered sufficient to capture, at minimum, the variations and deviations that occur during manufacturing and to assess that the process can withstand them. This number allows manufacturers to observe process behavior across different operational conditions, material lots, personnel shifts, and environmental variations that naturally occur in production settings. While three lots cannot capture all potential sources of variability, they provide a foundation for understanding the process’s robustness under typical manufacturing conditions.

4. Quality Assurance Perspective

In the pharmaceutical industry, product quality directly affects patient health, requiring a high level of quality assurance. The validation of three lots serves as a standard for demonstrating to customers and regulatory authorities that the process has been established and can provide consistently high-quality products. This requirement reflects the industry’s commitment to patient safety and recognizes that pharmaceutical products are not ordinary commodities but critical healthcare interventions where quality failures can have serious consequences.

5. Definition of Process Validation

This guideline defines process validation as “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 definition emphasizes the importance of documented evidence and the concept of “high degree of assurance,” which forms the foundation for the three-lot requirement. The focus on consistency recognizes that in pharmaceutical manufacturing, every batch must meet quality standards—occasional success is not sufficient.

6. Importance of Documentation

Since validation is conducted based on documented evidence, proper document management is essential. Without documentation, it is impossible to guarantee the reliability of a process. Documentation serves multiple purposes: it provides evidence for regulatory review, enables knowledge transfer, supports troubleshooting, and creates an institutional memory of how processes were developed and validated. The 1987 guideline emphasized that documentation must be contemporaneous, meaning records should be created at the time work is performed, not reconstructed afterward.

7. Process Stability

Manufacturing processes must be stable against variable factors such as temperature, humidity, and raw material quality. Maintaining product quality consistently is therefore required. Process stability is not merely about achieving target specifications but about demonstrating that the process operates within a “state of control” where sources of variation are understood and managed. The three-lot validation provides evidence that the process can maintain this state of control across multiple manufacturing campaigns.

8. PPQ (Process Performance Qualification)

The FDA recommends collecting data through the manufacture of at least three lots to verify process performance. This approach, known as Process Performance Qualification (PPQ), is an important step in demonstrating process stability. PPQ represents the culmination of process development work and serves as the bridge between development and commercial manufacturing. During PPQ, the process is executed according to its intended commercial manufacturing instructions, and comprehensive data collection confirms that the process performs as designed. The three-lot requirement for PPQ ensures that this critical transition is based on sufficient evidence rather than limited observations.

It is important to note that while three lots represent a minimum requirement, some processes may require additional lots for validation, particularly when dealing with complex manufacturing operations, critical quality attributes with narrow acceptance ranges, or processes with known sources of variability. The three-lot standard should be viewed as a starting point rather than an absolute rule applicable to all situations.

Overview of the 2011 Guideline

The FDA’s “Guidance for Industry: Process Validation: General Principles and Practices,” issued in January 2011, presents principles and practices for ensuring that pharmaceutical manufacturing processes can consistently produce high-quality products. This guideline represented a significant evolution in regulatory thinking, shifting from a traditional approach focused on initial validation campaigns to a more comprehensive lifecycle concept.

1. Process Validation Lifecycle

The 2011 guideline emphasizes that process validation should be implemented throughout the entire lifecycle. Specifically, data collection and evaluation are required at each stage, from process development through commercial production. This lifecycle approach recognizes that validation is not a one-time event but an ongoing commitment to process understanding and control. The guideline introduces a paradigm shift from “validate then manufacture” to “continuous validation throughout manufacturing.”

The lifecycle approach consists of three stages:

Stage 1: Process Design – During this stage, the commercial manufacturing process is defined based on knowledge gained through development and scale-up activities. Critical quality attributes (CQAs) are identified, and critical process parameters (CPPs) are established through risk assessment and scientific understanding. The goal is to design a process that is capable and robust before entering validation studies.

Stage 2: Process Qualification – This stage includes two components: design of the facility and qualification of utilities and equipment (often called Process Design Qualification), and confirmation that the process can consistently produce quality products when operated within established parameters (Process Performance Qualification or PPQ). The PPQ typically involves the manufacture of multiple lots (often three or more) under conditions that simulate routine production.

Stage 3: Continued Process Verification – This stage represents ongoing assurance gained during routine production that the process remains in a state of control. It includes monitoring and trending of process parameters and quality attributes, periodic review of process performance, and implementation of continuous improvement initiatives. This stage acknowledges that true process validation extends far beyond the initial three-lot campaigns.

