.  I.*. 
DEPARTMENT OF HEALTH  & HUMAN  SERVICES 
Public  Health  SW& 
food  and  Drug  AdminianatKxl 
Bethesda  MD  20892 
Date:  April  23,  1992 
From:  Director,  Center  for  BiOlOgiCS  Evaluation  and  Research 
SubJect:  Revrsed  Recommendations  for  Testing  Whole  Blood,  Blood 
Components,  Source  Plasma  and  Source  Leukocytes  for, 
Antibody  to  Hepatitis  C  Virus  Encoded  Antigen  (Anti- 
HCVI 
To:  All  Reqistered  Blood  Establishments 
I 
Thrs  memorandum  transmits  Recommendations  for  Testing  for 
Antibody  to  Hepatitis  C  Virus  Encoded  Antigen  (Anti-WV)  in  Blood 
Establishments,  April  1992.  These  recommendations  supersede 
those  issued  on  29  November  1990  which  should  be  archived. 
On  29  November  1990  the  Food  and  Drug  Administration  (FDA) 
recommended  that  ail  Whole  Blood  and  components  for  transfusion 
be  screened  to  eliminate  units  that  are  repeatedly  reactive  for 
antl-HCV.  At  that  time,  the  available  licensed  screening  tests 
contained  a  sinqle  recombinant  antigen  for  the  detection  of  anti- 
HCV.  Test  kit  manufacturers  have  recently  developed  kits  capable 
or  detectlnq  antibodies  to  additional  epitopes  of  the  hepatitis  C 
virus.  In  the  memorandum  of  29  November  1990,  the  FDA  did  not 
recommend  withholdinq  anti-HCV  reactive  plasma  from  further. 
nanutacture  Lnto  plasma  derivatives  because  the  impact  of  this 
onanae  on  the  safety  of  plasma  derivatives  such  as  immune 
globulin  products  had  not  been  established.  Information 
reaardrnq  zhe  sarety  of  such  products  has  been  collected  since 
Novemoer  1390  by  the  FDA. 
In  a  public  neetrnq  on  12  March  1992,  after  review  and  discussion 
or  $11  the,  relevant  information  available,  the  FDA  Blood  Products 
Advisory  Committee  iBPAC)  recommended  that  all  donations  of  Whole 
Blood  and  blood  components  intended  for  transfusion,  and  Source 
Plasma  and  Source  Leukocytes  intended  for  further  manufacture  be 
screened  tor  anti-HCV.  The  Committee  also  recommended  that  units 
repeatedly  reactive  for  anti-HCV  in  multi-antigen  tests  should 
not  be  transtused.  Accordingly,  CBER  is 
revising  its 
recommendations. 
FDA  ROW recommends  (1)  that  units  of  Whole  Blood  and  blood 
components  :ntended  for  transfusion,  and  Source  Plasma  and  Source 
Leukocytes  intended  for  further  manufacture,  be  screened  by  an 
FDA  iicensed  test  tor  anti-HCV  and  (21  that  no  products 
repeatedly  reactive  for  anti-HCV  be  used.  The  use  of  a  multi- 
ant:qen  test  ;n  the  testing  of  Whole  Blood  and  blood  components 
for  transrusron  should  be  implemented  as  soon  as  is  feasible- 
initially  reactrve  donor  samples  should  be  retested  in  duplicate  . 
to  determine  whether  they  are  nonreactive  (negative)  or 
repeatedly  reactive.  only  neqative  units  are  suitable  for 
transfusion  or  for  further  manufacture,  with  the  exception  of 
autoloqous  donatlons  under  specified  conditions.  Donors  should 
be  deferred  indefinitely  whenever  they  test  repeatedly  reactive 
for  anti-HCV.  A  donor  reentry  protocol  for  anti-HOI  cannot  be 
recommended  at  this  time  because  of  the  lack  of  an  available 
licensed  additional,  more  specific  test- 
Inventories  of  blood  and  blood  components  for  transfusion  that 
were  collected  before  the  multi-antigen  test  implementation  date 
should  also  be  tested  using  the  multi-antigen  test  if  possible. 
