Testing for antibody to Anti-HBc (9/10/91)
DATE:    September 10, 1991
FROM:    Acting Director, Center for Biologics Evaluation and
          Research
SUBJECT: FDA Recommendations Concerning Testing for Antibody to
         Hepatitis B Core Antigen (Anti-HBc)
TO:      All Registered Blood Establishments
The Food and Drug Administration (FDA) is now regulating as
licensed biologic products test kits that detect total (IgG and
IgM) antibody to hepatitis B core antigen (anti-HBc). After 31
March 1991 anti-HBc kits shipped in interstate commerce and
labeled for use in screening blood and blood products must bear a
U.S. license number.
When initially marketed, anti-HBc test kits were intended for use
as diagnostic devices only, and were regulated by the FDA under
the premarket approval application (PMA) mechanism. In
1987 blood banks in the United States voluntarily introduced
anti-HBc screening of blood and blood components intended for
transfusion as a surrogate, non specific, test for non A, non B
hepatitis. Thus, anti-HBc test kits were being used to screen
licensed, transfusable, biological products and determine donor
suitability. After review of this situation in a public meeting
on 18 November 1988, the FDA Blood Products Advisory Committee
recommended that FDA regulate these kits as licensed biologic
products. The FDA announced in the Federal Register (20 February
1990) that total (IgG and IgM) anti-HBc detection kits would be
regulated as licensed biologic products after 31 March 1991. On
18 January 1991, the policies and procedures for screening blood
and blood components for anti-HBc as described in this document
were discussed in a public meeting of the Blood Products Advisory
Committee. 
Studies of transfusion associated hepatitis prior to anti-HBC
testing indicated that hepatitis B still occurred despite the use
of sensitive tests for hepatitis B surface antigen (HBsAg). It
has also been demonstrated that transfusions of blood reactive
for anti-HBc, but negative for HBsAg, are associated with the
development of hepatitis in some recipients. Thus, FDA has
concluded that testing Whole Blood and components intended for
transfusion for anti-HBc contributes to the safety of the blood
supply by reducing the incidence of transfusion associated
hepatitis B infection.
Therefore, FDA now recommends that all donations of blood and
blood components intended for transfusion be screened by an FDA
licensed test to detect products that are repeatedly reactive for
anti-HBc and prevent their distribution for use in transfusion.
FDA is not recommending the exclusion of repeatedly reactive anti-HBc plasma from pools for further manufacture into plasma
derivatives because the exclusion of such products might result
in decreased safety of plasma derivatives by a likely reduction
of antibody to hepatitis B surface antigen (anti-HBs). For this
reason, testing of Source Plasma for further manufacturing is not
recommended at this time, Although recovered plasma is harvested
from donations that have been tested for anti-HBc, it may be
shipped for further manufacturing under a valid short supply
agreement regardless of the test results.
Donations intended for transfusion should be tested to determine
whether they are negative or repeatedly reactive. Only negative
units are suitable for transfusion, with the exception of -
autologous donations under specified conditions. Donors should
be deferred indefinitely from donating transfusible blood
components whenever they test repeatedly reactive for anti-HBc on
more than one occasion regardless of the time interval between
the two repeatedly reactive tests. A donor reentry protocol for
anti-HBc cannot be recommended at this time for lack of an
available confirmatory test.
The attached recommendations provide guidance on the testing,
labeling, quarantine, storage and shipment of units of blood and
blood components with respect to anti-HBc testing. Labeling,
informed consent forms, standard operating procedures, deferral
registries and recordkeeping procedures should be revised as
necessary to reflect the blood establishment's implementation of
anti-HBc testing. Licensed blood establishments may adopt
labeling consistent with this memorandum concurrently with
submitting revised labeling for licensed products for review to
the Division of Product Certification, OBPR, CBER.