2. Documented Evidence

This guideline aims to establish documented evidence that a specific process consistently produces products meeting predetermined specifications and quality attributes. While this appears similar to the 1987 definition, the 2011 guideline places greater emphasis on the scientific basis of that evidence. Documentation must not only record what happened but also explain why processes were designed certain ways, how decisions were made, and what knowledge was gained. This shift reflects the evolution toward science-based and risk-based approaches in pharmaceutical quality systems.

3. Risk-Based Approach

Process validation adopts a risk-based approach, requiring evaluation and management of potential risks at each stage of the manufacturing process. This approach aligns with ICH Q9 (Quality Risk Management) and recognizes that not all process parameters and quality attributes carry equal risk. By focusing validation efforts on areas of highest risk to product quality and patient safety, manufacturers can allocate resources more effectively. An effective strategy for maintaining product quality is thereby constructed, with validation activities proportionate to the risk posed by potential process failures.

The risk-based approach also influences how the three-lot requirement is applied. For well-understood processes with extensive development data, three lots may be sufficient for PPQ. However, for novel processes or those involving critical quality attributes, additional lots or enhanced monitoring may be appropriate. The guideline encourages manufacturers to justify their validation approach based on process understanding and risk assessment rather than following rigid numerical requirements.

Differences Between the 1987 and 2011 Guidelines

The FDA’s 1987 and 2011 guidelines on process validation have several important differences. The main distinctions are outlined below, reflecting the evolution of regulatory expectations and scientific understanding over nearly a quarter century.

Comparison Table: 1987 vs. 2011 FDA Process Validation Guidelines

Aspect	1987 Guideline	2011 Guideline
Core Focus	Documented procedures and compliance	Scientific evidence and lifecycle approach
Validation Timing	Primarily upfront (before commercial production)	Throughout product lifecycle (continuous)
Approach Structure	Three consecutive lots at qualification	Three-stage approach: Design, Qualification, Verification
Documentation Type	Procedural and protocol-driven	Science-based with rationale and justification
Risk Management	Limited emphasis	Central element aligned with ICH Q9
Process Understanding	Focus on meeting specifications	Emphasis on understanding relationships between parameters and quality
Statistical Methods	Basic acceptance criteria	Advanced statistical process control and trending
Revalidation Triggers	Change-based	Risk-based with continuous monitoring
Data Sources	Primarily validation batches	Integration of development, validation, and commercial data
Quality System Integration	Standalone validation activity	Integrated with overall pharmaceutical quality system (ICH Q10)

1. Change in Definition and Approach

The 1987 guideline defined process validation as “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 definition was primarily document-based, with strong emphasis on procedural aspects. The validation approach was largely retrospective, verifying that processes already in use were capable, or prospective, validating processes before routine use but treating validation as a distinct phase separate from ongoing manufacturing.

In contrast, the 2011 guideline shifted focus from documented evidence to “scientific evidence,” emphasizing data and information obtained during process execution. Process validation became defined within a broader context of process understanding and control throughout the product lifecycle. This evolution reflects the pharmaceutical industry’s growing sophistication in process analytical technology (PAT), quality by design (QbD), and risk management. The emphasis moved from simply demonstrating that a process can meet specifications to understanding why it meets those specifications and ensuring it continues to do so throughout its commercial life.

2. Validation Stages and Structure

The 1987 guideline typically required process validation to be conducted through the manufacture of at least three lots, representing the basic method for confirming process reproducibility. This approach was straightforward and easy to implement but sometimes led to a “validate and forget” mentality where manufacturers focused intensively on three validation batches but paid less attention to ongoing process performance.

The 2011 guideline introduced the “three-stage approach” to process validation, encompassing process development, commercial production, and monitoring throughout the product’s entire lifecycle. This approach demands a more flexible and scientific methodology. The three stages (Process Design, Process Qualification, and Continued Process Verification) create a continuum from development through commercial manufacturing, with each stage building upon knowledge gained in previous stages. This structure recognizes that process validation is not completed after three successful lots but continues throughout the product’s market life.

Stage 1 (Process Design) emphasizes establishing process understanding during development, identifying critical parameters, and designing robust processes. Stage 2 (Process Qualification) includes both facility and equipment qualification and PPQ through multiple lots. Stage 3 (Continued Process Verification) requires ongoing monitoring and statistical evaluation to ensure the process remains in control. This staged approach aligns with modern quality systems and provides a more comprehensive framework for process validation.

3. Emphasis on Risk Management

The 1987 guideline did not strongly emphasize the concept of risk management. Validation primarily focused on procedural aspects of the process, with relatively uniform requirements applied across different types of products and processes. Risk was addressed implicitly through testing and specification setting, but systematic risk assessment was not a central element of validation planning.

