The Origins of GMP (Good Manufacturing Practice)

The Thalidomide Tragedy as the Catalyst for GMP Establishment

The primary reason for establishing GMP (Good Manufacturing Practice) in the United States was the thalidomide tragedy.

The thalidomide tragedy that occurred in 1962 had a profound impact on the establishment of GMP. In this incident, thalidomide, a drug taken by pregnant women, caused severe birth defects and deaths in fetuses. This tragedy made the world recognize the critical importance of pharmaceutical safety and quality control, laying the foundation for modern pharmaceutical regulation.

Overview of the Thalidomide Tragedy

The thalidomide tragedy was a severe drug-induced disaster that occurred worldwide from the late 1950s to the early 1960s. This incident is remembered as one of the most significant public health crises in the history of pharmaceutical regulation.

Thalidomide was a sedative and hypnotic drug sold in over 40 countries from the late 1950s to the early 1960s. First marketed in West Germany in 1957, it was widely advertised as a safe sleeping pill available without prescription. Its effectiveness for morning sickness in pregnant women was particularly emphasized, and it was prescribed to many expectant mothers.

When taken during early pregnancy, especially between 34 and 49 days of gestation, the drug was found to cause birth defects (teratogenic effects) affecting the limbs, ears, and internal organs of fetuses. The most characteristic defect was phocomelia, a condition in which hands and feet were shortened or missing, resembling seal flippers.

Worldwide, an estimated 10,000 to 20,000 fetuses were affected, with approximately 1,000 cases in Japan. In Japan, 309 victims were officially recognized. About 40% of affected infants died within one year, and survivors faced lifelong severe physical disabilities.

The Situation in the United States

In the United States, Richardson-Merrell Company (later Richardson Vicks Company) applied to the FDA for approval of thalidomide under the brand name “Kevadon” in September 1960.

The company distributed approximately 2.5 million tablets of thalidomide to over 1,200 physicians, providing them free of charge under the guise of “clinical trials.” These “clinical trials” were conducted without proper documentation, using various dosages, formulations, and colors. This distribution resulted in tens of thousands of patients taking thalidomide.

A critical problem was that the company completely skipped animal testing and proceeded directly to human experiments. Despite confirming birth defects in rat studies, the company concealed these results and submitted only misleading partial data to the FDA.

As a result of this chaotic distribution, 17 cases of birth defects were confirmed in the United States, with dozens more suspected cases reported. Overall, the FDA failed to adequately investigate how widely thalidomide had become available in the United States.

To this day, the U.S. government has not provided compensation to these victims.

The Heroic Work of Dr. Frances Oldham Kelsey

Dr. Frances Oldham Kelsey (July 24, 1914 – August 7, 2015), a Canadian-born pharmacologist and physician, played an extraordinarily important role in the thalidomide tragedy.

Background and Career

Dr. Kelsey was born in Cobble Hill, Vancouver Island, British Columbia. She earned her Bachelor of Science degree from McGill University in 1934 and a Master’s degree in pharmacology in 1935. She then obtained her Ph.D. in pharmacology from the University of Chicago in 1938 and her M.D. in 1950.

At the University of Chicago, she conducted research under Dr. F. Ellis Kelsey, who would later become her husband. In 1937, she was involved in investigating another significant pharmaceutical regulation case of the 20th century: the “Elixir Sulfanilamide incident.” This experience provided her with deep insights into pharmaceutical safety that would prove invaluable in her later review of thalidomide.

Joining the FDA and Reviewing Thalidomide

In 1960, Dr. Kelsey was hired as a medical officer at the FDA. At that time, the FDA had only seven full-time physician reviewers and four part-time physician reviewers, making the new drug review system extremely vulnerable.

Just one month after joining, in September 1960, Dr. Kelsey was assigned to review the thalidomide application. Since the drug had already been approved in Canada and over 20 European and African countries, it was expected to be easily approved. Indeed, Richardson-Merrell Company anticipated approval within six months.

