“Lookback” for Hepatitis C Virus (HCV): Product Quarantine, Consignee Notification, Further Testing, Product Disposition, and Notification of Transfusion Recipients Based on Donor Test Results Indicating Infection with HCV: 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
“Lookback” for
Hepatitis C Virus (HCV):
Product Quarantine, Consignee
Notification, Further Testing, Product
Disposition, and Notification of
Transfusion Recipients
Based on Donor Test Results
Indicating Infection with HCV
Additional copies of this guidance are available from 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 email 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 listed above.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
August 2007
Updated December 2010

Guidance for Industry
“Lookback” for Hepatitis C Virus (HCV):
Product Quarantine, Consignee Notification,
Further Testing, Product Disposition, and
Notification of Transfusion Recipients Based
on Donor Test Results
Indicating Infection with HCV
NOTE: Changes have been made to update the guidance dated August 2007:
• 	Figure 1 and Table 1 of the guidance have been revised to reflect new technologies for
anti-HCV testing, and corresponding changes have been made to the text.
• 	The guidance has been updated to note that Title 21 Code of Federal Regulations 610.48
(21 CFR 610.48) (historical lookback) requires blood establishments to have completed a
number of actions by February 19, 2009, based on the review of historical testing records.
Note that the recommendations for implementing historical lookback as reflected in
Figures 2-4 and Tables 2-5 have been relocated to the new Appendix to this guidance.
• 	In section IV, “January 1, 1988” was revised to “February 20, 2008”.
• 	The recommendation with respect to notification by transfusion services, as consignees,
was expanded to include a recipient’s physician of record, as appropriate, consistent with
the regulations.
• 	The time frames in which blood establishments must perform appropriate procedures
after a donor tests reactive for evidence of HCV infection were clarified.
• 	A number of nonsubstantive changes were made throughout the document for
clarification purposes.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
August 2007
Updated December 2010

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i
Table of Contents
I. 	INTRODUCTION ............................................................................................................... 1
II. 	BACKGROUND ................................................................................................................. 2
III. 	DEFINITIONS .................................................................................................................... 4
IV. 	LOOKBACK REQUIREMENTS ..................................................................................... 5
V. 	CURRENT RECOMMENDATIONS ............................................................................... 6
VI. 	BLOOD AND BLOOD COMPONENTS INTENDED FOR MANUFACTURE INTO
NON-INJECTABLE PRODUCTS .................................................................................. 7
VII. 	REFERENCES .................................................................................................................. 10
APPENDIX .................................................................................................................................. 11

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Guidance for Industry
“Lookback” for Hepatitis C Virus (HCV):
Product Quarantine, Consignee Notification,
Further Testing, Product Disposition, and
Notification of Transfusion Recipients
Based on Donor Test Results
Indicating Infection with HCV
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 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.
I. 	INTRODUCTION
Multiple layers of safeguards, including donor screening and testing, are used to reduce the risk
of transmitting infection through blood transfusion. However, a person may donate blood early
in infection, during the period when the viral marker is not detectable by a screening test, but the
infectious agent is present in the donor’s blood (the “window period”). For example, if an
individual donates blood on a number of occasions and each donation tests nonreactive for
antibody to HCV, but the donor returns and tests repeatedly reactive for antibody to HCV at a
later date, prior collections from such a donor could be at increased risk for transmitting HCV.
In addition, a recipient of a transfusion of blood or blood components collected during the
“window period” from a donor who is now repeatedly reactive would not know that he or she
might be at increased risk of infection with HCV through the transfusion, unless he or she is
notified. Furthermore, untested collections from donors who later were found to be repeatedly
reactive when tested for antibodies to HCV since 1990 (when antibody tests for HCV became
available) might have been at increased risk for transmitting HCV due to a chronic infection in
the donor.
Chronic hepatitis due to HCV is a major health problem in the U.S. The infection is usually
clinically silent until the liver is seriously damaged. As a result, infected people usually are
unaware of their disease. Although transfusion-transmitted infections account for only a very
small proportion of HCV infections, it is possible to identify and “lookback” at prior donations
that might have been collected during the “window period.”

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This guidance document provides recommendations for complying with 21 CFR 610.47 and
21 CFR 610.481 to (1) blood establishments that collect blood or blood components, including
Source Plasma and Source Leukocytes, (2) hospitals, and (3) other consignees. This guidance
does not apply to autologous donations, pooled blood components intended solely for further
manufacturing into products that are manufactured using validated viral clearance procedures,
and blood and blood components that were intended for manufacture into non-injectable products
subject to the labeling described in Section VI.
This document supersedes the guidance document of the same title, dated August 2007. The
August 2007 document superseded the HCV sections of the Food and Drug Administration
(FDA) memorandum of July 19, 1996, entitled “Recommendations for the Quarantine and
Disposition of Units from Prior Collections from Donors with Repeatedly Reactive Screening
Tests for Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and Human T-Lymphotropic Virus
Type I (HTLV-I).” The August 2007 guidance document also superseded the September 1998
guidance entitled “Guidance for Industry: Current Good Manufacturing Practice for Blood and
Blood Components: (1) Quarantine and Disposition of Units from Prior Collections from
Donors with Repeatedly Reactive Screening Tests for Antibody to Hepatitis C Virus (Anti-
HCV); (2) Supplemental Testing, and the Notification of Consignees and Blood Recipients of
Donor Test Results for Anti-HCV.” Additionally, the August 2007 guidance finalized FDA’s
draft guidance dated June 1999 entitled “Guidance for Industry: Current Good Manufacturing
Practice for Blood and Blood Components: (1) Quarantine and Disposition of Prior Collections
from Donors with Repeatedly Reactive Screening Tests for Hepatitis C Virus (HCV); (2)
Supplemental Testing, and the Notification of Consignees and Transfusion Recipients of Donor
Test Results for Antibody to HCV (Anti-HCV).”
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances 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 guidances means that something is suggested or
recommended, but not required.
II. 	BACKGROUND
Lookback related to HCV testing has been discussed at open public meetings, including meetings
of FDA’s Blood Products Advisory Committee (BPAC), on multiple occasions since October
1989. As a response to these discussions, FDA provided detailed guidance in the July 19, 1996,
memorandum on the quarantine and disposition of certain prior collections of blood and blood
components from donors who subsequently test repeatedly reactive for anti-HCV. The 1996
memorandum recommended that blood establishments notify consignees (such as the transfusion
service, physician, or fractionator) for the purpose of quarantine and eventual disposition of
products made from prior collections. Prior to recent advances in medical diagnosis and therapy,
1 Section 610.48 (21 CFR 610.48) requires blood establishments to have completed a number of actions by February
19, 2009, based on the review of historical testing records. Recommendations for implementing historical lookback
required under 21 CFR 610.48 are included in Figures 2-4 and Tables 2-5, located in the Appendix.

