Guidance for Industry
 
 
Computer Crossmatch 
(Computerized Analysis of the 
Compatibility between the Donors 
Cell Type and the Recipients Serum 
or Plasma Type)
 
 
 
 
 
 
 
 
 
Additional copies of this guidance are available from the 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 or e-mail 
address listed above. 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
April 2011  Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  TERMS USED IN THIS GUIDANCE............................................................................3 
IV.  ELEMENTS OF A COMPUTER CROSSMATCH SYSTEM....................................5 
A.  Data Entry Review and Acceptance....................................................................5 
B.  Recipient Data Elements......................................................................................5 
C.  Donor Data Elements............................................................................................6 
D.  Donor RBC Antibody Assessment.......................................................................7 
E.  Decision Tables......................................................................................................7 
F.  Warning Messages................................................................................................7 
G.  Computer Downtime............................................................................................8 
V.  VALIDATION AND RE-VALIDATION.......................................................................8 
A.  Validation...............................................................................................................8 
B.  Re-Validation.......................................................................................................10 
VI.  RECORDS.......................................................................................................................10 
VII.  IMPLEMENTATION....................................................................................................11 
A.  Following this Guidance.....................................................................................11 
B.  Computer Crossmatch Systems in Use.............................................................11 
VIII.  REFERENCES................................................................................................................13 
 
 
i  Contains Nonbinding Recommendations 
 
Guidance for Industry 
 
Computer Crossmatch 
(Computerized Analysis of the Compatibility between the Donors 
Cell Type and the Recipients Serum or Plasma Type) 
 
 
This guidance represents the Food and Drug Administrations (FDAs) 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 
 
Computer crossmatch is a process used to ensure that blood released for transfusion is 
compatible with the intended recipient.1  We, FDA, are issuing this guidance to assist you, blood 
establishments that perform compatibility testing using a computer crossmatch system to 
perform computerized matching of blood, consistent with current good manufacturing practice 
(CGMP) requirements in 21 CFR Parts 210, 211 and 606.  Blood establishments must have 
standard operating procedures (SOPs) to demonstrate incompatibility between the donors cell 
type and the recipients serum or plasma type under the compatibility testing requirements in  
21 CFR 606.151(c).  This guidance describes practices that we believe satisfy the requirements 
in 21 CFR 606.151(c) to help ensure detection of an incompatible crossmatch when using a 
computerized system for matching a donors cell type with a recipients serum or plasma type. 
 
Recipient - donor compatibility may be evaluated by using either a serologic crossmatch or a 
computer crossmatch.  We consider computer crossmatch an acceptable method of compatibility 
analysis when it is properly designed, validated, implemented, and monitored.  However, the use 
of the computer crossmatch requires a high degree of testing and validation to ensure accuracy.   
 
In addition, this guidance contains recommendations for blood establishments performing 
compatibility testing that intend to implement a computer crossmatch procedure.  For licensed 
establishments, this guidance also describes how to report this manufacturing change to FDA 
under 21 CFR 601.12.  This guidance finalizes the draft guidance entitled Guidance for 
Industry:  Computer Crossmatch (Electronic Based Testing for the Compatibility between the 
Donors Cell Type and the Recipients Serum or Plasma Type) dated June 2007 (June 21, 2007, 
72 FR 34259).   
                                                 
1
 For the purpose of this document, the term computer crossmatch is defined as an assessment of donor and 
recipient blood compatibility that is done by substituting a computerized record review for the serologic crossmatch.  
The computerized record review follows strict decision rules to determine recipient criteria and donor blood 
compatibility.  This procedure is also known as an electronic crossmatch and is defined further in section III.   
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 
 
Before we finalized the regulation amending 21 CFR 606.151 in 2001 (Ref. 1), compatibility 
testing was required to be performed by serologic crossmatch.  Specifically, prior to September 
5, 2001, the effective date of amended 21 CFR 606.151, SOPs for compatibility testing were 
required to include [t]he testing of the donors cells with the recipients serum (major 
crossmatch) by a method that will demonstrate agglutinating, coating and hemolytic antibodies, 
which shall include the antiglobulin method (Ref. 2).  A computer crossmatch was permitted 
only if we granted you written approval to use computer crossmatch as an alternative to a 
serologic crossmatch.  Under 21 CFR 640.120, we approved requests for an alternative 
procedure such as a computer crossmatch when documentation of decision-making rules, 
validation records, and SOPs demonstrated the process was at least as safe as serologic 
crossmatch.   
 
