Labeling of Red Blood Cell Units with 
Historical Antigen Typing Results 
 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
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 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guid
ances/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 
December 2018 
 
 
 
OMB Control No. 0910-0862 
Expiration Date:  11/30/2021 
See additional PRA statement in Section VI of this guidance Contains Nonbinding Recommendations 
 
Table of Contents 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
A.  Non-ABO/Rh(D) Blood Group Antigens and Current Approaches for Typing 
RBC and Selecting Units for Transfusion .......................................................... 1 
B.  Current Approaches for Labeling RBC Units with Previously Determined 
(Historical) Non-ABO/Rh(D) Typing Results .................................................... 2 
C.  Previous Discussions about Historical RBC Antigen Typing ........................... 3 
III.  RECOMMENDATIONS .................................................................................................. 3 
A.  RBC Antigen Typing for Non-ABO/Rh(D) Antigens ........................................ 3 
B.  Labeling RBC Units with Historical RBC Antigen Typing Results ................. 4 
C.  Additional Procedures for Managing Units with Historical RBC Antigen 
Typing Results ....................................................................................................... 6 
IV.  REPORTING IMPLEMENTATION:  CHANGES TO AN APPROVED 
APPLICATION................................................................................................................. 6 
V.  REFERENCES .................................................................................................................. 8 
VI.  PAPERWORK REDUCTION ACT OF 1995 ................................................................ 9 
i  Contains Nonbinding Recommendations 
 
Labeling of Red Blood Cell Units with Historical Antigen  
Typing Results 
 
 
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 document to provide you, establishments that collect blood 
and blood components for transfusion, with recommendations for labeling Red Blood Cell 
(RBC) units with non-ABO/Rh(D) antigen typing results obtained from previous donations 
(historical antigen typing results).  This guidance provides recommendations to transfusion 
services for managing RBC units labeled with historical antigen typing results.  This guidance 
also provides licensed blood establishments that choose to implement labeling of RBC units with 
historical antigen typing results instructions regarding how to report the manufacturing and 
labeling changes under 21 CFR 601.12.  This guidance does not apply to test results for ABO 
and Rh(D) antigens.  For ABO and Rh(D) antigens, you must follow FDA requirements in  
21 CFR 640.5(b) and (c), and 606.121(c)(9) and (13), as well as all other applicable 
requirements.   
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the 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 
 
A.  Non-ABO/Rh(D) Blood Group Antigens and Current Approaches for Typing 
RBC and Selecting Units for Transfusion   
 
In addition to ABO and Rh(D) RBC antigens, there are over 300 antigens that have been 
recognized on RBCs (Ref. 1).  Some individuals develop antibodies to non-ABO/Rh(D) 
antigens that they lack on their own RBCs (alloantibodies), following exposure to foreign 
RBC antigens through blood transfusion or pregnancy.  The proportion of patients with 
1  Contains Nonbinding Recommendations 
 
non-ABO/Rh(D) RBC alloantibodies is estimated to be 1-2 percent in the general hospital 
population; however, it is much higher in patients who are chronically transfused and in 
multiparous females (Ref. 2).  Some alloantibodies may be clinically significant, causing 
a hemolytic transfusion reaction if the patient receives a transfusion of RBCs that have 
the corresponding antigen(s).  Therefore, pre-transfusion testing routinely includes tests 
to detect clinically significant RBC alloantibodies and to select RBC units that lack the 
corresponding antigen(s).  It is also common practice to provide RBC units that match a 
chronically transfused patients non-ABO/Rh(D) antigen phenotype to prevent the 
development of alloantibodies.  
 
When a prospective transfusion recipient has one or more clinically significant 
alloantibodies or needs antigen matched RBCs, the transfusion service obtains RBC units 
that lack the corresponding antigens.  The ease with which such antigen negative units 
can be found depends on several factors, including the prevalence of the RBC antigens in 
the donor population, the availability of reagents and tests to detect the antigens on donor 
RBCs, and the availability of RBC units from donors whose non-ABO/Rh(D) antigen 
types have been previously determined.  
 
