The Birth of the Validation Concept

Origin and Historical Background of the Validation Concept

The concept of validation originated from a major pharmaceutical contamination incident involving large volume parenterals (LVPs) that occurred in the United States in the early 1970s. This historic event fundamentally transformed the approach to quality assurance in pharmaceutical manufacturing.

Overview and Circumstances of the Incident

Between July 1970 and April 1971, multiple hospitals across the United States reported outbreaks of nosocomial (hospital-acquired) septicemia. The causative organisms were identified as Enterobacter cloacae or Enterobacter agglomerans. Epidemiological investigations revealed that all affected patients developed septicemia while receiving infusion products manufactured by a single manufacturer. Multiple fatalities were reported among patients who developed septicemia during the administration of these infusion products.

Manufacturing Process and Quality Control Practices

The implicated injectable products had undergone proper sterilization procedures during the manufacturing process and had passed sterility testing prior to distribution. The manufacturer, following the quality control standards of that era, confirmed that the products met the acceptance criteria for sterility testing and released them for distribution. Superficially, these products appeared to be problem-free and were distributed to the market.

Elucidation of the Contamination Mechanism

Detailed investigations conducted by the U.S. Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC), and the manufacturer revealed the cause of contamination. The core of the problem lay in the cooling process within the manufacturing procedure.

The specific contamination mechanism was as follows:

After sterilization, the vials were cooled using municipal water (tap water). This cooling water was contaminated with bacteria, but the manufacturer was unaware of this fact. Furthermore, the chlorine concentration in the municipal water used was frequently below the level necessary to inhibit bacterial growth.

Vials that had undergone heat sterilization developed a negative pressure (vacuum) inside as they cooled from their high-temperature state. This physical phenomenon caused contaminated cooling water to be drawn into the vials through microscopic gaps between the vial and rubber stopper, thereby contaminating the contents. Additionally, as the bottles continued to cool after removal from the sterilizer, ambient air and moisture infiltrated through the bottle threads and into the cap liner, further contributing to contamination.

Limitations of the Traditional Quality Assurance System

This incident revealed fundamental limitations of the traditional quality assurance approach. Quality control of that era relied on sampling inspection of the final product. Sterility testing was not conducted on the entire manufacturing lot but was performed on samples drawn from the lot. Consequently, if contaminated vials existed within a lot but were not selected for sampling inspection, their presence could not be detected.

In other words, this incident brought the painful recognition that passing final product testing guaranteed only the quality of the tested samples, not the quality of the entire manufacturing lot.

FDA Response and Regulatory Reform

In response to this serious pharmaceutical disaster, the FDA fundamentally reconsidered its approach to pharmaceutical quality assurance. The FDA recognized that focusing solely on final product quality test results was insufficient and that it was necessary to ensure that the manufacturing process itself was properly controlled and quality was assured.

Based on this recognition, on June 1, 1976, the FDA published a draft amendment to the Code of Federal Regulations titled “Current Good Manufacturing Practice in the Manufacture, Processing, Packing, or Holding of Large Volume Parenterals for Human Use (Part 212).” This was the first instance in which the FDA issued well-defined process standards for drug products.

This regulatory draft emphasized the importance of scientifically validating and documenting the manufacturing process. However, many manufacturers objected that the new regulations would impose limitations on manufacturing and create obstacles to technological innovation. As a result, both the draft regulations for large volume parenterals and the proposed regulations for small volume parenterals were withdrawn as formal rules.

Introduction of the Validation Concept into Regulations

Through the series of incident investigations and regulatory discussions, the FDA decided to introduce a new concept called “process validation” into pharmaceutical regulations. This concept required scientific data-based demonstration and documentation that a manufacturing process could consistently produce products of the intended quality.

In September 1978, the definition of process validation was officially presented for the first time in the FDA’s compliance program. Subsequently, in May 1987, the FDA issued the “Guideline on General Principles of Process Validation,” systematically presenting validation requirements.

Although the formal regulations of Part 212 were withdrawn, the concept of validation was voluntarily adopted by the industry and became established as a fundamental principle of quality assurance in subsequent pharmaceutical manufacturing.

Modern Validation: The Lifecycle Approach

The concept of validation has continued to evolve. In January 2011, the FDA issued “Process Validation: General Principles and Practices,” presenting a validation approach throughout the product lifecycle.

This modern approach defines validation as three integrated stages:

Stage 1 – Process Design

The stage in which the commercial manufacturing process is defined based on knowledge gained through development and scale-up activities. A robust manufacturing process is designed utilizing product development data, risk assessment, and scientific knowledge.

Stage 2 – Process Qualification

The stage in which the designed process is evaluated to determine if reproducible commercial manufacturing is possible. Qualification of facilities, equipment, and utilities is performed, and Process Performance Qualification (PPQ) demonstrates that the process can consistently manufacture products meeting quality standards.

Stage 3 – Continued Process Verification

The stage that provides ongoing assurance that the process remains in a state of control during routine commercial manufacturing. Through collection, analysis, and trend evaluation of manufacturing data, process variation is monitored and corrective actions are taken as necessary.

This lifecycle approach realized a paradigm shift from the traditional concept of simply manufacturing and documenting three validation batches to scientific understanding and continuous quality assurance throughout the product’s lifetime.

Fundamental Principles of Validation

The modern validation concept is based on the following fundamental principles:

1. Quality is built into the product: Quality is not assured by final product testing alone but is built in at each stage of development, design, and manufacturing.
2. Process control assures quality: Proper control of each manufacturing process forms the foundation for final product quality assurance.
3. Based on scientific evidence: Scientific data demonstrates that the process can consistently manufacture products of the intended quality.
4. Continuous improvement: Validation is not a one-time activity but is performed continuously throughout the product lifecycle.
5. Risk-based approach: Based on risk assessment, critical process parameters and quality attributes are identified, and focused control is implemented.

Summary and Contemporary Significance

The large volume parenteral incident of the 1970s became a catalyst for fundamentally transforming the approach to quality assurance in pharmaceutical manufacturing. The validation concept born from this tragic incident is practiced worldwide today as a fundamental principle of pharmaceutical manufacturing.

The modern pharmaceutical industry integrates concepts such as the lifecycle approach, quality risk management, and continuous improvement to build more sophisticated quality assurance systems. However, underlying these systems is the lesson learned from an incident over 50 years ago: “final product testing alone cannot assure quality.”

Validation is not merely a regulatory requirement but a scientific approach to protecting patient safety. Only through deep understanding, proper control, and continuous verification of manufacturing processes can the quality and safety of pharmaceuticals be truly assured. This fundamental principle is an important lesson that all professionals involved in pharmaceutical manufacturing should always keep in mind.