In March 1994, we approved the first alternative procedure permitting a blood establishment to 
use a computer crossmatch.  Between that time and implementation of the new rule on 
September 5, 2001 (Ref. 1), we approved requests from 33 blood establishments to utilize 
alternative procedures permitting use of a computer crossmatch.  Although 33 establishments 
represent only a small percentage of all blood establishments (there are over 5,000 blood 
establishments in the United States), these establishments have used the process for some time 
without reports of serious recipient-related injury or death.  In addition, we believe that 
additional establishments have implemented computer crossmatch since the rule became 
effective on September 5, 2001. 
 
The software, personnel, SOPs and hardware are all important parts of the computer crossmatch 
process.  The use of a computer reduces the risk of human error through the use of software-
controlled decision-making.  Computer crossmatch systems are included within some Blood 
Establishment Computer Software (BECS) systems cleared by FDA.2  The computer crossmatch 
systems include the following basic elements: 
 
  Instead of performing a serologic crossmatch, an establishment determines the 
compatibility of blood for transfusion on the basis of data entered and stored in the 
computer; 
                                                 
2 FDA issued a draft guidance entitled Guidance for Industry:  Blood Establishment Computer System Validation 
in the Users Facility dated October 2007 (October 29, 2007, 72 FR 61171), addressing the validation of a blood 
establishment computer system that incorporates BECS.  This draft guidance, when finalized, will represent FDAs 
current thinking on that topic.   
2  Contains Nonbinding Recommendations 
 
  The computer data are obtained by performing serologic tests on separate blood samples 
of the donor and recipient, with results stored in the computer; 
  The software interprets the data using a set of precisely defined rules (software-controlled 
decision-making); and 
  If the rule-based criteria for compatibility are not met, or if essential data are missing, the 
computer displays a warning message. 
 
Other computer crossmatch system elements that may be relevant are as follows:   
 
  Systems may be restricted for use with Red Blood Cell (RBC) products (note that some 
systems also release other blood components for transfusion); 
  Systems may require a serologic crossmatch for recipients exhibiting clinically 
significant RBC antibody(ies) (e.g., with a positive antibody screening test); or  
  Systems may require antigen negative RBCs for recipients with a history of clinically 
significant RBC antibody(ies). 
 
It should be noted that this guidance does not apply to those circumstances where the donors 
blood has not been screened for agglutinating, coating and hemolytic antibodies.  In such cases, 
21 CFR 606.151(d) requires that ...the recipients cells shall be tested with the donors serum 
(minor crossmatch) by a method that will so demonstrate.  
 
We believe that the published literature and observations of safe use over the past 16 years 
support the safety of properly implemented computer crossmatch systems (Refs. 3-10), and we 
regard computer crossmatch to be an acceptable method of compatibility demonstration when it 
is properly designed, validated, implemented, and monitored.  However, there are many issues 
that could affect the safety and effectiveness of blood products when you use computer 
crossmatch.  The quality of the process depends on careful user validation and proper quality 
management. 
 
 
III.  TERMS USED IN THIS GUIDANCE 
 
Antibody screen - The combining of recipient serum or plasma with reagent RBCs for detection 
of unexpected antibodies to red blood cell antigens; also known as the antibody detection test. 
 
Note:  It is widely recognized that not all unexpected RBC antibodies are clinically 
significant.  Furthermore, there is no single method of screening for unexpected RBC 
antibodies that will reliably detect all that are clinically significant.  The computer 
crossmatch switches the emphasis for safety of the compatibility test from the serologic 
crossmatch to the antibody screening (in addition to correct determination of ABO and Rh 
(D) types) (Ref. 5).  As with the immediate spin crossmatch (defined below), the absence of 
an antiglobulin crossmatch necessitates that your antibody screening techniques be 
sufficiently sensitive to detect clinically significant antibodies.  You must determine how you 
will ensure the appropriate level of sensitivity (e.g., use of potentiators, screening cell sets 
that contain RBCs with homozygous expression of clinically significant antigens). 
 
