The Historical Development of GMP Regulations and FDA Inspection Systems: Continuous Evolution in Protecting Patient Safety

In pharmaceutical quality assurance, Good Manufacturing Practice (GMP) has become an indispensable element. However, before this system was established, there were numerous tragic incidents and tireless efforts by people who worked to overcome them. By examining this history, we can understand what modern GMP aims to achieve.

The Birth and Early Development of GMP

The history of GMP traces back to 19th century America. At that time, the United States faced serious problems with substandard medicines imported from Europe and domestically manufactured drugs of inconsistent quality. During the Civil War, it is said that more people died from poor-quality medicines and food than from combat. To address this critical situation, eleven physicians gathered at the U.S. Capitol in Washington, D.C. in January 1820 to establish the United States Pharmacopeia (USP). This was the first important step in setting quality standards for medicines. The USP provided formulas for 217 drugs that were “most fully established and best understood” at the time, laying the foundation for ensuring consistency and quality in medicines.

However, the establishment of the USP alone was not sufficient. In 1901, a diphtheria antitoxin contaminated with tetanus resulted in the deaths of 13 children in St. Louis. This tragedy led to the enactment of the Biologics Control Act of 1902, establishing the first federal regulatory framework to ensure the safety of biological products.

In 1906, Upton Sinclair’s novel “The Jungle” exposed the unsanitary conditions in the meatpacking industry, causing public outrage. In response, the Pure Food and Drug Act was enacted the same year, prohibiting the manufacture, sale, and transportation of adulterated or misbranded food and drugs. This laid the foundation for what would become the Food and Drug Administration (FDA).

In 1937, the Elixir Sulfanilamide incident occurred. The S.E. Massengill Company manufactured a syrup containing the antibacterial drug sulfanilamide dissolved in toxic diethylene glycol, resulting in over 100 deaths. This incident clearly demonstrated that not only efficacy but also safety verification was necessary for drugs. In response, the Federal Food, Drug, and Cosmetic Act (FD&C Act) was enacted in 1938, granting the FDA authority to evaluate the pre-market safety of drugs and inspect manufacturing facilities. This became the foundation for modern GMP regulations.

The Establishment of cGMP in the United States

The true turning point came with the thalidomide tragedy that occurred in the 1960s. This sedative and sleeping pill caused severe birth defects in children born to women who took it during early pregnancy, affecting thousands of infants in Europe and Canada. In the United States, FDA reviewer Dr. Frances Kelsey carefully scrutinized the approval application and withheld approval due to insufficient safety data. This decision prevented large-scale harm in the United States. Dr. Kelsey’s contribution was highly recognized, including receiving the President’s Award for Distinguished Federal Civilian Service from President Kennedy.

Following this tragic event, the Kefauver-Harris Amendments were enacted in 1962. This law required drugs to demonstrate not only safety but also efficacy to obtain approval, and mandated informed consent in clinical trials. More importantly, this law granted the FDA authority to establish “Good Manufacturing Practices” and enabled regular inspections of manufacturing facilities.

In response, in 1963, the FDA issued the world’s first formal GMP regulations for pharmaceuticals. These established minimum standards for the manufacture, processing, packaging, and storage of drugs. Furthermore, in 1978, the FDA codified current Good Manufacturing Practice (cGMP) as 21 CFR Parts 210 and 211, establishing the modern framework for pharmaceutical manufacturing in the United States. The word “current” used here has significant meaning. It requires manufacturers to always incorporate the latest science and technology and ensure quality using methods appropriate for the times. This means that technologies and equipment that were state-of-the-art ten or twenty years ago may be insufficient by today’s standards.

This movement was supported by the World Health Organization (WHO), which adopted its first draft text on GMP in 1968 and recommended the WHO Certification Scheme in 1969. This led to the spread of GMP concepts to countries around the world. In Japan, introduction began in the 1980s, and it was established as a regulatory requirement with legal force in 1994.

