Requalification of Donors Previously 
Deferred for a History of Viral Hepatitis 
th
after the 11  Birthday
 
 
 
Guidance for Industry 
 
 
 
 
 
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 any time.  Submit electronic comments to http://www.regulations.gov.  Submit 
written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.  You should identify all comments with 
docket number FDA-2017-D-5152. 
 
Additional copies of this guidance are available from the Office of Communication, Outreach 
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, 
MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, 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 or email 
address listed above. 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
September 2017  Contains Nonbinding Recommendations 
 
Table of Contents 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DISCUSSION .................................................................................................................... 3 
IV.  RECOMMENDATIONS .................................................................................................. 4 
A.  Standard Operating Procedures for Requalification of Donors Previously 
Deferred for a History of Viral Hepatitis ........................................................... 4 
B.  Requalification of Donors Previously Deferred for a History of Viral 
Hepatitis ................................................................................................................. 4 
V.  IMPLEMENTATION ...................................................................................................... 5 
A.  Implementation without Modification or with More Restrictive Criteria ...... 5 
B.  Implementation with Modification ...................................................................... 6 
VI.  REFERENCES .................................................................................................................. 7 
i  Contains Nonbinding Recommendations 
 
Requalification of Donors Previously Deferred for a History of Viral 
Hepatitis after the 11th Birthday 
 
 
Guidance for Industry 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA 
or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
responsible for this guidance as listed on the title page.  
 
 
I.  INTRODUCTION 
 
We, FDA, are issuing this guidance to provide you, establishments that collect Whole Blood or 
blood components intended for transfusion or for further manufacture, including Source Plasma 
and Source Leukocytes, with recommendations for a requalification method under Title 21 of the 
Code of Federal Regulations (CFR) 630.35(b) (21 CFR 630.35(b)) for donors who had been 
indefinitely deferred for a history of viral hepatitis after the 11th birthday, prior to the elimination 
of the donor suitability requirement under 21 CFR 640.3(c)(1) and 21 CFR 640.63(c)(11).1  
 
This guidance also advises licensed manufacturers who choose to implement the 
recommendations on how to report the manufacturing change to FDA under 21 CFR 601.12.   
 
This guidance does not apply to individuals with reactive donor screening test results for 
hepatitis B virus (HBV) and hepatitis C virus (HCV) who are deferred under 21 CFR 610.41(a) 
or to the requalification methods after reactive donor screening test results for HBV and HCV 
under 21 CFR 610.41(b) recommended in separate guidance documents. 
 
This guidance supersedes the following memoranda to blood establishments:  Donor Suitability 
Related to Laboratory Testing for Viral Hepatitis and a History of Viral Hepatitis dated 
December 22, 1993 (1993 Memorandum) and Exemptions to Permit Persons with a History of 
Viral Hepatitis Before the Age of Eleven Years to Serve as Donors of Whole Blood and Plasma: 
Alternative Procedures, 21 CFR 640.120 dated April 23, 1992. 
 
                                                 
1 See Requirements for Blood and Blood Components Intended for Transfusion or for Further Manufacturing Use; 
Final Rule (80 FR 29842, May 22, 2015), effective May 23, 2016.  Sections 640.3 and 21 CFR 640.63 were 
removed in this final rule. 
1  Contains Nonbinding Recommendations 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe FDAs 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 FDAs guidances means that something is suggested or 
recommended, but not required. 
 
 
II.  BACKGROUND 
 
The longstanding requirement to evaluate donors for a history of hepatitis was introduced in the 
1950s before HBV and HCV were recognized and before specific laboratory tests became 
available to screen all donations.  The regulations, in place until May 23, 2016, precluded 
donation by individuals with a history of viral hepatitis after the 11th birthday from Whole 
Blood and Source Plasma donation (21 CFR 640.3(c)(1) and 21 CFR 640.63(c)(11), 
respectively).  The age-related exception was allowed because most cases of viral hepatitis that 
occurred in donors when they were younger than 11 years were attributed to hepatitis A virus 
(HAV).  HAV would not have caused a chronic and therefore potentially transfusion-
transmissible infection in the donor.  The regulations persisted for many years because it was 
unknown if there were viruses other than HBV and HCV that could cause chronic 
posttransfusion hepatitis.   
 
