Labeling In Vitro Diagnostic Products - 5 Best Practices to Ensure Compliance with FDA Regulations

    Ensure compliance with FDA's regulatory requirements for labeling in vitro diagnostic (IVD) products to avoid citations, Warning Letters and recalls.

    The FDA has been cracking down on non-compliance in vitro diagnostic products or IVDs recently. Manufacturers have not been adhering to the strict regulations governing the use of these products, and have been falling short when it comes to the compliant labeling of these devices. This article puts together five best practices that can help IVD manufacturers improve their compliance with labeling and avoid FDA citations, Warning Letters, product recalls and worse.

    Navigating through Maze

    What is An In Vitro Diagnostic Product?

    The FDA defines an in vitro diagnostic product or IVD as reagents, instruments, and systems intended for use in diagnosis of disease or other conditions. They can be used in determining the state of health of an individual so as to cure, mitigate, treat or prevent disease. IVDs are intended for use in the collection, preparation, and examination of specimens taken from the human body.

    Like medical devices, the FDA has classified IVDs into three distinct classes - Class I, Class II and Class III - and this classification determines the premarket process each device will have to undergo before approval. Class I devices are subject to the least regulatory control, and Class III devices subject to the most stringent regulatory control.

    • Class I (low to moderate risk): general controls
    • Class II (moderate to high risk): general controls and Special Controls
    • Class III (high risk): general controls and Premarket Approval (PMA)

    What are RUO and IUO In Vitro Diagnostic Devices?

    An RUO IVD refers to a Research Use Only device - this is an IVD product that is in the laboratory research phase of development and is being shipped or delivered for an investigation that is not subject to 21 CFR Part 812.

    The FDA has listed the following types of products as examples that it would consider to be in this research stage:

    • Tests that are in development to identify test kit methodology, necessary components, and analytes to be measured.
    • Instrumentation, software, or other electrical/mechanical components under development to determine correct settings,
    • subcomponents, subassemblies, basic operational characteristics, and possible use methods.
    • Reagents under development to determine production methods, purification levels, packaging needs, shelf life, storage conditions, etc.

    An IUO IVD refers to an Investigation Use Only device - one that is being shipped or delivered for product testing that is not subject to 21 CFR Part 812 prior to full commercial marketing. Products such as those being evaluated in comparison studies that use archived or fresh specimens to determine performance characteristics will be considered IUO devices.

    How Does the FDA Regulate IVDs?

    IVDs, like medical devices, are subject to premarket and post market controls by the FDA. They also have to comply with the Clinical Laboratory Improvement Amendments (CLIA '88) of 1988. The Center for Devices and Radiological Health (CDRH) and Center for Biologics Evaluation and Research (CBER) are responsible for the review of IVD products.

    IVDs have to comply with the FDA's quality control requirements for medical devices, current good manufacturing practices regulations and reporting requirements.

    Labeling rules

    The FDA has also listed specific labeling requirements for IVDs in 21 CFR Part 809 - before a manufacturer obtains clearance for the IVD product, it must comply with these labeling rules. A guidance document (published in November 2013) addressed the specific requirements for RUO and IUO labeling those manufacturers should follow in order to avoid non-compliance.

    5 Best Practices to Ensure Compliance with the FDA's IVD Labeling Requirements

    1. Label RUO and IUO IVDs Correctly
    2. This issue has gained increasing visibility due to the FDA's recent finalization of its guidance on the matter.

      As explained earlier in this article, the FDA has made clear the difference between RUO and IUO IVDs and the manufacturer has to label the product accordingly:

      • RUO IVDs alone should be labeled "For Research Use Only"
      • IUO IVDs alone should be labeled "For Investigational Use Only"

      In general, IVD products that are intended for clinical diagnosis or patient management must be labeled "For In vitro diagnostic use".

    3. Make Sure Immediate Container Label has All Necessary Information
    4. The following information must be included in the labeling on the immediate container of the IVD:

      • The established and proprietary names of the product, e.g., glucose meters;
      • A statement of warnings or precautions for users listed in 16 CFR part 1500 (hazardous substances) and any other warnings
      • appropriate to user hazards, and a statement "For In Vitro Diagnostic Use;"
      • Name and place of business of the manufacturer, packer, or distributor;
      • Lot or control number traceable to the production history
        • Multiple unit products must have traceability of the individual units;
        • Instrument lot numbers must allow for traceability of subassemblies; and
        • A multiple unit product that requires use of its components as a system should have the same lot number, or other
        • suitable uniform identification, on all units.