Large Volume Parenteral Contamination Incidents and the Introduction of Validation Concepts (1970s)

Between 1970 and 1971, outbreaks of nosocomial (hospital-acquired) septicemia were reported in many hospitals across the United States. Infections caused by Enterobacter cloacae and Enterobacter agglomerans occurred in all patients who had used Large Volume Parenterals (LVPs) manufactured by the same manufacturer. Investigation revealed that there was intrinsic contamination in the new elastomer screw-cap closure system used by this manufacturer.

Following this serious incident, on June 1, 1976, the FDA issued a draft rule on “Current Good Manufacturing Practice in the Manufacture, Processing, Packing, or Holding of Large Volume Parenterals for Human Use” (21 CFR Part 212). This was the first time the FDA provided clear process standards for drug products, with particular emphasis on the concept of process validation. Recognition spread that final product testing alone was insufficient, and that quality must be built into the entire manufacturing process. This concept forms the foundation of modern GMP.

Validation is the scientific demonstration that a manufacturing process consistently produces the intended results. The introduction of this concept fundamentally changed pharmaceutical manufacturing from a “manufacture and test” approach to a “design quality and build it into the process” approach.

The Heparin Sodium Incident (2008): Challenges of the Global Supply Chain

The 2008 heparin sodium incident highlighted new challenges in the era of globalization. Heparin is an anticoagulant drug widely used to prevent blood clotting, with 10 million Americans using it annually. In this incident, heparin supplied from raw material manufacturing facilities in China was contaminated with a foreign substance called oversulfated chondroitin sulfate (OSCS).

This contaminated heparin caused approximately 350 adverse events and 81 deaths in the United States. Additionally, the FDA received reports of 785 serious health injuries. Investigation revealed that OSCS is a chemical substance that does not occur naturally and, while much cheaper than authentic heparin, mimics the properties of real heparin in in vitro tests. This strongly suggested deliberate adulteration motivated by economic gain. At Chinese raw heparin manufacturing facilities, chondroitin was mixed in at high proportions ranging from 2% to 60%.

A serious aspect of this incident was that the contaminant could not be detected by the standard United States Pharmacopeia (USP) test methods available at the time. After Baxter Healthcare Corporation began recalling heparin products in February 2008, the FDA rapidly advanced its investigation, identifying the type of contaminant on March 5, 2008, and developing and sharing new testing methods that could distinguish contaminated from uncontaminated heparin by March 6. On March 17, OSCS was officially identified as the contaminant.

Following this incident, the FDA significantly strengthened its overseas inspection system. Inspections were conducted at 11 heparin manufacturing facilities in China, revealing that 12 Chinese companies were involved in the contamination. Furthermore, the FDA established overseas offices in China and India, strengthening surveillance systems in the Asian region. The USP also incorporated new testing methods into its monograph in June 2008, mandating capillary electrophoresis (CE) and proton nuclear magnetic resonance (H-NMR) testing for all heparin products.

This incident clearly demonstrated that in a globalized pharmaceutical supply chain, qualification assessment and continuous monitoring of active pharmaceutical ingredient (API) manufacturers are essential. In Europe as well, this incident significantly influenced the Falsified Medicines Directive, Good Distribution Practice (GDP) guidelines, and the EU GMP Guide (particularly sections on supplier qualification). Currently, pharmaceutical manufacturers are obligated to control GMP compliance of all API manufacturers.

Modern GMP Implementation Systems: Evolution of Risk-Based Approaches

Modern GMP adopts risk-based approaches. The FDA Safety and Innovation Act (FDASIA), signed into law on July 9, 2012, significantly reformed the inspection system. This law granted the FDA authority to collect user fees from the industry for reviews of innovator drugs, medical devices, generic drugs, and biosimilar biological products, strengthened drug supply chain safety, and promoted incorporation of patient perspectives into the regulatory process.

