Early 1900s: In the early years of the U.S., medical supplies were sold in the back of the wagons of four-wheeled delivery wagons, called mobile drug shows. Back then, people used a bottled ointment known as a miracle cure-all to treat pain, mucositis, rheumatism and gout. Of course, it worked on horses, too. Happily, such days are gone.
The Thirties: An FDA exhibition in 1933, entitled America's Chamber of Horrors, revealed the flaws of the 1906 Act. The famous exhibit showed the public dangerous foods, drugs, medical devices and cosmetics, including a uterine tray that could puncture the uterus if not used correctly, hair removers that could cause baldness, lotions and ointments that could lead to mercury poisoning, hair dyes that could lead to poisoning, and eyelash tints that could cause women to go blind. These exhibits were later taken to the White House to demand stronger government protections for consumers. Sulfonamides were discovered after 1935, when a number of manufacturers began producing the antimicrobials. One company used diethylene glycol, a toxic solvent and chemical analog of antifreeze, in sulfa spiritus for oral administration, and 107 people, mostly children, died before the problem was discovered. In response to this incident, Congress passed the Federal Food, Drug, and Cosmetic Act of 1938. For the first time, manufacturers were required to prove that their products were safe before they went on the market.
The 1940s and 1950s: In 1941, sulfathiazole tablets manufactured by a U.S. pharmaceutical company killed or injured nearly 300 people when they were contaminated with the sedative and sleeping drug phenobarbital. This incident prompted the FDA to overhaul regulations governing the manufacture and quality control of pharmaceuticals, which later evolved into today's GMPs.
The Public Health Service Act, passed in 1944, covered a considerable range of topics, including the regulation of biological products and the control of communicable diseases.
During World War II, the FDA required pharmaceutical companies to certify batches of a particular product. Samples taken from each batch had to be submitted to the FDA for testing, and the FDA then approved the product for sale. This requirement was enforced for insulin and penicillin beginning in 1941 and 1945, respectively, and was later extended to all antibiotics. This requirement for batch certification of drug production was later discontinued by 1983.
In 1955, Jonas Salk discovered the use of vaccination to prevent polio. Many manufacturers began producing their own vaccines. One company's failure to completely inactivate the virus in one batch of its products resulted in about 60 people becoming ill with the virus after receiving such a vaccine, and an additional 99 members of the family of those patients becoming infected with the virus.
The 1960s: Thalidomide was marketed in Europe as a sleeping pill to treat vomiting in women during pregnancy. Regulatory agencies at the time approved the drug for this indication with no knowledge of its serious teratogenic side effects. The drug can cause severe malformations in the developing fetus. Women who took the drug in the first trimester of pregnancy gave birth to babies with severely deformed hand walls and legs. It is estimated that 1,000 cases of deformities in babies in Europe have been linked to the use of the drug. The drug was not approved in the United States. The person responsible for reviewing the drug at the time was a woman scientist, Frances Kelsey, who in 1962 was awarded the Presidential Award for Distinguished Federal Citizen Service by then U.S. President John F. Kennedy, the highest honor a government employee can receive as a citizen. The thalidomide scandal caught the public's attention. Congress passed tougher regulations requiring pharmaceutical companies to ensure not only that their products are safe, but also that they are effective for the indicated indications; the revised regulations require that drugs be tested on animals before they can be used in humans, and they also provide for the regulation of clinical trials, making researchers responsible for the regulation of the drugs being studied; pharmaceutical manufacturers should inform subjects whether the drug is for research purposes and should obtain consent from subjects before conducting trials; pharmaceutical manufacturers must report unforeseen drug injuries (adverse events); and the FDA is authorized to regulate the advertising of prescription drugs.
Seventy years was a watershed. The GMPs for drug manufacturing (21CFR parts 210 and 211) and for medical devices (21CFR part 820) were finally approved in 1978 and were designed to ensure the safety and effectiveness of all these products. These regulations are the minimum Good Manufacturing Practices for methods, equipment, or controls currently used in the manufacture, handling, packaging, or assuring the safety of drug products so that they have the composition, efficacy, and meet the requirements for quality and purity traits of the sound labeling.GLP was established in 1979 for non-clinical laboratory studies conducted to obtain approval of an investigational or marketing application for a product regulated by the FDA. work, including food and colored additives, animal food additives, drugs for human or animal use, medical devices for human use, biologics, and electronic products, and were developed to ensure the quality and integrity of drug safety data.