FDA provided further recommendations for evaluating donors for a history of hepatitis in a 1993 
Memorandum (Ref. 1).  FDA advised manufacturers to assess donor suitability by asking the 
donor about physical signs or symptoms of clinical hepatitis (e.g., jaundice), history of liver 
disease, viral hepatitis or a positive test for hepatitis.  As a result, the deferral captured not only 
individuals with HBV or HCV, but also those who reported HAV or certain other, common viral 
infections associated with jaundice, such as cytomegalovirus (CMV) and infectious 
mononucleosis caused by Epstein-Barr virus (EBV), which do not cause chronic posttransfusion 
hepatitis.  The deferral rate exceeded 1 in 5,000 individuals who presented to donate blood each 
year (Ref. 2).  The policy ultimately resulted in the disqualification of thousands of individuals 
who did not have HBV or HCV and required blood establishments to maintain their names in 
donor deferral records (Ref. 3).  
 
In March 2000, FDA held a Blood Products Advisory Committee (BPAC) meeting to consider 
whether there was sufficient information to eliminate the exclusion of donors with a history of 
viral hepatitis (Ref. 3).  The points that emerged were that the regulations were likely useful in 
the past to prevent posttransfusion hepatitis, but their contribution to transfusion safety was 
questionable after the introduction of sensitive donor screening tests for HBV and HCV.  In 
addition, data presented at the BPAC meeting demonstrated the limited utility of asking 
questions about hepatitis, because most infected individuals did not report a history of hepatitis 
(Ref. 3).  The committee voted unanimously (13-0) that the exclusion of donors with a history of 
viral hepatitis should be eliminated or modified to exclude donors only for a limited time (e.g., 
for one year after disappearance of symptoms).  
 
2  Contains Nonbinding Recommendations 
 
Since the discovery of HCV as the cause of non-A/non-B transfusion-transmitted hepatitis, no 
additional viral hepatitis agents have been identified to cause chronic, asymptomatic infections in 
donors that might pose significant health risks to transfusion recipients based on a prior history 
of hepatitis (Refs. 4-7).  Moreover, public health initiatives to increase awareness have 
prioritized prevention strategies for HBV and HCV (Ref. 8).  Current donor screening tests have 
reduced the window periods of viral detection to 18.5  26.5 days for HBV and 7.4 days for 
HCV (Refs. 9 and 10).  The corresponding calculated transfusion risk of viral transmission per 
unit is 1:1,149,000 for HCV and 1:843,000  1:1,208,000 for HBV based on mathematical 
models (Refs. 9 and 10).   
 
On May 22, 2015 (80 FR 29842), FDA published revised regulations for the determination of 
blood donor eligibility and eliminated the requirement to defer donors with a history of viral 
hepatitis after the 11th birthday.  The revised regulations also include donor requalification 
requirements under 21 CFR 630.35.  This guidance describes an acceptable process for blood 
establishments to requalify donors previously deferred for a history of viral hepatitis, as required 
by 21 CFR 630.35(b).   
 
 
III.  DISCUSSION 
 
Individuals with a history of viral hepatitis after the 11th birthday who had been indefinitely 
deferred prior to the effective date of the revised donor eligibility regulations (80 FR 29842, May 
22, 2015, effective May 23, 2016) may be requalified as donors if the reason for the hepatitis-
related deferral was not infection with HBV or HCV and all other eligibility requirements are 
met.  
 