Particularly important is Title VII of FDASIA. This granted the FDA new authorities to ensure the safety, effectiveness, and quality of the drug supply chain. Through this law, Section 510(h) of the FD&C Act was amended, replacing the fixed minimum inspection interval for domestic facilities with a risk-based schedule. This enabled the FDA to determine inspection frequency based on risk, considering “known safety risks” regardless of facility location (domestic or foreign).

Introduction and Operation of the Site Selection Model (SSM)

Central to this reform is the Site Selection Model (SSM). This model is an innovative system for determining the priority of facilities for inspection based on scientific evidence. The SSM was actually introduced in fiscal year 2005, but FDASIA strengthened its legal basis, and in September 2018, the Center for Drug Evaluation and Research (CDER) published an official manual (MAPP 5014.1) to increase transparency. Furthermore, a revised version was issued on June 26, 2023, enabling more refined risk assessment.

The SSM calculates a risk score for each facility based on the following risk factors specified in Section 510(h)(4) of the FD&C Act:

1. Inherent Product Risk

Patient risk varies greatly depending on the type of drug. Products considered particularly high-risk include the following:

Anticancer drugs have very potent pharmacological effects, and slight variations in quality can significantly impact patient treatment outcomes and safety. Blood products and vaccines, being biological products, can have fatal consequences if contaminated with microorganisms or impurities. Highly potent substances exhibit significant pharmacological effects even in minute amounts, making prevention of cross-contamination during manufacturing extremely important. Injectable drugs, especially large volume parenterals, are administered directly into blood vessels, so particulate matter contamination, microbial contamination, or pyrogen contamination can cause serious health damage.

2. Site Type

Quality risk differs depending on facility function, such as manufacturing facilities, packaging facilities, and testing facilities (quality control laboratories). Manufacturing facilities handle the most complex and important processes, from API synthesis to final product manufacturing. Packaging facilities must manage risks of product mix-ups and cross-contamination. Quality control laboratories are the last line of defense ensuring products meet specifications, with the validity of test methods and reliability of test results being extremely important.

3. Patient Exposure

Facilities manufacturing products with high market share in the U.S. market or critical medicines with limited alternatives receive high risk scores. The greater the number of patients affected if supply is disrupted, the greater the public health risk. Facilities manufacturing emergency use drugs are also prioritized for inspection.

4. FDA Compliance History

Facilities that had serious findings (Official Action Indicated: OAI) in past inspections, facilities that received Warning Letters, and facilities subject to Consent Decrees receive high risk scores. The implementation status of corrective actions for findings and track record of continuous improvement are also evaluated. Conversely, facilities with no problems found in past inspections (No Action Indicated: NAI) or only minor findings (Voluntary Action Indicated: VAI) receive lower risk scores.

5. Time Since Last Surveillance Inspection

Facilities with long elapsed time since the last routine inspection receive higher risk scores because their current status is unknown. Before FDASIA implementation, inspections were required every two years for domestic facilities, but with the current risk-based approach, low-risk facilities have longer inspection intervals while high-risk facilities are inspected more frequently.

6. Hazard Signals

Product recall history, Field Alert Reports (reports of product quality issues), MedWatch reports (adverse event reports), Biological Product Deviation Reports, and the number and importance of consumer complaint reports are evaluated. These signals suggest potential problems in manufacturing processes or quality management systems.

7. Inspection by Foreign Regulatory Authorities

Whether inspection has been conducted by foreign government agencies under Section 809 of the FD&C Act is also considered. The FDA can enter into written agreements with foreign governments that it has determined have the capability to conduct inspections meeting FDA standards and utilize those inspection results. This enables more efficient allocation of limited resources.

8. Regional Compliance History

As a newly added risk factor in the 2023 revision, the compliance history of other facilities in the country or region where the facility is located is now considered. If there is a history of many violations related to exported products in a particular country or region, other facilities in that region may be assessed as high-risk.