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FDA did not recommend notification of recipients of blood from donors who subsequently test
positive for anti-HCV because no clear consensus on the public health benefit (i.e., disease
prevention and treatment) of such action had emerged.
Improvements in the management and treatment of chronic hepatitis C have occurred over time,
and there is a strong correlation between a positive test for anti-HCV in a supplemental assay
(e.g., the Chiron RIBA HCV 3.0 SIA2) and HCV infection (Refs. 1-4). Prior collections from
donors later found to be repeatedly reactive for anti-HCV might also be at increased risk of
transmitting HCV.
At public meetings on April 24 and 25, 1997, and August 11 and 12, 1997, the Public Health
Service (PHS) Advisory Committee on Blood Safety and Availability recommended notification
of recipients of transfused blood and blood components that are at increased risk of transmitting
HCV infection based on donor screening with a licensed multiantigen screening test (Enzyme
Immuno Assay (EIA) 2.0 or EIA 3.0) since 1992. Consistent with these recommendations, in
March 1998, FDA issued guidance for implementation and public comment regarding recipient
notification (63 FR 13675, March 20, 1998). In response to comments received, FDA issued a
revised guidance for implementation in September 1998 (63 FR 56198, October 21, 1998).
At public meetings on November 24, 1998, and January 28, 1999, the PHS Advisory Committee
on Blood Safety and Availability reconsidered the issue of recipient notification related to
repeatedly reactive results on the single antigen (EIA 1.0) screening test that was licensed in
1990. The PHS Advisory Committee recommended the expansion of the targeted HCV lookback
program to include recipients of blood and blood components from donors subsequently
identified as repeatedly reactive by the EIA 1.0 screening test. In addition, the PHS Advisory
Committee considered that, in cases where no supplemental test result is available, it is
reasonable to perform lookback for EIA 1.0 based on a signal to cutoff ratio of the screening test
of greater than 2.5 (S/CO > 2.5) to capture the vast majority of the true positives and minimize
unnecessary recipient notifications based on false reactive screening test results.
In accordance with the recommendations from the PHS Advisory Committee, FDA issued a draft
guidance on HCV Lookback dated June 1999 for public comment (64 FR 33309, June 22, 1999)
and published a proposed rule entitled “Current Good Manufacturing Practice for Blood and
Blood Components; Notification of Consignees and Transfusion Recipients Receiving Blood and
Blood Components at Increased Risk of Transmitting HCV Infection (“Lookback”) (65 FR
69378, November 16, 2000). In the Federal Register of August 24, 2007, (72 FR 48766), FDA
published the final rule entitled “Current Good Manufacturing Practice for Blood and Blood
Components; Notification of Consignees and Transfusion Recipients Receiving Blood and Blood
Components at Increased Risk of Transmitting Hepatitis C Virus Infection (“Lookback”)” and a
companion guidance document, dated August 2007 (72 FR 48658). The August 2007 guidance
provided recommendations for complying with 21 CFR 610.47 and 21 CFR 610.48.
2 The Chiron Corporation (Emeryville, CA) RIBA HCV 3.0 SIA is a strip immunoblot assay based on recombinant
antigens of HCV.

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III. 	DEFINITIONS
Alternative Test: A licensed test for anti-HCV that is of equal or greater sensitivity in
comparison to the licensed HCV EIA 3.0.
Blood and Blood Components: Whole Blood and blood components, including Source Plasma
and Source Leukocytes.
Lookback:
 	The identification of blood and blood components from prior collections from a donor
with:
1. 	a repeatedly reactive antibody screening test for anti-HCV; or
2. 	a reactive NAT3 for HCV; or
3. 	other reliable test results or information indicating evidence of HCV infection
(provided the testing was performed using a test approved by FDA by a laboratory
compliant with the Clinical Laboratory Improvement Amendments of 1988, or has
met equivalent requirements as determined by the Centers for Medicare and Medicaid
Services in accordance with the provisions of 42 CFR part 493); and
 	subsequent actions, such as:
1. 	quarantine of such blood and blood components that are not expired;
2. 	notification of consignees to quarantine such in-date blood products;
3. 	further testing of the donor;
4. 	destruction or relabeling of potentially infectious prior collections;
5. 	release from quarantine of blood and blood components that do not present a greater
risk of infection; and (if appropriate)
6. 	notification of recipients of identified blood and blood components, or the recipient’s
physician of record.
Lookback Donations: Collectively, the blood and blood components from prior collections
from the same donor.
Reactive NAT3 for HCV: A result for an HCV RNA test that uses only one set of primers
specific for HCV that is performed initially on an individual donation, or is performed as a
discriminatory NAT subsequent to a reactive multiplex NAT, which tests for multiple viruses,
including HCV RNA.
3 This guidance does not address testing, product disposition, donor management, and lookback for individual donor
samples that test reactive on a multiplex NAT or a minipool that test reactive on a multiplex NAT. In addition,
under 21 CFR 610.47 and 610.48, lookback is required for individual donor samples that test reactive on a multiplex
NAT but nonreactive for both HIV-1 and HCV when tested using discriminatory HIV-1 NAT and discriminatory
HCV NAT. See “Guidance for Industry: Nucleic Acid Testing (NAT) for Human Immunodeficiency Virus Type 1
(HIV-1) and Hepatitis C Virus (HCV): Testing, Product Disposition, and Donor Deferral and Reentry” dated May
2010, for FDA recommendations in these circumstances. The document may be accessed at
http://www.fda.gov/downloads/biologicsblood%20vaccines/guidancecomplianceregulatoryinformation/guidances/bl
ood/ucm210270.pdf accessed December 20, 2010.

