Revised Recommendations for Red Blood Cell Immunization Programs for Source Plasma Donors: Memorandum to Licensed Establishments

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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 .
•
~
Immunize up to 3 Recipients
r
Test 	recipients at 3, 	6, 	9,
and 12 months for a II
markers
•
NR
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