The Medical Device Amendments, signed in 1976, strengthened the FDA's authority to regulate medical devices. The passage of the amendment was prompted by a contraceptive device used by 2 million women that caused many serious injuries. The product was withdrawn from the market in 1975 because it was associated with high rates of pelvic infections, infertility, and some deaths. The amendment required manufacturers of most medical devices, especially moderately or highly hazardous ones, to provide the FDA with safety and effectiveness data on their products before they could be marketed, and additionally established a system of pre-market and post-market regulation of drugs, including FDA regulation of pharmaceutical companies' compliance with GMPs, proper documentation of product design and manufacture, and maintenance of the system in response to complaints.
In 1982, a 12-year-old child named Mary Kellerman took a powerful acetaminophen capsule (Taylor capsule) for a cold, and she died a few hours later; six others also died in the incident, for which Johnson & Johnson issued a worldwide recall of thirty-one million bottles of Taylor capsules for destruction. Later studies found that the culprit was an inadvertently opened seal that contaminated the capsules with cyanide, and the FDA issued a rule requiring tamper-resistant packaging for all over-the-counter medications, enshrined in GMPs, and Congress passed the Federal Tampering Act in 1983, which made it a criminal offense to tamper with packaged consumer products. The Taylor capsule incident had a tremendous impact on the pharmaceutical industry. It is a reminder that not only do we need to continually train our employees on GMPs, but we also need to be aware that our products can be killers that jeopardize public safety.
In the 1980s, the FDA began publishing a series of guidance documents that were instrumental in understanding the current GMP rules. One of these was the 1983 publication of Guidelines for the Examination of Computerized Systems in Drug Product Handling, which provided an early vision of the capabilities of computers and may have marked the beginning of computer-based certification.In 1989, the famous Guidelines for General Principles in Process Certification summarized our current thinking and expectations for process certification of drugs and devices.
Active Pharmaceutical Ingredients were formerly known as Bulk Pharmaceutical Chemicals. This recent change in terminology reflects the fact that some active ingredients are produced using biological rather than chemical methods. The term New Chemical Entity is now often expressed as New Molecular Entity for the same reason.
Naturally occurring L-tryptophan and 5-hydroxytryptophan have often been used as food supplements in the past as an adjunctive treatment for insomnia, depression, obesity, and attention-deficit-deficit children, and in 1989 it was discovered that the onset of an epidemic, the eosinophilic polycythemia vera-myalgia syndrome, had been linked to L-tryptophan-containing food supplements. The Centers for Disease Control identified more than 1,500 cases, including at least 38 deaths, and ultimately determined that the disease was related to L-tryptophan.Tests conducted by the FDA in conjunction with the Mayo Clinic*** showed that some of the L-tryptophan products on the market contained impurities, one of which, known as Peak X. Although the significance of the substance is not known at this time, a substance was found to have been present in 1991 in a case associated with L -tryptophan was found in a case related to L-tryptophan.
70 to 80 percent or more of the medicinal active ingredients used in production in the United States come from offshore manufacturers who do not have high production standards. In light of this, the European Union and the United States have recently published a draft document for guidance on the manufacture of medicinal active ingredients. The Guidance for Industry in the Manufacture, Handling or Holding of Pharmaceutical Active Ingredients was published in 1989, and the GMPs for pharmaceuticals (CFR Parts 210 and 211) apply equally to the production of pharmaceutical active ingredients.
The revision of GMPs for drugs and biologics has not been completed since the 1990s, but it truly represents FDA's current thinking. The Final Rule on Electronic Records (21CFR Part 11) requires certain controls to ensure the security and accuracy of all data and computer systems.
The International Conference on Harmonization (ICH) is an association organization where many documents on quality, safety, and effectiveness are discussed by peers from Europe, North America, and Japan. Many of these documents were ultimately adopted or developed by the organization and have become industry regulatory norms in all member countries.The E6 guidance on GCP adopted by the International Conference on Harmonization in 1996 is now the de facto standard for conducting clinical trials. A number of other guidance documents have recently been issued, including a draft guidance on the handling of abnormal trial results, which is likely to be adopted soon as the current industry regulatory norm.
In 1992, the U.S. Congress passed the Generic Drug Enforcement Act, which prohibits and penalizes illegal practices in some streamlined new drug applications. The act arose from a case of bribery and counterfeiting. The manager of a generic drug company bribed the FDA's new drug reviewers to submit to the FDA not test results for his own product, but for the trademarked drug. The person involved was eventually purged from the pharmaceutical industry and banned from ever working in the industry again.