3  Contains Nonbinding Recommendations 
 
Compatibility testing - The procedures performed to establish the matching of a donors blood 
or blood components with that of a potential recipient (21 CFR 606.3(j)). 
 
Computer crossmatch - Assessment of donor and recipient blood compatibility that is done by 
substituting a computerized record review for the serologic crossmatch (see below).  The 
computerized record review follows strict decision rules (see below) to determine recipient 
criteria and donor blood compatibility.  This procedure also is known as an electronic 
crossmatch. 
 
Crossmatch - A general term for any test that combines a sample of blood from a blood donor 
and a sample of blood from a recipient to determine compatibility prior to transfusion.  The 
crossmatch is one element of the more general compatibility testing. 
 
Decision rules - The rules applied in software-controlled decision-making.  The software 
vendor, the user, or both, may be responsible for control of such rules. 
 
Decision tables - Decision tables are tables included in your software system. 
 
Immediate spin crossmatch - A serologic test of recipient serum or plasma with donor RBCs, 
consisting of centrifugation of samples and immediate examination for agglutination or 
hemolysis, which primarily detects ABO incompatibility.  There is no incubation and no 
antiglobulin test. 
 
Major crossmatch - A serologic test of recipient serum or plasma with donor RBCs consisting 
of incubation and testing with anti-human globulin to detect incompatibility.  In a computer 
crossmatch system, a major crossmatch may be required to assess compatibility when the 
recipient sample demonstrates the presence of an atypical RBC antibody(ies). 
 
Minor crossmatch - A serologic test of donor serum or plasma with recipient RBCs consisting 
of incubation and testing with anti-human globulin to detect incompatibility.  Contrast with 
major crossmatch (above).  
 
Potentiator - A reagent solution added to enhance in vitro antibody-antigen reactions. 
 
Serologic crossmatch - A physical, in vitro laboratory test of recipient serum or plasma with 
donor RBCs.  Contrast with computer crossmatch (above). 
 
Note:  One of the functions of a serologic crossmatch, especially the immediate spin 
crossmatch, has been the detection of ABO incompatibilities (Ref. 9).  Adequate 
compatibility testing in the absence of a serologic crossmatch may rely upon the performance 
characteristics of the ABO reagents.  For example, it is important to know how monoclonal 
reagents react with samples that have unusual ABO groups such as weak subgroups, acquired 
B antigen, and the B(A) phenomenon. 
 
 
4  Contains Nonbinding Recommendations 
 
IV.  ELEMENTS OF A COMPUTER CROSSMATCH SYSTEM 
 
The following are critical process elements of decision rules for a computer crossmatch system. 
 
A.  Data Entry Review and Acceptance  
 
You should have a method for a user to review and verify data before it can be used in 
the decision process.  Some examples are: 
 
  The user enters data, reviews it on screen and then accepts the entry; or 
  The user enters data twice and the system accepts the entry if there is a match; 
or 
  Data is entered from an interfaced instrument and the user confirms 
information on a printed report before acceptance. 
 
B.  Recipient Data Elements 
 
The electronic database should include these data elements: 
 
  Unique identification number; 
  RBC antibody assessment; 
  ABO group/Rh (D) type and interpretation; 
  Recipient Sample; and  
  Special transfusion requirements (i.e., leukocyte reduced, CMV antibody 
negative). 
 
1.  Recipient RBC Antibody Assessment 
 
You must have procedures to demonstrate incompatibility between the donors cell 
type and the recipients serum or plasma type (21 CFR 606.151(c)).  These 
procedures usually include instructions to perform an antibody screening test.  You 
must use fresh recipient serum or plasma samples less than 3 days old for all 
pretransfusion testing if the recipient has been pregnant or transfused within the 
previous 3 months (21 CFR 606.151(b)).  The acceptable sample age should be 
determined with the collection of the specimen at day 0 and the sample expiring at 
midnight on day 3.  You must follow the specimen requirements described in the 
instructions for use provided by the manufacturer of the antibody screening cells (21 
CFR 606.65(e)).  If testing of the recipients specimen shows that the recipient has 
clinically significant RBC antibodies (antibodies known to cause transfusion 
reactions) or records show a history of clinically significant RBC antibodies, you 
should not rely on a computer crossmatch.  Under those circumstances, your 
procedures should provide for compatibility testing using serologic crossmatch 
techniques. 
 