However, Dr. Kelsey discovered critical flaws in the submitted materials. The application documents lacked scientific methodology, and she recognized that the authors of the provided testimonials had a history of publishing suspicious articles. Furthermore, she was concerned about insufficient animal testing data and the absence of studies on placental transfer and fetal effects.

Refusal to Approve and Resistance to Pressure

Under FDA regulations at the time, a decision to approve or reject a new drug application had to be made within 60 days, and if no decision was made, the drug would be automatically approved. Dr. Kelsey skillfully utilized this rule, continuously requesting additional information every 60 days, keeping the application “incomplete” and resetting the review period.

Over approximately one year, she received more than 50 visits from Richardson-Merrell Company, facing strong pressure to expedite approval. The company’s representatives were frustrated with her response and attempted to appeal to her superiors, but FDA leadership consistently supported her judgment.

Dr. Kelsey proceeded with her review cautiously, sometimes having her husband verify her conclusions. From late 1960 to 1961, upon learning of increasing reports of neurological disorders in Europe, she heightened her vigilance. Her previous research experience led her to suspect that these neurological side effects might be related to mechanisms of birth defects.

Discovery of Thalidomide’s Dangers

In November 1961, the link between birth defects in Europe and Australia and thalidomide became clear. Researchers in Germany and Australia connected clusters of rare severe birth defects with thalidomide.

In March 1962, Richardson-Merrell Company finally withdrew its FDA application. By this time, 17 cases of birth defects had been confirmed through “clinical trials” in the United States, with dozens more suspected.

Recognition and Continued Contributions

Dr. Kelsey’s careful review ensured that thalidomide was never formally approved in the United States. This prevented large-scale thalidomide damage in the U.S. Her judgment was completely vindicated when thalidomide’s teratogenic effects later became clear.

In July 1962, The Washington Post featured Dr. Kelsey’s achievements on its front page, and she became a national hero overnight. In August of the same year, Dr. Kelsey received the President’s Award for Distinguished Federal Civilian Service from President John F. Kennedy, becoming only the second woman to receive this honor. President Kennedy praised her, stating that “her exceptional judgment prevented a major tragedy of birth deformities in the United States.”

Subsequently, Dr. Kelsey became head of the FDA’s Investigational Drugs Branch and from the late 1960s through the 1990s led the Division of Scientific Investigations, supervising clinical trials and ensuring scientific integrity of data. She contributed to building a system that supervised clinical investigators and ensured the scientific integrity of data.

In 2010, the FDA awarded Dr. Kelsey the first “Dr. Frances O. Kelsey Drug Safety Excellence Award,” announcing that this award would bear her name. Since then, this award has been presented annually to one FDA staff member.

In July 2014, Dr. Kelsey celebrated her 100th birthday and moved from Washington, D.C., to London, Ontario, Canada, to live with her daughter that fall. In June 2015, she was awarded the Order of Canada by the Canadian government.

Dr. Frances Kelsey passed away on August 7, 2015, at the age of 101. The New York Times described her “double legacy” in her obituary, praising her two achievements: preventing a medical tragedy and improving drug protections.

The author once had the honor of seeing her when she was introduced as a surprise guest at a DIA (Drug Information Association) event during her lifetime. I still remember how the entire venue gave her a standing ovation. Dr. Kelsey was a true hero, and her courageous judgment and scientific rigor saved countless lives and had a lasting impact on the history of pharmaceutical regulation. Her achievements stand as a symbolic example of the vital role of women in healthcare.

Regulatory Reform: The Path to GMP Establishment

Following the thalidomide tragedy, pharmaceutical regulation in the United States was significantly strengthened. This reform went beyond mere legal amendments and transformed the very nature of pharmaceutical development and manufacturing.

