Creative Ideas for Teaching GMP
By Madison Area Technical College Biotechnology Department
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REGULATION OF THE PHARMACEUTICAL / BIOTECHNOLOGY INDUSTRY AND GOOD MANUFACTURING PRACTICES1
Author: Lisa A. Seidman, Ph.D.
Madison Area Technical College
Madison, WI 53704
July 18, 2000
This introductory text briefly discusses how the pharmaceutical industry is regulated and the relationship between that industry and the Food and Drug Administration. The legislation that authorized thecurrent Good Manufacturing Practices that guide the production of pharmaceuticals is introduced.
The production of pharmaceutical and other medical products is stringently regulated by the federal government and these regulations also have a profound effect many biotechnology companies. The regulated characteristics of such products relate to safety, honesty (as in labeling), effectiveness and reliability.
While we take for granted that the government regulates the production of drugs, this was not always the case, as is illustrated dramatically in the history of drug and food regulation in the U.S. Much of this history involves tragedies and abuses that led to increasingly stringent regulation of drug and food production. A few important incidents and enactments are:
* Upton Sinclair recorded filthy conditions and unacceptable practices in the food industry in his novel The Jungle. As a result, the original Food Drug and Cosmetic Act (FDCA) was passed in 1906 to prevent the commerce of unacceptable food and drugs. The 1906 FDCA authorized regulations to ensure that pharmaceutical manufacturers did not adulterate or mislabel their products but did not deal with the safety or effectiveness of drugs.
* In 1927 a separate law enforcement agency was formed, first known as the Food, Drug and Insecticide Administration, and then, in 1930, as the Food and Drug Administration (FDA) to enforce legislation relating to food and drugs.
* In 1937, a batch of sulfanilamide was dissolved in the industrial solvent, diethylene glycol. There were 358 poisonings and 107 deaths, mostly children. As a result of this incident, the revised Food, Drug and Cosmetic Act was passed in 1938 which required drugs to be tested for safety before release.
* In 1955 some children vaccinated with polio vaccine contracted paralytic polio. Fifty one people were paralyzed and ten died. The problem was traced to one manufacturer who apparently did not properly inactivate the virus used to make the vaccine. This incident and others like it led to increased factory inspections and testing of the safety of products before their release to the public.
* One of the great successes of the FDA occurred in the early 1960s. At that time the drug thalidomide was commonly prescribed for insomnia and nausea in pregnant women in Europe. Unfortunately, this drug led to the birth of thousands of children without arms or legs. Thalidomide was not used commercially in the U.S. because Dr. Frances Kelsy of the FDA refused to accept it in the U.S. until it was proven safe. News of the thalidomide tragedy influenced the U.S. congress in 1962 to pass the Kefauver-Harris Amendments which required that drugs be proven to be both safe and effective before release.
* In 1963 the first set of Good Manufacturing Practices, GMP, regulations were published. These regulations guide companies in the production of safe and effective drugs.
* A number of injuries and deaths in the 1960s and 1970s caused by contaminated products led to the revised GMPs in the late 1970s. These regulations included requirements for standard operating procedures, validated systems, and extensive documentation.
* Inspections of pharmaceutical animal testing laboratories revealed that toxicology studies supporting new drug applications were poorly conceived and improperly conducted. These inadequacies led to the promulgation of the Good Laboratory Practices Regulations in 1976, whose goal is to assure the quality of data submitted to FDA in support of the safety of new products.
* In 1982 insulin produced by recombinant DNA methods became the first such "modern biotechnology" product to be approved for market and sale.
This brief historical summary illustrates that the regulation of food and medical products is generally driven by a tragedy, a problem, or an advance in science and technology. The public and their elected officials respond by enacting a law(s) that is intended to reduce risks while maximizing benefits. A governmental regulatory agency is empowered to interpret and enforce the law through a system of regulations (see Figure 1).