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Repeatedly Reactive Screening Test: The result when an initially reactive screening test is
repeated in duplicate samples on the same test run and one or both samples are reactive.
NOTE: In the HCV Lookback regulations, 21 CFR 610.47 and 610.48, we refer to screening
tests as “reactive” instead of “repeatedly reactive” to accommodate the different testing
algorithms established for NAT and other screening tests. However, in this guidance we refer to
reactive antibody screening test results for anti-HCV as “repeatedly reactive” to accurately reflect
the established testing algorithm for anti-HCV.
Transfusion Recipient Notification: The actions taken by a hospital, transfusion service, or
recipient’s physician of record to notify recipients that they received a transfusion of a Lookback
Donation that is at increased risk of transmitting HCV infection.
IV. 	LOOKBACK REQUIREMENTS
In this guidance, FDA addresses lookback related to donor screening by a licensed anti-HCV test
and NAT. Under 21 CFR 610.47 and 21 CFR 610.48, blood establishments must search records
of prior collections from donors whose test results on current or historical review donations show
evidence of infection with HCV (either repeatedly reactive on screening tests for anti-HCV or
reactive on NAT for HCV RNA). Blood establishments must search their records to identify
prior collections dating back 10 years (for current donations) or dating back to January 1, 1988
for historical review donations. If an establishment maintains computerized electronic records
relating to collections made before February 20, 2008, the blood establishment must perform a
historical review search of those records dating back indefinitely, as far back as they exist in
computerized, electronic form (21 CFR 610.48(b)(1)(i)). The blood establishment must search
records of prior collections, if available, back to the date 12 months prior to the donor’s most
recent nonreactive licensed multiantigen screening test for anti-HCV (if applicable), if that is a
shorter period, since prior infection in the donor is highly unlikely based on the known duration
of the window period (see 21 CFR 610.47(a)(1)(i) and 21 CFR 610.48(b)(1)(iii)(A)). FDA
believes that this date (12 months prior to the last nonreactive multiantigen screening test for
anti-HCV) will antedate the window period for infection in that donor.
FDA believes that results for NAT are of value in (1) lookback related to current collections
when a NAT result exists and (2) in historical lookback, when a NAT result, including NAT
performed under an Investigational New Drug Application (IND), exists in the record of the
previous donation(s). Blood establishments should consider a reactive NAT result to be
presumptive evidence of ongoing HCV infection. A reactive NAT must serve as a basis for
initiating lookback (i.e., both quarantine and recipient notification) (21 CFR 610.47(a)(1)). Note
that certain licensed HCV NAT have been labeled with a “limited supplemental claim.” When
current donor test results are repeatedly reactive on an anti-HCV screening test and reactive on
HCV NAT, the reactive NAT acts as a positive supplemental test and it is not necessary to
perform a licensed multiantigen supplemental test for anti-HCV. However, a nonreactive NAT
should not be a reason for not performing lookback for a donation that is repeatedly reactive on

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an anti-HCV screening test. This recommendation is based on current research that indicates that
in about 15-25% of cases of HCV infection, viremia may be intermittently detectable (Ref. 5) or
resolved (Ref. 6).
Blood establishments must initiate lookback based on a reactive NAT although a screening test
or supplemental test for antibodies to HCV performed on the same collection is nonreactive
(21 CFR 610.47(a)(1)). In this situation, blood establishments must search records of prior
collections for the 12 months prior to the date of the NAT-reactive donation
(21 CFR 610.47(a)(1)(ii) and 21 CFR 610.48(b)(1)(iii)(B)), since this configuration of test results
is consistent with recent HCV infection in the donor (Ref. 7).
Blood establishments that collect blood or blood components, including Source Plasma and
Source Leukocytes, must establish, maintain and follow appropriate procedures4 for the
following actions within specified timeframes after a donor tests reactive for evidence of HCV
infection (21 CFR 610.47(a)); or during an historical record review, after identifying donors who
tested reactive for evidence of HCV infection (21 CFR 610.48(b)):
• 	quarantine prior collections that remain in inventory;
• 	notify consignees to quarantine prior collections;
• 	further test the donor and notify consignee of test results; and
• 	destroy or relabel potentially infectious prior collections.
Under 21 CFR 610.47(b) and 21 CFR 610.48(c), transfusion services, as consignees, must
establish, maintain and follow an appropriate system for the following actions within specified
timeframes, when notified by the collecting establishment:
• 	quarantine prior collections that remain in inventory;
• 	destroy or relabel potentially infectious prior collections; and
• 	notify transfusion recipients who received blood or blood components from a donor
who is later determined to be infected with HCV, if appropriate, or the recipient’s
physician of record, as appropriate.
NOTE: Recommendations for implementing historical lookback required under 21 CFR 610.48
are included in Figures 2-4 and Tables 2-5, located in the Appendix.
V. 	CURRENT RECOMMENDATIONS
Current lookback recommendations are provided in Figure 1 and Table 1 to assist blood
establishments in complying with the regulations in 21 CFR 610.47.
4 See 21 CFR 606.100(b)(19)(i) through (vi) and 606.160(b)(1)(viii) for requirements for standard operating
procedures and records concerning the activities performed under 21 CFR 610.46, 610.47, and 610.48.

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VI. 	BLOOD AND BLOOD COMPONENTS INTENDED FOR MANUFACTURE
INTO NON-INJECTABLE PRODUCTS
There may be some limited uses for quarantined prior collections identified in the lookback
either for current donations or for historical review donations that are not suitable for release
from quarantine for their original intended use. We recommend that you do not use such prior
collections for transfusion or for manufacturing into injectable products. You should destroy
these prior collections as a general practice; however, in limited situations, release for research or
for further manufacture is acceptable. If released for research or for further manufacture into in
vitro diagnostic reagents, you must relabel the prior collections with a “BIOHAZARD” legend
(21 CFR 610.40(h)(2)(ii)(B)). In addition, we recommend that you relabel the prior collections
with two of the following statements:
- 	“Collected from a donor who subsequently tested reactive for anti-HCV or HCV
RNA. An increased risk of transmission of HCV is present.”
and either
- 	“Caution: For Further Manufacturing Into In Vitro Diagnostic Reagents For
Which There Are No Alternative Sources.”
or
- 	“Caution: For Laboratory Research Use Only.”
If you release the units for further manufacture into injectable products, the units must include a
statement on the container label indicating the exempted use specifically approved by FDA
(21 CFR 610.40(h)(2)(ii)(D)).

