Requalification Method for Reentry of Donors Who Test Hepatitis B Surface Antigen (HBsAg) Positive Following a Recent Vaccination against Hepatitis B Virus Infection: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry
Requalification Method for Reentry of
Donors Who Test Hepatitis B Surface
Antigen (HBsAg) Positive Following a
Recent Vaccination against Hepatitis B
Virus Infection
This guidance is for immediate implementation
FDA is issuing this guidance for immediate implementation in accordance with 21 CFR
10.115(g)(4)(i). Submit one set of either electronic or written comments on this guidance at
anytime. Submit electronic comments to http://www.regulations.gov. Submit written comments
to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. You should identify all comments with the
Docket No. FDA-2011-D-0829 for this guidance.
Additional copies of this guidance are available from the Office of Communication, Outreach
and Development (OCOD), (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-
1448, or by calling 1-800-835-4709 or 301-827-1800, or e-mail ocod@fda.hhs.gov, or from the
Internet at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm.
For questions on the content of this guidance, contact OCOD at the phone numbers or e-mail
address listed above.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
November 2011

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION....................................................................................................................... 2
II. 	BACKGROUND ......................................................................................................................... 2
III. 	RECOMMENDATIONS ........................................................................................................... 5
IV. 	IMPLEMENTATION................................................................................................................ 7
V. 	REFERENCES............................................................................................................................ 8
i

Contains Nonbinding Recommendations
Guidance for Industry
Requalification Method for Reentry of Donors Who Test Hepatitis B
Surface Antigen (HBsAg) Positive Following a Recent Vaccination
against Hepatitis B Virus Infection
This guidance represents 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 alternate approach if the approach satisfies the requirements
of the applicable statutes or regulations. If you want to discuss an alternate 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.
I. 	INTRODUCTION
This guidance document is intended for blood establishments that manufacture Whole Blood and
blood components for transfusion or for further manufacture, including Source Plasma and
Source Leucocytes. This guidance provides recommendations for a requalification method or
process for the reentry of deferred donors who test repeatedly reactive for hepatitis B surface
antigen (HBsAg), confirmed positive by neutralization, following a recent vaccination against
hepatitis B virus (HBV) infection, and who are not infected by HBV.
FDA issued a memorandum to all registered blood establishments on December 2, 1987, entitled,
“Recommendations for the Management of Donor and Donations that are Initially Reactive for
Hepatitis B Surface Antigen (HBsAg)” (FDA 1987 Memorandum) (Ref. 1). This guidance
supplements the FDA 1987 Memorandum.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidance documents describe 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 guidance documents means that something is
suggested or recommended, but not required.
II. 	BACKGROUND
Under Title 21 Code of Federal Regulations 610.40(a) (21 CFR 610.40(a)), you, blood
establishments that collect blood and blood components, must test each donation of human blood
or blood component intended for use in preparing a product for evidence of infection due to
certain communicable disease agents, including HBV. Under § 610.40(h)(1), you must not ship
or use human blood or blood components that have a reactive screening test for evidence of
infection due to communicable disease agents, including HBV infection, except under certain
circumstances. Similarly, donors that test reactive for HBV must be deferred, with certain
2

Contains Nonbinding Recommendations
exceptions (§ 610.41(a)). Note that under § 610.41(b), a deferred donor subsequently may be
found to be suitable as a donor of blood or blood components by a requalification method or
process found acceptable for such purposes by FDA. Such a donor is considered no longer
deferred.
The recommendations in the FDA 1987 Memorandum established procedures for reevaluating
donors who were repeatedly reactive for HBsAg. This guidance supplements the FDA 1987
Memorandum by providing recommendations for a requalification method for reentry of
deferred donors who test repeatedly reactive for HBsAg, confirmed by neutralization, following
a recent vaccination against HBV, and who are not infected with HBV.
A. 	Prevalence, Transmission, and Testing for HBV Infection
1. 	Prevalence of HBV Infection
HBV infection is a severe global health problem due to its high
prevalence. The world-wide number of infected individuals is estimated
to be over 2 billion, and more than 400 million are in the chronic phase of
infection (Ref. 2). In the United States (U.S.), approximately 200,000 to
300,000 acute HBV infections occur each year, more than 1 million
individuals have chronic HBV infection and approximately 5,000
individuals die each year from HBV induced hepatocellular carcinoma and
chronic liver disease (Refs. 3 and 4). Antigens and antibodies associated
with HBV infection include HBsAg and antibody to HBsAg (anti-HBs),
hepatitis B core antigen (HBcAg) and antibody to HBcAg (anti-HBc), and
hepatitis B e antigen (HBeAg) and antibody to HBeAg (anti-HBe).
Currently, all donations of Whole Blood and blood components and
Source Plasma are tested for HBsAg. The average time from exposure to
detection of HBsAg is 30 days (range: 6 to 60 days) (Refs. 5 and 6).
2. 	Transmission of HBV Infection
HBV can be transmitted by blood transfusion, through puncture wounds
acquired during work in the health-care field (medical, dental, laboratory
or other), by sharing needles used for injection of drugs, and by
unprotected sex with an HBV infected partner (Ref. 2). It has also been
suggested that there is a possibility of HBV transmission through breast
milk, as HBV markers such as HBsAg and HBV deoxyribonucleic acid
(DNA) are detected in breast milk (Ref. 7). However, studies have shown
that there is no increased risk of HBV transmission from infected mothers
to their children through breast-feeding (Ref. 8).
3. 	Testing for HBV Infection
In accordance with § 610.40(a)(3), each donation of blood and blood
components must be tested for infection with HBV. Consistent with the
3