5  Contains Nonbinding Recommendations 
 
2.  Recipient ABO/Rh (D) Type and Interpretation 
 
You should determine a recipients ABO and Rh (D) antigens (Ref. 11).  You should 
either perform or maintain a record of a second test, confirming the recipients 
ABO/Rh (D).  For example, this second test may be a record of a test performed 
previously, or a repeat test on a second, separately drawn specimen.  Repeating ABO 
and Rh (D) tests on the same specimen is not recommended, as the major cause of 
ABO errors is wrong blood in tube (WBIT).  Performing tests on two separately 
drawn specimens is preferred, as this lessens the likelihood of errors because 
specimens have been drawn in error.  In certain situations, however, only one 
specimen may be available for testing, such as in emergencies or when only one 
sample is received for home transfusion.  At those times, repeat testing may be 
performed on the same specimen, but the repeat test should be performed either by a 
different technologist or by the same technologist using different reagents. 
 
If ABO typing discrepancies exist, you should not rely on a computer crossmatch.  
This is particularly important if there is mixed field red cell reactivity, missing serum 
reactivity, or apparent change in blood type following hematopoietic stem cell 
transplantation.  Under those circumstances, your procedures should provide for 
compatibility testing using serologic crossmatch techniques. 
 
3.  Recipient Sample 
 
Our regulations do not specify a specimen age restriction for a recipient who has not 
been transfused or pregnant within the last three months.  Based on your ability to 
obtain a reliable recipient history and to store positively identified recipient 
specimens, you should define appropriate specimen age limits.  Your procedures must 
be consistent with any limitations described in the reagent manufacturers directions 
for use (21 CFR 606.65(e)). 
 
C.  Donor Data Elements 
 
The electronic database should include: 
 
  Unique identification number; 
  Component name;  
  ABO group/Rh (D) type and interpretation; 
  Special manufacturing requirements (e.g., leukocyte reduced, CMV antibody 
negative, irradiation); and 
  Donor RBC antibody assessment. 
 
6  Contains Nonbinding Recommendations 
 
D.  Donor RBC Antibody Assessment 
 
If tests for unexpected antibodies are positive, blood and blood components intended for 
transfusion must be labeled by the blood collecting facility with the name of the antibody 
(21 CFR 606.121(e)(1)(iii), (e)(2)(ii) and (e)(4)).  Using this information, you should 
determine if the donor has clinically significant RBC antibodies.  If the donor has 
clinically significant RBC antibodies, you should not rely on a computer crossmatch.  
Under those circumstances, your procedures should provide for compatibility testing 
using serologic crossmatch techniques capable of detecting such clinically significant 
antibodies. 
 
E.  Decision Tables 
 
Your written procedures should explain where the decision tables are located and how to 
populate or configure them with the specific decision rules used to determine 
donor/recipient compatibility for the computer crossmatch.  The software manufacturers 
documentation, e.g., Users Manual(s), usually provides this information.  The decision 
rules are usually defined by you.  However, they may be pre-defined by the software 
manufacturer in the programming code (this situation is referred to as hardcoding) and 
cannot be modified by you.  After you clearly understand the rules - whether defined by 
you or the manufacturer - you should verify that the decision rules are appropriate for 
your practices by checking the results of data entry.  Once you verify that the rules for 
software controlled decision-making are appropriate, you should validate the 
performance of the computer crossmatch process in your establishment, as recommended 
in this guidance.   
 
Identification of the product to be transfused is important for software-controlled 
decisions.  For example, if you issue Whole Blood using the computer crossmatch, the 
decision table should include ABO compatibility definitions for minor crossmatches.  
Alternatively, you may limit the use of computer crossmatch to those situations where 
you release only RBC components.   
 
Unless the manufacturer has hardcoded the decision rules, you may usually modify 
software-controlled decision rules to include procedures appropriate for you (e.g., by 
including other recipient criteria or compatibility elements in your donor/recipient 
compatibility decision tables).   
 
