ISSUE SUMMARY
BLOOD PRODUCTS
ADVISORY COMMITTEE MEETING
MARCH 17, 2005
Gaithersburg,
MD
Topic II: REVIEW OF STANDARDS FOR PLASMA PRODUCTS FOR
TRANSFUSION
ISSUE: FDA seeks advice from the Committee on the extent
to which the available scientific data may support potential changes to further
standardize processing of plasma products for transfusion, and on additional
scientific studies that would be helpful to resolve current areas of
uncertainty.
BACKGROUND:
Currently,
plasma products for transfusion as described in the CFR and in the AABB
Circular of Information lack definition and/or specifications for many
processing conditions. Furthermore,
scientific uncertainty exists on the extent to which conditions of plasma
product preparation may affect the final products. We therefore are seeking to evaluate data acquired from all
available sources in order to consider the possible development of minimal
standards for these products that would further ensure their clinically
relevant safety, purity and potency.
At a recent FDA workshop on
plasma standards, data were presented suggesting that multiple parameters can affect the
composition and potentially the quality of plasma products for transfusion,
e.g. Fresh Frozen Plasma and Cryoprecipitate.
These include the time and temperature of separation of plasma from
cells, the anticoagulant used, conditions of freezing, storage, thaw, and post
thaw. Subsequent to the workshop, FDA
has engaged in a more detailed review of the literature on plasma processing,
and obtained additional information from industry.
This
session will consist of a review of the key literature on plasma processing and
a presentation on the clinical use of plasma products.
DISCUSSION:
On
August 31- September 1, 2004, FDA sponsored a workshop on Plasma
Standards. One objective of the
workshop was to obtain information that would help in the development of
standards for recovered plasma. Another goal was to review scientific data, regulatory
requirements, and current industry practices regarding the freezing, storage,
and shipping of plasma to ensure the safety, purity, and potency of both labile
and non-labile plasma components. We
also explored the possibility of harmonizing our requirements with those of
other regulatory bodies.
This meeting and subsequent review of the literature indicated that there are multiple parameters that potentially could affect the quality, and safety of plasma products used for transfusion. These parameters include the time and temperature of separation of plasma from cells, the anticoagulant used, conditions of freezing, residual cellular content of plasma, storage, thaw and post thaw conditions.
Plasma
products for transfusion as described in the Code of Federal Regulations (CFR)
and AABB Circular of Information do not have specifications for many of these
parameters. We are in the process of
reviewing scientific evidence that might help in the potential development of
minimal standards. We will discuss the
current definition of plasma products in the CFR and AABB Circular of
Information, the labeled uses of these plasma products, safety hazards
associated with transfusion of these products, and potential areas to consider
in improving current standards. A
major focus will be on temperature related parameters that affect plasma
quality.
Products
under review include the following, as defined in the CFR and the AABB, ABC,
ARC Circular of Information for the Use of Human Blood and Blood Components
Fresh
Frozen Plasma (FFP) 21CFR 640.34 (b) The plasma shall be separated from the red blood cells,
and placed in a freezer within 8 hrs or within the timeframe specified in the
directions for use for the blood collecting, processing, and storage system,
and stored at -18 oC or colder.
The
AABB circular includes additional information: [FFP] Consists of the fluid
portion of blood that is separated and placed at <-18 oC or below within 8 h
of collection of whole blood if the anticoagulant is CPD….Plasma collected in
ACD … must be placed at <-18 oC within 6 h. Plasma components may be prepared from whole
blood collection or by apheresis.
Thawed Plasma is derived
from FFP prepared in a way that ensures sterility (closed system), thawed at
30-37 °C, and
maintained at 1-6 °C for 1-5
days. Note that this product, unlike
others in this list, is not a licensed product and is not described in the CFR.
Cryoprecipitate: Prepared by thawing FFP between 1-6 oC and recovering the
precipitate. Each unit should contain >
80 IU FVIII and the Circular, but not the CFR, also indicates that the product
should contain >150 mg fibrinogen in approximately 15ml plasma.
Plasma,
Cryoprecipitated Reduced is prepared from FFP that is thawed and centrifuged, with
the cryoprecipitate removed by centrifugation.
Plasma
frozen within 24 hours after phlebotomy must be separated and placed at <-18
°C within 24
hours of whole blood collection.
