The History of Good Manufacturing Practices (GMP): From Tragedy to Trust
Introduction
Good Manufacturing Practices (GMP) are foundational regulations that ensure the safety, quality, and efficacy of drugs, medical devices, food, and cosmetics. These practices are not merely bureaucratic formalities—they are the direct result of historic tragedies, evolving science, and global regulatory coordination. This blog explores the chronological development of GMP, highlighting key events, regulatory changes, and their outcomes, and examines how GMP evolved into a critical component of public health.
1. Pre-GMP Era: Tragedies That Shaped Modern Regulation
Before GMP, the production of medicines and food was largely unregulated. Quality control was inconsistent, and manufacturers were not required to test for purity, safety, or effectiveness. Two key tragedies in the United States—one involving contaminated vaccines and the other a toxic drug formulation—were pivotal in catalyzing federal regulatory oversight.
1.1 The 1901 St. Louis Tetanus Outbreak
In 1901, 13 children died in St. Louis after receiving diphtheria antitoxin contaminated with tetanus. The antitoxin had been manufactured from a horse that later contracted tetanus, but the manufacturer failed to test the serum properly. This led to the Biologics Control Act of 1902, the first federal law in the U.S. to regulate the manufacture of biological products [FDA, 2023].
1.2 The 1937 Elixir Sulfanilamide Tragedy
One of the most consequential events was the Elixir Sulfanilamide Disaster of 1937. The S.E. Massengill Company created a sulfanilamide formulation using diethylene glycol—a toxic solvent. Over 100 people died, including many children. At the time, there was no requirement to test the safety of drugs before marketing.
This led to the passage of the Federal Food, Drug, and Cosmetic Act (FD&C Act) of 1938, granting the U.S. Food and Drug Administration (FDA) authority to regulate drugs, mandate safety testing, and inspect manufacturing facilities [FDA History Office, 2023].
2. The Birth of GMP Regulations (1960s)
The modern concept of GMP emerged as a subset of the FD&C Act, evolving through amendments and increasingly rigorous enforcement.
2.1 Thalidomide Crisis and the Kefauver-Harris Amendments (1962)
While the U.S. narrowly avoided the worst of the thalidomide disaster—a drug prescribed for morning sickness that caused thousands of birth defects in Europe—it spurred major changes in U.S. law. Dr. Frances Kelsey of the FDA refused to approve thalidomide without more data, potentially preventing a public health disaster.
This event led to the Kefauver-Harris Drug Amendments of 1962, which introduced requirements for:
Demonstrating efficacy before approval
Informed consent for clinical trials
Enhanced FDA oversight of manufacturing practices
Importantly, the law emphasized good manufacturing processes as a requirement for maintaining product approvals [NIH, 2019].
2.2 Introduction of Formal GMP Regulations (1963-1978)
In 1963, the FDA published its first set of GMP regulations for drugs, under the authority of Section 501(a)(2)(B) of the FD&C Act. These regulations established minimum standards for manufacturing, processing, packing, or holding of drugs to assure quality and purity.
In 1978, the FDA finalized and codified current Good Manufacturing Practices (cGMPs) into 21 CFR Parts 210 and 211, forming the modern framework for pharmaceutical manufacturing in the United States.
3. The Globalization of GMP
As pharmaceutical markets globalized, regulators around the world began adopting similar GMP frameworks. Efforts to harmonize GMP became essential to enable cross-border drug approvals and to uphold global supply chain integrity.
3.1 WHO GMP Guidelines (1969)
The World Health Organization (WHO) issued its first GMP guidelines in 1969, aimed at guiding member states on pharmaceutical quality assurance. This was especially important for countries without robust regulatory systems.
WHO GMP guidelines were widely adopted in Asia, Africa, and Latin America, forming the backbone of many national regulatory systems [WHO TRS 961].
3.2 Pharmaceutical Inspection Convention and Cooperation Scheme (PIC/S)
In 1970, ten European countries formed the Pharmaceutical Inspection Convention (PIC) to harmonize GMP inspections. This later evolved into PIC/S (Pharmaceutical Inspection Co-operation Scheme), an international body promoting common standards and mutual recognition of GMP inspections.
PIC/S now includes over 50 member authorities—including the U.S., Canada, Australia, and many EU countries—and serves as a platform for global GMP harmonization and training [PIC/S website, 2024].
3.3 EU GMPs
The European Union introduced its own GMP Directive in 1991, formalized under Directive 91/356/EEC and later consolidated under EudraLex Volume 4. These regulations, consistent with WHO and ICH standards, govern all aspects of drug manufacture in the EU.
4. GMP and Modern Quality Systems (2000s–Present)
The 21st century saw a shift in GMP from compliance checklists toward risk-based quality systems, reflecting advances in manufacturing science and regulatory expectations.
4.1 ICH Q7 – GMP for APIs (2000)
The International Council for Harmonisation (ICH) released ICH Q7: GMP for Active Pharmaceutical Ingredients in 2000. It provided the first internationally harmonized GMP standard specifically for APIs, covering everything from raw materials to packaging and lab controls. ICH Q7 was a landmark in promoting consistency across regions [ICH.org].