F.  Warning Messages 
 
A warning message is a software-generated message that is displayed to notify you when 
an action does not conform to the decision rules.  We believe that a warning message is 
adequate if it is obtrusive enough to assure that the operator will notice and heed it.  Your 
software should also document warning messages and the circumstances surrounding 
their display (e.g., date, time, name of operator).  You should decide what alert level is  
7  Contains Nonbinding Recommendations 
 
necessary at each decision point in order to provide an acceptable margin of safety.  You 
should use different levels appropriate for the importance of each situation.  Some 
possible alert levels would include displaying a warning message and: 
 
  Allowing the user to proceed; or 
  Requiring the user to enter a code before proceeding; or 
  Requiring a supervisors code before the user can proceed; or 
  Not allowing the user to proceed under any circumstances. 
 
G.  Computer Downtime 
 
In the event you need to make compatibility determinations when the computer system is 
down, you must have written procedures explaining how to perform compatibility testing 
and release blood during computer downtime (21 CFR 606.100(b) and 606.151(c)).  Your 
downtime SOP should address recovery after the computer is again operational (e.g., 
entry of test results completed during the downtime, including sample date and time). 
 
 
V.  VALIDATION AND RE-VALIDATION 
 
A.  Validation 
 
User validation is testing new equipment or a new process in the environment where it 
will be used to ensure that it will reliably produce a product that meets predetermined 
qualifications and quality standards (Refs. 12, 13, and 14).  Electronic equipment, 
including computer systems, must be routinely checked according to a written program 
designed to assure proper performance (21 CFR 211.68(a)).  In addition, input to and 
output from the computer or other records or data must be checked for accuracy  
(21 CFR 211.68(b)).  Therefore, before you start user validation, you must develop a 
validation protocol and acceptance criteria to ensure the system is performing properly 
(21 CFR 211.68(a)).  The validation protocol is your plan for the testing, evaluation, and 
final acceptance of the process.  You should perform validation testing at your location 
using the same software, hardware, SOPs, and personnel who will perform the process 
after it is formally implemented (Refs. 12 and 13).  You should perform the validation 
tests in a software partition set aside for such tests, and not on your live system where 
actual recipient and inventory records are in use. 
 
When you plan your validation protocol, you should address: 
 
  Routine functions  the most common circumstances of daily work; 
  At-risk functions  the riskiest parts of the operation, such as the release of ABO 
incompatible blood or the release of blood when the recipient has a history of 
clinically significant antibody(ies); 
  Strategies or test methods you will use to test each function; 
8  Contains Nonbinding Recommendations 
 
  Decision values  the quantitative decisions made by the computer, such as 
evaluating the number of days of a sample age.  You should test at just below, and 
just above, the decision value; 
  Unexpected outcomes and events  test issues which you do not expect to occur 
but which may occur, such as the release of Whole Blood, even though you rarely 
stock Whole Blood or the simultaneous entry of conflicting results; 
  Security and authority levels  if your system allows override of a warning only 
by those assigned a particular level of authority, you should challenge the system 
to document that the authority limitations are enforced; 
  Predetermined acceptance and completion criteria; 
  Criteria for failure investigation, corrective action and follow-up, including 
criteria for re-testing; and 
  Final review or sign-off authority. 
 
Under the regulations, you must inspect and routinely validate your computer crossmatch 
process according to a written program designed to assure proper performance 
(21 CFR 211.68(a)).  See also 21 CFR 211.100(a), 606.100(b)(14), and 606.151(c).  A 
written program is not designed to assure proper performance unless it requires user 
validation prior to routine use, on a routine basis, and any time a change is made to the 
program that has the potential to affect the computer crossmatch process.  Therefore, you 
must perform user validation of any new computer system or functionality prior to 
routine use by testing and documenting the new system or functionality in your facility 
(21 CFR 211.68(a), 211.100(a), 606.100(b)(14), and 606.151(c)). 
 
In addition, as discussed in greater detail below, you must inspect and routinely validate 
all of the critical elements of your computer crossmatch process (21 CFR 211.68(a)), 
including: 
 
  Hardware (including bar code readers and printers); 
  Software (including interfaces with other systems); and 
  User performance, including a mechanism to test the ability of the user to 
understand and correctly interface with the computer system. 
 
