Revised Recommendations for Testing Whole Blood, Blood Components, Source Plasma and Source Leukocytes for Antibody to Hepatitis C Virus Encoded Antigen (Anti-HCV)

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

. I.*. DEPARTMENT OF HEALTH & HUMAN SERVICES 	Public Health SW&
food and Drug AdminianatKxl
Bethesda MD 20892
Date: 	April 23, 1992
From: 	Director, Center for BiOlOgiCS Evaluation and Research
SubJect: Revrsed Recommendations for Testing Whole Blood, Blood
Components, Source Plasma and Source Leukocytes for,
Antibody to Hepatitis C Virus Encoded Antigen (Anti-
HCVI
To: 	All Reqistered Blood Establishments
I
Thrs memorandum transmits Recommendations for Testing for
Antibody to Hepatitis C Virus Encoded Antigen (Anti-WV) in Blood
Establishments, April 1992. These recommendations supersede
those issued on 29 November 1990 which should be archived.
On 29 November 1990 the Food and Drug Administration (FDA)
recommended that ail Whole Blood and components for transfusion
be screened to eliminate units that are repeatedly reactive for
antl-HCV. At that time, the available licensed screening tests
contained a sinqle recombinant antigen for the detection of anti-
HCV. Test kit manufacturers have recently developed kits capable
or detectlnq antibodies to additional epitopes of the hepatitis C
virus. In the memorandum of 29 November 1990, the FDA did not
recommend withholdinq anti-HCV reactive plasma from further.
nanutacture Lnto plasma derivatives because the impact of this
onanae on the safety of plasma derivatives such as immune
globulin products had not been established. Information
reaardrnq zhe sarety of such products has been collected since
Novemoer 1390 by the FDA.
In a public neetrnq on 12 March 1992, after review and discussion
or $11 the, relevant information available, the FDA Blood Products
Advisory Committee iBPAC) recommended that all donations of Whole
Blood and blood components intended for transfusion, and Source
Plasma and Source Leukocytes intended for further manufacture be
screened tor anti-HCV. The Committee also recommended that units
repeatedly reactive for anti-HCV in multi-antigen tests should
not be transtused. Accordingly, CBER is revising 	its
recommendations.
FDA ROW recommends (1) that units of Whole Blood and blood
components :ntended for transfusion, and Source Plasma and Source
Leukocytes intended for further manufacture, be screened by an
FDA iicensed test tor anti-HCV and (21 that no products
repeatedly reactive for anti-HCV be used. The use of a multi-
ant:qen test ;n the testing of Whole Blood and blood components
for transrusron should be implemented as soon as is feasible-
initially 	reactrve donor samples should be retested in duplicate

.
to determine whether they are nonreactive (negative) or
repeatedly reactive. only neqative units are suitable for
transfusion or for further manufacture, with the exception of
autoloqous donatlons under specified conditions. Donors should
be deferred indefinitely whenever they test repeatedly reactive
for anti-HCV. A donor reentry protocol for anti-HOI cannot be
recommended at this time because of the lack of an available
licensed additional, more specific test-
Inventories of blood and blood components for transfusion that
were collected before the multi-antigen test implementation date
should also be tested using the multi-antigen test if possible.
Inventories of products intended for further manufacture and
collected before the test implementation date need-not be tested
retroactively.
The attached recommendations provide guidance on the testing,
Labelinq, quarantine, storaqe and shipment of units of-blood and
blood components with respect to anti-H07 testing.
informed consent forms, Labeling,
standard operating procedures, deferral
reqistries and recordkeeping procedures should be revised as
necessary to reflect the blood establishment's implementation of
anti-HCV testinq.
Licensed manufacturers of Whole-Blood and blood components may
adopt labelinq consistent with this Memorandum concurrently with
submittinq any chanqes in labeling (Section II) to the Division
of Product Certification. 	Licensed manufacturers of Source
Plasma should submrt, within 90 days after receipt of this
document, revrsed labelinq for review and approval (Section ~_
1II.A.). Approved Labeling changes should be implemented within
180 days.
Section 111.8. contains labeling recommendations of special.
interest to those Lnvolved in supplyinq Source Plasma, recovered
plasma and red blood cells for research and for further
manufacturinq Into noninjectable products. The labelinq
recommendations rn Sections II and III should be implemented
within 180 days after the receipt of this document.
Questions concernlnq testing may be directed in writing to the
Food and Druq Admlnistration, Division of Transfusion Science,
Laboratory of Hepatitis, HFB-930, 8800 Rockville Pike, Bethesda,
MD 20892, FAX: (3011 227-6764. Questions concerninq labeling may
be directed in wrltinq to the Food and Druq Administration,
Division of Product CertificationaHF 	8800 Rockville Pike,
Bethesda, MD 20892. FAX: (

