The Birth of the Validation Concept

Historical Background: The 1970s Pharmaceutical Tragedy

The concept of validation in pharmaceutical manufacturing originated from a tragic incident involving large-volume injectable solutions in the United States during the 1970s. This pharmaceutical disaster became the catalyst that fundamentally transformed how the pharmaceutical industry approaches quality assurance.

The problematic injectable solution had undergone sterilization during the manufacturing process and had passed sterility testing at the time of release. The manufacturer confirmed compliance with test results before shipment. However, patients who received this product subsequently died in a series of tragic incidents that shocked the pharmaceutical world.

The root cause of these fatalities was traced to contaminated cooling water used in the manufacturing process. After heat sterilization, the internal pressure within the vials decreased, creating a vacuum. This negative pressure drew the contaminated cooling water through the gap between the vial and rubber stopper, thereby contaminating the internal solution. The release testing employed sampling-based sterility testing rather than 100% inspection of all units. Consequently, the presence of contaminated vials went undetected, allowing them to reach patients with fatal consequences.

Regulatory Response and the Emergence of Validation

This tragedy prompted the U.S. Food and Drug Administration (FDA) to recognize a fundamental limitation in pharmaceutical quality control. The agency realized that focusing solely on final product quality was insufficient; it became essential to ensure that quality was built into products throughout the manufacturing process itself. In response, FDA strengthened inspections of manufacturing processes at production facilities. More significantly, in 1976, the agency incorporated the validation concept into current Good Manufacturing Practice (cGMP) regulations, marking a paradigm shift in pharmaceutical quality assurance.

FDA’s Definition of Process Validation

In 1987, FDA issued the “Guideline on General Principles of Process Validation,” which established the fundamental definition of validation in pharmaceutical manufacturing:

“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 characteristics.”

In Japanese: バリデーションとは、あらかじめ定めた仕様や品質にあった製品を継続的に生産するプロセスに対して、高度の保証を与え、文書化された証拠を確立するものである。

This definition emphasizes that validation is forward-looking in nature. It provides a high degree of assurance that products manufactured in the future will consistently meet predetermined specifications and quality attributes. In other words, batch number 1, batch number 10, batch number 100, and batch number 1,000 must all be manufactured with the same quality and specifications. This consistency requirement represents the fundamental principle underlying validation.

The Purpose and Benefits of Validation

Through validation, manufacturers can prevent the production of defective products caused by insufficiently robust manufacturing processes and reduce the likelihood of quality testing failures or oversights. Validation serves as a proactive quality assurance measure rather than a reactive inspection approach.

The concept recognizes that quality cannot be tested into products; it must be designed and built into the manufacturing process from the beginning. This fundamental principle continues to guide modern pharmaceutical manufacturing practices worldwide.

Evolution of Validation Guidance

2011 FDA Revision: The Lifecycle Approach

In January 2011, FDA updated its validation guidance with “Process Validation: General Principles and Practices,” which replaced the 1987 guidance. This revision introduced a comprehensive lifecycle approach to validation consisting of three stages:

Stage 1 – Process Design: The commercial manufacturing process is defined based on knowledge gained through development and scale-up activities. This stage emphasizes science-based design and understanding of the process.

Stage 2 – Process Qualification: The process design is evaluated to determine whether the process is capable of reproducible commercial manufacturing. This stage includes Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ).

Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control. This represents a shift from viewing validation as a one-time event to recognizing it as an ongoing activity throughout the product lifecycle.

The 2011 guidance moved away from the traditional “three batch” approach as the sole validation strategy, instead emphasizing that the number of batches needed for validation should be scientifically justified based on process knowledge and risk assessment.

Implementation in Japan

Initial Introduction (1995)

In Japan, the validation concept was first officially introduced in 1995 through the “Validation Standards” (薬発第158号, Notification from the Director of the Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare to Governors of all prefectures, dated 1995).

