Who Originated the Three Principles of GMP?

Definition of GMP and the Three Principles

GMP (Good Manufacturing Practice) establishes standards for quality control and manufacturing control in the production of pharmaceuticals, food products, and other regulated items. GMP is internationally recognized as a comprehensive management system standard for ensuring product quality, translated in Japanese as “Tekisei Seizō Kihan” (Proper Manufacturing Standards) or “Standards for Manufacturing Control and Quality Control of Drugs and Quasi-drugs.”

The Three Principles of GMP consolidate the fundamental concepts for implementing GMP in practice. These principles form the foundation of GMP systems in Japan and other countries worldwide. The Three Principles of GMP consist of the following three elements:

1. Minimize human error
2. Prevent contamination and quality deterioration of pharmaceuticals
3. Design systems that ensure high quality

These principles are believed to have evolved with reference to the WHO-GMP guidelines developed by the World Health Organization. WHO-GMP systematically organized these concepts as fundamental elements of pharmaceutical quality assurance and presented them as international standards.

Origins and Historical Background of the Three Principles of GMP

The specific individual or organization that first clearly articulated the Three Principles of GMP has not been definitively identified in the literature. However, it is understood that the concepts underlying these three principles were gradually systematized during the formation of the fundamental concepts of WHO-GMP.

The history of GMP began its full-scale development in response to drug-related disasters in the United States during the 1960s. Notably, in 1962, the U.S. Food and Drug Administration (FDA) legally mandated production and quality control standards through amendments to the Federal Food, Drug, and Cosmetic Act, which became the foundation of modern GMP. This legislation was significantly influenced by serious drug disasters such as the thalidomide tragedy that occurred from the late 1950s to early 1960s, leading to a societal recognition of the importance of ensuring pharmaceutical safety.

The thalidomide tragedy was a devastating drug disaster in which many newborns suffered congenital malformations (such as limb deficiencies) when pregnant women took thalidomide, a sedative and hypnotic drug. This incident led to a strong recognition of the importance of safety testing during the pharmaceutical development stage, as well as the necessity of quality control during the manufacturing stage.

GMP has continued to evolve over time. The concept of quality assurance in pharmaceutical manufacturing has been continuously improved through various cases and experiences, developing into a more comprehensive system. Today, it is understood as a quality management system that encompasses all processes from raw material procurement to final product shipment, going beyond mere manufacturing process control.

International Development and Evolution of GMP

In 1969, the World Health Organization (WHO) officially established “WHO-GMP (WHO Good Manufacturing Practices)” and recommended that member countries conduct pharmaceutical trade based on a GMP certification system. This recommendation aimed to internationally standardize pharmaceutical quality in each country and establish quality assurance in pharmaceutical trade. WHO-GMP has been regularly revised since then to respond to advances in pharmaceutical manufacturing technology and changes in regulatory requirements.

Following this recommendation, individual countries proceeded to implement their own GMP systems. In Japan, GMP was developed through the following stages:

Year	Event
1974	Published as “Pharmaceutical GMP Guidance Standards” (commenced as administrative guidance)
1980	Legally enacted and enforced as Preparation GMP (acquired legal binding force through Pharmaceutical Affairs Act amendment)
1982	Active Pharmaceutical Ingredients Industry Association established GMP Committee and created draft self-regulatory standards for API GMP
1988	API GMP standards indicated through Bureau Director Notice
1994	Pharmaceutical GMP including APIs promulgated, establishing a GMP system encompassing both preparations and APIs
2005	Completely revised as GMP Ministerial Ordinance under amended Pharmaceutical Affairs Act
2013	Amended Pharmaceutical Affairs Act (later the Pharmaceuticals and Medical Devices Act) introduced a more comprehensive quality management system concept

Throughout this historical development, Japan’s GMP evolved uniquely to suit the circumstances of Japan’s pharmaceutical industry while initially referencing WHO-GMP. Subsequently, amid the international harmonization movement, alignment with ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines and PIC/S (Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme) standards has been achieved, resulting in the current establishment of an internationally acceptable GMP system.

The Role and Activities of the FDA

The predecessor of the FDA was established in 1906, and it adopted its current name in 1930. The FDA aims to ensure the safety and efficacy of various products that consumers encounter in daily life, including food, pharmaceuticals, cosmetics, medical devices, and veterinary drugs.

The primary reason the FDA promoted GMP was to ensure the safety and efficacy of pharmaceuticals and protect public health. The FDA ensures pharmaceutical quality assurance through the following activities:

• Product review and approval: Rigorous inspection before new drugs enter the market
• Safety assurance of marketed products: Post-marketing safety surveillance (pharmacovigilance)
• Regulatory oversight of manufacturers: Conducting regular GMP inspections
• Defective product recall orders: Rapid response when quality issues are discovered
• Monitoring product information through media and social media: Preventing dissemination of false information
• Enforcement against violative products: Preventing distribution of violative products and legal measures
• Clinical trial supervision: Ensuring ethical conduct of clinical trials and data accuracy
• Appropriate classification and regulation of OTC and prescription drugs: Promoting consumer protection and proper use
• Ensuring prescription drug administration under medical professional guidance: Promoting appropriate pharmaceutical use

The FDA realized the legalization of GMP through the 1962 Kefauver-Harris Amendment (an amendment to the Federal Food, Drug, and Cosmetic Act). This legal amendment, in response to lessons from the thalidomide tragedy, mandated proof of pharmaceutical safety and efficacy while legally establishing the importance of quality control in manufacturing processes.