Recommendations for Testing
for
Antibody to Hepatitis C Virus Encoded Antigen (Anti-HCV)
in
Blood Establishments
April 1992
U.S. Xepartment of Health and Human Services
Public Health Service
Food and Drug Administration
Center for Siologics Evaluation and Research
8800 Rockville Pike, Bethesda, MD 20892

Table of Contents
Page
r. Performance of Anti-HCV Testing and Donor Suitability...3
II. Labeling of Whole Blood and Components
Intended for Transfusion . . . . . . . . . . . . . . ..-....-.......... 	5
III. Labeling of Whole Blood and Blood Components
Xntended for Further Manfacturing or Research . . . . . . . . . . . 7
r
IV. Quarantine and Disposition of Repeatedly
Reactive Donations . . . . . . . . . . . . . . . . . . . ..-................ 	a
V. Lookback . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..=-.......... 	9
2

RECOMMENDATIONS FOR TESTING FOR ANTIBODY
TO HEPATITIS C VIRUS ENCODED ANTIGEN 	I
(ANTI-HCV) IN BLOOD ESTABLISHMENTS
April 1992 I
I. PERFORMANCE OF ANTI-HCV TESTING AND DONOR SUITABILITY
A. Anti-HCV testing, using multi-antigen tests, should be
performed and test results interpreted according to the I
manufacturer's instructions in the package insert.. (
Instructions for currently licensed kits may be
summarized as follows:
I. A single enzyme immunoassay (EIA) test for anti-
HCV should be performed on a donor sample for each
unit of whole blood or blood component intended
for transfusion, and on each unit of plasma or
leukocytes for further manufacture. This EIA will
hereafter be referred to as the "initial test".
2. If the initial test result is nonreactive, the
donor sample is considered to be negative for
anti-HCV.
3. If the initial test result is reactive, the donor
sample is considered to be initially reactive.
The sample should be retested in duplicate, within
a single run, using the same procedure and same
manufacturer's test kit as that used for the .-.
initial test.
a. If both duplicate repeat test results are
nonreactive, the sample is considered to be
negative for anti-HCV.
b. If either one or both of the duplicate repeat
test results are reactive, the test is
considered to be repeatedly reactive for
anti-HCV and the products should not be used
for transfusion or for further manufacture.
Possible exceptions to permit use of anti-HCV
reactive products in special circumstances
are described in Section I.C. and Section
111-B. NO further screening tests for anti-
HCV should be performed on samples from this
unit in an effort to qualify it as suitable.
B. Donors who are repeatedly reactive for anti-HCV, using
multi-antigen tests, should be deferred indefinitely
from donating blood and blood components for
transfusion, Source Plasma and Source Leukocytes for
3 	~