4.2 ICH Q8–Q10: Quality by Design and Quality Systems
Between 2005 and 2008, the ICH published:
Q8: Pharmaceutical Development
Q9: Quality Risk Management
Q10: Pharmaceutical Quality System
These documents emphasized Quality by Design (QbD) and risk management, encouraging manufacturers to understand processes deeply, build in quality from the start, and maintain a lifecycle approach to GMP compliance [ICH, 2008].
4.3 FDA’s Risk-Based Inspection Model
Responding to increasing global complexity, the FDA adopted a risk-based inspection model. Factors such as a facility’s compliance history, product risk, and supply chain complexity inform inspection frequency. This strategy focuses limited resources on the highest risk to public health [FDA, 2019].
4.4 Data Integrity in the Digital Era
With increased automation and digitization, data integrity has become a focal point. Numerous warning letters and regulatory findings (especially from 2014 onward) exposed issues with falsified test results, uncontrolled electronic records, and backdating.
In response, the FDA and other regulators issued guidance such as:
FDA Data Integrity Guidance for Industry (2018)
MHRA GxP Data Integrity Definitions and Guidance (2018)
These guidances define ALCOA+ principles (Attributable, Legible, Contemporaneous, Original, Accurate, + Complete, Consistent, Enduring, and Available) as the cornerstone of GMP-compliant data systems.
5. Lessons from Major GMP Enforcement Actions
5.1 Ranbaxy Laboratories (2013)
One of the largest GMP enforcement actions in history involved Ranbaxy Laboratories, an Indian generic drug manufacturer. The FDA cited data falsification, non-compliance with validation protocols, and incomplete documentation. The company paid $500 million in penalties and faced a consent decree.
Outcome: The case underscored the global impact of poor GMP and the need for robust supplier oversight [U.S. Department of Justice, 2013].
5.2 NECC Meningitis Outbreak (2012)
The New England Compounding Center produced contaminated steroid injections, leading to 64 deaths and over 750 illnesses due to fungal meningitis. The facility operated under the guise of compounding but essentially functioned as a drug manufacturer without meeting GMP standards.
Outcome: Congress passed the Drug Quality and Security Act (DQSA) of 2013, creating a new class of outsourcing facilities subject to full FDA GMP oversight [FDA DQSA Overview, 2013].
6. GMP in the COVID-19 Era and Beyond
6.1 Accelerated Production, Same Standards
The urgency of the COVID-19 pandemic led to unprecedented speed in vaccine and therapeutic development. Yet, regulators emphasized that GMP requirements remained unchanged.
Manufacturers like Pfizer and Moderna had to validate production at scale, conduct rigorous quality testing, and demonstrate data integrity—all under the intense scrutiny of global regulatory bodies.
6.2 Remote Inspections and Digital Transformation
With travel restricted, regulatory agencies like the FDA and EMA adopted remote inspection tools, such as live video walkthroughs, cloud-based document review, and secure data transfer protocols. This shift accelerated the digital transformation of GMP compliance, reinforcing the need for robust electronic records and audit trails [EMA, 2021].
6.3 AI and GMP: The Next Evolution
As AI tools become embedded in manufacturing—monitoring deviations, predicting maintenance, and aiding in batch review—regulators are again adapting. The FDA’s Center for Drug Evaluation and Research (CDER) has initiated frameworks for the responsible use of AI in GMP environments, with a focus on transparency, traceability, and human oversight [FDA, 2024].
Conclusion
GMP has evolved over the last century from a reaction to tragedy into a sophisticated global framework ensuring the quality and safety of medicinal products. From handwritten ledgers to AI-driven quality systems, the journey of GMP reflects broader shifts in science, technology, and global collaboration
But the core mission remains unchanged: protecting patients by ensuring that every batch of medicine meets the highest standard of safety, quality, and efficacy.
As we enter an era of digital transformation, personalized medicine, and complex biologics, GMP will continue to evolve—but its foundational principles of integrity, accountability, and scientific control will remain steadfast.
References
U.S. Food and Drug Administration. “Milestones in U.S. Food and Drug Law.” FDA.gov.
FDA History Office. “The Elixir Sulfanilamide Tragedy.” FDA.gov.
NIH. “Dr. Frances Oldham Kelsey and the Fight Against Thalidomide.” NIH.gov.
WHO. “WHO Good Manufacturing Practices: Main Principles.” Technical Report Series No. 961.
ICH Q7. “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients.” ICH.org.
ICH Q8–Q10. “Pharmaceutical Quality System Guidelines.” ICH.org.
FDA. “Data Integrity and Compliance With Drug CGMP: Guidance for Industry.” 2018.
PIC/S. “History and Mission.” PIC/S.org.
Department of Justice. “Ranbaxy Pleads Guilty and Agrees to Pay $500 Million.” May 2013. Justice.gov.
FDA. “Drug Compounding and the Drug Quality and Security Act.” FDA.gov.
EMA. “Reflection Paper on Remote Inspections.” EMA.europa.eu.
FDA. “Artificial Intelligence and Machine Learning in Drug Manufacturing.” 2024. FDA.gov.