Inventories  of  products  intended  for  further  manufacture  and 
collected  before  the  test  implementation  date  need-not  be  tested 
retroactively. 
The  attached  recommendations  provide  guidance  on  the  testing, 
Labelinq,  quarantine,  storaqe  and  shipment  of  units  of-blood  and 
blood  components  with  respect  to  anti-H07  testing.  Labeling, 
informed  consent  forms,  standard  operating  procedures,  deferral 
reqistries  and  recordkeeping  procedures  should  be  revised  as 
necessary  to  reflect  the  blood  establishment's  implementation  of 
anti-HCV  testinq. 
Licensed  manufacturers  of  Whole-Blood  and  blood  components  may 
adopt  labelinq  consistent  with  this  Memorandum  concurrently  with 
submittinq  any  chanqes  in  labeling  (Section  II)  to  the  Division 
of  Product  Certification.  Licensed  manufacturers  of  Source 
Plasma  should  submrt,  within  90  days  after  receipt  of  this 
document,  revrsed  labelinq  for  review  and  approval  (Section  ~_ 
1II.A.).  Approved  Labeling  changes  should  be  implemented  within 
180  days. 
Section  111.8.  contains  labeling  recommendations  of  special. 
interest  to  those  Lnvolved  in  supplyinq  Source  Plasma,  recovered 
plasma  and  red  blood  cells  for  research  and  for  further 
manufacturinq  Into  noninjectable  products.  The  labelinq 
recommendations  rn  Sections  II  and  III  should  be  implemented 
within  180  days  after  the  receipt  of  this  document. 
Questions  concernlnq  testing  may  be  directed  in  writing  to  the 
Food  and  Druq  Admlnistration,  Division  of  Transfusion  Science, 
Laboratory  of  Hepatitis,  HFB-930,  8800  Rockville  Pike,  Bethesda, 
MD  20892,  FAX:  (3011  227-6764.  Questions  concerninq  labeling  may 
be  directed  in  wrltinq  to  the  Food  and  Druq  Administration, 
Division  of  Product  CertificationaHF  8800  Rockville  Pike, 
Bethesda,  MD  20892.  FAX:  (  Recommendations  for  Testing 
for 
Antibody  to  Hepatitis  C  Virus  Encoded  Antigen  (Anti-HCV) 
in 
Blood  Establishments 
April  1992 
U.S.  Xepartment  of  Health  and  Human  Services 
Public  Health  Service 
Food  and  Drug  Administration 
Center  for  Siologics  Evaluation  and  Research 
8800  Rockville  Pike,  Bethesda,  MD  20892  Table  of  Contents 
Page 
r.  Performance  of  Anti-HCV  Testing  and  Donor  Suitability...3 
II.  Labeling  of  Whole  Blood  and  Components 
Intended  for  Transfusion  . . . . . . . . . . . . . . ..-....-..........  5 
III.  Labeling  of  Whole  Blood  and  Blood  Components 
Xntended  for  Further  Manfacturing  or  Research  . . . . . . . . . . . 7 
r 
IV.  Quarantine  and  Disposition  of  Repeatedly 
Reactive  Donations  . . . . . . . . . . . . . . . . . . . ..-................  a 
V.  Lookback  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..=-.......... 
9 
2  RECOMMENDATIONS  FOR  TESTING  FOR ANTIBODY 
TO  HEPATITIS  C  VIRUS  ENCODED  ANTIGEN  I 
(ANTI-HCV)  IN  BLOOD  ESTABLISHMENTS 
I 
April  1992 
I.  PERFORMANCE  OF  ANTI-HCV  TESTING  AND  DONOR SUITABILITY 
A.  Anti-HCV  testing,  using  multi-antigen  tests,  should  be  I 
performed  and  test  results  interpreted  according  to  the 
( 
manufacturer's  instructions  in  the  package  insert.. 
