Gamma Irradiation of Blood Products (7/22/93)
 
Date:	  July 22, 1993
 
To:	  All Registered Blood Establishments
 
From:	  Acting Director, Office of Blood Research and Review
 
Subject: 	 Recommendations Regarding License Amendments and
 
Procedures for Gamma Irradiation of Blood Products
 
This memorandum transmits recommendations regarding license
 
amendments and procedures pertinent to irradiated blood and blood
 
products.  Irradiation of these products is a practice which has
 
developed over many years to reduce the risk of transfusion-
associated graft-versus-host disease in recipients at this
 
complication.  Since labeling of blood and blood products as
 
irradiated pertains to safety and intended use, irradiated and
 
non-irradiated products are considered different products by the
 
Center for Biologics Evaluation and Research. Recommendations are
 
provided here regarding manufacturing and quality control
 
procedures, labeling and other aspects of production and use of
 
irradiated blood and blood products.  When the products are
 
intended for interstate shipment, license amendments are
 
required, as described in the recommendations.

 /s/

 Gerald V. Quinnan, Jr., M.D.
 
_____________________________ 
RECOMMENDATIONS REGARDING LICENSE AMENDMENTS AND PROCEDURES
 
FOR GAMMA IRRADIATION OF BLOOD PRODUCTS
 
TABLE OF CONTENTS
 
I.	  INTRODUCTION 

II.	  BACKGROUND
 
A.  TRANSFUSION-ASSOCIATED GVHD
 
     B.  IRRADIATION OF BLOOD PRODUCTS TO PREVENT GVHD
 
     C. 	 EFFECTS OF GAMMA IRRADIATION ON PRODUCT QUALITY

 AND STABILITY
 
III.	  LICENSE AMENDMENTS FOR IRRADIATION OF BLOOD AND 

BLOOD PRODUCTS
 
A.  STANDARD OPERATING PROCEDURES (SOPs)
 
B.  IRRADIATION BY CONTRACTOR
 
C.  RADIATION DOSAGES AND VALIDATION
 
D.  REMOVAL OF PLASMA PRIOR TO RELEASE
  E.  LABELING 
IV.  RECORDS 
V.  REPORTING FATALITIES 
VI.  INFORMATION SOURCES 
VII.  REFERENCES 
___________________________________ 
I.  INTRODUCTION
 
Graft-versus-host disease (GVHD) is a common complication after
 
bone marrow transplantation.  GVHD has also been reported after
 
transfusion in immunocompromised hosts, though such reports have
 
been uncommon. 1,2 More recently, cases of transfusion-associated
 
GVHD in immunocompetent patients have been reported when both
 
donor and recipient share genes for HLA determinants, a situation
 
most likely to occur when family members serve as donors. 3,4 

While irradiation of blood components intended for
 
immunocompromised patients has been used for over 30 years, more
 
recently, irradiation of directed blood donations from first
 
degree family members (parents, children, siblings) was
 
recommended by the American Association of Blood Banks (AABB) to
 
reduce the risk of graft versus host disease (GVHD) and,
 
effective 1 May 1993, the AABB's recommendation was extended to
 
blood derived from all donors who are genetically related to the
 
recipient. 5  This memorandum provides information on preparing
 
blood products irradiated with gamma or ionizing radiation.
 
Conclusive data are not available regarding all potential effects
 
of radiation on blood cells.  This memorandum describes quality
 
control applicable to the manufacture of irradiated blood
 
products and procedures applicable to licensure of such products,
 
including quality control, stability and labeling.  The
 
uncertainties which exist regarding product quality are addressed
 
in discussion of labeling procedures
 
II.  BACKGROUND 

A.  TRANSFUSION-ASSOCIATED GVHD.
 
GVHD occurs when viable T lymphocytes in transfused blood
 
or blood components engraft, multiply, and react against
 
the tissues of the recipient.  GVHD may be seen when blood
 
components are transfused to immunocompromised recipients,
 
such as bone marrow transplant patients, patients with
 
malignancies receiving aggressive chemotherapy and persons
 
with congenital immune deficiency syndromes. Luban and
 
Sacher have suggested that several factors affect the
 
incidence of transfusion-associated GVHD: 1)
 