      The following information can also be included if there's enough space on the immediate container - else, it must appear on the outer container label only:

      - The intended use or uses, e.g., pregnancy detection, diabetes screening, etc.

      - In the case of reagents:

      • Established (common or usual) name;
      • Quantity, proportion, or concentration of all active ingredients; e.g., mg., weight per unit volume, mg./dl etc., and for reagents derived from biological materials the source and measure of its activity, e.g., bovine, I.U., etc.;
      • Storage instructions adequate to protect the stability of the product, i.e., temperature, humidity, etc.;
      • Instructions for manipulation of products requiring mixing or reconstitution, along with instructions for storage of products that have been reconstituted or mixed;
      • Means to assure that the product meets appropriate standards of purity, quality, etc., at the time of use, including one or more of the following:
        • expiration date (date beyond which the product is not to be used);
        • statement of any visual indication of alteration;
        • Instructions for a simple check to assure product usefulness;
      • The net quantity of contents.

    5. Include Required Information in Inserts and Outer Packaging
    6. Package inserts and outer packaging should have the following information except in cases where the information is not applicable.

      • The proprietary and established product name;
      • The intended use of the product and whether it is a qualitative or quantitative type of procedure, e.g., screening, physician's office, home use, etc.;
      • Summary and explanation of the test, including a short history containing methodology and the special merits and
      • limitations of the test;
      • The chemical, physical, physiological, or biological principles of the procedure.

      There is a difference in requirements for reagents and instruments:

      Reagents Instruments
      The common name, if any, and quantity, proportion, or concentration or each reactive ingredient; and for biological material, the source and measure it its activity; Use or function;
      Appropriate cautions or warnings listed in 16 CFR Part 1500; the statement: "For In Vitro Diagnostic Use;" and any other limiting statements appropriate to the intended use of the product; Installation procedures and requirements;
      Adequate directions for reconstitution, mixing, dilution, etc.; Principles of operation;
      Appropriate storage instructions; Performance characteristics and specifications;
      A statement of purification or treatment required for use; and Operating instructions;
      Physical, biological, or chemical indications of instability or deterioration. Calibration procedures, including equipment and/or materials;
      Operational precautions and limitations; Hazards; and
      Service and maintenance information

      The following information should also be included:

      • Specimen collection and preparation for analysis, describing;
        • Special precautions/preparations;
        • Additives necessary to maintain specimen integrity;
        • Known interfering substances; and
        • Recommended specimen storage, handling, and shipping instructions.
      • A step-by-step outline of recommended procedures from the reception of the specimen to the obtaining of results. In addition to the following, this should include a list of any points that might improve precision or accuracy:
        • A list of materials provided and instruction for use, e.g., reagents, equipment, etc.;
        • A list of necessary materials that are not provided (include details such as sizes, numbers, types, and quality);
        • A description of the amounts of reagents necessary, and parameters such as time, temperature etc.;
        • A statement related to final reaction stability and any time restrictions on accurate measurements;
        • Details of calibration, identifying and listing and necessary preparation of the reference materials, samples, and blanks.
        • Describe the calibration range including the highest and lowest values measured; and
        • Details of necessary quality control procedures and materials, e.g., positive and negative controls, acceptable performance limits
      • Explanation of the procedure for calculating the unknown, including the definition of each component of the formula, a sample calculation, and the number of significant figures appropriate for the answer;
      • Limitations of the procedure, e.g., identify situations which will have an adverse impact on test results. If further testing either more specific or more sensitive, is indicated in all cases where certain results are obtained, the need for the additional test shall be stated;
      • Expected values including how the range(s) was established and identify the populations on which it was established;
      • Specific performance characteristics as appropriate including accuracy, specificity, precision, and sensitivity;
      • Bibliography;
      • Name and place of business of the manufacturer, packer, or distributor; and
      • Date of issuance of the last labeling revision by the firm.

    7. Ensure Home-Use IVD Labels have Adequate Directions for Use
    8. The labeling of home-use IVDs should meet the agency's "adequate directions for use requirements".