Contains Nonbinding Recommendations
FDA 1987 memorandum, donations of Whole Blood and blood
components for transfusion are tested for HBsAg and anti-HBc. All
Source Plasma collections in the U.S. are tested for HBsAg. However,
FDA does not recommend that Source Plasma donors be tested for anti-
HBc because plasma units that are untested, non-reactive or repeatedly
reactive for anti-HBc are currently acceptable for manufacture of plasma
derivatives. Under § 610.41(a)(4), a deferred donor, who otherwise is
determined to be suitable for donation and tests reactive for anti-HBc may
serve as a donor of Source Plasma. Under § 610.40(h)(2)(v), anti-HBc
reactive donations, otherwise non-reactive when tested as required under
this section, may be used for further manufacturing into plasma
derivatives.
In addition, excluding anti-HBc reactive units in certain plasma products
might compromise the safety of those products. Anti-HBc and anti-HBs
usually occur together in pools used for the manufacture of plasma
derivatives. If anti-HBc reactive units were excluded from these pools,
titers of anti-HBs in the pools would be expected to diminish. Because the
presence of neutralizing anti-HBs is believed to contribute to the safety of
certain plasma products such as immunoglobulins, reducing the titers of
anti-HBs would have a negative effect on the safety of these products.
B. 	Rationale for Requalification Method for Reentry of Deferred Donors Who
Test Repeatedly Reactive for HBsAg Following Hepatitis B Vaccination
Hepatitis B vaccination has been shown to be a very effective measure to prevent
HBV infection (Ref. 9). Since 1982, recommendations for hepatitis B vaccination
have evolved into a comprehensive strategy to eliminate HBV transmission in the
U.S. (Refs. 10, 11, and 12). These recommendations advise the vaccination of
adults at risk for HBV infection as well as neonates, older children and
adolescents.
Currently manufactured HBV vaccines consist of recombinant antigenic, non-
infectious HBsAg protein that elicits production of protective, neutralizing, anti-
HBs when injected into individuals. As viral HBsAg forms the outer envelope of
HBV, anti-HBs neutralizes HBV, thus providing protection to the vaccinated
individual from HBV infection. Recombinant, non-infectious HBsAg from the
vaccine remains in the circulation for several weeks after vaccination. This
circulating, non-infectious recombinant HBsAg tests repeatedly reactive using
screening tests for HBsAg, and it is confirmed positive by HBsAg neutralizing
tests. Consequently, many donors who have been vaccinated against HBV and
who do not have hepatitis B infection are deferred. The deferral of non-infected
hepatitis B vaccinated individuals is consistent with the FDA 1987 memorandum
(Ref. 1).
Following hepatitis B vaccination, HBsAg can be transiently detected in blood for
4