Pharmaceuticals have a long life cycle involving extensive development, testing, an approval process, marketing and post-marketing surveillance. Only about 1 in 10 potential drugs performs successfully during testing and is actually marketed.
The idea for a product is researched in the laboratory during the early stages of research and development (R&D). Until recently, FDA was not involved in the early R&D phases of a product. However, FDA is beginning to inquire about the results, documentation, and experiments that were performed during R&D because the ultimate quality of a product depends on the foundation built during development.
If a potential product shows promise in the laboratory, toxicity tests are performed in animals to determine whether the substance is safe for human testing. Before the mid-1970s, the conduct of animal testing was not scrutinized by the FDA. However, in 1975, FDA inspections of several pharmaceutical testing laboratories revealed poorly conceived and carelessly executed experiments, inaccurate record-keeping, poorly maintained animal facilities, and a variety of other problems. These deficiencies led the FDA to institute the Good Laboratory Practice2 regulations (GLPs) to govern animal studies of pharmaceutical products. GLPs require that testing laboratories follow written protocols and standard operating procedures (SOPs), have adequate facilities and equipment, provide proper animal care, properly record data, have well-trained and competent personnel, and conduct high quality, valid toxicity tests.
If a potential new product appears safe in animal studies, then scientists prepare a plan to investigate the product in human volunteers. The company submits their plan to the FDA, including a description of the product, the results of animal tests, and the plans for further testing. The FDA then decides whether or not the company's materials are sufficiently complete that the company can begin testing the product in humans.
Good Clinical Practices (GCPs) relate to the performance of clinical trials of drug safety and efficacy in human subjects. GCPs aim to protect the rights and safety of human subjects and to ensure the scientific quality of the studies. Clinical trials are conducted in stages, each of which must be successful before continuing to the next phase.
Phase I clinical trials are the first introduction of the proposed drug into humans. During Phase I trials, the safety of the drug is carefully evaluated and its metabolic and pharmacologic properties in healthy humans are determined. If a drug meets the safety requirements at this phase and appears to have the desired properties, then it enters Phase II clinical trials. Phase II trials are performed on a small number of diseased patients to determine the drug's efficacy. If the drug continues to meet safety requirements and demonstrates efficacy at Phase II, it progresses to a broader Phase III trial involving hundreds or thousands of patients. At this point, the safety and efficacy of the drug continue to be evaluated, dosages are determined, a risk versus benefit analysis is performed, drug interactions are explored, and other data are collected.
If a drug passes all three phases of testing, the company may submit to the FDA an application which provides convincing evidence that the new drug or biologic is safe, reliable and effective. Note that FDA itself does not actually test each drug product. Rather, FDA expert reviewers examine test results and information submitted by the company to determine whether a product is acceptable. If the review team decides the evidence is sufficient, the new product is approved by FDA and can be manufactured for commercial sale.
As a therapeutic agent progresses through these various phases, the requirements for its manufacture become more and more stringent. Once in commercial production, the manufacture, labeling, packaging, shipping, storing, quality control, and marketing of the product must meet all GMP and other relevant requirements.
An important part of the enforcement of GMP is unannounced inspections of pharmaceutical facilities by FDA inspectors. Inspectors note practices that violate GMP requirements on a form called a "483". Generally, companies are able to correct deficiencies noted by inspectors. Occasionally the FDA seizes and destroys products that it believes were not properly manufactured, or levies fines against a company. In more extreme cases, where individuals or companies act deceitfully or refuse to comply with regulations, individuals may be charged as criminals and may be imprisoned if convicted.
FDA thus plays many roles in the development of a pharmaceutical product. These regulatory functions include:
Footnotes:Basic Laboratory Methods for Biotechnology: Textbook and Laboratory Reference by Lisa A. Seidman and Cynthia J. Moore, Prentice Hall (January 19, 2000). Paperback, 800 pages, spiral edition, ISBN: 0137955359.
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