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4.3: The Code of Federal Regulations (CFR)

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    39493
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    The CFR is a massive set of regulations, published annually, where all the federal agencies post their rules. It provides information (based on quality techniques) on quality systems in the laboratory (QSR), manufacturing practices, laboratory practices, and clinical practices. Due to the sheer volume of information available through the CFR, it is useful to know how it is organized.

    CFR Organization

    1. Titles represent broad areas subject to Federal regulations.
    2. Titles are divided into chapters that are assigned to various federal agencies.
    3. Chapters are divided into parts covering specific regulatory areas.
    4. Each part or subpart is then divided into sections – the basic unit of the CFR.
    5. Sometimes sections must be subdivided further into paragraphs or subsections.
    Part Regulatory Purview
    100 series Food – 110 CGMPs; Dietary supplements – 111 CGMPs
    200 & 300 series Pharmaceuticals – 210 & 211 CGMPs
    500 series Animal feeds & medications
    600 series Biological products – 606 CGMPs
    700 series Cosmetics (limited regulations)
    800 series Medical Devices
    900 series Mammography quality requirements
    1000 series Radiation emitting device
    1200 series Non-FD&C Act Rulings
    other GLP-58; GCP-50,54,56; Electronic records-11

    CFR Title 21 Chapter 1: Food and Drugs

    Title 21 Chapter 1 of the CFR contains all regulations concerning the safe production of food, drug, medical device, diagnostic, and biologic products for human and animal use under FDA supervision. The 21 CFR regulations can be accessed at the following: http://www.ecfr.gov

    Test Your Knowledge!

    Go into the eCFR database, in the pull-down menu, choose Title 21, and press ‘go.' Click on parts 200.

    1. What is the part of labeling?
    2. What is the subpart for labeling requirements for over the counter
      drugs?
    3. What are the content requirements for OTC drug product labeling?

    Significant 21 CFR Regulations in the Biotechnology Sector

    • 21 CFR 11: Electronic Records; Electronic Signatures
    • 21 CFR 201: Labeling
    • 21 CFR 314: Applications for FDA Approval to Market a New Drug
    • 21 CFR 610: General Biological Product Standards
    • 21 CFR 803: Medical Device Reporting
    • 21 CFR 1271: Human Cells, Tissues, & Cellular and Tissue-based Products

    Current Good Manufacturing Practices (CGMPs)

    GMP regulations are included in Title 21 Chapter 1 of the CFR, in three regulations dealing with different types of manufactured products:

    • for drugs (21 CFR 211)
    • for medical devices (21 CFR 820)
    • for blood and blood components (21 CFR 606)

    The general principles of CGMP that all these regulations have in common:

    1. Quality, safety, and effectiveness are designed and built into the product, not tested or inspected into the product.
    2. Each step in the manufacturing process is documented and controlled to ensure that the finished product meets design and compendia specifications.
    3. Process documentation provides evidence of compliance with CGMPs.

    Three primary criteria used by the FDA in the design of these CGMP regulations:

    1. Regulations should contain objectives and not detailed specifications. They should allow latitude for different manufacturers to find a means of compliance.
    2. Regulations should contain requirements that are considered feasible and valuable as recognized and considered by experts as assuring quality.
    3. If a practice can be established to be achievable and useful, then it can be required even though it does not exist in the regulations.

    Setting standards for quality in the biotechnology industry is difficult due to the often new and complex manufacturing processes involved. How should the FDA set quality standards, for example, for chromatographic purification systems? These processes are difficult to validate and represent ‘gray’ areas where quality regulations are concerned. For this reason, companies frequently rely on regulations that the FDA has not yet finalized, and they comply voluntarily with CGMPs and Guidelines.

    21 CFR 58: Good Laboratory Practices (GLPs)

    Animal studies of pharmaceutical products are regulated by Good Laboratory Practices (GLP) as covered in 21 CFR 58. These regulations came about in 1975 because of an FDA inspection of several testing laboratories where conditions were, frankly, appalling and animals treated inhumanely. Any laboratory wanting to run animal tests today must maintain clean, adequate facilities, provide proper care for the animals, and conduct valid tests. All non-clinical safety studies of new drugs and new drug applications, drug biologics, veterinary drugs, and some food additives fall under the purview of GLP regulations.

    Good Clinical Practices (GCPs)

    Good Clinical Practices (GCPs) are a similar set of standards that apply to human subjects of clinical trials and experiments. More to come in later chapters!

    Regulatory History of GCPs

    • By the 1980s, it became apparent that representative populations needed to be included in clinical trials - factors that may influence the effectiveness and side effects of drugs include age (children, older patients), sex, and even ethnicity!
    • In 1989, the FDA issued guidelines asking manufacturers to determine whether a drug is likely to have significant use in older people
    • In 1993, the FDA issued the Gender Guideline, which called for assessments of medication responses in both sexes.
    • In 1998, the FDA required that a marketing application analyze data on safety and effectiveness by age, gender, and race, called the Demographic Rule.
    • In 2002, the Best Pharmaceuticals for Children Act was passed to improve the safety and effectiveness of medicines for children.
    • In 2003, the FDA was given clear authority under the Pediatric Research Equity Act to require drug sponsors to conduct clinical research into pediatric applications for new drugs.

    Clinical Studies

    Although there is no regulation specifically entitled “Good Clinical Practice,” there are several regulations, which govern the conduct of clinical trials.

    • Volunteers participating in a clinical study must be able to give informed consent. Informed consent means educating each potential subject on the treatment they are to receive as a part of the study as well as any risks that may be associated with their participation. FDA regulations entitled "Protections of Human Subjects" (21 CFR 50) set forth the requirements for informed consent.
    • Clinical trials must be reviewed by a committee independent of the study sponsor called an Institutional Review Board (IRB) (21 CFR 50). The regulations specify the organization and personnel who make up this board, as well as the records and reports that are to be kept.
    • 21 CFR 312 Subpart D outlines the responsibilities of trial sponsors and investigators during a trial. Additionally, the FDA “Guideline for the Monitoring of Clinical Investigations” explains monitoring and documentation.

    This page titled 4.3: The Code of Federal Regulations (CFR) is shared under a CC BY license and was authored, remixed, and/or curated by Jack O'Grady.

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