Kefauver-Harris Amendments (1962)

In 1962, the U.S. Congress passed the Kefauver-Harris Amendments, which significantly amended the FD&C Act (Federal Food, Drug, and Cosmetic Act). The main provisions of this amendment were:

• Requirement to Prove Efficacy: Previously only safety proof was required, but now scientific proof of efficacy became necessary for drug approval
• Informed Consent: Obtaining prior consent from clinical trial subjects became mandatory
• Investigational Drug Notification: Manufacturers were required to notify the FDA that a drug was under investigation
• Adverse Event Reporting: Manufacturers were obligated to report unexpected adverse events to the FDA
• Prescription Drug Advertising Regulation: The FDA gained authority to regulate prescription drug advertising
• Legal Basis for GMP Requirements: Most importantly, the FDA was granted authority to establish GMP (Good Manufacturing Practice)

This amendment established a clear link between drug approval and manufacturing quality. Maintaining proper manufacturing control became a legal requirement for maintaining product approval.

First GMP Regulations (1963)

Following the 1962 legal amendments, the FDA promulgated the first GMP regulations in 1963 under Section 501(a)(2)(B) of the FD&C Act. These regulations were initially specified in 21 CFR Part 133 and established minimum standards for the manufacture, processing, packaging, or holding of drugs.

The main objectives of these first GMP regulations were:

1. Prevention of Human Error: Building systems to minimize human errors in manufacturing processes
2. Prevention of Drug Contamination and Quality Degradation: Establishing controls to prevent cross-contamination, mix-ups, and quality deterioration
3. Design of Systems to Ensure High Quality: Implementing systematic approaches to ensure consistent quality

These regulations established the recognition that pharmaceutical manufacturing should be a carefully controlled quality assurance system, not merely a chemical process.

Expansion and Modernization of GMP Regulations (1978)

In 1978, the FDA significantly expanded GMP regulations, codifying them as 21 CFR Parts 210 and 211, which form the foundation of modern U.S. GMP regulations. This revision strengthened the following elements:

• Facility and equipment requirements
• Manufacturing process controls
• Quality control systems
• Record and documentation requirements
• Personnel qualifications and training

That same year, the FDA also finalized GMP regulations for medical devices (21 CFR Part 820), applying similar quality control standards to medical products other than pharmaceuticals.

International Developments

The establishment of GMP in the United States had a significant impact on subsequent global developments.

Between 1967 and 1968, WHO (World Health Organization) consultants drafted the first text on GMP, which was adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations in 1968.

In 1969, the World Health Assembly recommended that member countries adopt the GMP certification scheme, leading to the legalization of pharmaceutical GMP in countries worldwide. WHO GMP is now used by pharmaceutical regulators and the pharmaceutical industry in over 100 countries.

In 1991, the European Union (EU) introduced the EU GMP Directive as Directive 91/356/EEC, later consolidated as EudraLex Volume 4. These regulations, consistent with WHO and ICH (International Council for Harmonisation) standards, apply to all pharmaceutical manufacturing within the EU.

21st Century GMP: Evolution toward Risk-Based Approaches

Since the 2000s, GMP has evolved from checklist-type compliance to risk-based quality systems.

In 2000, ICH published “ICH Q7: GMP for Active Pharmaceutical Ingredients,” providing the first internationally harmonized GMP standard for API manufacturing.

In 2006, the FDA launched the “Pharmaceutical CGMPs for the 21st Century” initiative, introducing a quality system model incorporating risk management. This approach aims to concentrate resources on higher-risk areas and promote innovation.

Subsequently, guidelines such as ICH Q8 (Quality by Design: QbD), Q9 (Quality Risk Management), and Q10 (Pharmaceutical Quality System) were published, recommending an approach that builds quality from the early stages based on deep understanding of manufacturing processes.

Thus, GMP, established in the United States following the thalidomide tragedy, became an important standard for pharmaceutical manufacturing management and quality control, significantly contributing to the improvement of pharmaceutical safety worldwide. GMP is not merely a regulatory requirement but a comprehensive quality assurance philosophy to protect patient safety, and it continues to evolve today.