Blood collection establishments and transfusion services can locate suitable antigen 
negative RBC units by randomly testing units from their inventory; however, the process 
can be time consuming, labor and resource intensive, and difficult to complete in 
emergency situations.  If records of RBC antigen typing results are retained and linked to 
donors, historical typing results can be used to select current antigen negative units in 
inventory that match the types needed by the recipient.  Blood collection establishments 
may confirm the historical typing results by testing samples from the current donations 
before labeling the units with the test results.  
 
Blood establishments typically perform serologic testing for non-ABO/Rh(D) RBC 
antigens using FDA licensed typing reagents.  If a licensed typing reagent for a particular 
antigen is not available, blood establishments might choose to use an unlicensed typing 
reagent with appropriate positive and negative controls (Ref. 3).  Some blood 
establishments use FDA approved molecular tests (i.e., gene sequence-based) to 
determine donors predicted RBC phenotypes.  When an unapproved molecular test is 
used, the results are usually verified by testing the RBCs for selected antigens using 
serologic tests or approved molecular tests, when feasible.   
 
B.  Current Approaches for Labeling RBC Units with Previously Determined 
(Historical) Non-ABO/Rh(D) Typing Results 
 
To convey historical RBC antigen typing results to transfusion services, blood collection 
establishments have traditionally used either a separate document included with the 
shipment of RBC units or a tie-tag attached to each unit that lists the historical RBC 
typing results and associates them with the current donations.  Statements on the 
document or the tie-tag may indicate that the results are historical, whether they were 
obtained on one or more previous donations, and whether the results were confirmed by 
testing the current donation prior to labeling. 
2  Contains Nonbinding Recommendations 
 
 
Some transfusion services confirm historical antigen typing results provided by the blood 
collection establishment by repeating the testing on the current donations.  The practice 
of a transfusion service may be to confirm results regardless of whether they were 
obtained on previous donations or the current donation, or to confirm only historic 
results.  The ability of a transfusion service to repeat the typing depends on whether an 
intended recipients condition allows time for the testing to be performed and whether the 
necessary reagents/tests are available.  
 
C.  Previous Discussions about Historical RBC Antigen Typing  
 
FDAs Blood Products Advisory Committee (the Committee) discussed this topic on 
December 4, 2012.  Following presentations that described current practices in the United 
States, the Canadian experience labeling RBC units with historical RBC antigen typing 
results, and the AABB workgroup suggestions and RBC antigen typing using molecular 
tests, the Committee supported the concept of using historical RBC antigen typing results 
to label RBC units (Ref. 4).   
 
The Committee agreed that current processes to ensure donor identification and accurate 
linkage of sequential donations with the donor were adequate to allow the labeling of 
current donations with historical RBC antigen typing results.  The Committee 
recommended that labeling with historical RBC antigen typing results should occur only 
if results from two previous donations were available.  Most Committee members did not 
think that confirmation of historical RBC antigen typing results on the current donations 
prior to transfusion was necessary, and agreed that serologic or molecular tests were 
acceptable to determine non-ABO/Rh(D) RBC antigen types. 
 
AABB has revised its standards to include accommodations for labeling RBC units with 
historical RBC typing results.  According to the 30th Edition of the AABB Standards for 
Blood Banks and Transfusion Services (Standards) (Ref. 5), RBC units may be labeled as 
RBC antigen negative without testing the current donation if two previous separate 
donations were tested by the collection facility and results of RBC typing were found to 
be concordant.  The Standards indicate that facilities have the option to put the non- 
ABO/Rh(D) historical antigen typing results on a tie-tag or directly on the container 
label.  
 
