Date:	  March  14,  1995 
From:	  Director,  Center  for  Biologics  Evaluation  and 
Research 
Subject:	  Revised  Recommendations  for  Red  Blood  Cell 
Immunization  Programs  for  Source  Plasma  Donors. 
To:	  All  Licensed  Establishments  Performing  Red  Blood 
Cell  Immunizations 
Introduction 
On  August  14,  1974,  the  Food  and  Drug  Administration  (FDA) 
issued  a  guideline  recommending  immunization  schedules  for 
Source  Plasma  donors  participating  in  red  blood  cell 
immunization  programs.  FDA  revised  the  guideline  in  June, 
1980,  with  additional  recommendations  concerning  red  blood 
cell  donor  criteria,  volume  and  frequency  of  collections, 
laboratory  tests,  preparation  of  antigen,  and  record  keeping. 
Subsequently,  the  Center  for 'Biologics  Evaluation  and  Research 
(CBER),  FDA,  issued  a  memorandum  on  October  7,  1988,  entitled 
"Recommendations  for  Changeover  from  Use  of  Fresh  Immunizing 
Red  Blood  Cells  to  Use  of  Frozen  Immunizing  Cells  Stored  a 
Minimum  of  Six  Months  Prior  to  Use".  This  memorandum 
recommended  the  use  of  immunizing  red  blood  cells  stored  for  a 
minimum  of  six months  prior  to  use  to  permit  re-testing  of  red 
blood  cell  donors  for  infectious  diseases,  including  anti-HIV, 
HBsAg,  anti-HBc,  and  alanine  aminotransferase  (ALT)  testing. 
A  follow-up  memorandum,  dated  December  16,  1992,  and  entitled 
"Revision  of  October  7,  1988  Memorandum  Concerning  Red  Blood 
Cell  Immunization  Programs",  recommended  extending  the  frozen 
storage  period  of  red  blood  cells  for  immunization  to  twelve 
months. 
This  memorandum  also  recommended  testing  of  the  red  blood  cell 
donor  and  immunized  recipients  for  Hepatitis  C  virus  (HCV)  by 
a  multi-antigen  test. 
The  use  of  new,  licensed,  multi-antigen  assays  that  detect 
antibody  to HCV  (anti-HCV),  was  addressed  again  in  a  FDA 
memorandum  to  all  registered blood  establishments,  dated 
August  5,  1993,  and  entitled  "Revised  Recommendations  for 
Testing  Whole  Blood,  Blood  Components,  Source  Plasma  and 
Source  Leukocytes  for  Antibody  to  Hepatitis  C  Virus  Encoded 
Antigen  (Anti-HCV)".  The  FDA  now  believes  that  the  increased  sensitivity of  the  anti-HCV  test will  permit  donors  and 
intended  recipients  of  red  blood 
cells  for  immunization  to  be  tested  on  a  less  frequent  basis 
during  the  twelve  month  period  after  a  possible  exposure  to 
HCV.  It should  no  longer  be  necessary  to  test  red  blood  cell 
donors  every  two  months  for  anti-HCV  during  the  year  before 
initial  recipient  immunization. 
Improvements  in  the  technology  of  detecting markers  for  anti
HCV  have  contributed  to  increased  knowledge  in  the  biology  and 
immunochemistry  of  HCV.  Based  on  this  more  recent  knowledge, 
CBER  is  revising  its  recommendations  for  red  blood  cell 
immunization  programs  regarding  suitability of  red blood  cell 
donors  for  immunization  programs.  This  memorandum  supersedes 
the  FDA  memorandum  of  December  16,  1992,  and  serves  as  an 
addendum  to  the  June,  1980,  "Guideline  for  the  Immunization  of 
Source  Plasma  (Human)  Donors  with  Blood  Substances". 
Recommendations 
Blood  establishments  should  test  new  donors  who  supply  red 
blood  cells  for  immunization  at  the  time  of  donation  for  all 
required  and  recommended  infectious  disease  tests,  using 
licensed  assays  for  anti-HIV-l,  anti-HIV-2,  HBsAg,  anti-HBc, 
anti-HCV,  and  anti-HTLV-I.  Donors  should  also  be  tested  for 
elevated  levels  of  alanine  aminotransferase  (ALT)  and  with  a 
serologic  test  for  syphilis.  Blood  establishments  should 
follow  all  other  requirements  and  recommendations  applicable 
to  donors  of  red  blood  cells  for  transfusion.  If all  the 
laboratory  test  results  are  acceptable,  the  donor's  red  blood 
cells  should  be  stored  frozen  for  a  minimum  period of  twelve 
months  and  should  not  be  used  to  immunize  recipients  during 
this  initial  12  month  period.  After  the  twelve  month  period 
has  elapsed,  the  donor  and  up  to  three  intended  recipients 
should  be  tested  for  all  of  the  above  listed  infectious 
disease  tests,  elevated ALT  levels,  and  with  a  serologic  test 
for  syphilis.  Red  blood  cell  recipients  should  not  have  been 
previously  transfused  in  the  past  twelve  months  or  have 
participated in  a  red  cell  immunization  program  in  the  past 
twelve  months.  If all  of  the  tests  are  negative  for  both  the 