These elements are comprehensively evaluated, and the Office of Quality Surveillance (OQS) within the Office of Pharmaceutical Quality (OPQ) develops an inspection plan (Site Surveillance Inspection List: SSIL) at the beginning of the year. The Office of Regulatory Affairs (ORA) plans and conducts actual inspections based on this list.

This scientific approach enables the most effective use of limited resources. Notably, this system is designed to reflect actual public health risks rather than being a mere mechanical evaluation. Risk factor assessment is based on empirical evidence collected by the FDA, expert judgment, or both.

The goal of the SSM is to ensure parity in inspection frequency between domestic and foreign facilities. In other words, it is based on the principle that facilities with equivalent risk should be inspected with equal frequency regardless of geographic location (domestic or foreign) or product type. Newly registered facilities are expected to be inspected within 30 days of registration.

Quality System Effectiveness Assessment

The 2023 revised MAPP emphasizes that the focus of inspections is on determining quality system effectiveness. The FDA seeks to determine in inspections whether the quality system produces a robust state of control and promotes a quality culture that exceeds cGMP standards. In other words, cGMP compliance is the minimum requirement, and the FDA expects companies to exceed these standards.

This means it is important not only to meet regulatory requirements but also to demonstrate commitment to continuous improvement and excellence. Quality culture refers to a state where commitment to quality is shared at all levels of the organization, and all employees are actively involved in quality improvement.

Future Prospects: Digital Technology and International Cooperation

With the advancement of digital technology, quality control methods continue to evolve. Adding the utilization of artificial intelligence (AI) and big data analysis to risk-based approaches like the SSM enables more effective quality assurance. For example, systems that monitor manufacturing data in real-time and detect quality deviations early, and AI models that learn quality risk patterns from vast historical data are being developed.

International cooperation among regulatory authorities is also advancing. Through the Pharmaceutical Inspection Co-operation Scheme (PIC/S) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), mutual utilization of inspection results and information sharing are becoming more active. This reduces the burden on globally operating pharmaceutical companies of receiving duplicate inspections in each country, while enabling regulatory authorities to build more efficient surveillance systems.

ICH guidelines such as ICH Q9 (Quality Risk Management), ICH Q10 (Pharmaceutical Quality System), and ICH Q12 (Lifecycle Management) provide an international framework to promote risk-based approaches and continuous improvement. These guidelines support manufacturers in identifying, evaluating, and managing quality risks based on scientific evidence and ensuring quality throughout the product lifecycle.

Furthermore, with the introduction of advanced technologies such as Process Analytical Technology (PAT) and Real-Time Release Testing (RTRT), it is becoming possible to understand manufacturing processes more deeply and assure quality in real-time. These technologies are accelerating the transition from the traditional “manufacture and test” approach to an approach of “assuring quality by understanding and controlling processes.”

Conclusion: Learning from History and Building the Future

GMP is not merely a regulatory requirement. It is an important framework for protecting patients’ lives and health. Building a quality assurance system that can flexibly respond to new challenges while utilizing lessons from the past will continue to be required in the future. As the globalization of pharmaceuticals advances, the importance of GMP will undoubtedly increase further.

More than 200 years have passed since the establishment of the USP in 1820, and pharmaceutical quality assurance today continues to evolve with the progress of science and technology. However, the underlying principles remain unchanged. That is, prioritizing patient safety and practicing quality control based on scientific evidence.

Past tragedies such as the Elixir Sulfanilamide incident, thalidomide tragedy, large volume parenteral contamination incidents, and heparin incident have given us important lessons. We have learned from these events and built systems to prevent the same mistakes from happening again. Concepts supporting modern GMP, such as risk-based approaches, process validation, supply chain management, and international cooperation, all emerged from these experiences.

The importance of “learning from history” in pharmaceutical quality assurance will never change in the future. Learning from past cases, responding to current challenges, and building a better future. That is the essential mission of GMP. The common goal is for the pharmaceutical industry, regulatory authorities, healthcare professionals, and patients to work together to continue providing safer and more effective medicines.