further manufacture. General guidance in regard to the
testinq, counseling, and evaluation of donors tested
for hepatitis viruses is described in the Public Health
Senrlce Interagency Guidelines for Screening Donors of
Blood, Plasma, Organs, Tissues, and Semen for Evidence
of Hepatitis B and Hepatitis C, MMWR 1991; 40 (M-4):
l-17.
C. No individual should be used as a source of Whole
Blood, blood components, Source Plasma or Source
Leukocytes as follows:
1. .Individuals with a history of close contact within
one year of donation with another individual
having viral hepatitis.
2. Individuals with a history of having received
within one year human blood or any derivative of
human blood which the FDA has advised the licensed
establishment is a possible source of viral
hepatitis (except in the case of specific
immunization of Source Plasma donors (21 CFR
640.661).
In addition it is recommended that individuals be
deferred from donating Whole Blood, blood components,
Source Plasma or Source Leukocytes, who within one year
of donation have undergone acupuncture, ear piercing or
tattooing in which sterile procedures were not Used.
D. Detailed guidance on the use of autologous Units that
are repeatedly reactive for anti-HCV was issued on 11
September 1991. FDA believes that public health
considerations dictate the need for caution in the
distribution and use of autologous products reactive
for anti-HCV. Accordingly, repeatedly reactive units
for autologous use should bear a restrictive label.as
recommended in Section 1I.B. Additionally, use of
autologous blood that is repeatedly reactive for anti-
HCV is acceptable provided that a report of the test
result has been made available to the patient's
physlcian. This recommendation differs from those
issued on 15 March 1989 concerning the use of
autologous blood positive for some other disease
markers. The attending 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
autoioqous products reactive for anti-HCV.
E. Test reactivity may represent a "false positive"
reactron. In the absence of a licensed confirmatory
test, it 1s suggested that an aliquot of serum or
4

plasma from each repeatedly reactive unit be frozen at
-2oOc or colder and stored for possible future use in
verlfyrnq the screening test result in the context of a
donor reentry algorithm.
F. Xn the absence of a licensed Confirmatory test for
anti-HCV, the blood center may wish to utilize related
test results when counseling the donor. The alanine
aminotransferase (ALT) level of a donor sample may
assist in the evaluation of the significance of a
repeatedly reactive anti-HCV screening test result.
However, reqardless of the risk assessment from
evaluation of other tests, donors who are repeatedly
reactive for anti-HCV should be deferred indefinitely
from donatinq whole blood and components for
transfusion and plasma or leukocytes for further
manufacture (See Section I.E.).
The American Blood Resources Association (ABRA) has
prepared a guideline (Guideline for Anti-Hcv screening
in Plasmapheresis Facilities, Oct. 9, 1991) that may be
referenced as an acceptable Standard Operating
Procedure (S.O.P.) for the implementation of testing by
manufacturers of Source Plasma.
G. Informed consent forms, standard operating procedures
and recordkeepinq procedures should be revised as
necessary to reflect the blood establishment's
implementation of testing using FDA-licensed multi-
antiqen test kits.
II. LABELING OF WHOLE BLOOD AND COMPONENTS INTENDED FOR
TRANSFUSION
A. Whole Blood and Blood Components Intended for
Alloqenerc Transfusion
Consistent with the labeiinq for other infectious
disease marker tests as described in 21 CFR 606.121 and
. 	.in the current mft GUue for the YD&Qrm J,abellna
of Blood a& Blood Co- 	neqative anti-HCV test
results need not appear on th; container label but
should be included in the inStrUCtiOn circular. An
appropriate statement is:
” .,.neqative by a test for anti-HCV-"
This statement may be combined with other statements
concernlnq tests for infectious disease markers. For
5

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 antibodies to human immuncdeficiency virus
(anti-HIV), hepatitis B Surface antigen (EBSAg),
antibody to hepatitis B core antigen (anti-HBc),
antibody to hepatitis C virus (anti-HCV), and antibody
to human T-cell 	1yrphotrOpiC 	virus, type I (anti-HTLV-
t\ n
8. Whole Blood and Blood Components Intended for
Autologous Transfusion
The guidance for autologous blood and blood components
issued on 15 March 1989 included recommendations for
labeling autologous blood. When the test for anti-HCV
is repeatedly reactive, the blood product should be
permanently labeled with the special "FOR AUTOLOWUS
USE ONLY” and ~*BIOHAZARDol labels described in the
. 	.current me 	for the Unlform~abellna of Blood and
Blood* 	The CirCUlar of Information
distributed with blood products should include an
appropriate explanation concerning use of the biohazard
label when an autologous unit tests repeatedly reactive
for anti-HOI.
C. Units of Whole Blood or Components Not Tested for Anti-
HCV or Not Tested for Anti-HCV Using a Multi-Antigen
Assay.
on rare occasions, it may be necessary to ship a unit
not tested for anti-HCV 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
followlnq:
YMJTION: Test for anti-HCV has not been donea.
If testing for anti-H07 has been performed using a
single-antigen assay only, and not a multi-antigen
assay, the container label should include a statement
such as the following:
“CAUTION : Test for anti-HCV performed using a less
sensitive test than one currently available".
6