donor  and  the  intended  recipients,  up  to  three  recipients  may 
be  immunized  with  the  donor's  red  blood  cells. 
These  initial  recipients  should  be  evaluated  for  a  minimum 
period  of  twelve  months  subsequent  to  red  blood  cell 
2  immunization  by  testing  at  3,  6,  9,  and  14  months  post 
immunization  for  all  required and  recommended  infectious 
disease  tests.  The  red  blood  cell  donor  does  not  need  to 
undergo  further  infectious  disease  testing  after  immunization 
of  these  first  recipients,  unless  the  infectious  disease 
testing  is  performed  to  evaluate  a  new  collection  of  red  blood 
cells.  If all  the  laboratory  results  are  negative  over  this 
time  period,  the  donor's  frozen  red  blood  cells  are  qualified 
for  routine  use  (see  attachment  #1).  If any  of  the  test 
results  on  the  recipients  are  positive  during  this  period,  the 
frozen  red  blood  cells  cannot  be  used  to  immunize  any  more 
recipients  unless  the  blood  establishment  documents  that  the 
immunizing  red  blood  cells  were  not  the  cause  of  the  positive 
test  result (s) . 
Red  blood  cell donors  who  have  completed  the  two  year 
qualification period  outlined above  will  be  considered 
pedigreed  donors.  Pedigreed  donors  donating  red  blood  cells 
for  use  in  immunization  programs  should  be  tested  initially 
for  all  required  and  recommended  infectious  disease  tests. 
Their  red  blood  cells  are  then  collected and  stored  frozen  for 
twelve  months.  At  the  end  of  this  twelve  month  period,  the 
donor  is  re-tested  for  all  required  and  recommended  infectious 
disease  tests.  If all of  the  laboratory  tests  are  negative, 
the  frozen  red  blood  cells  are  qualified  for  routine  use  (see 
attachment  #2). 
If  the  red  blood  cell  donor  or  immunized  recipient  donates 
Whole  Blood,  blood  components,  or  Source  Plasma  during  the 
evaluation  period,  the  results  of  the  laboratory  tests  done  on 
these  collections  should  also  become  a  part  of  the  evaluation 
record.  Source  Plasma  collections  from  immunized  plasma  donors 
should  not  be  used  until  there  is  documentation  that  all  tests 
for  infectious  diseases  are  negative,  and  the  ALT  level  is 
within  normal  limits.  Red  blood  cell  immunizations  should  be 
evaluated  for  development  of  unexpected  antibody  responses  and 
reports  of  these  unexpected  antibody  responses  should  be 
available  for  FDA  review  during  inspections. 
License  Supplements 
Blood  establishments  wishing  to  implement  red  cell 
immunization  programs  should  file  a  product  license 
application  or  supplement  to  collect  Source  Plasma  from  donors 
to  be  immunized  with  red  blood  cells  for  each  immunizing 
location  of  the  establishment.  Blood  establishments  currently 
3  licensed  for  red  cell  immunization  programs  should  submit 
revised  Standard  Operating  Procedures  (SOP)  for  a  red  blood 
cell  immunization  program  that  incorporates  these 
recommendations  to  the  Center  for  Biologics  Evaluation  and 
Research  (CBER)  within  sixty  days  of  receipt  of  this 
memorandum.  After  CBER  approval  of  the  revised  SOPs,  licensed 
manufacturers  may  implement  the  current  recommendations 
concerning  red  blood  cell  immunization  programs. 
Questions  may  be  directed  in  writing  to  the  Division  of  Blood 
Applications,  Food  and  Drug  Administration,  Center  for 
Biologics  Evaluation  and  Research,  Office  of  Blood  Research 
and  Review,  HFM-370,  1401  Rockville  Pike,  Rockville,  MD  20852
1448.  Questions  may  also  be  directed by  facsimile  to  the  Blood 
and  Plasma  Branch,  Division  of  Blood  Applications  (301-594
6431) . 
Kathryn  C.Zoon,  Ph.D. 
Attachments:  1.  Immunization  Flow  Chart  for  New  Donors 
2.	  Immunization  Flow  Chart  for  Pedigreed 
Donors 
4
  ATTACHMENT 1 
REVISED IMMUNIZATION FLOW 
CHART  (NR=Non-Reactive) 
NEW RBC DONORS 
Test potential donor for all 
infectious disease markers. 
NR 
,Ir 
Collect Red  Blood Cells and 
store frozen for 12 months 
,Ir 
Test donor and intended 
recipients for all  markers. 

NR 
~
 
Immunize up to 3  Recipients 
r 
Test recipients at 3,  6,  9, 
and 12 months for aII 
markers 

NR 
+
 
Frozen cells qualified for
 
routine use
 
Donor is pedigreed"
  ATTACHMENT 2 
REVISED IMMUNIZATION 
RJJWCHART 
(NR=Non-Reactive) 
PEDIGREED RBC DONORS 
[Test  donor for all infectious 
disease markers. 
NR 
,,. 

Collect Red Blood Cells and 
store frozen for 12  months 
Retest donor for all 
infectious disease markers. 
I 
NR 
!
 
Frozen Red  Blood Cells 
qualified for routine  use