 
III.  RECOMMENDATIONS 
 
A.  RBC Antigen Typing for Non-ABO/Rh(D) Antigens 
 
When typing RBC units for non-ABO/Rh(D) antigens, you should perform RBC antigen 
typing using FDA licensed serologic reagents or FDA approved molecular tests.  If you 
choose to use an unlicensed reagent or unapproved molecular test, for example, because a 
licensed reagent for a rare antigen is not available, we recommend the following: 
 
3  Contains Nonbinding Recommendations 
 
1.  Unlicensed RBC typing reagents, including serum/plasma prepared for in-house 
use as RBC typing reagents, expired licensed RBC antigen typing reagents, and 
unapproved molecular tests should be used only with the approval of the 
responsible physician (Ref. 3).  The responsible physician may choose to approve 
the use of unlicensed reagents or unapproved tests on a case by case basis or the 
responsible physician may choose to approve standard operating procedures that 
describe the conditions under which unlicensed reagents or unapproved tests may 
be used.  The procedures should include testing of subsequent donations for each 
RBC antigen using a licensed reagent or approved test, when feasible.   
 
2.  Unlicensed RBC typing reagents, including serum/plasma prepared for in-house 
use as RBC typing reagents, and expired licensed RBC antigen typing reagents 
should be used only with appropriate positive and negative controls.  You must 
maintain laboratory control procedures that include adequate provisions for 
monitoring the reliability, accuracy, precision and performance of test procedures 
and instruments, and records of such tests must be maintained consistent with  
21 CFR 606.140(b) and 606.160. 
 
3.  Unapproved molecular tests for in-house use in RBC antigen typing should be 
used only with appropriate positive and negative controls.  You must maintain 
laboratory control procedures that include adequate provisions for monitoring the 
reliability, accuracy, precision and performance of test procedures and 
instruments, and records of such tests must be maintained consistent with  
21 CFR 606.140(b) and 606.160.   
 
4.  Historical RBC antigen typing results obtained using molecular test kits that were 
for research use only (RUO) or for investigational use only (IUO) at the time the 
testing was performed are considered as having been obtained using an 
unapproved test.   
 
5.  Your Standard Operating Procedures (SOPs) should describe how your non-
ABO/Rh(D) RBC antigen typing will be performed and documented and how 
reagents and tests will be evaluated for their capacity to perform as expected.  We 
note that under 21 CFR 606.100(b), you must have written SOPs that describe 
your non-ABO/Rh(D) RBC antigen typing process.  You must use reagents and 
tests in a manner consistent with instructions provided by the manufacturer, in 
accordance with 21 CFR 606.65(e).  You must maintain records of non-
ABO/Rh(D) antigen typing results in accordance with 21 CFR 606.160(b). 
 
B.  Labeling RBC Units with Historical RBC Antigen Typing Results 
 
The following recommendations apply to blood establishments that wish to label RBC 
units with historical non-ABO/Rh(D) RBC antigen typing results.   
 
4  Contains Nonbinding Recommendations 
 
1.  You should convey to transfusion services your practices for repeating historical 
RBC typing results on current donations and for labeling RBC units with 
historical RBC antigen typing results.    
 
2.  You should use historical antigen typing results to label a unit only if two 
previous separate donations from the donor were tested by your blood collection 
establishment and antigen typing results were found to be concordant.  The two 
concordant antigen typing results may be obtained using serological or molecular 
tests or a combination thereof.  
 
3.  We recommend the use of the container label or a tie-tag to convey historical 
RBC typing results, based on whether the historical testing was performed using 
licensed reagents/approved tests or unlicensed reagents/unapproved tests, 
respectively.  See recommendations in sections a. and b. below:   
 
a.  You should place historical RBC typing results directly on the container label 
only if two concordant test results were obtained using licensed reagents or 
approved tests.  If RBC antigen typing results are printed directly on the 
container label, you should use a standard labeling format such as ISBT 128 
or another format accepted by FDA.    
 