The key issues that should be covered during your user validation of a computer 
crossmatch process are presented below.  You must check according to a written program 
designed to assure proper performance (21 CFR 211.68(a)).  Accordingly, you should 
develop your own test cases based on your system, its intended use and functionality, and 
your work environment.   
 
As discussed above, you must routinely check or validate all of the critical elements of 
your crossmatch process (21 CFR 211.68(a) and (b)).  These validation activities should 
include: 
 
  On-site validation:  Validate the computer crossmatch process at your location 
using the same hardware, software, SOPs and personnel that will be routinely 
used. 
9  Contains Nonbinding Recommendations 
 
  Elements of the decision rules:  Challenge the system using combinations of 
concordant and discordant or missing results; acceptable and unacceptable 
specimens; and acceptable and unacceptable selections of components.  Challenge 
these elements to evaluate: 
o  Specimen acceptability; 
o  Donor and recipient ABO/Rh (D) confirmation; 
o  Antibody screen; 
o  Donor/recipient compatibility; and 
o  Component selection. 
  Warnings:  Challenge the system with all combinations to demonstrate that 
unacceptable situations will trigger appropriate warning messages. 
 
B.  Re-Validation 
 
As discussed above, the regulations require that you inspect and routinely validate your 
computer crossmatch process according to a written program designed to assure proper 
performance (21 CFR 211.68(a)).  See also 21 CFR 211.100(a), 606.100(b)(14), and 
606.151(c).  A written program is not designed to assure proper performance unless it 
specifically requires user validation prior to routine use, on a routine basis, and any time 
a change is made to the program that has the potential to affect the computer crossmatch 
process.  Therefore, you must also perform re-validation any time you make a change that 
might affect the computer crossmatch process.  This would include such things as 
software upgrades, changes in decision tables, revised SOPs, or new hardware.  
Validation in these cases is usually focused on the specific performance characteristics, 
which may have been altered by the particular change (21 CFR 211.68(a) and (b)).  
 
 
VI.  RECORDS 
 
You must maintain documentation of all significant activities, including compatibility testing, 
concurrently with the performance of each significant step (21 CFR 606.160(a)(1)).  Under  
21 CFR 606.160(b)(4), you must also maintain records of all compatibility tests, including 
crossmatching, testing of patient samples, antibody screening and identification, and the results 
of confirmatory testing. 
 
Under 21 CFR 606.160(b)(5), you must maintain quality control records relating to calibration 
and standardization of equipment, and performance checks of equipment and reagents.  These 
records should include your validation protocol, test results, evaluation of the results, any follow-
up changes or corrections made in response to the testing, results of the re-testing of the system 
following the corrections and final approval/acceptance of the system.  After the initial 
validation, when you make changes, you must also keep records of your process change and 
re-validation (21 CFR 211.68(a) and (b)). 
 
You must keep such records for no less than 10 years after the records of processing are 
completed (e.g., the date of the last computer crossmatch), or until six months after the latest 
expiration date for the individual product, whichever is the later date (21 CFR 606.160(d)).  
10  Contains Nonbinding Recommendations 
 
Records may be kept electronically as long as you comply with the appropriate requirements of 
21 CFR Part 11, as further described in previous FDA guidance (Ref. 15).   
 
 
VII.  IMPLEMENTATION 
 
A.  Following this Guidance 
 
If you hold a biologics license and are implementing a computer crossmatch procedure 
for the first time, or are changing a computer crossmatch procedure that is already 
approved under your license, you must report the change to FDA under 21 CFR 601.12.  
The regulation provides that manufacturing changes must be reported to FDA by means 
of different mechanisms, depending on the degree to which the change has the potential 
to have an adverse effect on the identity, strength, quality, purity, or potency of the 
product, as they may relate to the safety or effectiveness of the product.  We believe that 
a computer crossmatch procedure that follows the recommendations in this guidance 
meets the standard for reporting in an annual report (21 CFR 601.12(d)) (Ref. 16). 
 