Instructions  for  currently  licensed  kits  may  be 
summarized  as  follows: 
I.  A  single  enzyme  immunoassay  (EIA)  test  for  anti- 
HCV  should  be  performed  on  a  donor  sample  for  each 
unit  of  whole  blood  or  blood  component  intended 
for  transfusion,  and  on  each  unit  of  plasma  or 
leukocytes  for  further  manufacture.  This  EIA  will 
hereafter  be  referred  to  as  the  "initial  test". 
2.  If  the  initial  test  result  is  nonreactive,  the 
donor  sample  is  considered  to  be  negative  for 
anti-HCV. 
3.  If  the  initial  test  result  is  reactive,  the  donor 
sample  is  considered  to  be  initially  reactive. 
The  sample  should  be  retested  in  duplicate,  within 
a  single  run,  using  the  same  procedure  and  same 
manufacturer's  test  kit  as  that  used  for  the  .-. 
initial  test. 
a.  If  both  duplicate  repeat  test  results  are 
nonreactive,  the  sample  is  considered  to  be 
negative  for  anti-HCV. 
b.  If  either  one  or  both  of  the  duplicate  repeat 
test  results  are  reactive,  the  test  is 
considered  to  be  repeatedly  reactive  for 
anti-HCV  and  the  products  should  not  be  used 
for  transfusion  or  for  further  manufacture. 
Possible  exceptions  to  permit  use  of  anti-HCV 
reactive  products  in  special  circumstances 
are  described  in  Section  I.C.  and  Section 
111-B.  NO  further  screening  tests  for  anti- 
HCV  should  be  performed  on  samples  from  this 
unit  in  an  effort  to  qualify  it  as  suitable. 
B.  Donors  who  are  repeatedly  reactive  for  anti-HCV,  using 
multi-antigen  tests,  should  be  deferred  indefinitely 
from  donating  blood  and  blood  components  for 
transfusion,  Source  Plasma  and  Source  Leukocytes  for 
3  ~  further  manufacture.  General  guidance  in  regard  to  the 
testinq,  counseling,  and  evaluation  of  donors  tested 
for  hepatitis  viruses  is  described  in  the  Public  Health 
Senrlce  Interagency  Guidelines  for  Screening  Donors  of 
Blood,  Plasma,  Organs,  Tissues,  and  Semen  for  Evidence 
of  Hepatitis  B  and  Hepatitis  C,  MMWR 1991;  40  (M-4): 
l-17. 
C.  No  individual  should  be  used  as  a  source  of  Whole 
Blood,  blood  components,  Source  Plasma  or  Source 
Leukocytes  as  follows: 
1.  .Individuals  with  a  history  of  close  contact  within 
one  year  of  donation  with  another  individual 
having  viral  hepatitis. 
2.  Individuals  with  a  history  of  having  received 
within  one  year  human  blood  or  any  derivative  of 
human  blood  which  the  FDA  has  advised  the  licensed 
establishment  is  a  possible  source  of  viral 
hepatitis  (except  in  the  case  of  specific 
immunization  of  Source  Plasma  donors  (21  CFR 
640.661). 
In  addition  it  is  recommended  that  individuals  be 
deferred  from  donating  Whole  Blood,  blood  components, 
Source  Plasma  or  Source  Leukocytes,  who  within  one  year 
of  donation  have  undergone  acupuncture,  ear  piercing  or 
tattooing  in  which  sterile  procedures  were  not  Used. 
D.  Detailed  guidance  on  the  use  of  autologous  Units  that 
are  repeatedly  reactive  for  anti-HCV  was  issued  on  11 
September  1991.  FDA  believes  that  public  health 
considerations  dictate  the  need  for  caution  in  the 
distribution  and  use  of  autologous  products  reactive 
for  anti-HCV.  Accordingly,  repeatedly  reactive  units 
for  autologous  use  should  bear  a  restrictive  label.as 
recommended  in  Section  1I.B.  Additionally,  use  of 
autologous  blood  that  is  repeatedly  reactive  for  anti- 
HCV  is  acceptable  provided  that  a  report  of  the  test 
result  has  been  made  available  to  the  patient's 
physlcian.  This  recommendation  differs  from  those 
issued  on  15  March  1989  concerning  the  use  of 
autologous  blood  positive  for  some  other  disease 
markers.  The  attending  physician's  written  request  is 
necessary  for  release  of  units  that  test  reactive  for 
anti-HIV  and  HBsAg,  but  is  not  required  for  release  of 
autoioqous  products  reactive  for  anti-HCV. 