Currently, FDA GMP regulations are codified as 21 CFR Part 210 and Part 211, and pharmaceutical manufacturers are legally obligated to comply with these regulations. Additionally, the FDA actively participates in international regulatory harmonization efforts and plays an important role in developing international guidelines such as ICH Q10 (Pharmaceutical Quality System).

Fundamental Philosophy and Contemporary Significance of the Three Principles of GMP

The underlying philosophy of the Three Principles of GMP is that “systems must be established to ensure that products of consistent and high quality are manufactured regardless of who performs the work or when it is performed.” This philosophy is based on the principle that those involved in pharmaceutical manufacturing must prioritize the safety of both patients who use the pharmaceuticals and workers who manufacture them under all circumstances.

To realize this fundamental philosophy, the Three Principles of GMP require the following specific approaches:

1. Minimize Human Error

Humans are not infallible under any circumstances and have the potential to make mistakes. Therefore, it is important to establish systems that do not affect product quality even when human errors occur in the manufacturing process. This includes the following elements:

• Creation of clear and easily understandable procedures
• Implementation of appropriate education and training
• Introduction of double-check systems
• Minimization of human intervention through automation and mechanization
• Design to prevent human error (fool-proof, fail-safe mechanisms)

2. Prevent Contamination and Quality Deterioration of Pharmaceuticals

Pharmaceuticals are directly administered to the human body, and quality deterioration due to foreign matter contamination, microbial contamination, chemical changes, etc., can have a direct adverse effect on patient health. Therefore, the following measures are required:

• Maintenance of manufacturing environments with controlled cleanliness
• Area control to prevent cross-contamination
• Establishment of appropriate cleaning and disinfection procedures
• Quality control of raw materials and materials
• Setting and maintaining appropriate storage conditions
• Implementation of environmental monitoring

3. Design Systems That Ensure High Quality

Product quality must be confirmed and assured at each stage of the manufacturing process. This includes the following elements:

• Process validation (verification of manufacturing process validity)
• Implementation of quality control testing
• Deviation management and change control
• Establishment of document management systems
• Implementation of corrective and preventive actions (CAPA)
• Regular self-inspection and internal audits
• Introduction of quality risk management

Contemporary Development of GMP

While maintaining its fundamental philosophy, the Three Principles of GMP have evolved into more advanced concepts in response to advances in pharmaceutical manufacturing technology and changes in regulatory requirements.

In recent years, the following new concepts have been integrated into GMP:

Quality Risk Management (ICH Q9): A risk-based approach that concentrates limited resources on the most critical areas

Pharmaceutical Quality System (ICH Q10): A comprehensive quality management system concept that encompasses GMP

Data Integrity: Requirements for ensuring the completeness, accuracy, and reliability of electronic data

Continuous Improvement: Promotion of continuous quality improvement throughout the product lifecycle

Process Analytical Technology (PAT): Technology enabling real-time quality control

These new concepts represent the adaptation of the fundamental philosophy of the Three Principles of GMP to modern technology and regulatory environments, aiming to realize more efficient and scientifically based quality assurance.

Conclusion

The Three Principles of GMP serve as important guidelines for implementing quality control and manufacturing control standards in the production of pharmaceuticals, food products, and other regulated items. Their origins are strongly influenced by WHO-GMP and have evolved through continuous efforts by international organizations such as the FDA and WHO.

The fundamental philosophy that “products of consistent and high quality must be manufactured regardless of who performs the work or when it is performed” represents the universal value in pharmaceutical manufacturing of prioritizing patient safety. This philosophy constitutes the core principle of pharmaceutical manufacturing that remains unchanged despite the passage of time and technological advances.

The Three Principles of GMP were not created at once by a specific individual or organization but represent collective wisdom that has been gradually formed through many experiences and lessons learned in the history of the pharmaceutical industry. Lessons from tragic drug disasters such as the thalidomide tragedy, efforts by WHO, FDA, and regulatory authorities in various countries, and practical initiatives by pharmaceutical companies have crystallized into the current form of the Three Principles of GMP.

In the future, the interpretation and implementation methods of the Three Principles of GMP will continue to evolve with advances in pharmaceutical manufacturing technology, introduction of new regulatory requirements, and progress in international regulatory harmonization. However, the fundamental principle underlying them—”prioritizing patient safety and always providing high-quality pharmaceuticals”—is expected to remain unchanged as a guiding principle for pharmaceutical manufacturing.