We believe that changes regarding computer crossmatch procedures that do not follow 
the recommendations in this guidance present a moderate or substantial potential to have 
an adverse affect on the identity, strength, quality, purity, or potency of the product, as 
they may relate to the products safety and effectiveness, and therefore require the 
submission of a preapproval or other supplement submission, depending on the nature of 
the change (21 CFR 601.12(b) and (c)). 
 
If you plan to implement a computer crossmatch procedure and have questions about how 
to report the change to FDA, contact the Division of Blood Applications at (301) 827-
3543.  Unlicensed manufacturers are not required to report manufacturing changes to 
FDA under 21 CFR 601.12. 
 
We believe that the procedures described in this guidance are consistent with CGMP 
requirements and may be used to satisfy the requirement in 21 CFR 606.151(c) that you 
have procedures to address compatibility determinations. 
 
B.  Computer Crossmatch Systems in Use 
 
1.  Validated Computer Crossmatch System 
 
Before September 5, 2001, we approved prior approval supplement requests for 
alternative procedures for the use of a computer crossmatch system that included a 
manual check of some records, such as a check of recipient records for a history of an 
antibody.  We now believe that the adoption of a validated computer crossmatch 
system with manual enforcement of some decision rules that has been fully and 
properly validated and is consistent with the recommendations in this guidance would 
have a minimal potential to have an adverse effect on the identity, strength, quality, 
purity, or potency of blood products as they relate to the safety or effectiveness of the 
11  Contains Nonbinding Recommendations 
 
product.  Accordingly, if licensed establishments choose to implement a computer 
crossmatch procedure in a manner that is consistent with the recommendations in this 
guidance, they must report this change in their annual report (21 CFR 601.12(d)).  
 
2.  Unvalidated Computer Crossmatch System 
 
If your computer crossmatch process has not been fully and properly validated, you 
should perform serologic testing to satisfy the compatibility testing requirements in 
21 CFR 606.151(c), until you complete your user validation following this guidance.  
If you have been using an unvalidated computer crossmatch process, your history of 
use does not substitute for a proper validation.  Although you may analyze your 
routine records of use as part of your validation, the validation should be a planned 
activity that challenges your process in both routine and unusual circumstances. 
 
 
12  Contains Nonbinding Recommendations 
 
VIII.  REFERENCES 
 
1.  Final Rule: Revisions to the Requirements Applicable to Blood, Blood Components, and 
Source Plasma 66 FR 40886, Aug. 6, 2001. 
 
2.  21 CFR 606.151(c) from April 1, 1999 edition of the Code of Federal Regulations. 
 
3.  Butch S. H., Judd W. J., Steiner E. A., et al.  Electronic Verification of Donor Recipient 
Compatibility:  The Computer Crossmatch, Transfusion, 34:  105-09, 1994. 
 
4.  Butch s. h., Oberman H.A., The Computer or Electronic Crossmatch, Transfusion 
Medicine Reviews, 11(4):  256-64, 1997. 
 
5.  Chapman J. F., Milkins C., Voak D., The Computer Crossmatch:  A Safe Alternative to the 
Serological Crossmatch, Transfusion Medicine, 10:  251-56 (2000). 
 
6.  Cheng G., Experiences with Self Service Electronic Blood Banking, Vox Sanguinis, 74 
Suppl. (2):  427-29 (1998). 
 
7.  Georgsen J., Kristensen T., From Serological to Computer Cross-matching in Nine 
Hospitals, Vox Sanguinis, 74 Suppl. (2):  419-25 (1998). 
 
8.  Judd W.J., Requirements for the Electronic Crossmatch, Vox Sanguinis, 74 Suppl. (2) 409-
17 (1998).  
 
9.  Judd W. J., The Electronic Crossmatch, ADVANCE for Medical Laboratory Professional, 
16-24 (July 20, 1998). 
 
10. Garratty G.  How Concerned Should We Be About Missing Antibodies to Low Incidence 
Antigens? Transfusion, 43(7):844-7 (2003).   
 
11. Memorandum to All Registered Blood Establishments from the FDA Office of Biologics 
Research and Review on Equivalent Methods for Compatibility Testing, dated December 
14, 1984.   
(http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryIn
formation/OtherRecommendationsforManufacturers/MemorandumtoBloodEstablishments/U
CM063017.pdf) accessed April 26, 2011. 
 
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