E.  Test  reactivity  may  represent  a  "false  positive" 
reactron.  In  the  absence  of  a  licensed  confirmatory 
test,  it  1s  suggested  that  an  aliquot  of  serum  or 
4  plasma  from  each  repeatedly  reactive  unit  be  frozen  at 
-2oOc  or  colder  and  stored  for  possible  future  use  in 
verlfyrnq  the  screening  test  result  in  the  context  of  a 
donor  reentry  algorithm. 
F.  Xn  the  absence  of  a  licensed  Confirmatory  test  for 
anti-HCV,  the  blood  center  may  wish  to  utilize  related 
test  results  when  counseling  the  donor.  The  alanine 
aminotransferase  (ALT)  level  of  a  donor  sample  may 
assist  in  the  evaluation  of  the  significance  of  a 
repeatedly  reactive  anti-HCV  screening  test  result. 
However,  reqardless  of  the  risk  assessment  from 
evaluation  of  other  tests,  donors  who  are  repeatedly 
reactive  for  anti-HCV  should  be  deferred  indefinitely 
from  donatinq  whole  blood  and  components  for 
transfusion  and  plasma  or  leukocytes  for  further 
manufacture  (See  Section  I.E.). 
The  American  Blood  Resources  Association  (ABRA)  has 
prepared  a  guideline  (Guideline  for  Anti-Hcv  screening 
in  Plasmapheresis  Facilities,  Oct.  9,  1991)  that  may  be 
referenced  as  an  acceptable  Standard  Operating 
Procedure  (S.O.P.)  for  the  implementation  of  testing  by 
manufacturers  of  Source  Plasma. 
G.  Informed  consent  forms,  standard  operating  procedures 
and  recordkeepinq  procedures  should  be  revised  as 
necessary  to  reflect  the  blood  establishment's 
implementation  of  testing  using  FDA-licensed  multi- 
antiqen  test  kits. 
II.  LABELING  OF WHOLE  BLOOD  AND  COMPONENTS  INTENDED  FOR 
TRANSFUSION 
A.  Whole  Blood  and  Blood  Components  Intended  for 
Alloqenerc  Transfusion 
Consistent  with  the  labeiinq  for  other  infectious 
disease  marker  tests  as  described  in  21  CFR  606.121  and 
.  . 
in  the  current  mft  GUue  for  the  YD&Qrm  J,abellna 
of  Blood  a&  Blood  Co-  neqative  anti-HCV  test 
results  need  not  appear  on  th;  container  label  but 
should  be  included  in  the  inStrUCtiOn  circular.  An 
appropriate  statement  is: 
  .,.neqative  by  a  test  for  anti-HCV-" 
This  statement  may  be  combined  with  other  statements 
concernlnq  tests  for  infectious  disease  markers.  For 
5  example,  the  following  combined  statement  is 
acceptable: 
"A  sample  from  each  donation  intended  for  homologous 
use  has  been  tested  by  FDA-licensed  tests  and  found 
negative  for  antibodies  to  human  immuncdeficiency  virus 
(anti-HIV),  hepatitis  B  Surface  antigen  (EBSAg), 
antibody  to  hepatitis  B  core  antigen  (anti-HBc), 
antibody  to  hepatitis  C  virus  (anti-HCV),  and  antibody 
to  human  T-cell  virus,  type  I  (anti-HTLV- 
1yrphotrOpiC 
t\  n 
8.  Whole  Blood  and  Blood  Components  Intended  for 
Autologous  Transfusion 
The  guidance  for  autologous  blood  and  blood  components 
issued  on  15  March  1989  included  recommendations  for 
labeling  autologous  blood.  When  the  test  for  anti-HCV 
is  repeatedly  reactive,  the  blood  product  should  be 
permanently  labeled  with  the  special  "FOR  AUTOLOWUS 
USE  and  ~*BIOHAZARDol  labels  described  in  the 
ONLY  .  . 