Contains Nonbinding Recommendations
up to 21 days in neonates (Ref. 13) and up to 18 days in adults (Refs. 14 and 15).
In these cases, the presence of HBsAg in the vaccine recipients does not signify
infection with HBV, as anti-HBc and HBV DNA are not detectable and there are
no clinical signs and symptoms of viral hepatitis. Based on the transient detection
of HBsAg, a deferral period of 28 days after the date of Hepatitis B vaccination
should rule out the possibility of a positive screening test due to the vaccination.
However, if vaccination has been given to a previously exposed individual
(exposure by needle stick, risk behavior, etc.) as a prophylactic measure, a non-
reactive test result for HBsAg up to a period of 28 days after exposure does not
necessarily rule out HBV infection.
Based on the possibility of a positive screening test due to Hepatitis B
vaccination, FDA is providing recommendations for a requalification method for
reentry of donors deferred due to repeatedly reactive screening tests for HBsAg,
confirmed by neutralization, following a recent vaccination against HBV, and
who are not infected with HBV.
III. 	RECOMMENDATIONS
Consistent with FDA 1987 Memorandum, a donor who tests repeatedly reactive for HBsAg, is
confirmed positive by neutralization1, and who tests non-reactive for anti-HBc, is permanently
deferred and the donation must not be used (Ref. 1). Donors may be informed of the possibility
for reentry based on Hepatitis B vaccination history when they are notified of their deferral.
A. 	When Hepatitis B vaccination was given for protection from possible future
exposure or as a part of an approved Source Plasma HBV immunization
program:
The donor would be eligible for reentry 56 days after the donation that tested
repeatedly reactive for HBsAg and confirmed positive by neutralization2, if:
1. 	The blood establishment determines that the donor received the
vaccination against HBV infection within 28 days prior to collection of the
specimen that tested confirmed positive for HBsAg;
1Some HBV NAT assays received a limited supplemental indication for repeatedly reactive HBsAg test results. If a
donor tests HBsAg repeatedly reactive and positive for HBV DNA using an HBV NAT with such a limited
supplemental test indication, the HBsAg test result can be considered as HBsAg positive without performing HBsAg
neutralization. These test results are indicative of HBV infection and are not caused by Hepatitis B vaccination.
Therefore, such a donor should be deferred permanently. If a donor tests HBsAg repeatedly reactive in a screening
test and negative for HBV DNA using an HBV NAT with such a limited supplemental test indication, an HBsAg
neutralization test should be performed. The result of the neutralization test serves as the test of record.
2 While not yet eligible for routine donation, Source Plasma donors actively participating in an approved HBV
immunization program may be eligible for reentry into the HBV immunization program prior to 56 days, provided
the donor tests non-reactive for HBsAg and all other donor suitability criteria are met at the time of the next
donation.
5

Contains Nonbinding Recommendations
2. 	The vaccination was given solely to protect the donor from possible HBV
infection because of potential future exposure to HBV or as part of an
approved HBV immunization program for Source Plasma donors (i.e., it
was not performed for the purpose of HBV infection prophylaxis
following a specific incident of potential exposure, such as needlesticks,
risk behavior, etc.); and
3. 	All other donor suitability criteria are met when the donor presents to
donate.
Additional testing (for the purpose of reentry) prior to the next donation is not
recommended.
B. 	When Hepatitis B vaccination was given as a prophylaxis following a specific
incident of potential exposure:
The donor would be eligible for reentry after the donation that tested repeatedly
reactive for HBsAg and confirmed positive by neutralization, if:
1. 	The blood establishment determines that the donor received the
vaccination against HBV infection within 28 days prior to collection of the
specimen that tested confirmed positive for HBsAg for the purpose of
HBV infection prophylaxis following a specific incident of potential
exposure;
2. 	A follow up sample, collected at least 12 months after the potential
exposure, tests non-reactive for HBsAg, non-reactive for anti-HBc and
negative for HBV DNA by individual donation (ID) NAT; and
3. 	All other donor suitability criteria are met when the donor presents to
donate.
Note:
1) A donation that tests repeatedly reactive for HBsAg should not be used, whether or
not it is confirmed positive.
2) If test results for anti-HBc are repeatedly reactive, whether or not HBsAg test results
are positive, refer to FDA’s published recommendations and guidance (Refs. 16 and
17).
3) A donor who was deferred because of previous HBsAg test results, whether or not
these test results were caused by infection with HBV, may donate Source Plasma for
use in the preparation of Hepatitis B Immune Globulin (Human), provided the current
donation tests non-reactive for HBsAg and the donor is otherwise determined to be
suitable (§ 610.41(a)(3)).
6