Histocompatibility factors and lymphocyte subsets; 2) Type
  of blood component, dosage of immunocompetent cells per
 
transfusion and rate of infusion;  3) Underlying medical
 
condition;  4) Type of immunosuppressive therapy or
 
chemotherapy; 5) Age of patient; and 6) Microbial factors.
 
6 
There are recent reports of GVHD occurring in apparently
 
non-immunocompromised recipients following transfusion of
 
blood donated by family members, 7-10 and the probability
 
of such occurrences has been estimated using accepted
 
genetic principles. 4,11,12  While the true incidence of
 
transfusion-associated GVHD is not known, estimates of
 
frequency are available from theoretical calculations, from
 
limited studies in selected populations outside the U.S.,
 
and from survey data:
 
. 1990 AABB Questionnaire of 1,999 hospitals showed 12
 
cases of transfusion-associated GVHD among 14,296,314 blood
 
components administered, of which 570,859 had been
 
irradiated. 13
 
. A retrospective study of 63,257 patients who had
 
undergone cardiac surgery in Japan yielded 96 cases of GVHD
 
attributed to transfusion (incidence = 1 case/659
 
transfusions). 7
 
. There is consensus that transfusion of blood from HLA
 
homozygotes to HLA heterozygotes with a shared haplotype
 
constitutes a situation that is high risk for occurrence of
 
transfusion-associated GVHD.  Calculations of the frequency
 
of this occurrence in the U.S. vary from 1/500 14 to
 
1/7174. 11  These numbers vary due to differences in the
 
databases used for calculation and in the definitions of
 
HLA compatibility. 

. There are additional reports describing methods for
 
calculating risk estimates among relatives, e.g., if donor
 
and recipient are related as grandparent, uncle or aunt,
 
the risk is one-half that which would pertain if donor and
 
recipient were parent and child. 4,12 

In cases of family member transfusions, GVHD may occur more
 
frequently than in random donor transfusions because family
 
members are more likely to share the same HLA haplotypes
 
than people in the population at large.  In many of these
 
cases, it was found that the donors were HLA homozygous for
 
one of the recipient's haplotypes.  In such situations, the
 
recipient's lymphocytes do not recognize HLA antigens on
 
the donor lymphocytes as foreign, and the donor lymphocytes
 
can survive indefinitely and may react immunologically
 
against the recipient's tissues.  Immunocompromised
 
patients who are suitable candidates for receiving
 
irradiated blood products have been categorized in the
  scientific literature according to risk status. 15-22  AABB
 
now recommends the irradiation of directed donations from
 
all family member donors to immunocompetent recipients. 5
 
Platelets; Platelets, Pheresis; Granulocytes, Pheresis;
 
Whole Blood; and Red Blood Cells contain 100,000 or more
 
lymphocytes per unit and have been implicated  in cases of
 
GVHD. Red Blood Cells, Deglycerolized may contain small
 
numbers of residual T lymphocytes, but no case reports of
 
GVHD associated with this product have been published. 23 

There are sufficient lymphocytes in single donor plasma to
 
initiate GVHD in immunocompromised patients and GVHD
 
possibly related to fresh frozen plasma has been reported
 
in an infant with congenital immunodeficiency. 24 

Cryoprecipitated AHF has not been reported to be associated
 
with GVHD.  Methods of producing leukocyte-reduced whole
 
blood and components (including washing, filtration, and
 
centrifugation) reduce the number of viable T lymphocytes,
 
but may not decrease tho risk of GVHD as effectively as
 
irradiation.1,25,26   White cell filters have not been
 
effective to date, but their use continues under
 
investigation.
 