Current regulations require that donors must be in good health and free from transfusion-
transmitted infections (21 CFR 630.10(a)). Blood establishments must assess the donors 
medical history to identify clinical evidence of a relevant transfusion-transmitted disease  
(21 CFR 630.10(e)).  In the context of this guidance, clinical evidence of HBV or HCV includes 
a medical diagnosis of HBV or HCV at any age regardless of symptoms, including a history of 
spontaneous resolution, treatment, or diagnostic test results that indicate current or past HBV or 
HCV infection.   
 
Individuals are not eligible to donate if the purpose of donating is to obtain test results for a 
relevant transfusion-transmitted infection (RTTI) (21 CFR 630.10(e)(2)(vi)).  Individuals with 
reactive test results for RTTI including HBV and HCV are deferred under 21 CFR 610.41(a). 
 
 
3  Contains Nonbinding Recommendations 
 
IV.  RECOMMENDATIONS 
 
A.  Standard Operating Procedures for Requalification of Donors Previously 
Deferred for a History of Viral Hepatitis 
 
Blood establishments that choose to requalify donors must:  a) establish a standard 
operating procedure (SOP) to include the criteria used to determine donor eligibility for 
those individuals who were previously deferred for a history of viral hepatitis after the 
11th birthday (21 CFR 606.100(b)(1)).  The SOP should describe processes to evaluate 
the previous reason for deferral and assess the donors eligibility for reentry.  The process 
could include but is not limited to reviewing donor records, re-interviewing the donor or 
obtaining further medical consultation, as appropriate.  The blood establishment should 
have a process to manage information provided by the donor or reliable third party at any 
stage in the screening process. 
 
With respect to the recommendations for the responsible physician to assess an individual 
donors eligibility, as described below in section IV.B.3, the determination cannot be 
delegated to a trained person or physician substitute.  However, the responsible physician 
may make this eligibility determination by telephonic or other offsite consultation. 
 
Blood establishments must follow their SOPs for documenting the criteria used to 
determine donor eligibility for those individuals who were previously deferred for a 
history of viral hepatitis after the 11th birthday (21 CFR 606.100(b)).  We recommend 
that requalified individuals be removed from the donor deferral registry.  
 
B.  Requalification of Donors Previously Deferred for a History of Viral 
Hepatitis 
 
Individuals who have had HBV or HCV infection at any age, regardless of symptoms, 
spontaneous resolution or treatment, must be indefinitely deferred (21 CFR 630.10(a)) 
and are not eligible for reentry.   
 
Currently, FDA has not identified an acceptable method or process for requalification of 
previously deferred individuals with the following history:  
 
a.  Clinical diagnosis or confirmed laboratory tests for HBV at any age. 
OR 
b.  Clinical diagnosis or confirmed laboratory tests for HCV at any age. 
 
4  Contains Nonbinding Recommendations 
 
1.  History of viral hepatitis or specific diagnosis of hepatitis other than HBV or 
HCV  
 
The following donors may be eligible for reentry without performing predonation 
testing if the donor otherwise meets all eligibility criteria:   
 
a.  Previous reason for deferral was for HAV. 
b.  Previous reason for deferral was for infectious mononucleosis or viral 
hepatitis due to EBV or CMV.  
 
2.  History of viral hepatitis with an unknown or uncertain clinical diagnosis    
 
If the deferred donor is uncertain about his or her medical diagnosis, test results or 
whether they had HBV or HCV, the responsible physician should determine if the 
donor qualifies for reentry.  The responsible physicians assessment may include but 
is not limited to interviewing the donor, interpreting the results of laboratory testing 
for HCV and HBV, if available, and/or referring the donor for further evaluation as 
necessary.  
 
If the blood establishment performs testing for HBV and HCV to obtain additional 
information about the donors infection status, a sample should be drawn separate 
from a donation.  The test results should be available and be negative/non-reactive 
before donations can begin.  
 
If the responsible physician determines that the previously deferred donor does not 
have evidence of current or past HBV or HCV infection, the donor may be eligible 
for reentry provided all eligibility criteria are met.  
 
