Guidance for Industry

Nucleic Acid Testing (NAT) to Reduce the Possible Risk of Parvovirus B19 Transmission by Plasma-Derived Products

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DRAFT GUIDANCE

This guidance document is for comment purposes only.

Submit comments on this draft guidance by the date provided in the Federal Register notice announcing the availability of the draft guidance. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Submit electronic comments to either http://www.fda.gov/dockets/ecomments or http://www.regulations.gov. You should identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.

Additional copies of this draft guidance are available from the Office of Communication, Training and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at http://www.fda.gov/cber/guidelines.htm.

For questions on the content of this guidance, contact Mahmood Farshid, Ph.D., at 301-496-0952, or by Fax at 301-402-2780.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
July 2008

Contains Nonbinding Recommendations

Draft - Not for Implementation

Table of Contents

  1. INTRODUCTION

  2. BACKGROUND

  3. RECOMMENDATIONS

  4. REFERENCES

Guidance for Industry

Nucleic Acid Testing (NAT) to Reduce the Possible Risk of Parvovirus B19 Transmission by Plasma-Derived Products

This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the appropriate FDA staff. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.

  1. INTRODUCTION

    2. We, FDA, are issuing this guidance to provide you, manufacturers of plasma-derived products, with recommendations for performing parvovirus B19 nucleic acid testing (NAT) as an in-process test for Source Plasma and recovered plasma used in the further manufacturing of plasma-derived products. Such testing will identify and help to prevent the use of plasma units containing high levels of parvovirus B19. This guidance also recommends how to report to the FDA implementation of parvovirus B19 NAT.

    We recognize that in the current business practice for parvovirus B19 NAT in-process testing, several weeks can elapse between collection of the units of Source Plasma or recovered plasma and identification of B19 NAT-positive pools or units. We encourage manufacturers of plasma-derived products to employ practices that will reduce the time between product collection and in-process testing to allow for the meaningful notification of blood and plasma collection establishments of positive test results within the dating period of components.

    FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the FDA's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA's guidances means that something is suggested or recommended, but not required.

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  2. BACKGROUND

    3. Parvovirus B19 is a small, non-enveloped single strand DNA virus. This virus is highly resistant to all commonly used inactivation methods, including heat and solvent/detergent (S/D) treatment, and is also difficult to remove because of its small size. The parvovirus B19 can be transmitted by blood components and certain plasma derivatives, and may cause morbidity to susceptible recipients such as pregnant women (and their fetuses exposed in utero), persons with underlying hemolytic disorders, and immune compromised individuals (Refs. 1 and 2). The disease transmission by transfusion of blood components is rare; however, extremely high levels of parvovirus B19, up to 1012 IU/mL, in plasma of acutely infected but asymptomatic donors may present a greater risk in plasma derivatives due to pooling of large numbers of plasma units in the manufacture of these products. The virus can be detected by NAT in plasma pools when there are high levels of parvovirus B19 DNA in viremic donations. For example, the parvovirus B19 DNA can be detected in various plasma-derived products, particularly in coagulation factors (Refs. 3 and 4). There have been a few reports of parvovirus B19 infection associated with the administration of coagulation factors (Refs. 5 and 6) and S/D Treated Pooled Plasma (Refs. 1 and 7). Parvovirus B19 DNA is less frequently detected in albumin and immunoglobulin products and, when detected, the levels are usually low. There are no confirmed reports that albumin and immunoglobulin products have transmitted parvovirus B19 infection.

    We have held or participated in several meetings to discuss the potential risk of parvovirus B19 infection by plasma-derived products, and the strategy for reducing such risk. The meetings included FDA-sponsored NAT workshops in 1999 and 2001 (Refs. 8 and 9), Blood Products Advisory Committee (BPAC) meetings in 1999, and 2002 (Refs. 10, 11, and 12), the National Heart, Lung, and Blood Institute-sponsored Parvovirus B19 workshop in 1999 (Ref. 1), and an ad hoc Public Health Service (PHS) panel in 2002 (discussed at the 2002 BPAC meeting (Ref. 12)). In these meetings, it was recognized that the scientific data indicate that parvovirus B19 is highly resistant to the available viral inactivation methodologies, and is difficult to remove because of its small size. The viral inactivation/removal steps routinely used in the manufacturing process of plasma-derived products do not alone appear to be sufficient to completely clear the virus if high viral load is present in the starting material. Therefore, in these meetings, a common recommendation for mitigating the risk of parvovirus B19 transmission by plasma derivatives has been to limit the virus load in the manufacturing plasma pool by testing the plasma donations for high titer parvovirus B19 DNA, using a minipool format. This viral load reduction strategy combined with the ability of the manufacturing process to clear the residual virus could greatly reduce the risk of parvovirus B19 infection by plasma-derived products.