Thalidomide Today

Thalidomide has undergone significant changes since the drug-induced disaster and is now used as an important therapeutic agent under strict management.

Re-approval as Medicine and Current Uses

In 1998, thalidomide was re-approved in the United States as a treatment for erythema nodosum leprosum (ENL), a complication of Hansen’s disease (leprosy). This was based on the 1964 discovery by Israeli physician Jacob Sheskin, who found that administering thalidomide to a critically ill leprosy patient dramatically improved ENL symptoms.

In 2006, thalidomide obtained FDA approval as a treatment for multiple myeloma. This was the first new treatment for multiple myeloma in over a decade and attracted significant attention in the medical community.

In 2008, it was also approved in Japan as a treatment for multiple myeloma.

Currently, thalidomide is used to treat the following conditions:

• Multiple myeloma (as first-line treatment in combination with dexamethasone or melphalan + prednisone)
• Acute episodes and maintenance therapy of erythema nodosum leprosum (ENL) in leprosy
• Weight loss associated with tuberculosis and AIDS
• Diabetic retinopathy
• Graft-versus-host disease
• Off-label uses including Kaposi’s sarcoma and myelofibrosis

Market Size and Economic Aspects

The market for thalidomide and its derivatives is growing steadily. The global market size in 2023 was estimated at approximately 1.5-1.6 billion USD (approximately 230 billion yen), and is projected to reach 2.5-2.6 billion USD (approximately 380 billion yen) by 2030. The annual growth rate is approximately 5-6.6%.

However, the description in the original manuscript that it is “a blockbuster drug with annual sales exceeding 1 trillion yen” does not match current market data. This expression may refer to the broader “thalidomide-class drug market” including its derivatives (such as lenalidomide and pomalidomide), but thalidomide alone does not reach this scale.

In terms of pricing, thalidomide has become a relatively expensive drug. In the United States, when reintroduced in 1998, a 50mg tablet cost approximately $7.50, but by 2004, it had risen to over $30. The fact that prices have increased despite growing demand continues to be a subject of health economics debate.

Strict Management Systems

To manage the teratogenic risk of thalidomide, strict safety management systems have been implemented in various countries.

In the United States, the “THALOMID REMS® (Risk Evaluation and Mitigation Strategy)” program is implemented, with the following requirements:

• Registration system for prescribing physicians, pharmacists, and patients
• Mandatory contraception and regular pregnancy tests for female patients of childbearing potential
• Appropriate contraception guidance for male patients
• Comprehensive patient education programs

In Japan, the “TERMS (Thalidomide Education and Risk Management System)” has been introduced. This system includes:

• Registration and education of prescribing physicians
• Registration and education of pharmacists
• Patient registration and consent
• Strict contraception management for women of childbearing potential
• Regular compliance verification

Similar Pregnancy Prevention Programmes are implemented in Europe.

Through the introduction of these management systems, thalidomide can now be used relatively safely. However, new thalidomide damage continues to be reported in some countries where these systems are absent or through illegal distribution channels.

Contribution to New Drug Discovery

As understanding of thalidomide’s mechanism of action has advanced, it has contributed to the development of new drug discovery technologies.

In 2010, researchers at Tokyo Institute of Technology discovered that thalidomide binds to a protein called “cereblon (CRBN)” and leads to the degradation of specific proteins. This discovery explained both the teratogenic and anti-tumor effects of thalidomide and had a significant impact on new drug development.

Currently, the following research and development are underway:

1. Thalidomide Derivatives: Development of new compounds that reduce teratogenicity while maintaining or enhancing anti-blood cancer effects. Representative examples include:
   1. Lenalidomide: Has more powerful anti-tumor effects and reduced neurotoxicity
   1. Pomalidomide: A third-generation immunomodulatory drug for multiple myeloma treatment
   1. Iberdomide: A fourth-generation compound under clinical development
2. PROTAC Technology: PROTAC (PROteolysis TArgeting Chimera) technology has been developed, applying thalidomide’s targeted protein degradation mechanism. This technology can selectively degrade specific disease-related proteins and has become an important platform for next-generation drug development.
3. Discovery of Drug Targets: Research on the thalidomide-cereblon system has led to the continuous discovery of new drug targets, with applications expected beyond cancer to other diseases.