 
V.  IMPLEMENTATION 
 
A.  Implementation without Modification or with More Restrictive Criteria  
 
We consider the recommendations in this guidance to be an acceptable method or process 
within the meaning of 21 CFR 630.35(b), for requalifying donors who were previously 
deferred for a history of viral hepatitis.  
 
If the recommendations in this guidance are implemented without modification in their 
entirety or if a more restrictive process is adopted, we consider this to be a minor change.  
Blood establishments should report the change as follows:   
 
1.  Licensed blood establishments must report this change to FDA in the annual 
report under 21 CFR 601.12(d), noting the date the method or process was 
implemented.  See 21 CFR 601.12(a)(3). 
2.  Unlicensed blood establishments are not required to report this change to FDA.  
 
5  Contains Nonbinding Recommendations 
 
B.  Implementation with Modification   
 
Procedures for determining donor eligibility potentially may have an adverse effect on 
the identity, strength, quality, purity, or potency of blood and blood components, as they 
may relate to the safety or effectiveness of the product.  Therefore, implementing a 
method or process that is less restrictive than the recommendations in this guidance is a 
major change.   
 
Therefore, blood establishments must report modified, less restrictive donor 
requalification processes to FDA as follows: 
 
Licensed blood establishments must report the change as a Prior Approval 
Supplement (PAS) under 21 CFR 601.12(b).  We recommend that the supplement 
include the following:  
 
a.  Form FDA 356h Application to Market a New or Abbreviated New Drug or 
Biologic for Human Use which may be obtained at 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm.  
b.  A cover letter describing the request and the contents of the submission.  
c.  A written SOP describing the requalification method or process.  
 
Similarly, before an unlicensed establishment implements a modified, less restrictive 
requalification method or process from that described in this guidance, FDA must first 
find the method or process to be acceptable for such purpose (21 CFR 630.35(b)). 
 
6  Contains Nonbinding Recommendations 
 
VI.  REFERENCES  
 
1.  Memorandum:  Donor Suitability Related to Laboratory Testing for Viral Hepatitis and a 
History of Viral Hepatitis, December 22, 1993.  
 
2.  Eder, AF and Bianco, C, Screening Blood Donors, AABB Press, Bethesda MD, 2007; p.xvi. 
 
3.  FDA Blood Products Advisory Committee, Sixty-fifth meeting Blood Donor Deferral for a 
History of Hepatitis, March 16, 2000; 179-252.  Available at 
https://www.fda.gov/ohrms/dockets/ac/cber00.htm#Blood%20Prducts. 
 
4.  Akiba J, et al.  SEN virus: epidemiology and characteristics of a transfusion-transmitted 
virus.  Transfusion 45:1084-1088 (2005). 
 
5.  Alter MJ, et al.  Acute non-A-E hepatitis in the United States and the role of hepatitis G virus 
infection.  New Engl J Med 336:741-746 (1997).  
 
6.  Moorman AC, et al.  Baseline characteristics and mortality among people in care for chronic 
viral hepatitis:  The chronic hepatitis cohort study.  Clin Infect Dis 56:40-50 (2013). 
 
7.  CDC, Viral hepatitis:  Statistics and Surveillance.  Available at 
https://www.cdc.gov/hepatitis/statistics/index.htm. 
 
8.  Department of Health and Human Services, National Virus Hepatitis Action Plan 2017-2020.  
Available at https://www.cdc.gov/hepatitis/policy/strategicplansrpts.htm. 
 
9.  Zou S, et al.  Prevalence, incidence, and residual risk of human immunodeficiency virus and 
hepatitis C virus infections among United States blood donors since introduction of nucleic 
acid testing.  Transfusion 50:1495-1504 (2010). 
 
10. Stramer, SL, Notari, EP, Krysztof, DE, Dodd, RY.  Hepatitis B virus testing by minipool 
nucleic acid testing: does it improve blood safety?  Transfusion 53:2449-58 (2013).   
 
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