III. LABELING OF BLOOD AND BLOOD COMPONENTS INTENDED FOR FURTHER
MANUFACTURING OR RESEARCH
A. Plasma Intended for Further Manufacture into Injectable
Products
source Plasma and recovered plasma (shipped under short
supply agreements) container labels should bear the
statement, "Negative by a test for anti+iCP. 	This
statement may be combined with the statement(s)
regarding anti-HIV and HBsAg test results.
1.
2,
3.
8. 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 b y&
diagnostic reagents or for use in research studies 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:
"Negative by a test for anti-HCV.w
"Not tested for anti-HCV.w
'Reactive by a test for ax~ti.-HCV.~
If the product is not tested for anti-HCV or is
reactive for anti-HCV, labels should also include:
“CAUTION : For further manufacture only of b via
diagnostic reagents for which there are no alternative
sources. n or
"Not for use in products subject to license under
Section 351 of the Public Health Service Act."
or . I
"For Laboratory research use only."
The labeling statements addressed above pertain to units of
blood or plasma collected from a donor that was not
previously known to be anti-HCV reactive. The collection of
source Plasma from donors known to be anti-HCV reactive
requires advance approval by the Director, CBEIR, of a
specrfic product license application or amendment.
7

IV. QUARANTINE AND DISPOSITION OF REPEATEDLY REACTIVE DONATIONS
All donations that are repeatedly reactive for anti-HCV should be
quarantined and either destroyed or restricted to appropriate use
other than transfusion or manufacture into injectable products.
Provisions of FDA's 6 April 1988 memorandum to all registered
blood establishments, Control of Unsuitable Blood and Rw
CDmDOnentS, apply.
A. Whole Blood, blood components, Source Plasma and Source
Leukocytes that have been found to be repeatedly
reactive for anti-HCV should be moved from the general
quarantine area for storage of untested units to a
special quarantine area designated for units unsuitable
for use due to infectious disease test results.
8. Anti-HCV repeatedly reactive units should not be used
for alloqeneic transfusion or for further manufacture
into injectable products. FDA suggests that
establishments 	destroy the units and laboratory samples
(except an aliquot of serum or plasma for future
verification of donor status as noted in Section I.D.)
by saturated steam autoclaving at 121.5'C maintained
for 60 minutes, or by incineration. 	While awaiting
destruction, Whole Blood and blood components, Source
Plasma and source Leukocytes should be quarantined and
prominently labeled "NOT FOR TRANSFUSION: anti-HCV
reactive" in accordance with 21 CFR 606.121 (f). _ ~-._
C. Plasma, Whole Blood and blood components repeatedly
reactive for anti-HCV should be distributed to
consignees in a manner consistent with 21 CF'R 606.40
(a)(6) and (7), and 606.100, 606.120, 606.121 and
606.165. Additional information 	Concerning 	the
shipment of biological products and clinical specimens,
includinq donor blood samples, may be found in the
followlnq CFX sections:
1. Postal Service: 39 CFR Part 111. See also (a) the
Domestic Mail Manual, which is incorporated by
reference into the CF'R, and (b) the International
Hall Manual, for materials to be transported by
dls-.
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 (with a revision on
17 April 1991) for collection of blood or blood
8

t
products from "high risk" donors need not be applied at
this time to collections from donors known to be anti-
HCV repeatedly reactive, whose blood or plasma may be
needed for autoloqous use, or for use in further
manufacturing for b vitro products and in research
(Section III). However, it is emphasized 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. 	(See:
Centers for Disease Control. Update: Universal
precautions for prevention of transmission of human _
immunodeficiency virus, hepatitis B virus, and other
blood-borne pathogens in health-care settings. MMWR
L908:37:377-386.1
v. "LOOKBACK"
A targeted @*lookback" program in relation to previously collected
products from donors testing repeatedly reactive for anti-HCV is
not recommended at this time.
9