The recommendations for the labeling of units intended for use in
further manufacturing (Section III) will be of special interest
to those involved in supplying Source Plasma, recovered plasma
and red blood cells for research and for further manufacturing
into non-injectable products. The Labeling recommendations in
Sections II and III should be implemented within 90 days.
Questions may be directed by telephone to the Division of
Transfusion Science, Laboratory of Hepatitis, (301) 496-4288, or
in writing.  
                          Gerald V, Quinnan, Jr., M.D.
_____________________________________________________
RECOMMENDATIONS FOR TESTING FOR ANTIBODY
TO HEPATITIS B CORE ANTIGEN
(ANTI-HBc) IN BLOOD ESTABLISHMENTS
I.   PERFORMANCE OF ANTI-HBc TESTING      A.    For blood and blood components intended for
           transfusion, anti-HBc testing should be performed,
           using an FDA-licensed test kit, and test results
           interpreted according to the manufacturer's
           instructions as described in the package insert.
           Instructions for testing may be summarized as follows:
           1.   A single test for anti-HBc should be performed on
                a donor sample for each unit of blood or blood
                component intended for transfusion (the initial
                test).
           2.   If the initial test result is nonreactive, the
                test is interpreted as negative and the product
                may be released for transfusion if all other
                donor suitability criteria are met. 
           3.   If the initial test result is reactive, the donor
                sample is initially reactive. The sample should
                be retested in duplicate in a single test run,
                using a test kit of the same format and from the
                same manufacturer as the kit used for the initial
                test.
                a.   If both duplicate repeat test results-are
                     nonreactive, the test is interpreted as
                     negative for anti-HBc, and the unit may be
                     released for transfusion if all other donor
                     suitability criteria are met.
                b.   If one or both of the duplicate repeat test
                     results are reactive, the test is
                     interpreted as repeatedly reactive for
                     anti-HBc. In this case:
                     i.   The products should not be used for
                          transfusion. No further screening tests
                          for anti-HBc should be performed on the
                          products in an effort to qualify them
                          as suitable for transfusion.
                    ii.   Blood establishments should include in
                          their donor deferral system a method
                          for identifying any previous anti-HBC
                          test results which were repeatedly
                          reactive.
                   iii.   Blood establishments should include in
                          their donor history questionnaire a
                          question regarding any previous
                          anti-HBc test results which were
  repeatedly reactive. B. If the donor is repeatedly reactive for anti-HBc on a
second occasion, regardless of the time interval
(even if less than 8 weeks), the donor should be
indefinitely deferred and the product(s) should not
be used for transfusion.  An explanation and
evaluation of the role of anti-HBc testing in donors
is provided in the following article: Hoofnagle, J.
H., Post transfusion Hepatitis B, Transfusion 1990;
30: 384-386. In addition, general guidance in regard
to the testing, counseling, and evaluating of donors
tested for hepatitis viruses is described in the
Public Health Service Interagency Guidelines for
Screening Donors of Blood, Plasma, Organs, Tissues,
and Semen for Evidence of Hepatitis B and Hepatitis
C. MMWR 1991; 40 (RR-4); 1-17.
C. FDA believes that public health considerations
dictate the need for caution in the distribution and
autologous use of anti-HBc reactive products.
Accordingly, repeatedly reactive units for autologous
use should bear a restrictive label as recommended
below in Section Il.B. Additionally, use of
autologous blood repeatedly reactive for anti-HBc is
acceptable on the condition that a report of the test
result has been made available to the patient's
physician. This recommendation differs from those
which issued on 12 February 1990 concerning the use
of autologous blood positive for disease markers. The
physician's written request is necessary for release
of units that test - reactive for anti-HIV and HBsAg,
but is not required for release of autologous
products reactive for anti-HBc.
D. Test reactivity may represent a "false positive"
reaction. In the absence of a licensed confirmatory
test, it is suggested that an aliquot of serum or
plasma from each repeatedly reactive unit be frozen
at -20 C or colder and stored for possible future use
in verifying the screening test result in the context
of a donor reentry algorithm.