B.  IRRADIATION OF BLOOD PRODUCTS TO PREVENT GVHD.
 
Gamma irradiation of blood products has been in routine use
 
in conjunction with bone marrow transplantation for
 
approximately twenty years.  The evidence in support of
 
gamma irradiation of blood products for transfusion in
 
prevention of GVHD is: 

1.  Gamma irradiation can abrogate the ability of
 
lymphocytes to proliferate in vitro.  1500 cGy of
 
gamma radiation reduce lymphocyte response to
 
mitogens by 90%, 27  while 5000 cGy result in a 98%
 
decrease in mitogen stimulation. 28  Published
 
studies indicate that doses of 1500 to 2000 cGy
 
reduce mitogen-responsive lymphocytes by 5 to 6
 
orders of magnitude. 19  Similar effects have been
 
reported using 1500 to 2500 cGy. 25 

2.  Various studies have shown that the incidence of
 
GVHD can be reduced if lymphocytes are physically or
 
immunologically removed from donor bone marrow. 

3.  Limited studies 2 support the contention that
 
gamma irradiation of blood products may prevent
 
transfusion-associated GVHD. 

4.  Clinical observation over approximately 30 years
 
during which transfusion of irradiated blood has been
 
practiced has resulted in only 2 case reports of GVHD
 
in recipients of irradiated blood products, and these
  cases involved use of a suboptimal dose of
 
irradiation. 19,29
 
C.  EFFECTS OF GAMMA IRRADIATION ON PRODUCT QUALITY AND
 
STABILITY.
 
1.  Damage to cellular products.  Gamma irradiation
 
has been shown to affect red cells 28,30,31 so that
 
use of the component should be modified. 

a.  RED BLOOD CELLS 

i.  The 24 hour recovery of irradiated
 
red blood cells, after storage, is
 
decreased compared to controls. 

Published data from several laboratories
 
show that red blood cells irradiated
 
within 24 hours of collection maintain
 
satisfactory viability up to 28 days,
 
while cells stored for 42 days had
 
unsatisfactory viability (for cells
 
irradiated on the day of collection and
 
stored for 42 days, the 24 hour
 
autologous recovery is 68.5 + 8.1% vs
 
78.4 + 7.1% for non-irradiated
 
controls).30 

Other data have been interpreted to
 
suggest that red cells irradiated within
 
24 hours of collection can be stored
 
satisfactorily for up to 35 days and that
 
red cells irradiated as late as 14 days
 
after collection may be satisfactorily
 
stored for an additional 28 days (G.
 
Moroff, personal communication).
 
ii.  Units of red blood cells which have
 
been irradiated have been shown to
 
contain approximately twice as much
 
extracellular potassium after equivalent
 
periods of storage as non-irradiated
 
controls. 31-33  The data show that
 
irradiation of red blood cells may
 
increase the rate of potassium ion
 
leakage upon storage.  Therefore, a high
 
plasma potassium level may result if a
 
significant portion of the total blood
 
volume is replaced with irradiated red
 
cell components .
 
iii.  Red blood cells which have been
 
irradiated have been shown to contain
 
more cell-free hemoglobin (approximately
  50% increase) than control cells after
 
equivalent periods of storage. 31,33 

b.  PLATELETS 

Significant changes in cell function have not
 
been demonstrated in platelet products and
 
changes in storage are not required for
 
platelets irradiated on the day of collection.
 
34-35  Platelets irradiated at times up to 5
 
days after collection showed no
 
post-irradiation change in function. 36,37
 
2.   Theoretical risks associated with use of
 
irradiated blood Products. 

a.  POTENTIAL FOR MALIGNANT TRANSFORMATION OF
 
IRRADIATED NUCLEATED CELLS CAPABLE OF SURVIVAL
 
IN THE RECIPIENT. Radiation of nucleated cells
 
may result in malignant transformation. 