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Identify1 and quarantine2 prior collections.
Notify2 consignees, request them to quarantine.
If anti-HCV test is repeatedly reactive, test current sample using an 	If NAT Reactive only,
appropriate3 licensed multiantigen supplemental test 4 	destroy or relabel
prior collections
______________________________________________________________________________________________ 	obtained within 12 months 6
Supp. Test Positive, 	Supp. Test Indeterminate, 	Supp. Test Indeterminate, 	Supp. Test Negative, 	Supp. Test Negative,
NAT Reactive or 	NAT Reactive 	NAT Nonreactive 	NAT Reactive 	NAT Nonreactive 	Notify consignees
Nonreactive 	of test results 5
Destroy or 	Destroy or 	Destroy or 	Destroy or 	Release prior 	Transfusion services:
relabel prior 	relabel prior 	relabel prior 	relabel prior 	collections 	notify recipients7
collections 	collections 	collections 	collections6 	of prior collections
Notify 	dating back 12 months
Notify 	Notify 	Notify 	Notify 	consignees
consignees 	consignees 	consignees 	consignees 	of test results5
of test results5 	of test results5 	of test results5 	of test results5
Recipients
Transfusion 	Transfusion 	need not 	Transfusion services:
services: 	services: 	be notified 	notify recipients7
notify recipients7 	notify recipients7 	of prior collections
dating back 12 months
1 If repeatedly reactive for anti-HCV, prior collections should be identified from the same donor dating back to the date 12 months prior to the donor’s most recent nonreactive licensed
multiantigen screening test. If NAT-reactive only, prior collections should be identified from the same donor dating back 12 months prior to the reactive NAT.
2 Within 3 calendar days after the day of obtaining the reactive NAT result or repeatedly reactive anti-HCV screening test result.
3 An appropriate supplemental test is one that includes all the antigens contained in the screening test that was performed.
4 Certain licensed HCV NAT have been labeled with a “limited supplemental claim.” When current donor test results are repeatedly reactive on an anti-HCV screening test and
reactive on HCV NAT, the reactive NAT acts as a positive supplemental test and it is not necessary to perform a licensed multiantigen supplemental test for anti-HCV.
5 Notify consignees of all test results within 45 calendar days of the current repeatedly reactive anti-HCV or NAT-reactive test result.
6 Prior collections obtained more than 12 months prior to the date of the NAT-reactive donation may be released.
7 Transfusion services must identify and notify recipients of identified prior collections, or the recipient’s physician of record, as appropriate.
Current Repeatedly Reactive Licensed Anti-HCV Screening Test,
or Reactive Licensed or Investigational NAT
Figure 1 	Lookback for Hepatitis C Virus (HCV) Based on Current Donor Test Results Using a
Licensed Screening Test for HCV Antibody or a Licensed or Investigational NAT for HCV RNA

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Table 1 	Current Review
You must take the following steps when donor test results for antibody to Hepatitis C Virus (anti-HCV) by a licensed screening
test are repeatedly reactive, or a licensed or investigational HCV RNA Nucleic Acid Test (NAT) is reactive. You must
identify and quarantine prior collections, notify the consignees and request them to quarantine prior collections. Then…
If the initial test is a
licensed …
And the additional testing 1 is a licensed
or investigational …
Then …
Notify
Consignee of
test result
Destroy/
Relabel prior
collection
Transfusion
services notify
recipients or
recipient’s
physician of
record
Release prior collection
Anti-HCV 	NR
NAT 	Reactive
X 	X3 	X3
Anti-HCV 	RR
Appropriate
Multiantigen
Supplemental
Test
Positive
X 	X 	X
NAT 	Nonreactive
Anti-HCV 	RR
Appropriate
Multiantigen
Supplemental
Test
Positive
X 	X 	X
NAT2 	Reactive
Anti-HCV 	RR
Appropriate
Multiantigen
Supplemental
Test
Indeterminate
X 	X
NAT 	Nonreactive
Anti-HCV 	RR
Appropriate
Multiantigen
Supplemental
Test
Indeterminate
X 	X 	X
NAT2 	Reactive
Anti-HCV 	RR
Appropriate
Multiantigen
Supplemental
Test
Negative
X 	X
NAT 	Nonreactive
Anti-HCV 	RR
Appropriate
Multiantigen
Supplemental
Test
Negative
X 	X3 	X3 	X4
NAT2 	Reactive
1Appropriate additional testing includes all the antigens contained in the screening test that was performed
2Certain licensed HCV NAT have been labeled with a “limited supplemental claim.” When current donor test results
are repeatedly reactive on an anti-HCV screening test and reactive on HCV NAT, the reactive NAT acts as a positive
supplemental test and it is not necessary to perform a licensed multiantigen supplemental test for anti-HCV.
3
Collections during the 12 months prior to the date of the donation testing NAT reactive
4Release collections from more than 12 months prior to the date of the donation testing NAT reactive
NR means nonreactive
RR means repeatedly reactive

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VII. 	REFERENCES
1. Sayers, M.H., and Gretch, D.R. Recombinant immunoblot and polymerase chain reaction
testing in volunteer whole blood donors screened by a multi-antigen assay for hepatitis C virus
antibodies. Transfusion 33:809-813 (1993).
2. Kleinman, S. et al. Increased detection of hepatitis C virus (HCV)-infected blood donors by a
multiple-antigen HCV enzyme immunoassay. Transfusion 32:805-813 (1992).
3. Yun, Z. et al. Detection of Hepatitis C Virus (HCV) RNA by PCR Related to HCV
Antibodies in Serum and Liver Histology in Swedish Blood Donors. J Med Virol 39:57-61
(1993).
4. Dow, B.C. et. al. Relevance of RIBA-3 Supplementary Test to HCV PCR Positivity and
Genotypes for HCV Confirmation of Blood Donors. J Med Virol 49:132-136 (1996).
5. Alter, H.J. To C or Not to C: These Are the Questions. Blood 85:1681-1695 (1995).
6. CDC. Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection
and HCV-Related Chronic Disease. MMWR Morb Mortal Wkly Rep 47 (RR-19) (1998).
7. Schreiber, G.B. et al. The Risk of Transfusion-Transmitted Viral Infections. N Engl J Med
334:1685-1690 (1996).

