Regulation of The Pharmaceutical/Biotechnology Industry And Good Manufacturing Practices 1
Historical introduction to regulation of medical products
Introduction:
The production of pharmaceutical and other medical products is stringently regulated by the federal government and these regulations (laws) also have a profound effect on many biotechnology companies. The regulations relating to pharmaceuticals and related products are called current Good Manufacturing Practices (cGMP). These regulations outline a quality system that is intended to ensure that medical products are safe, reliable, and effective. (Click here for a brief introduction to quality systems.)
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:
| Early drug products made outrageous claims and were often ineffective at best, and lethal at worst. For examples, see the FDA gallery, http://www.fda.gov/cder/about/history/gallery/gallery1.htm |
- 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 theFood 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 that 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.
- The thalidomide incident in the early 1960s led to the passage of the Kefauver-Harris Amendments, which required that drugs be proven to be safe and effective before release. (Click here for more information about the thalidomide incident).
- 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 Regulations1 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 shown in Figure 1. For example, the Food and Drug Administration is a regulatory agency responsible for ensuring the safety, effectiveness and reliability of medical products, foods and cosmetics as set forth in various federal legislative acts, most notably, the Food Drug and Cosmetic Act of 1938. A brief, but critical quote from that act is shown in Figure 2.
Figure 1
Regulation Of Pharmaceutical Product |
Congress enacted the Food, Drug and Cosmetics Act (FDCA) that states that food and drugs should not be “adulterated” and empowers the FDA to enforce food and drug laws.
One of the key clauses in the FDCA is “A drug is adulterated...if the methods used in...its manufacture...do not conform to...current good manufacturing practice...” |
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| The FDA devises regulations that outline in more detail the meaning of “good manufacturing practices” (GMP). These are published in The Code of Federal Regulations (CFR), a document published annually, which contains all federal regulations. |
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| The FDA periodically publishes Guidelines to more fully interpret technical details relevant to GMP practices. The Guidelines do not have the force of law, but a company should follow them or be prepared to justify any deviation. “Points to Consider” are FDA documents that discuss issues relating to innovative technologies. |
| Figure 1. AN EXAMPLE OF REGULATION. Congress passed an act and authorized a federal agency to interpret and enforce the Act. The agency devises regulations and enforcement strategies to bring about compliance with the intent of Congress. |
Figure 2 |
Federal Food, Drug, and Cosmetic Act Adulterated Drugs
501 [351] A drug or device shall be deemed adulterated-- (a) (1) if it consists in whole or in part of any filthy...substance; or (2) (A) if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth... or (B) if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated...in conformity with current good manufacturing practice to assure that such drug meets the requirements of the Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess... |
Figure 2. A BRIEF, BUT IMPORTANT, EXCERPT FROM THE FDCA OF 1938. This act forbids adulteration of food and drugs and authorizes the regulation of food and drug quality in the United States. This is where the FDA is empowered to develop and enforce “current good manufacturing practice”. |
The Life Cycle Of A Pharmaceutical Product
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 Practice1 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 trained and competent personnel, and conduct high quality, valid 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 that 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. Note also that even with this extensive testing regime, a drug may still be found to have adverse effects when it is used by millions of people.
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 FDA’s regulatory functions include:
- Establishing rules that ensure consumer protection
- Communicating the rules to industry and educating the public
- Monitoring industry compliance with the rules
- Performing scientific review and providing information and support to ensure that the rules are up-to-date
- Enforcing applicable laws and regulations
PRACTICE PROBLEMS
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These problems are based on information from the FDA publication “Human Drug cGMP Notes”. The notes consist of questions FDA staff are asked, and their responses. Here, the questions are posed as problems and the answers are FDA’s responses. See if you can figure out FDA’s responses. (http://www.fda.gov/CDER/cgmpnotes.htm)
- In Japan and in Canada there are “oxygen spa bars” where people are administered oxygen. Oxygen spa bar advertising claims that the oxygen is useful for treating: skin problems, hangovers, fatigue, migraine headaches, and other ailments. In the U.S., would such “spas” be regulated by FDA? (December 1996)
- Are scuba diving air tanks regulated as medical gases? (September 1996)
- There is a published guideline on stability testing of new drug substances. Can an FDA inspector cite a company for failing to adhere to this guideline? (June, 1996 )
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Answers To Problems:
- Since the spas claim that the oxygen treats medical ailments, the oxygen is regulated as a new drug and would be required to undergo testing and approval if brought to the U.S. and if medical claims are made. Furthermore, if approved, it would require a prescription.
- No. (Note, however, that scuba diving tanks and their accessories are regulated by the Consumer Product Safety Commission and empty tanks are regulated by the Department of Transportation.)
- While adherence to guidelines is recommended, it is not required. However, if a company says it is following the guideline and then fails to do so, it is appropriate to cite the company for failing to follow through on their own commitments.
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