|Regulations & Standards|
|Linda Staswick is a regulatory affairs representative for
CBER- and CDRH-regulated HIV and hepatitis products, and Christopher Bentsen is the manager of regulatory affairs, quality assurance, and clinical affairs at Bio-Rad Laboratories (Redmond, WA). They can be reached HERE and HERE, respectively.
IVD manufacturers are required to comply with many of the regulations in Title 21 of the Code of Federal Regulations (CFR). One of these regulations is 21 CFR 610.40–42. Although at first glance this regulation appears to apply specifically to biological products, it is also applicable to IVDs that incorporate human blood or blood components, such as positive and negative kit controls and calibrators. By requiring that blood and blood components used in IVDs be tested for infectious disease agents, this regulation helps to ensure the safety of those who use these types of IVDs.
History of the Final Rule
All of the general biological product standards are covered by 21 CFR 610. Although this statute primarily relates to licensed products (e.g. vaccines, antitoxins, blood, and blood products), certain sections of Part 610 also apply to manufacturers of some Class I, II, and III IVDs. For example, 21 CFR 610.40–42 applies to all IVDs that contain blood or blood products and have been either licensed, approved via a premarket approval (PMA), or received a premarket notification (510(k)) clearance from FDA. In addition, human plasma and serum that are manufactured as quality control products or calibrators for IVD kits are subject to this regulation.
Within 21 CFR 610, Part 610.40 establishes the specific requirements for testing human blood and blood components that are used in medical devices for communicable disease agents. These agents include human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), human T-lymphotrophic virus (HTLV), and syphilis. Through the inspection process, FDA found that blood establishments were generally following the various guidance documents regarding the testing of blood and blood components. However, the agency noticed variations in testing and in determining suitability based on test results.
To address these concerns, FDA revised the human blood testing standards and published a final rule on June 11, 2001, in the Federal Register, which became effective on December 10, 2001.1 The purpose of this final rule was to protect the safety and ensure the quality of the nation’s blood supply, enhance the safety of medical devices containing blood and blood components, provide FDA with clear enforcement authority, and promote consistency in the industry.
Section 610.40(a) of the final rule requires screening tests for HIV (types 1 and 2), HBV, HCV, and HTLV (types I and II) for each donation of human blood and blood components that is intended to be used in preparing various products and medical devices. This section also clarifies that HTLV-I and -II testing is only required if the final device contains viable leukocytes. Section 610.40(b) further specifies that testing regimens should utilize one or more approved screening tests and that FDA must approve the screening tests for such use, in accordance with the manufacturer’s instructions. Those blood donations that test positive during screening must undergo further supplemental testing with more-specific tests.
In addition, under 21 CFR 610.40, blood establishments must not ship or use blood that has a reactive serological test for syphilis (STS), unless that blood will be used to manufacture a control serum for an STS. 21 CFR 640.5 requires an STS for each unit of blood collected from donors.
At the time the final rule was released, FDA believed certain tests would adequately and appropriately reduce the risk of transmitting communicable disease agents (see Table I). Current information on which HIV, HTLV, and hepatitis tests are currently licensed and approved by FDA for this testing may be accessed on the FDA Web site (www.fda.gov/cber/products/testkits.htm).
Approved supplemental tests for STS, anti-HIV, HIV-1 Ag, HBsAg, and anti-HCV are available. For example, a neutralization assay is performed as part of the screening-test procedure for repeatedly reactive samples tested for HIV-1 antigen and HBsAg. However, at this time, there are no approved supplemental or confirmatory tests for HTLV-I and -II.
Several established testing methodologies are used for supplemental testing of blood specimens that test positive in screening tests for infectious disease agents. These methodologies include recombinant immunoblot assay (RIBA), Western blot, and immunofluorescent assay (IFA). FDA currently licenses a RIBA test for confirming repeatedly reactive HCV EIA results. Both Western blot and IFA tests are also licensed for supplemental testing of repeatedly reactive HIV-1 antibody results. In addition, FDA licenses nucleic acid amplification technology for donor screening and patient monitoring for HIV-1.
Test Lab Registration
|Table I. Screening tests for blood and blood components that FDA believed would adequately and appropriately reduce the risk of transmitting communicable disease agents.|
Only those laboratories registered with FDA’s Center for Biologics Evaluation and Research (CBER) in accordance with 21 CFR 607 are allowed to perform testing of donor blood and blood components for infectious disease agents. Registration of labs that are involved in any activity to prepare, propagate, compound, or process blood products must be completed annually. The labs must also be certified to perform testing under the Clinical Laboratory Improvement Amendments (CLIA) or have met equivalent requirements as determined by the Centers for Medicare and Medicaid Services.