current  me  for  the  Unlform~abellna  of  Blood  and 
Blood*  The  CirCUlar  of  Information 
distributed  with  blood  products  should  include  an 
appropriate  explanation  concerning  use  of  the  biohazard 
label  when  an  autologous  unit  tests  repeatedly  reactive 
for  anti-HOI. 
C.  Units  of  Whole  Blood  or  Components  Not  Tested  for  Anti- 
HCV  or  Not  Tested  for  Anti-HCV  Using  a  Multi-Antigen 
Assay. 
on  rare  occasions,  it  may  be  necessary  to  ship  a  unit 
not  tested  for  anti-HCV  because  a  tested  unit  is  not 
available.  For  example,  untested  Red  Blood  Cells, 
Frozen,  with  no  serum  or  plasma  available,  may  be 
required  to  meet  an  emergency  need  for  a  rare 
phenotype.  The  container  label  of  such  an  untested 
product  should  include  a  statement  such  as  the 
followlnq: 
YMJTION:  Test  for  anti-HCV  has  not  been  donea. 
If  testing  for  anti-H07  has  been  performed  using  a 
single-antigen  assay  only,  and  not  a  multi-antigen 
assay,  the  container  label  should  include  a  statement 
such  as  the  following: 
CAUTION  :  Test  for  anti-HCV  performed  using  a  less 
sensitive  test  than  one  currently  available". 
6  III.  LABELING  OF  BLOOD AND  BLOOD  COMPONENTS  INTENDED  FOR  FURTHER 
MANUFACTURING  OR  RESEARCH 
A.  Plasma  Intended  for  Further  Manufacture  into  Injectable 
Products 
source  Plasma  and  recovered  plasma  (shipped  under  short 
supply  agreements)  container  labels  should  bear  the 
statement,  "Negative  by  a  test  for  anti+iCP.  This 
statement  may  be  combined  with  the  statement(s) 
regarding  anti-HIV  and  HBsAg  test  results. 
8.  Plasma  and  Red  Blood  Cells  Intended  for  Further 
Manufacture  into  Noninjectable  ProdUCtS;  Whole  Blood, 
Blood  Components,  and  Samples  for  Research  Use 
Products  intended  for  further  manufacture  into  b  y& 
diagnostic  reagents  or  for  use  in  research  studies  are 
often  provided  to  consignees  on  an  "as  needed"  basis, 
rather  than  as  routine  shipments.  Therefore,  FDA  is 
recommending  that  such  products  be  labeled  with  one  of 
the  following  statements  to  indicate  test  status: 
1.  "Negative  by  a  test  for  anti-HCV.w 
2,  "Not  tested  for  anti-HCV.w 
3.  'Reactive  by  a  test  for  ax~ti.-HCV.~ 
If  the  product  is  not  tested  for  anti-HCV  or  is 
reactive  for  anti-HCV,  labels  should  also  include: 
CAUTION  :  For  further  manufacture  only  of  b  via 
diagnostic  reagents  for  which  there  are  no  alternative 
sources.  n 
or 
"Not  for  use  in  products  subject  to  license  under 
Section  351  of  the  Public  Health  Service  Act." 
. I 
or 
"For  Laboratory  research  use  only." 
The  labeling  statements  addressed  above  pertain  to  units  of 
blood  or  plasma  collected  from  a  donor  that  was  not 
previously  known  to  be  anti-HCV  reactive.  The  collection  of 
source  Plasma  from  donors  known  to  be  anti-HCV  reactive 
requires  advance  approval  by  the  Director,  CBEIR,  of  a 
specrfic  product  license  application  or  amendment. 