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APPENDIX
Recommendations for implementing historical lookback required under 21 CFR 610.48 are
included in Figures 2-4 and Tables 2-5.

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Historical Repeatedly Reactive Licensed Anti-HCV Screening Test or Reactive Licensed or Investigational NAT
Identify1 and quarantine 2 prior collections.
Notify2 consignees, request them to quarantine.
If Anti-HCV test was repeatedly reactive, review record of 	If NAT- 	Supplemental
previous multiantigen supplemental test 	reactive only, Test Not Done
destroy or 	on Historical
relabel prior 	Repeatedly Reactive
Licensed or Investigational RIBA 2.0 	Licensed or Investigational RIBA 3.0 3 	collections 	Donation
obtained within (Continued
Positive 	Negative 	Indeterminate 	May test again4 	Positive 	Negative 	Indeterminate 	12 months 	on Figure 3)
Destroy 	If NAT- 	If NAT-reactive, 	If NAT- 	If NAT-reactive, If EIA 2.0 was run, may perform 	Destroy or 	If NAT- 	If NAT-reactive, 	If NAT- 	If NAT-reactive, 	Notify
or relabel 	nonreactive 	destroy or 	nonreactive 	destroy or 	licensed EIA 3.0 or alternative test6 	relabel prior 	nonreactive 	destroy or 	nonreactive 	destroy or 	consignees
prior 	or not done, 	relabel prior 	or not done, 	relabel prior 	collections 	or not done, relabel prior 	or not done, 	relabel prior 	of test results
collections 	and if 	collections 	and if 	collections 	Nonreactive 	Repeatedly 	release 	collections 	destroy or 	collections
screening 	obtained 	not tested 	Reactive 	Notify 	prior 	obtained 	relabel prior
Notify 	test was 	within 12 mos.5 	again, 	Notify 	consignees collections within 12 mos. 5 collections 	Notify 	Transfusion services:
consignees 	EIA 2.0, 	destroy or 	consignees 	of test results 	consignees 	notify recipients
of test 	release 	Notify 	relabel prior 	of test results 	Release 	If not tested 	May test 	Notify 	Notify 	Notify of test results 	(or physician of record) of
results 	prior 	consignees 	collections 	prior 	again, 	again on 	consignees 	consignees 	consignees 	prior collections
collections5 	of test results 	collections7 destroy or licensed or 	Transfusion of test 	of test results 	of test result 	dating back 12 months
Notify 	Transfusion 	relabel prior investigational 	services: 	results 	Transfusion
Transfusion 	Notify 	consignees 	services: 	Notify 	collections 	RIBA 3.0 	notify 	Recipients 	services: notify
services: 	consignees 	Transfusion 	of test 	notify 	consignees 	recipients8 	Transfusion 	need not 	recipients8
notify 	of test 	services: notify 	results 	recipients8 	of test 	Notify 	services: notify 	be notified
recipients8 	results 	recipients (or physician 	results consignees 	recipients (or physician
of record) of prior 	of test results 	of record) of prior collections
collections dating back 	Transfusion 	dating back 12 months
12 months 	services: 	Transfusion services:
notify recipients8 	notify recipients8
1 If repeatedly reactive, prior collections should be identified from the same donor dating back to the date 12 months prior to the donor’s most recent nonreactive licensed multiantigen screening test. If
NAT-reactive only, prior collections should be identified from the same donor dating back 12 months prior to the date of the NAT-reactive donation.
2 Within 3 calendar days after the day of identifying the reactive NAT result or repeatedly reactive anti-HCV screening test result.
3 Testing already performed as an in-house service by Chiron Corp. using the Chiron RIBA HCV 3.0 SIA, or testing already performed using an investigational RIBA 3.0 in accordance with previous
guidance, is also acceptable.
4 A previously frozen serum or plasma sample from the repeatedly reactive/RIBA 2.0 indeterminate donation or a fresh sample from the same donor may be tested again. Notify consignees within 45
calendar days of completing the additional testing.
5 If the repeatedly reactive screening test was EIA 3.0 and the negative supplemental test was RIBA 2.0, destroy or label prior collections and notify transfusion recipients. Alternatively, may test again
using RIBA 3.0 (see outcomes at right). Notify consignees within 45 calendar days of completing the supplemental test result.
6An alternative test for anti-HCV is a test of equal or greater sensitivity in comparison to the licensed HCV EIA 3.0.
7If a RIBA 2.0 or RIBA 3.0 is negative, prior collections obtained more than 12 months prior to the date of the NAT-reactive donation may be released.
8 Transfusion services must identify and notify recipients, or the recipient’s physician of record, as appropriate, of identified prior collections dating back to the date 12 months prior to the donor’s most
recent nonreactive licensed multiantigen screening test for anti-HCV.
Licensed Screening Test for HCV Antibody or a Licensed or Investigational NAT for HCV RNA
Figure 2 	Lookback for Hepatitis C Virus (HCV) Based on Historical Donor Test Results Using a