First Major Revision (2013)

The validation requirements were substantially revised in 2013 as part of GMP reform. The document “Handling of the Ministerial Ordinance on Standards for Manufacturing Control and Quality Control of Drugs and Quasi-Drugs” (医薬品及び医薬部外品の製造管理及び品質管理の基準に関する省令の取扱いについて, Notification No. 薬食監麻発0830第1号, dated August 30, 2013, from the Director of the Compliance and Narcotics Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare) updated the “Validation Standards” (バリデーション基準).

This 2013 revision was significant as it incorporated quality risk management concepts and aligned Japanese requirements more closely with international standards, particularly in preparation for Japan’s accession to PIC/S (Pharmaceutical Inspection Co-operation Scheme) in 2014.

Latest Reform (2021): From “Standards” to “Guidelines”

The most recent and comprehensive reform occurred in 2021, representing the first major revision of the GMP Ministerial Ordinance in 16 years. On April 28, 2021, the Ministry of Health, Labour and Welfare issued the “Partial Amendment of the Ministerial Ordinance on Standards for Manufacturing Control and Quality Control of Drugs and Quasi-Drugs” (医薬品及び医薬部外品の製造管理及び品質管理の基準に関する省令の一部改正について, Notification No. 薬生監麻発0428第2号, dated April 28, 2021), which came into effect on August 1, 2021.

In conjunction with this GMP Ministerial Ordinance reform, the “Validation Standards” (バリデーション基準) was redesignated as “Validation Guidelines” (バリデーション指針). This change from “Standards” to “Guidelines” reflects several important shifts:

Increased Flexibility: The new guidelines allow manufacturers to reference either the Japanese Validation Guidelines or equivalent or superior international guidelines, such as PIC/S GMP Annex 15 “Qualification and Validation.” This provides companies with greater flexibility in implementing validation programs that align with global operations.

International Harmonization: The 2021 reform was driven primarily by the need to achieve greater harmonization with PIC/S GMP Guidelines, which Japan committed to following after joining PIC/S in 2014. The reform also aligns with ICH (International Council for Harmonisation) guidelines, particularly ICH Q8 (Pharmaceutical Development), ICH Q9 (Quality Risk Management), and ICH Q10 (Pharmaceutical Quality System).

Enhanced Quality Systems: The 2021 GMP reform introduced the Pharmaceutical Quality System (PQS) as a central requirement, reflecting the principles of ICH Q10. This system emphasizes a lifecycle approach to pharmaceutical quality, continuous improvement, and the integration of quality risk management throughout all stages of product development and commercial manufacturing.

Key Principles in Current Validation Practice

Modern validation practices, as reflected in both international and Japanese guidelines, emphasize several fundamental principles:

Risk-Based Approach: Validation activities should be scaled according to the risk to product quality. Higher-risk processes require more extensive validation, while lower-risk processes may require less rigorous approaches.

Continuous Verification: Rather than viewing validation as a one-time activity, current practice emphasizes ongoing process verification throughout the commercial manufacturing lifecycle.

Scientific Justification: Validation protocols and acceptance criteria should be based on sound scientific principles and understanding of the process, rather than arbitrary standards such as the traditional “three batch” requirement.

Lifecycle Management: Validation is now understood as a continuous activity spanning from process design through commercial manufacturing and product discontinuation, rather than a discrete event.

Conclusion

The validation concept, born from a tragic pharmaceutical disaster in the 1970s, has evolved into a sophisticated, science-based approach to ensuring pharmaceutical quality. From FDA’s initial 1987 guidance through the 2011 revision and the ongoing evolution of international standards, validation has progressed from a compliance-driven activity to a comprehensive quality assurance strategy integrated throughout the product lifecycle.

In Japan, the evolution from the 1995 Validation Standards through the 2013 revision and culminating in the 2021 reform reflects the nation’s commitment to international harmonization and patient safety. The transition from “Validation Standards” to “Validation Guidelines” in 2021 represents not merely a semantic change but a fundamental shift toward greater flexibility, scientific rigor, and alignment with global best practices.

Understanding this historical context and regulatory evolution is essential for pharmaceutical professionals, as it provides the foundation for implementing effective validation programs that ensure patient safety while maintaining regulatory compliance in an increasingly globalized pharmaceutical industry.