If the results were obtained using licensed reagents or approved tests, the 
container label need not indicate that the typing results are historical.  Blood 
establishments that want to distinguish historical RBC typing results from the 
results obtained on the current donation may include this information on the 
container label or other labeling, such as shipping documents.     
 
b.  You should use a tie-tag to convey historical RBC typing results if one or 
more than one historical RBC antigen typing result was obtained using an 
unlicensed reagent or unapproved test.  The tie-tag should provide the current 
donation identification number of the unit.  The tie-tag should indicate that the 
typing results are historical and that the results were obtained using unlicensed 
reagents or unapproved tests.  The transfusion service receiving the unit may 
use this information to determine whether additional confirmation of the 
typing is warranted. 
 
Notes:  
 
1.  You should use a validated process to confirm the donors identification and 
accurate linkage that relates the current donation to the non-ABO/Rh(D) typing 
results from previous donations.  
 
2.  Blood establishments may choose to use a tie-tag rather than the container label to 
convey historical typing results when two concordant test results were obtained 
using licensed reagents or approved tests.  If the results were obtained using 
5  Contains Nonbinding Recommendations 
 
licensed reagents or approved tests, the tie-tag does not need to indicate that the 
typing results are historical.  
C.  Additional Procedures for Managing Units with Historical RBC Antigen 
Typing Results 
 
We recommend or require the following additional procedures to for managing RBC 
units labeled with historical RBC antigen typing results: 
 
1.  You should initiate an investigation whenever any of the following occurs: 
 
a.  Historical RBC antigen typing results are not concordant.  
 
b.  The transfusion service receiving an RBC unit labeled with historical RBC 
antigen typing results repeats an antigen typing test and reports a discordant 
result.  
 
c.  The recipient has a transfusion reaction because of an RBC antibody and the 
transfused unit was labeled as negative for the corresponding antigen. 
 
d.  The transfusion service reports that a recipient developed an alloantibody to 
an RBC antigen and the transfused unit was labeled as negative for that 
antigen.  
 
2.  The transfusion service must include in its SOPs any procedures used to confirm 
relevant historical RBC typing results prior to transfusion, in accordance with  
21 CFR 606.100(b).  
 
3.  The transfusion services SOPs must include procedures to demonstrate 
incompatibility between the donors cell type and recipients serum or plasma 
type, consistent with 21 CFR 606.151(c).  If the recipient has or has had a 
clinically significant alloantibody, the transfusion services SOPs should include 
using appropriate serologic tests to demonstrate compatibility between the 
intended recipients plasma/serum and donor RBCs (Ref. 6). 
 
 
IV.  REPORTING IMPLEMENTATION:  CHANGES TO AN APPROVED 
APPLICATION 
 
Licensed blood establishments must report changes in accordance with 21 CFR 601.12.  The 
following is intended to assist such establishments in reporting changes in testing procedures and 
changes in labeling of RBC units with historical RBC antigen typing results:  
 
6  Contains Nonbinding Recommendations 
 
1.  FDA considers changes made to implement the recommendations in this guidance to 
be minor.1  Report such changes in your annual report under 21 CFR 601.12(d), 
noting the date the process was implemented.  
 
2.  Changes made to implement different procedures than those described in this 
guidance are considered to have a moderate potential to adversely affect the safety or 
effectiveness of the product.  Report such changes to FDA as a Changes Being 
Effected (CBE) supplement under 21 CFR 601.12(c)(5).  You should include the 
following in your CBE submission: 
 
a.  Cover letter, describing the change or procedures that you will use.  
 
b.  Form FDA 356h, Application to Market a New or Abbreviated New Drug or 
Biologic for Human Use. 
 
c.  Written SOP(s) incorporating the details of your process for labeling RBC 
units with historical non-ABO/Rh(D) RBC antigen typing results and any 
related documents.  
 
d.  The container labels and/or tie-tags that you will use to convey historical RBC 
typing results to transfusion services.  The submission should include 
examples of labels showing the format that will be used to distinguish the 
various RBC antigens, such as C and c and Jka and Jkb.  
 