Quantitative risk assessment of this phenomenon
 
occurring in irradiated blood has not been
 
performed, but there is evidence that this
 
theoretical risk is extremely remote.  First,
 
there are no reports of non-autologous
 
malignancy in recipients of irradiated blood.
 
Second, studies with murine cells indicate that
 
the amount of radiation used for blood
 
components is much more likely to cause
 
complete cell death than a single
 
transformation event.  It is also known that
 
murine cells are much more susceptible to
 
radiation-induced transformation than human
 
cells. Thus, although existing data are
 
insufficient to prove that there is no risk of
 
transformation, there are no data to
 
substantiate such a risk, and the data that are
 
available indicate a very low risk. 38-40 

b.  ACTIVATION OF LATENT VIRUSES 

Gamma irradiation has been shown to disrupt the
 
latency or viruses which are potential contaminants
 
of blood products. Despite the theoretical risks of
 
viral activation, no reports of adverse events
 
reflecting such occurrences have been published or
 
received by FDA, and it is likely that the amount of
 
radiation routinely used substantially exceeds
 
amounts associated with this risk.
 
III.  LICENSE AMENDMENTS FOR IRRADIATION OF BLOOD AND BLOOD
 
PRODUCTS
  Facilities irradiating blood products to be shipped in interstate
 
commerce should submit applications for amendments to those
 
license affected.  The amendments should be submitted in
 
duplicate with the appropriate product license application for
 
and include the following:
 
A.  STANDARD OPERATING PROCEDURES (SOPs).
 
The SOPs for irradiation of Whole Blood and blood
 
components should describe: 

i.  the irradiator; 

ii.  the dose delivered to the center of the
 
container, corrected for air - liquid differences 41
 
(including dosage validation data); 

iii.  the strength of the source; 

iv.   the length of time required to deliver the
 
irradiation; and 

v.    how monitoring will be performed to determine
 
that the intended dose is actually delivered (see
 
III.C).
 
B.  IRRADIATION BY CONTRACTOR.
 
If product irradiation is to be performed in a different
 
facility (e.g., a hospital radiation therapy department),
 
the terms of the agreement with such facility should be
 
included. Establishments performing the irradiation are
 
participating in the manufacture of a product and should
 
register with the FDA in accord with 21 CFR 607.
 
The terms of the agreement should specify that the
 
operations are under the control of the blood establishment
 
with respect to the procedures for irradiation of blood
 
products, including the activities specified above, and for
 
review of training and audit by the blood establishment. 

The documentation should allow FDA to determine that the
 
contractor performing the irradiation is operating
 
effectively as part of the licensed establishment. 

C.  RADIATION DOSAGES AND VALIDATION.
 
Cesium-137 is the most commonly used source for irradiation
 
of blood and blood components; use of Cobalt-60 or a linear
 
accelerator may also be acceptable.1,15,25,28,42,43  The
 
dose of irradiation delivered should be 2500 cGy targeted
 
to the central portion of the container and 1500 cGy should
 
be the minimum dose at any other point.  It should be
 
recognized that the irradiation delivered to the instrument
 
canister (as identified by isodose curves supplied by the
  manufacturer) may differ from the actual dose delivered to
 
the blood bag or container (as quantified by
 
thermoluminescence dosimeter (TLD) chips or other direct
 
method of measurement).  Validation studies should be
 
performed to establish the performance of the irradiator
 
within these limits, and maintenance procedures established
 
to ensure satisfactory ongoing performance.6,15,44 

Validation should be done annually and after mechanical
 
repairs, especially those involving the sample-handling
 
apparatus (e.g., the turntable).  Use of indicator devices,
 
which signal exposure of the blood product container to
 
radiation, is encouraged. 

D.  REMOVAL OF PLASMA PRIOR TO RELEASE. 

Elevated potassium levels have been reported in irradiated
 
red blood cell products.31,33  Removal of residual plasma
 
may reduce tho risks associated with high plasma potassium.
 