E. In the absence of licensed confirmatory tests for
anti-HBc, the blood center may wish to utilize
related test results when counseling the donor. The
alanine aminotransferase (ALT) level of an HBsAg
nonreactive donor sample may assist in the evaluation
of the significance of a repeatedly reactive anti-HBC
screening test result. However, regardless of the
risk assessment from evaluation of related tests,
donors who are repeatedly reactive for anti-HBc on
more than one occasion should be deferred
indefinitely from donation of whole blood and
components for transfusion (See Section I.B.). II.  LABELING OF WHOLE BLOOD AND COMPONENTS INTENDED FOR
     TRANSFUSION
A. Whole Blood and Blood Components Intended for
Homologous Transfusion
Consistent with the labeling for other infectious
disease marker tests as described in 21 CFR 606.121
and in the current Guideline for the Uniform Labeling
of Blood and Blood Components, negative anti-HBc test
results need not appear on-the container label but
should be included in the instruction circular. An
appropriate statement is:
"...nonreactive for anti-HBc."
This statement may be combined with other statements
concerning tests for infectious disease markers. For
example, the following combined statement is
acceptable:
"A sample from each donation intended for homologous
use has been tested by FDA-licensed tests and found
negative for antibody to human immunodeficiency virus
(anti-HIV-1), and nonreactive for hepatitis B surface
antigen (HBsAg), antibody to hepatitis B core antigen
(anti-HBc), antibody to hepatitis C virus (anti-HCV),
and antibody to human T-cell lymphotropic virus, type
I (anti-HTLV-I)."
B. Whole Blood and Blood Components Intended for
Autologous Transfusion
The guidance for autologous blood and blood
components issued on 15 March 1989 includes
recommendations for labeling autologous blood. When
the test for anti-HBc is repeatedly reactive, the
blood product should be permanently labeled with the
"Autologous use only" and special BIOHAZARD labels
described in the current Guideline for the Uniform
Labeling of Blood and Blood
Components. The Circular of Information distributed
with blood products should be amended to include use
of the biohazard label when an autologous unit tests
repeatedly reactive for anti-HBc.
C. Units of Whole Blood or Components Not Tested for
Anti-HBc.
On rare occasions, it may be necessary to ship a unit
not tested for anti-HBc because a tested unit is not
available. For example, untested Red Blood Cells,
Frozen, with no serum or plasma available, may be required to meet an emergency need for a rare
phenotype. The container label of such an untested
product should include a statement such as the
following:
"Caution: Test for anti-HBc has not been done."
III. LABELING OF BLOOD AND BLOOD COMPONENTS INTENDED FOR FURTHER
     MANUFACTURING OR RESEARCH
A. Plasma Intended for Further Manufacture into
Injectable Products
At this time, Source Plasma and recovered plasma
under short supply agreements may be shipped to U.S.
licensed fractionators for further manufacture into
injectable products without labeling as to anti-HBc
test status.  Additional recommendations for the
labeling of such units are being considered.
          Note: Source Plasma and recovered plasma for further
          manufacture into injectable products by licensed
          manufacturers are prepared, labeled, shipped, and
          accepted, using approved procedures. Products and
          samples being shipped under other circumstances,
          however, need to be appropriately labeled, as addressed
          below.
B. Plasma and Red Blood Cells Intended for Further
Manufacture into Noninjectable Products; Whole Blood,
Blood Components, and Samples for Research Use 
Products intended for further manufacture into in
vitro diagnostic reagents or for use in research
studies (Section IV.B.) are often provided to
consignees on an "as needed" basis, rather than as
routine shipments.  Therefore, FDA is recommending
that such products be labeled with one of the
following statements to indicate test status:
1. "Negative by an FDA licensed test for
anti-HBc."
2. "Not tested for anti-HBc."