7  IV.  QUARANTINE  AND  DISPOSITION  OF  REPEATEDLY  REACTIVE  DONATIONS 
All  donations  that  are  repeatedly  reactive  for  anti-HCV  should  be 
quarantined  and  either  destroyed  or  restricted  to  appropriate  use 
other  than  transfusion  or  manufacture  into  injectable  products. 
Provisions  of  FDA's  6  April  1988  memorandum  to  all  registered 
blood  establishments,  Control  of  Unsuitable  Blood  and  Rw 
CDmDOnentS,  apply. 
A.  Whole  Blood,  blood  components,  Source  Plasma  and  Source 
Leukocytes  that  have  been  found  to  be  repeatedly 
reactive  for  anti-HCV  should  be  moved  from  the  general 
quarantine  area  for  storage  of  untested  units  to  a 
special  quarantine  area  designated  for  units  unsuitable 
for  use  due  to  infectious  disease  test  results. 
8.  Anti-HCV  repeatedly  reactive  units  should  not  be  used 
for  alloqeneic  transfusion  or  for  further  manufacture 
into  injectable  products.  FDA  suggests  that 
establishments  destroy  the  units  and  laboratory  samples 
(except  an  aliquot  of  serum  or  plasma  for  future 
verification  of  donor  status  as  noted  in  Section  I.D.) 
by  saturated  steam  autoclaving  at  121.5'C  maintained 
for  60  minutes,  or  by  incineration.  While  awaiting 
destruction,  Whole  Blood  and  blood  components,  Source 
Plasma  and  source  Leukocytes  should  be  quarantined  and 
prominently  labeled  "NOT  FOR TRANSFUSION:  anti-HCV 
reactive"  in  accordance  with  21  CFR  606.121  (f). 
_  ~-._ 
C.  Plasma,  Whole  Blood  and  blood  components  repeatedly 
reactive  for  anti-HCV  should  be  distributed  to 
consignees  in  a  manner  consistent  with  21  CF'R 606.40 
(a)(6)  and  (7),  and  606.100,  606.120,  606.121  and 
606.165.  Additional  information  the 
Concerning 
shipment  of  biological  products  and  clinical  specimens, 
includinq  donor  blood  samples,  may  be  found  in  the 
followlnq  CFX  sections: 
1.  Postal  Service:  39  CFR  Part  111.  See  also  (a)  the 
Domestic  Mail  Manual,  which  is  incorporated  by 
reference  into  the  CF'R,  and  (b)  the  International 
Hall  Manual,  for  materials  to  be  transported  by 
dls-. 
2.  Department  of  Transportation:  49  CFR  Part  173 
3.  Department  of  Health  and  Human  Services,  Centers 
for  Disease  Control:  42  CFR  Part  72 
D.  The  FDA's  26  October  1989  guideline  (with  a  revision  on 
17  April  1991)  for  collection  of  blood  or  blood 
8  t 
products  from  "high  risk"  donors  need  not  be  applied  at 
this  time  to  collections  from  donors  known  to  be  anti- 
HCV  repeatedly  reactive,  whose  blood  or  plasma  may  be 
needed  for  autoloqous  use,  or  for  use  in  further 
manufacturing  for  b  vitro  products  and  in  research 
(Section  III).  However,  it  is  emphasized  that  all 
staff  should  be  instructed  to  follow  universal  blood 
and  body-fluid  precautions  in  all  situations  where 
contact  with  human  blood  can  be  anticipated.  (See: 
Centers  for  Disease  Control.  Update:  Universal 
precautions  for  prevention  of  transmission  of  human  _ 
immunodeficiency  virus,  hepatitis  B  virus,  and  other 
blood-borne  pathogens  in  health-care  settings.  MMWR 
L908:37:377-386.1 
v.  "LOOKBACK" 
A  targeted  @*lookback"  program  in  relation  to  previously  collected 
products  from  donors  testing  repeatedly  reactive  for  anti-HCV  is 
not  recommended  at  this  time. 
9