    The recommended limit in this guidance for viral load of parvovirus B19 DNA in the manufacturing plasma pool (i.e., not to exceed 104 IU/mL) was primarily derived from studies that were conducted on the transmission of parvovirus B19 associated with S/D Treated Pooled Plasma (Refs. 1, 7, and 10). In principle, testing in a minipool format to measure the viral load for parvovirus B19 DNA in a manufacturing plasma pool is acceptable in order to exclude only the high-titer plasma donations, thereby avoiding too great a loss of plasma for further manufacturing. Furthermore, during the viremic period for parvovirus B19 infected donors, which can be very lengthy, low levels of parvovirus B19 coexist with parvovirus B19 antibodies (potentially complexing with and neutralizing the virus). Therefore, it is undesirable to remove plasma units with low levels of B19 DNA, because it would diminish the parvovirus B19 antibody levels in plasma pools and in some of the resulting plasma-derived products (Refs. 13 and 14).

  3. RECOMMENDATIONS

    4. We recommend that you implement the following procedures to detect the presence of parvovirus B19 DNA:

    • For all plasma-derived products, you should perform parvovirus B19 NAT as an in-process quality control test to ensure that the viral load of parvovirus B19 DNA in the manufacturing pools does not exceed 104 IU/mL.
    • Use parvovirus B19 NAT on minipool samples to screen plasma units intended for further manufacturing into plasma-derived products. The sensitivity of the NAT assay, in any size minipool, should be at least 106 IU/mL for detection of any single donation when tested in the minipool (i.e., if the titer of an individual unit is 106 IU/mL or higher, the test result on the minipool will be positive). Primers and probes selected for parvovirus B19 NAT should detect all known genotypes of the virus (Ref. 15).
    • When identified, you should not use individual plasma units intended for further manufacturing into plasma-derived products, when such units are found to have a titer of parvovirus B19 DNA at or above 106 IU/mL, or when use of a positive unit might result in plasma manufacturing pools exceeding a parvovirus B19 DNA titer of 104 IU/mL.

    You should maintain validation data demonstrating the accuracy, sensitivity, specificity, reproducibility, and other performance characteristics of the parvovirus B19 NAT assay used for the detection of parvovirus B19 DNA in the Source Plasma and recovered plasma, and for demonstrating that the viral load of parvovirus B19 DNA in the manufacturing pool does not exceed 104 IU/mL.

    If the recommendations are implemented, you must notify FDA of the changes to an approved application under 21 CFR 601.12(c)(5) ("Supplement-Changes Being Effected"), and submit the information required in 21 CFR 601.12(b)(3)(i) through (vii).

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  4. REFERENCES

    1. Brown, K.E., Young N.S., Alving, B.M., Luiz, H., and Barbosa, L.H. Parvovirus B19 implications for transfusion medicine. Transfusion (2001) 41:130-135.

    2. 2Young, N.S., and Brown, K.E. Parvovirus B19. The New England Journal of Medicine (2004) 350:586-597.

    3. Saldanha, J., and Minor, P. Detection of human parvovirus B19 DNA in plasma pools and blood products derived from these pools: implications for efficiency and consistency of removal of B19 DNA during manufacture. British Journal of Haematology (1996) 93:714-719.

    4. Schmidt, I., Blumel, J., Seitz, H., Willkommen, H., and Lower, J. Parvovirus B19 DNA in plasma pools and plasma derivatives. Vox Sanguinis (2001) 81:228-235.

    5. Blumel, J., et al. Parvovirus B19 transmission by heat-treated clotting factor concentrates. Transfusion (2002) 42:1473-1481.

    6. Wu, C.G., et al. Parvovirus B19 transmission by a high-purity factor VIII concentrate. Transfusion (2005) 45:1003-1010.

    7. Koenigbauer, U.F., Eastlund, T., and Day, J.W. Clinical illness due to parvovirus B19 infection after infusion of solvent/detergent-treated pooled plasma. Transfusion (2000) 40:1203-1206.

    8. Transcript of Workshop on Implementation of Nucleic Acid Testing, December 14, 1999. http://www.fda.gov/cber/minutes/nucleic121499.pdf.

    9. Transcript of Application of Nucleic Acid Testing To Blood Borne Pathogens and Emerging Technologies Workshop, December 4, 2001. http://www.fda.gov/cber/minutes/nuclacd1204p1.pdf. http://www.fda.gov/cber/minutes/nuclacd1204p2.pdf.

    10. Transcript of FDA's Blood Products Advisory Committee (BPAC) Meeting, September 1999. http://www.fda.gov/cber/advisory/bp/bpmain.htm.

    11. Transcript of FDA's Blood Products Advisory Committee (BPAC) Meeting, December 2002. http://www.fda.gov/cber/advisory/bp/bpmain.htm.

    12. Transcript of FDA's Blood Products Advisory Committee (BPAC) Meeting, March 14, 2002. http://www.fda.gov/cber/advisory/bp/bpmain.htm.

    13. Lefrere, Jean-Jacques, et al. Persistent B19 infection in immunocompetent individuals: implications for transfusion safety. Blood (2005) 106(8):2890-2895.

    14. Cassinotti, P., Siegl, G. Quantitative evidence for persistence of human parvovirus B19 DNA in an immunocompetent individual. Eur J Clin Microbiol Infect Dis (2000) 19:886-895.

    15. Servant, A., et al. Genetic diversity within human erythroviruses: identification of three genotypes. J Virol (2002) 76:9124-34.

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Updated: July 30, 2008