If this practice is used in manufacture of irradiated blood
 
products, it should be described in the amendment.
 
E.  LABELING.
 
1.  Irradiated blood product containers should be
 
permanently labeled as irradiated.  Removable
 
tie-tags are not acceptable for this purpose.
 
2.  The license number should not appear on the
 
container label unless the blood establishment is
 
licensed by FDA for preparation of the irradiated
 
blood product.
 
3.  The circular of information should be modified to
 
include a discussion of appropriate indications for
 
irradiated blood products and appropriate warnings
 
based on the known safety concerns, namely: 

Irradiated blood products are indicated for use in
 
patients at risk of transfusion-associated GVHD.
 
Caution should be used when administering irradiated
 
red cell products to patients at risk for
 
hyperkalemia, if supernatant plasma has not been
 
removed from the product just prior to transfusion.
 
4.  The dating period for red blood cell products
 
(Red Blood Cells,  Whole Blood) should be not more
 
than 28 days from the date of irradiation, but
 
otherwise not more than the dating period of the
 
non-irradiated product. 

5.  The dating period for Platelets and Platelets,
 
Pheresis should be in accord with established
  regulations and guidelines, regardless of the day of
 
irradiation.34-37 

6.  Approved product names and drug codes will be
 
provided by FDA at the time of application for
 
licensure.
 
IV.  RECORDS
 
Records must be maintained according to 21 CFR 606.160, to
 
document the following significant steps in the irradiation of
 
each product:
 
A.  The radiation source: Identify the strength of the
 
source, duration and level/dose (number of cGy) of
 
irradiation, and identity of operator, and the date and
 
time of irradiation.
 
B.    Total irradiation: If a product is irradiated more
 
than once, the documentation should clearly indicate the
 
steps taken; individual irradiation doses should be
 
cross-referenced and the total (additive) irradiation dose
 
recorded.
 
C.  Sit of irradiation:  If the irradiating facility is
 
different from the collecting facility, the records should
 
include information regarding this irradiating facility.
 
D.  Quality control of the irradiating device: Quality
 
Control should include calibration and documentation of the
 
procedures discussed in the SOP section of this memorandum
 
or equivalent procedures. 

E.  Personnel training:  Training should include safety
 
procedures, and radiation monitoring.
 
V.  When a fatality due to transfusion-related GVHD has been
 
confirmed, the FDA must be notified as soon as possible by
 
telephone with a written report of the investigation to follow
 
within seven days after the fatality [21 CFR 606.170 (b)]. Direct
 
such notifications to the:

 Director

 Office of Compliance, HFM-600

 Center for Biologics Evaluation and Research

 1401 Rockville Pike, Suite 200N

 Rockville, MD  20852-1448

 Telephone: 301-594-1191
 
Fatal GVHD in bone marrow transplant recipients who received
 
Whole Blood or blood components during the post-transplantation
 
period need not be reported if the fatality was caused by the
 
marrow graft.
  VI.	  INFORMATION SOURCES
 
Technical questions, information and comments may be directed to
 
the:

 Division of Blood Collection and Processing, HFM-350

 1401 Rockville Pike, Suite 200N

 Bethesda, MD  20852-1448

 Phone: (301) 594-6700     FAX: (301) 594-6431
 
Questions, information and comments concerning labeling or
 
shipment may be directed to the:

 Division of Blood Establishment and 

Product Applications, HFM-370

 1401 Rockville Pike, Suite 200N

 Bethesda, MD  20852-1448

 Phone: (301) 594-2012     FAX: (301) 594-1973
 
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33.	  Ramirez AM, Woodfield DG, Scott R, et al. High potassium
 
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1988; 28:446-450.
 
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38.	  Linden JV, Pisciotto PT. Transfusion-associated
 
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40.	  Brach MA, Hass R, Sherman ML, et al. Ionizing radiation
 
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