Contains Nonbinding Recommendations
13
Figure 3 	Lookback for Hepatitis C Virus (HCV) Based on Historical Donor Test Results Using a
Licensed EIA 2.0 or EIA 3.0 Test for HCV Antibody or a Licensed or Investigational NAT for HCV RNA (Cont.)
Historical Repeatedly Reactive Licensed 	Identify and quarantine prior collections.
Anti-HCV EIA 2.0 or 3.0 	Notify consignees, request them to quarantine.
Supplemental Test Not Done on Historical Repeatedly Reactive Donation
If Stored Sample 1 or Fresh 	If Stored Sample 1 or Fresh
Sample from the Same Donor is Available: 	Sample from the Same Donor is Not Available:
If repeatedly reactive on an EIA 2.0: 	If repeatedly reactive on an EIA 3.0
or alternative test: 	Destroy or relabel
prior collections
Perform 	Perform licensed EIA 3.0 	Perform licensed 	Perform 	Notify consignees
licensed RIBA 2.0 or 	or alternative test 3 	or investigational NAT 	licensed RIBA 3.0 2 	of repeatedly
RIBA 3.0 2 	reactive result
Nonreactive 	Repeatedly 	Reactive 	Nonreactive 	(See outcomes
(See outcomes 	Reactive 	for RIBA 3.0
for RIBA 2.0 	in Figure 2)
or RIBA 3.0 	May test 	If not tested 	May test 	Transfusion services:
in Figure 2) 	Release 	Perform 	If not tested 	again on 	again, destroy 	again on 	notify recipients 4
prior 	licensed 	again, destroy 	licensed 	or relabel prior 	licensed
collections 	RIBA 3.0 	or relabel prior 	RIBA 3.0 	collections 	RIBA 3.0
collections
Notify 	(See outcomes 	(See outcomes 	Notify consignees 	(See outcomes
consignees 	for RIBA 3.0 	Notify consignees 	for RIBA 3.0 	of test results5 	for RIBA 3.0
of test results5 	in Figure 2) 	of test results5 	with a reactive 	with a nonreactive
NAT in Figure 2) 6 	NAT in Figure 2)
Transfusion services:
Transfusion services: 	notify recipients4
notify recipients4
1 A previously frozen serum or plasma sample from the same repeatedly reactive donation.
2 If a licensed RIBA 2.0 test or an investigational RIBA 3.0 test was performed consistent with previous guidance, refer to Figure 2 for outcomes.
3 An alternative test for anti-HCV is a test of equal or greater sensitivity in comparison to the licensed HCV EIA 3.0.
4 Transfusion services must identify and notify recipients, or the recipient’s physician of record, of identified prior collections dating back to the date 12 months prior to the donor’s most recent nonreactive licensed multiantigen
screening test for anti-HCV.
5 Notify consignees within 45 calendar days of completing the additional testing.
6 If a NAT is reactive and further testing by RIBA 3.0 is negative or indeterminate, transfusion services should identify and notify recipients, or the recipient’s physician of record, of identified prior collections dating back 12
months prior to the date of the NAT-reactive donation. If the RIBA 3.0 is negative, prior collections obtained more than 12 months prior to the date of the NAT-reactive donation may be released. If the RIBA 3.0 is
indeterminate, prior collections should be destroyed or labeled consistent with section VI of this guidance. Note that a nonreactive NAT does not obviate lookback for a repeatedly reactive donation.

Contains Nonbinding Recommendations
14
Figure 4 	Lookback for Hepatitis C Virus (HCV) Based on Historical Donor Test Results
Using an EIA 1.0 for HCV Antibody
Historical Repeatedly Reactive 	Identify1 and quarantine prior collections.
Licensed Anti-HCV EIA 1.0 	Notify2 consignees, request them to quarantine.
Additional testing performed. 	No additional testing performed.
Stored sample3 or fresh sample 	Stored sample was tested on RIBA 1.0, Neut-Peptide EIA, or RIBA 2.0, 	S/CO < 2.5 	S/CO > 2.5 or cannot
from the same donor was tested on 	or stored or fresh sample from the same donor 	be calculated
EIA 2.0, EIA 3.0, or alternative test4 	was tested on RIBA 3.0 or NAT4
Destroy or 	Destroy or
relabel prior 	relabel prior
Repeatedly 	Nonreactive 	Reactive 	Positive 	Indeterminate 	Indeterminate 	Negative 	Negative 	collections 	collections
Reactive 	NAT 	Supplemental 	RIBA 1.0 or Neut- 	RIBA 3.0 	RIBA 2.0 or 	RIBA 1.0 or
Test 	Peptide EIA or RIBA 2.0, 	RIBA 3.0 	Neut-Peptide EIA 	Notify 	Notify
or Nonreactive NAT 	consignees 	consignees
No 	May test 	Release 	If no 	May test 	Release 	of test 	of test
additional 	again 5 using 	prior 	additional again using 	Destroy or 	prior 	If no 	May test 	results 	results
test 	RIBA 2.0 or 	collections 	test is 	RIBA 2.0 or 	Destroy or 	relabel prior 	collections 	additional 	again using
RIBA 3.0 or 	performed, 	RIBA 3.05 	relabel prior 	If no 	May test 	collections 	test is 	EIA 2.0, 	Recipients
NAT 	Notify 	destroy or 	(See 	collections 	additional 	again using 	Notify 	performed, 	EIA 3.0, or 	need not 	Transfusion
Destroy or 	consignees relabel prior outcomes 	test is 	EIA 3.0 or 	Notify 	consignees 	destroy or 	alternative test4,5 	be notified 	services:
relabel prior 	(See outcomes 	of test 	collections 	for 	Notify 	performed, 	alternative test4,5 consignees 	of test 	relabel prior 	or RIBA 3.0 	notify
collections 	for RIBA 2.0, 	results6 	RIBA 2.0 7 	consignees 	destroy or 	or RIBA 3.0 	of test 	results6 	collections 	or NAT 	recipients8
RIBA 3.0, 	Notify 	or RIBA 3.07 	of test 	relabel prior 	results6
Notify 	or NAT 	consignees 	with a 	results6 	collections 	(See outcomes 	Notify 	(See outcomes
consignees 	in the bracket 	of test 	reactive 	for EIA 3.0 	Recipients 	consignees 	for EIA 2.0 or
of test results6 to the right)7 	results6 	NAT 	Notify 	or RIBA 3.0 	need not 	of test 	EIA 3.0 in the
in Fig.2) 	Transfusion consignees 	in Figure 2) 	be notified 	results 	bracket at far left,
services: 	of test 	or for RIBA 3.0
Transfusion 	Transfusion 	notify 	results 	Recipients 	or NAT in this
services: 	services: 	recipients8 	need not 	bracket to the left)6
notify 	notify 	be notified
recipients8 	recipients8 	Transfusion
services:
notify
recipients8
1Previously distributed units should be identified dating back 12 months prior to the donor’s most recent nonreactive licensed screening test for anti-HCV.
2Within 3 calendar days after the day of identifying the repeatedly reactive anti-HCV screening test results.
3 A previously frozen serum or plasma sample from the same repeatedly reactive donation.
4 An alternative test for anti-HCV is a test of equal or greater sensitivity in comparison to the licensed HCV EIA 3.0.
5 The supplemental test performed should include all the antigens contained in the screening test that was performed.
6 Notify consignees within 45 calendar days of obtaining the supplemental or additional test result.
7 If a NAT is reactive and further testing by RIBA 2.0 or RIBA 3.0 is negative, prior collections obtained more than 12 months prior to the date of the NAT-reactive donation may be released, and transfusion services must
identify and notify recipients of prior collections dating back 12 months prior to the date of the NAT-reactive donation. If the RIBA 2.0 is indeterminate, destruction or labeling of prior collections and notification of recipients
are not limited to collections within 12 months prior to the NAT-reactive donation. If the RIBA 3.0 is indeterminate, destruction or labeling of prior collections is not limited to collections within 12 months prior to the NAT-
reactive donation, but notification of recipients should extend back only 12 months prior to the NAT-reactive donation. Note that a nonreactive NAT does not obviate lookback for a repeatedly reactive donation.
8 Transfusion services must identify and notify recipients, or recipient’s physician of record, as appropriate, of identified prior collections.