Contains Nonbinding Recommendations
IV. 	IMPLEMENTATION
We consider the recommendations in this guidance to be an acceptable requalification method or
process, within the meaning of § 610.41(b), for reentry of donors deferred due to repeatedly
reactive screening tests for HBsAg, confirmed positive by neutralization, following a recent
vaccination against HBV.
Licensed establishments implementing these recommendations must report this change to FDA
as required under 21 CFR 601.12(a). We consider implementation of recommendations in this
guidance in their entirety and without modification to be a minor change to an approved license
application. Therefore, licensed establishments are not required to have FDA prior approval and
may submit a statement of this change in an annual report under § 601.12(d), indicating the date
that the revised standard operating procedures were implemented. Unlicensed establishments
implementing recommendations in this guidance in their entirety and without modification are
not required to report this change.
Section 610.41(b) requires that a donor requalification method or process used to requalify a
donor be acceptable to FDA. Accordingly, before you implement an alternative requalification
method or process from that described in this guidance, FDA must first find the alternative method
or process to be acceptable for such purpose. Licensed establishments intending to use an
alternative requalification method must submit a supplement for prior approval, as required
under § 601.12(b). Similarly, FDA must find an alternative requalification method proposed by
an unlicensed establishment to be acceptable before it is implemented.
7

Contains Nonbinding Recommendations
V. 	REFERENCES
1. 	FDA Memorandum to All Registered Blood Establishments: Recommendations for the
Management of Donor and Units that are Initially Reactive for Hepatitis B Surface Antigen
(HBsAg), December 2, 1987.
2. 	Lai, CL, et al., Viral Hepatitis B. Lancet 2003; 362:2089-94.
3. 	Margolis HS, et al., Hepatitis B: Evolving Epidemiology and Implications for Control.
Semin Liver Dis.1991; 11:84-92.
4. 	Alter MJ, et al. The Changing Epidemiology of Hepatitis B in the United States: Need for
Alternative Vaccination Strategies. JAMA 1990; 263:1218-22.
5. 	Krugman S, et al., Viral Hepatitis, Type B. Studies on Natural History and Prevention Re-
Examined. N Engl J Med 1979; 300:101-6.
6. 	Hoofnagle JH, et al., Serologic Diagnosis of Acute and Chronic Viral Hepatitis. Semin Liver
Dis 1991; 11:73-83
7. 	de Oliveira PR, et al., Hepatitis B Viral Markers in Banked Human Milk Before and after
Holder Pasteurization. J Clin Virol 2009; 45:281-4.
8. 	Hill JB, et al., Risk of Hepatitis B Transmission in Breast-Fed Infants of Chronic Hepatitis B
Carriers. Obstet Gynecol 2002; 99;1049-52.
9. 	Bloom BS, et al., A Reappraisal of Hepatitis B Virus Vaccination Strategies Using Cost
Effectiveness Analysis. Ann Intern Med 1993; 118:298-306.
10. Centers for Disease Control and Prevention. A Comprehensive Immunization Strategy to
Eliminate Transmission of Hepatitis B Virus Infection in the United States.
Recommendations of the Advisory Committee on Immunization Practices (ACIP) Part 1:
Immunization of Infants, Children, and Adolescents. MMWR 2005; 54(RR16); 1-23.
11. Centers for Disease Control and Prevention. A Comprehensive Immunization Strategy to
Eliminate Transmission of Hepatitis B Virus Infection in the United States
Recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II:
Immunization of Adults. MMWR 2006; 55(RR16); 1-40.
12. Department of Health and Human Services. Combating the Silent Epidemic of Viral
Hepatitis: Action Plan for Prevention Care and Treatment of Viral Hepatitis. Available at
http://www.hhs.gov/ash/initiatives/hepatitis/.
8

Contains Nonbinding Recommendations
9
13. Koksal N, et al., Transient Hepatitis B Surface Antigenemia after Neonatal Hepatitis B
Immunization. Acta Paediatr 1996; 85:1501-2.
14. Kloster B, et al., Hepatitis B Surface Antigenemia in Blood Donors Following Vaccination.
Transfusion 1995; 35:475-7.
15. Lunn ER, et al., Prolonged Hepatitis B Surface Antigenemia after Vaccination. Pediatrics
2000; 105:E81.
16. FDA Memorandum to All Registered Blood Establishments: Recommendations Concerning
Testing for Antibody to Hepatitis B Core Antigen (Anti-HBc), September 10, 1991.
http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/Licens
edProductsBLAs/BloodDonorScreening/InfectiousDisease/ucm077899.htm.
17. Guidance for Industry: Requalification Method for Reentry of Blood Donors Deferred
Because of Reactive Test Results for Antibody to Hepatitis B Core Antigen (anti-HBc), May
2010.