For assistance in preparing your supplement and completing the Form FDA 356h, see FDAs 
guidance document entitled Guidance for Industry:  For the Submission of Chemistry, 
Manufacturing and Controls and Establishment Description Information for Human Blood and 
Blood Components Intended for Transfusion or for Further Manufacture and For the Completion 
of the Form FDA 356h Application to Market a New Drug, Biologic or an Antibiotic Drug for 
Human Use, dated May 1999 (Ref. 7). 
 
For assistance in using FDAs eSubmitter program, see guidance document entitled Guidance 
for Industry:  Availability of FDAs eSubmitter Program for Regulatory Submissions from 
Licensed Blood Establishments, dated August 2011 (Ref. 8). 
 
                                                 
1 See 21 CFR 601.12(a)(3).  
7  Contains Nonbinding Recommendations 
 
V.  REFERENCES  
 
1.  Daniels G, Reid ME. Blood groups: the past 50 years. Transfusion. 2010 Feb; 50(2):281-289. 
2.  Poole J, Daniels G. Blood group antibodies and their significance in transfusion medicine. 
Transfus Med Rev 2007; 21:58-71. 
3.  Compliance Program Guidance Manual, Chapter 42  Blood and Blood Components, 
Inspection of Licensed and Unlicensed Blood Banks, Brokers, Reference Laboratories, and 
Contractors  7342.001, June 1, 2016. 
http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-bio-
gen/documents/document/ucm337001.pdf 
4.  Blood Products Advisory Committee Meeting Transcripts  December 4, 2012. 
https://wayback.archive-
it.org/7993/20170113014718/http://www.fda.gov/AdvisoryCommittees/CommitteesMeeting
Materials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/ucm344648.
htm 
5.  AABB, Standards for Blood Banks and Transfusion Services, 30th edition. 
6.  FDA Guidance for Industry: Computer Crossmatch (Computerized Analysis of the 
Compatibility between the Donors Cell Type and the Recipients Serum or Plasma Type), 
April 2011. 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryIn
formation/Guidances/Blood/UCM252894.pdf  
7.  FDA Guidance for Industry:  For the Submission of Chemistry, Manufacturing and Controls 
and Establishment Description Information for Human Blood and Blood Components 
Intended for Transfusion or for Further Manufacture and For the Completion of the Form 
FDA 356h Application to Market a New Drug, Biologic or an Antibiotic Drug for Human 
Use, May 1999.  
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryIn
formation/Guidances/Blood/ucm080803.pdf 
8.  FDA Guidance for Industry:  Availability of FDAs eSubmitter Program for Regulatory 
Submissions from Licensed Blood Establishments, August 2011. 
https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryIn
formation/Guidances/Blood/UCM267005.pdf 
   
8  Contains Nonbinding Recommendations 
 
VI.  PAPERWORK REDUCTION ACT OF 1995 
 
The guidance document contains information collection provisions that are subject to review by 
the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (the 
PRA) (44 U.S.C. 3501-3520).  The guidance refers to the collections of information for putting 
the non-ABO/Rh(D) historical antigen typing results on a tie-tag or directly on the container 
label.  These collections of information have been approved under OMB control number 0910-
0862. 
 
The guidance also refers to previously approved collections of information found in FDA 
regulations.  The collections of information in 21 CFR part 601 and Form FDA 356h have 
been approved under OMB control number 0910-0338; and the collections of information in 
21 CFR part 606 have been approved under OMB control number 0910-116.  An agency may 
not conduct or sponsor, and a person is not required to respond to, a collection of information 
unless it displays a currently valid OMB control number.  The OMB control number for this 
information collection is 0910-0862 (expires 11/30/2018). 
 
 
9