In the final rule, Part 640.42(a) was changed to require labeling for all medical devices that contain blood or blood components, and not just IVDs. When blood or blood components are reactive to infectious disease agents after performing a screening test, the device’s labeling must have a warning indicating the status of the blood. This warning should indicate that the blood came from a donation found by a screening test to be reactive to certain identified communicable disease agents and should include the biohazard symbol.
The labeling on IVDs that contain any blood or blood components must also disclose the status of the blood material regarding communicable disease agents. Moreover, this requirement applies to materials that test either positive or negative for these agents. Some examples of statements from the warnings and precautions sections of various IVD package inserts regarding human-origin material include “source material was found negative when tested in accordance with current FDA recommendations” and “material used in the preparation of this product has been tested by FDA-licensed methods and found nonreactive for HIV-1/HIV-2 Ab, HTLV-I/II, HBs Ag, and HCV Ab.”
At the same time, FDA has stated that it is also allowing for exemptions to the statement of warning in those circumstances in which the reactivity of the human blood or blood components in the device presents no significant health risk when the device is used. However, FDA has not set up any official guidance on how to obtain this exemption. For information about obtaining this exemption, IVD manufacturers with products regulated by the Center for Devices and Radiological Health (CDRH) should contact the Office of In Vitro Diagnostic Device Evaluation and Safety, or the Division of Small Manufacturers, International, and Consumer Assistance. Manufacturers with products regulated by CBER should contact the Division of Emerging and Transfusion Transmitted Diseases at the Office of Blood Research and Review.
Non-U.S. manufacturers that sell IVDs in the United States have several options for meeting the requirements of 21 CFR 610.40. Plasma or blood products can be purchased from U.S. sources in which the screening tests have already been performed. Samples from each unit of blood or plasma can also be tested in the country of manufacture using tests that are licensed by FDA. The testing laboratory in the foreign country has to meet CLIA requirements and be registered with FDA. Alternatively, overseas manufacturers may seek to obtain an exemption from FDA to use blood or plasma from foreign sources. However, this method has not been proposed in any FDA guidance or regulation.
Since the final rule was published, FDA has issued guidance documents that present the agency’s latest thinking on the appropriate testing of human blood donors for various communicable disease agents. While FDA has not specified the test or tests that should be used to comply with the regulation, the agency has listed the test or tests it believes adequately reduce the risk of transmitting communicable disease agents.
As technology advances, FDA plans to continue to issue regularly updated guidance documents describing those tests that could adequately reduce the risk of communicable diseases. For example, a draft guidance document issued in March 2002 recommended that blood establishments incorporate a licensed nucleic acid test (NAT) for HIV-1 and HCV within six months after a final guidance is released.2
Another example is the NAT for West Nile virus (WNV). Test-kit manufacturers and blood and plasma establishments initiated this testing under investigational new drug applications. In October 2002, FDA called for the development of WNV blood donor screening and supplemental tests, and held a public workshop meeting in November 2002. The agency cleared the first test for detecting IgM antibodies to WNV in patients with clinical symptoms of the disease in July 2003. However, no donor-screening test has yet been licensed. A CBER guidance document issued in May 2003 recommended donor deferral for individuals with symptoms consistent with the disease.3
FDA has also been evaluating the effect of bovine spongiform encephalopathy (BSE) and severe acute respiratory syndrome (SARS) on blood safety. The agency issued guidance documents in January 2002 and September 2003, respectively, recommending donor deferral after risk of exposure to BSE or SARS, but no additional testing at this time.4,5
The regulations in 21 CFR 610 were enacted to ensure the safety of not only the blood supply but also those who use medical devices containing blood or blood components. IVD manufacturers should familiarize themselves with these regulations to make sure that the appropriate testing of blood and blood components is performed for the required infectious disease agents. When testing is not performed using assays that have been approved by FDA, IVD manufacturers must work with the agency to ensure that they comply with FDA requirements.
1. Federal Register, 66 FR 112, June 11, 2001.
2. Draft Guidance for Industry Use of Nucleic Acid Tests on Pooled and Individual Samples from Donors of Whole Blood and Blood Components for Transfusion to Adequately and Appropriately Reduce the Risk of Transmission of HIV-1 and HCV (Rockville, MD: U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research, 2002).
3. Final Guidance for Industry Revised Recommendations for the Assessment of Donor Suitability and Blood and Blood Product Safety in Cases of Known or Suspected West Nile Virus Infection (Rockville, MD: U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research, 2003).
4. Final Guidance for Industry: Revised Recommendations for the Assessment of Donor Suitability and Blood Product Safety in Cases of Suspected Severe Acute Respiratory Syndrome (SARS) or Exposure to SARS (Rockville, MD: U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research, 2003).
5. Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products (Rockville, MD: U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research, 2002).
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