Thus, thalidomide is used as a valuable medicine under strict management and is also attracting attention as a foundational technology for new drug development. The ironic aspect exists that a past tragedy is contributing to the progress of modern medicine.

Conclusion

The thalidomide tragedy represents one of the most important turning points in the history of pharmaceutical regulation. The lessons learned from this tragedy demonstrate not only the importance of strengthening regulations but also of establishing a culture that prioritizes patient safety at all stages of drug development, approval, manufacturing, and use.

Dr. Frances Kelsey’s courageous actions are a symbolic example of how one public servant’s judgment and sense of responsibility can save countless lives. Her legacy continues in the activities of regulatory authorities worldwide, including today’s FDA.

GMP was born following the thalidomide tragedy and has continued to evolve for over 70 years. Modern GMP has developed from mere manufacturing standards into a comprehensive quality system integrating risk management, Quality by Design, and continuous improvement.

Meanwhile, thalidomide itself has been revived as an important therapeutic agent under strict management and has become the foundation for new drug discovery technologies, simultaneously demonstrating the progress of science and the importance of regulation. Learning from tragedy and converting it into future benefits can be said to be the essence of pharmaceutical regulation and medical progress.

Today, pharmaceutical regulation is globally harmonized, and through international organizations such as ICH, WHO, and PIC/S, mechanisms have been established to protect the safety of patients worldwide. However, we must not forget that at the foundation lies the tragedy of the thalidomide incident and the courage of people like Dr. Kelsey who stood against it.

Comparative Table: Evolution of Pharmaceutical Regulation

Period	Key Event	Regulatory Response	Impact on GMP
1937	Elixir Sulfanilamide Tragedy (107 deaths)	Federal Food, Drug, and Cosmetic Act (1938)	Established FDA authority over drug safety
1960-1962	Thalidomide Tragedy (10,000-20,000 affected worldwide)	Kefauver-Harris Amendments (1962)	Mandated proof of efficacy and authorized FDA to establish GMP
1963	Implementation of regulations	First GMP Regulations (21 CFR Part 133)	Established minimum standards for manufacturing
1978	Expansion and modernization	Comprehensive GMP Regulations (21 CFR Parts 210-211)	Created modern framework for pharmaceutical manufacturing
1968-1969	International harmonization begins	WHO GMP adopted	Globalization of quality standards
2000	API standards established	ICH Q7 published	Harmonized standards for active ingredients
2006	Modern approach introduced	FDA’s “21st Century cGMP” Initiative	Shift to risk-based quality systems

Thalidomide: From Tragedy to Treatment

Aspect	Historical Period (1957-1962)	Modern Period (1998-Present)
Status	Over-the-counter sedative in many countries	Strictly controlled prescription medication
Indication	Sleep aid, morning sickness, anxiety	Multiple myeloma, leprosy complications, specialized conditions
Safety Testing	Minimal testing, no teratogenicity studies	Comprehensive testing, strict risk management
Distribution	Widely available, minimal controls	Registered prescribers and patients only
Patient Protection	None	REMS (US), TERMS (Japan), PPP (Europe)
Pregnancy Prevention	No measures	Mandatory contraception, regular pregnancy testing
Market Size	Unknown (withdrawn 1961-1962)	Approximately $1.5-1.6 billion globally (2023)
Scientific Understanding	Unknown mechanism	Cereblon binding, targeted protein degradation
Legacy	Birth of modern pharmaceutical regulation	Foundation for immunomodulatory drug development

This table illustrates how thalidomide transformed from an uncontrolled tragedy to a carefully managed therapeutic option, demonstrating the effectiveness of modern pharmaceutical regulation and safety systems.