The 2011 guideline introduced a risk-based approach, placing importance on risk assessment and management at each stage of the manufacturing process. This change reflects the adoption of ICH Q9 (Quality Risk Management) principles and recognizes that validation efforts should be proportionate to risk. More effective strategies for maintaining product quality are thereby constructed through prioritization of validation activities based on potential impact on product quality and patient safety.

Risk-based approaches enable manufacturers to focus resources on areas of greatest concern while applying less intensive validation strategies to well-understood, low-risk process steps. This approach also facilitates more rapid response to changes, as risk assessment can guide decisions about the extent of revalidation required. The integration of risk management throughout the validation lifecycle represents a fundamental shift from universal application of fixed rules to tailored approaches based on scientific assessment.

4. Need for Scientific Basis

The 1987 guideline relied on documented procedures, and evidence based on actual data was relatively limited. Success was often judged by conformance to written procedures rather than by demonstrated understanding of process behavior. While data from validation batches were collected and evaluated, the emphasis was on showing that specifications were met rather than on understanding process behavior or relationships between parameters and quality attributes.

The 2011 guideline places emphasis on collection and analysis of data based on scientific evidence, requiring an empirical approach to ensure process stability and reproducibility. This shift reflects broader trends in pharmaceutical manufacturing toward process analytical technology (PAT), quality by design (QbD), and statistical process control. Modern validation requires understanding not just whether specifications are met but why they are met, how process parameters influence quality attributes, and what normal process variation looks like.

Scientific basis is developed through design of experiments, mechanistic studies, scale-up investigations, and ongoing monitoring of process performance. This knowledge enables more robust processes, more meaningful acceptance criteria, and better-informed decisions about process changes. The emphasis on scientific understanding also facilitates continuous improvement, as manufacturers can make process enhancements based on mechanistic understanding rather than simply demonstrating compliance with existing procedures.

5. Integration with Modern Quality Concepts

While not explicitly stated as a separate category, an important difference between the guidelines is how they integrate with broader quality system concepts. The 1987 guideline existed largely as a standalone requirement, with validation conducted as a distinct activity primarily driven by regulatory compliance needs.

The 2011 guideline explicitly connects process validation to ICH Q8 (Pharmaceutical Development), Q9 (Quality Risk Management), and Q10 (Pharmaceutical Quality System). This integration creates a more cohesive quality framework where validation is one element of an overall strategy for achieving product quality. The guideline acknowledges that process validation builds upon development knowledge (Q8), applies risk management principles (Q9), and operates within a comprehensive quality system (Q10).

This integrated approach enables more efficient and effective validation strategies. Development data can support validation, reducing the need for extensive qualification studies. Risk assessment guides validation scope and intensity. The quality system provides the framework for maintaining process control throughout the product lifecycle. This integration represents a maturation of pharmaceutical quality management from a collection of separate activities to a comprehensive, science-based system.

Relationship to International Standards and Current Trends

While this column focuses on FDA guidance, it is important to note that similar concepts have been adopted internationally. The European Medicines Agency (EMA) and other regulatory authorities have published comparable guidance emphasizing lifecycle approaches and risk-based validation. ICH guidelines, particularly Q8, Q9, and Q10, provide harmonized principles that underpin modern validation approaches across regions.

Current industry trends continue to evolve beyond the 2011 guideline. Continuous manufacturing, real-time release testing, advanced process monitoring with artificial intelligence and machine learning, and enhanced process analytical technology are changing how validation is conceptualized and executed. However, the fundamental principle that adequate evidence (whether three lots or another scientifically justified approach) must demonstrate process capability and control remains central to pharmaceutical quality assurance.

Conclusion

These differences emerged as the FDA recognized the need for the pharmaceutical industry to adopt a more scientific and risk-based approach to improving quality control. The evolution from the 1987 to 2011 guidelines reflects growing process understanding, advances in analytical technology, and recognition that quality cannot be tested into products but must be built into processes.

The three-lot requirement, while still relevant, is now understood within a broader context of lifecycle validation and continuous process verification. Modern pharmaceutical manufacturers must demonstrate not only that three consecutive lots meet specifications but also that they understand their processes sufficiently to maintain control throughout commercial production. This evolution has created more robust pharmaceutical manufacturing processes that better serve patient safety and public health.

The journey from the 1987 guideline’s procedural focus to the 2011 guideline’s scientific and risk-based approach represents significant progress in pharmaceutical quality assurance. As technology and understanding continue to advance, validation approaches will undoubtedly continue to evolve, but the commitment to ensuring consistent product quality through robust process validation will remain a cornerstone of pharmaceutical manufacturing.