3. "Reactive by an FDA licensed test for
anti-HBc."
If the product is not tested for anti-HBc or is
reactive for anti-HBc, labels should also include:
          "CAUTION: For further manufacture only into
          in vitro diagnostic reagents for which there
          are no alternative sources."                          or
          "For laboratory research only."
          If the product is not licensed or is not provided
          to a U.S. licensed in vitro diagnostics
          manufacturer under a short supply agreement, the
          following statement should also appear on the
          label:
          "Not for use in products subject to license
          under Section 351 of the Public Health
          Service Act."
IV.  QUARANTINE AND DISPOSITION OF REPEATEDLY REACTIVE DONATIONS
Whole blood and blood components that are repeatedly reactive for
anti-HBc should be quarantined and either destroyed as if
infectious for hepatitis or restricted to appropriate use other
than transfusion. Provisions of FDA's 6 April 1988 memorandum to
all registered blood establishments, Control of Unsuitable Blood
and Blood Components, apply.
A. Whole Blood or blood components that have been found
to be repeatedly reactive for anti-HBc should be
moved from the general quarantine area for storage of
untested units to a special quarantine area
designated for units unsuitable for transfusion due
to infectious disease test results.
          NOTE; Recovered plasma may remain in general quarantine
          with other units intended for manufacture of plasma
          derivatives. A mechanism should be in place, however,
          to ensure that a unit of anti-HBc reactive plasma will
          not be released inadvertently as plasma for
          transfusion.
B. Anti-HBc repeatedly reactive blood and blood
components should not be used for homologous
transfusion. FDA suggests that establishments destroy
the blood or blood components (and laboratory
samples, except as noted in I.D.) by autoclaving at
121.5 C maintained for 60 minutes by saturated steam,
or by incineration. While awaiting destruction, the
whole blood or blood components should be prominently
labeled "NOT FOR TRANSFUSION; anti-HBc reactive" in
accordance with 21 CFR 606.121(f).
C. Whole Blood and blood components repeatedly reactive
for anti-HBc should be distributed to consignees in a
manner consistent with 21 CFR 606.40(a)(7), 606.100,
and 606.165. Additional information concerning the
shipment of biological products and clinical specimens, including donor blood samples, may be
found in the following CFR sections:
           1.   Postal Service: 39 CFR Part 111. See also
                (a) the Domestic Mail Manual, which is
                incorporated by reference into the CFR, and
                (b) the International Mail Manual, for
                materials to be transported by air.
           2.   Department of Transportation: 49 CFR Part 173
           3.   Department of Health and Human Services,
                Centers for Disease Control: 42 CFR Part 72
D. The FDA's 26 October 1989 guideline for collection of
blood or blood products from "high risk" donors need
not be applied at this time to collections from
donors known to be anti-HBc repeatedly reactive,
whose blood or plasma may be needed for use in
research or further manufacture. It is emphasized,
however, that all staff should be instructed to
follow universal blood and body-fluid precautions in
all situations where contact with human blood can be
anticipated.
V.   "LOOKBACK"
A targeted "lookback" program in relation to previously collected
products from donors testing repeatedly reactive for anti-HBc is
not recommended at this time.
VI.  PLASMA FOR FURTHER MANUFACTURE
A. Source Plasma: The FDA does not currently recommend
that Source Plasma donors be tested for anti-HBc. If
anti-HBc reactive units were excluded from pools used
for the manufacture of plasma derivatives, titers of
anti-HBs in those pools would be expected to
diminish, as both these antibodies usually occur
together in plasma. The presence of anti-HBs is
believed to contribute to the safety of certain
plasma products such as the immunoglobulins. '
B. Recovered plasma: Plasma units that are untested,
nonreactive, or repeatedly reactive for anti-HBc are
currently acceptable for the manufacture of plasma
derivatives under short supply agreements (see 21 CFR
601.22) with U.S. licensed plasma fractionators.