      According to the FDA, the labeling of home-use IVDs must be simple, concise, easy to understand, make liberal use of illustrations and drawings, use bold print or other methods to highlight warnings and precautions, and provide color coding of reagent containers whenever practicable. The FDA also says:

      • The intended use statement should clearly indicate on the outside packaging container the type of procedure that is offered, i.e., screening, monitoring, or diagnostic, and the specific disorder, condition, or risk factor of interest for which the test is intended.
      • In addition, a statement also should be presented indicating who should use the test and the conditions for its use, followed by a contraindication statement(s), if necessary.
      • The quantity, proportion, concentration, or activity of each reactive ingredient included with the test kit need only be presented when information is necessary for proper lay use of the test.

      The package insert or any other labeling accompanying home-use IVDs should include the following information:

      • The intended use statement
      • Summary and explanation of the test may be combined with principles of the procedure. This combined section should include a discussion of both the medical benefits and limitations of the test with respect to its intended use in addition to providing a simple explanation of how the test works.
      • A separate information section, interpretation of test results, should be presented and should include limitations of the procedure. Thus, this section should indicate the significance of the test results in light of the test's intended use and provide specific information as to what appropriate follow-up action should be taken by the user. Additionally, this section should explain the meaning of false-positive and false-negative test results and cite possible sources and implications of false results.
      • A separate information section should be presented which discusses/lists any foods, medications, or other possible interfering substances that would affect test results. Such information should specify what substances should be avoided and for how long prior to testing.
      • Test procedure: All information should be presented in the combined section if applicable, in addition to the following:
        • As previously stated, the quantity, proportion, concentration, or activity of each reactive ingredient included in the test kit need not be presented unless this information is necessary for proper use of the test. However, such information should be presented elsewhere in a premarket submission for CDRH review.
        • Discussion of specimen collection, preparation, and analysis steps should be enhanced by the use of pictures and illustrations, preferably in color.
      • Information about test results should be presented. This section also should include troubleshooting information.
      • Test performance characteristics. This section should summarize the data (separately) from both the laboratory evaluation and the consumer field evaluation and should include a concise discussion and/or presentation of data relative to the test's accuracy should be presented and should include false-positive and false-negative levels. Such information should be presented for both the laboratory and the consumer field evaluations.
      • Manufacturers should provide a toll-free telephone number or an address to write to should questions occur concerning the use of the device.
      • Any significant labeling changes should be shown by including special inserts with device packaging which highlight key labeling changes.

    9. Label General Purpose Reagents and Equipment Appropriately
    10. Items such as routine laboratory reagents like hydrochloric acid and equipment like glassware whose uses are generally known by persons trained in their use would fall under the general-purpose category. The labels for these do not need the directions for use described earlier in this article if their labeling meets the following requirements:


      • A declaration of the established name, if any, and quantity, proportion, or concentration of the reagent ingredient stated in a system generally recognized by the user;
      • A statement of the purity and quality including a qualitative statement of any impurities. This can be satisfied by using a statement of conformity with a generally recognized and available standard;
      • A statement of warnings or precautions for users, and the statement: "For Laboratory Use;"
      • Net quantity of contents in terms of weight or volume, or numerical count, or any combination thereof;
      • Appropriate storage instructions;
      • Name and place of business of the manufacturer, packer, or distributor;
      • A lot or control number traceable to the manufacturing history of the product; and.
      • A statement indicating the presence of and characterizing any catalytic or nonreactive ingredients e.g., buffers, preservatives, stabilizers.


      • Product labeling need include only a statement adequately describing the product, its composition, and physical characteristics if necessary for its proper use.

    Comply with FDA Labeling Requirements to Avoid Enforcement

    The FDA's increasing scrutiny of IVD devices is leaving manufacturers with no room for error as recent cases have shown. The best practices explained above can help manufacturers ensure that their products stay in compliance with the FDA's strict labeling requirements. The guidance document the FDA published relating to the correct labeling of RUO and IUO IVD products has brought some clarity to what the agency has always identified as a problem area. Manufacturers have to ensure that their IVD labeling specifics are in order before seeking marketing approval for their product and adhere to the rules that govern these devices in order to avoid harmful enforcement actions.

    How can compliance training help?

    The areas highlighted above are just a small part of the wide range of practices and processes that ensure IVD and medical device manufacturers comply with regulations. Subjects such as device compliance are multi-faceted and complex and can be better understood after attending a training course such as the ones offered by ComplianceOnline. Our courses are available as live webinars, training recordings and seminars. We also offer customized training courses developed in conjunction with organizations that wish to train large groups of their employees.

    If you need customized training courses or specialist GRC consulting services, please contact us through email [email protected] or call us at this toll-free number: +1-888-717-2436.