Contains Nonbinding Recommendations
15
Table 2 	Historical Review
You must take the following steps when donor test results for antibody to Hepatitis C Virus (anti-HCV) by a licensed screening
test are repeatedly reactive, or a licensed or investigational HCV RNA Nucleic Acid Test (NAT) is reactive. You must
identify and quarantine prior collections, notify the consignees and request them to quarantine prior collections. Then …
If the historical
initial test is a
licensed …
And the historical additional
testing 1 is a licensed or
investigational …
Then …
Notify
Consignee of test
result
Destroy/
Relabel prior
collection
Transfusion
services notify
recipients or
recipient’s
physician of
record
Release prior collection
EIA 2.0
or
3.0
RR 	NFT 	Sample available 	See Table 4
EIA 2.0
or 3.0
RR
RIBA 2.0 	Positive
X 	X 	X	
NAT 	Reactive,
Nonreactive or NP
EIA 2.0 	RR 	RIBA 2.0 	Negative 	X 	X
NAT 	Nonreactive or NP
EIA 3.0 	RR 	RIBA 2.0 	Negative 	X 	X 	X
NAT 	Nonreactive or NP
EIA 2.0 	RR
RIBA 2.0 	Negative
X 	X2 	X2 	X3
NAT 	Reactive
EIA 3.0 	RR
RIBA 2.0 	Negative
X 	X 	X	NAT 	Reactive
EIA 2.0
or 3.0
RR
RIBA 2.0 	Indeterminate
X 	X 	X	NAT 	Nonreactive or NP
EIA 2.0
or 3.0
RR
RIBA 2.0 	Indeterminate
X 	X 	X
NAT 	Reactive
EIA 2.0 	RR
RIBA 2.0 	Indeterminate
X 	X
(MTA)
EIA 3.0 or
alternative
Nonreactive
NAT 	Nonreactive or NP
EIA 2.0 	RR
RIBA 2.0 	Indeterminate
X 	X 	X
(MTA)
EIA 3.0 or
alternative 	Reactive
NAT 	Nonreactive or NP
EIA 2.0
or 3.0
RR
RIBA 2.0 	Indeterminate
See Table 3	
NAT 	Nonreactive or NP
RIBA 3.0
EIA 2.0
or 3.0
NR 	NAT only 	Reactive 	X 	X2 	X2
1Appropriate additional testing includes all the antigens contained in the screening test that was performed
2Collections during the 12 months prior to the date of the donation testing NAT reactive
3Release collections more than 12 months prior to the date of the donation testing NAT reactive
NR means non-reactive
RR means repeatedly reactive
MTA means may test again
NFT means not further tested
NP means not performed

Contains Nonbinding Recommendations
16
Table 3 	Historical Review
You must take the following steps when donor test results for antibody to Hepatitis C Virus (anti-HCV) by Licensed HCV
EIA 2.0 or EIA 3.0 are repeatedly reactive, or a licensed or investigational HCV RNA Nucleic Acid Test (NAT) is
reactive. You must identify and quarantine prior collections, notify the consignees and request them to quarantine prior
collections. Then …
If the historical initial
test is a licensed …
And the historical additional
testing 1 is a licensed or
investigational …
Then …
Notify
Consignee of test
result
Destroy/
Relabel prior
collection
Transfusion
services notify
recipients or
recipient’s
physician of
record
Release prior
collection
EIA 2.0 or 3.0 	RR
RIBA 3.0 	Positive
X 	X 	X
NAT 	Reactive,
Nonreactive or NP
EIA 2.0 or 3.0 	RR
RIBA 3.0 	Negative
X 	X
NAT 	Nonreactive or NP
EIA 2.0 or 3.0 	RR
RIBA 3.0 	Negative
X 	X2 	X2 	X3
NAT 	Reactive
EIA 2.0 or 3.0 	RR
RIBA 3.0 	Indeterminate
X 	X
NAT 	Nonreactive or NP
EIA 2.0 or 3.0 	RR
RIBA 3.0 	Indeterminate
X 	X 	X
NAT 	Reactive
1Appropriate additional testing includes all the antigens contained in the screening test that was performed
2Collections during the 12 months prior to the date of the donation testing NAT reactive
3Release collections more than 12 months prior to the date of the donation testing NAT reactive
RR means repeatedly reactive
NFT means not further tested
NP means not performed

Contains Nonbinding Recommendations
17
Table 4 	Historical Review
You must take the following steps when donor test results for antibody to Hepatitis C Virus (anti-HCV) by Licensed HCV
EIA 2.0 or EIA 3.0 are repeatedly reactive, or a licensed or investigational HCV RNA Nucleic Acid Test (NAT) is
reactive. You must identify and quarantine prior collections, notify the consignees and request them to quarantine prior
collections. Then …
If the historical
initial test is a
licensed …
And the historical additional testing 1
is a licensed or investigational …
Then …
Notify
Consignee of test
result
Destroy/
Relabel prior
collection
Transfusion
services notify
recipients or
recipient’s
physician of
record
Release prior
collection
EIA 2.0 	RR
RIBA 2.0 	See Table 2
RIBA 3.0 	See Table 3
EIA 2.0 	RR
EIA 3.0 or
alternative 	Nonreactive 	X 	X
EIA 2.0 	RR
EIA 3.0 or
alternative 	Reactive
X 	X 	X
(NFT)
EIA 2.0 	RR
EIA 3.0 or
alternative 	Reactive
See Table 3
RIBA 3.0
EIA 3.0 	RR
RIBA 3.0
See Table 3
EIA 2.0
or 3.0
RR
NAT 	Nonreactive
See Table 3	
(MTA)
RIBA 3.0
EIA 2.0
or 3.0
RR
NAT
Nonreactive or
Reactive
X 	X2 	X2 	X3
(NFT)
EIA 2.0
or 3.0
RR
NAT 	Reactive
See Table 3
(MTA)
RIBA 3.0
EIA 2.0
or 3.0
RR 	(NFT) 	No Sample
Available
X 	X 	X
1Appropriate additional testing includes all the antigens contained in the screening test that was performed
2Collections during the 12 months prior to the date of the donation testing NAT reactive
3Release collections more than 12 months prior to the date of the donation testing NAT reactive
RR means repeatedly reactive
MTA means may test again
NFT means not further tested

Contains Nonbinding Recommendations
18
Table 5 	Historical Review
You must take the following steps when donor test results for antibody to Hepatitis C Virus (anti-HCV) by Licensed HCV
EIA 1.0 are repeatedly reactive. You must identify and quarantine prior collections, notify the consignees and request
them to quarantine prior collections. Then …
If the historical initial test is
a licensed …
And the additional testing 1 is a
licensed or investigational …
Then …
Notify
Consignee of test
result
Destroy/
Relabel prior
collection
Transfusion
services notify
recipients or
recipient’s
physician of
record
Release prior
collection
EIA 1.0 	S/CO
≤ 2.5
(NFT)
X 	X
EIA 1.0
S/CO >2.5 or
cannot be
calculated
(NFT)
X 	X 	X
EIA 1.0 	RR
EIA 2.0 or 3.0
or alternative
Reactive
X 	X 	X
(NFT)
EIA 1.0 	RR
EIA 2.0 or 3.0
or alternative
Reactive
See Below	(MTA)
RIBA 2.0 or
3.0 or NAT
EIA 1.0 	RR
EIA 2.0 or 3.0
or alternative
Nonreactive
X 	X
EIA 1.0 	RR
NAT 	Reactive
X 	X 	X
(NFT)
EIA 1.0 	RR
NAT 	Reactive
(MTA)
RIBA 2.0 Negative 	X 	X2 	X2 	X3
Indeterminate 	X 	X 	X
(MTA)
RIBA 3.0 Negative 	X 	X2 	X2 	X3
Indeterminate 	X 	X 	X2
EIA 1.0 	RR
RIBA 1.0, 2.0,
or 3.0; or
Neut-Peptide
EIA
Positive
X 	X 	X

Contains Nonbinding Recommendations
19
Table 5 (Continued) 	Historical Review
1
Appropriate additional testing includes all the antigens contained in the screening test that was performed
2
Collections during the 12 months prior to the date of the donation testing NAT reactive
3
Release collections more than 12 months prior to the date of the donation testing NAT reactive
NR means non-reactive
RR means repeatedly reactive
MTA means may test again
NFT means not further tested
You should take the following steps when donor test results for antibody to Hepatitis C Virus (anti-HCV) by Licensed HCV
EIA 1.0 are repeatedly reactive. You should identify and quarantine prior collections, notify the consignees and request
them to quarantine prior collections. Then …
If the historical
initial test is a
licensed …
And the additional testing 1 is a
licensed or investigational …
Then …
Notify
Consignee of test
result
Destroy/
Relabel prior
collection
Transfusion
services notify
recipients or
recipient’s
physician of
record
Release prior
collection
EIA 1.0 	RR
RIBA 1.0 or 2.0;
or Neut-Peptide
EIA
Indeterminate
X 	X 	X
(NFT)
EIA 1.0 	RR
NAT 	Nonreactive
X 	X 	X	(NFT)
EIA 1.0 	RR
RIBA 1.0 or 2.0;
or Neut-Peptide
EIA
Indeterminate
X 	X
NAT 	Nonreactive
(MTA) EIA 3.0 or
alternative; or
RIBA 3.0
See Table 3
EIA 1.0 	RR
RIBA 1.0 or 2.0;
or Neut-Peptide
EIA
Indeterminate
X 	X	NAT 	Nonreactive or NP
(MTA) EIA 3.0 or
alternative; or 	Nonreactive
RIBA 3.0 	Negative
EIA 1.0 	RR 	RIBA 3.0 	Indeterminate 	X 	X
EIA 1.0 	RR
RIBA 2.0 or 3.0 	Negative
X 	X
NAT 	Nonreactive or NP
EIA 1.0 	RR
RIBA 2.0 or 3.0 	Negative
X 	X3
NAT 	Reactive
EIA 1.0 	RR
RIBA 1.0 or Neut-
Peptide EIA
Negative
X 	X
(NFT)
EIA 1.0 	RR
RIBA 1.0 or Neut-
Peptide EIA
Negative
See outcomes above
(MTA) EIA 2.0 or
3.0 or alternative;
or RIBA 3.0; or
NAT