Plasma;
Liquid Plasma is separated no later than 5 days after the expiration date
of the Whole Blood. Plasma may be
stored at <-18 °C. Liquid Plasma is stored at refrigeration
temperature (1-6 °C).
The
AABB Circular describes the uses of these products.
FFP:
·
Management of preoperative or bleeding patients who require
replacement of multiple plasma coagulation factors (e.g., liver disease).
·
Patients with massive transfusion who have clinically
significant coagulation deficiencies.
·
Patients on warfarin who are bleeding or need to undergo an
invasive procedure…
·
For transfusion or plasma exchange in patients with
thrombotic thrombocytopenic purpura (TTP).
·
Management of patients with selected coagulation factor
deficiencies, congenital or acquired, for which no specific coagulation
concentrates are available
·
Management of patients with rare specific plasma protein
deficiencies, such as C-1-esterase.”
24 h Plasma; Thawed Plasma; Liquid plasma: Serve
as a source of defective or deficient plasma proteins except for FV and
FVIII. Indications are the same as for
FFP except not to be a source of FV or FVIII.
Cryoprecipitate: Provides FVIII, fibrinogen, vWF, FXIII. Used as
second-line therapy for vWD and hemophilia A. Control of bleeding associated
with fibrinogen deficiency, and to treat FXIII deficiency.
Plasma, Cryoprecipitate Reduced: Provides for defective or deficient plasma proteins except fibrinogen, FVIII, vWF, FXIII. Used for TTP refractory to FFP.
Side effects and hazards of plasma
transfusion components
The
transfusion of plasma components is associated with a number of potential side
effects and hazards (AABB Circular).
Immediate immunologic complications include febrile nonhemolytic
reactions, allergic reactions, anaphylactoid reactions, and transfusion-related
acute lung injury (TRALI). Delayed
immunologic complications include alloimmunization to antigens of red cells,
white cells, platelets, or plasma proteins.
Besides these complications, there is always the potential of human
blood products to transmit infectious agents, because of viral, bacterial, or
prion contamination. Transfusions also
carry the risks of circulatory overload, hypothermia, or metabolic
complications.
Given
these risks, transfusion of blood components should be appropriately
minimized. To that end, increasing the
potency of products could help to reduce exposure to products.
Parameters to consider that might improve the quality of plasma.
The
CFR and AABB standards do not specify many conditions of plasma collection,
freezing, storage, thaw and post thaw conditions that could affect the quality and
safety of plasma components. At an
international forum on critical factors that affect the quality of FFP, held in
1983, [Allain, 1983] the following parameters were highlighted as being
significant. They are not inclusive and
further suggestions are welcome.
Anticoagulant: CPD or ACD: The literature is mixed on the differing effect of
these anticoagulants on FVIII recovery.
Some studies indicate FVIII activity is reduced in ACD compared to CPD.
Is there an anticoagulant-related difference in coagulation factors or other
plasma proteins in frozen or liquid plasma that develop over time?
Cellular content in plasma components. Residual cells and cellular breakdown products in plasma have the potential of causing immunological reactions and release of proteolytic enzymes, leading to some side effects seen in plasma product transfusions. There are no standards for the cellular content of plasma products, but plasma products must be ABO compatible. Plasma separation techniques can vary widely yielding differing quantities of residual cells.
Plasma contact with cellular components—Temperature effects Cold activation of the coagulation and plasma kinin system is of concern [Over, 1990]. A recent study [Favaloro, 2004] suggests that significant reduction in FVIII and vWF activity can occur in plasma separated from whole blood after 3.5 hr at 4°C, compared to plasma separated after 3.5 hr at 22
°C.
Time, Temperature from
draw to freezing Allowable times and temperatures vary among
different regulatory bodies [see tables below]. Importantly, conditions that are optimal for plasma collection
may or may not be optimal for cellular components [Hogman, 1998; Pietersz, 1989]. In evaluating the literature and considering
the development of standards, we need to be mindful that these standards can
affect both plasma products and cellular components.
Rate of freezing plasma, final temperature of freezing,
storage time and temperature, thawing and post thawing conditions are
additional factors that can affect the quality of plasma products. They were discussed extensively at the
Plasma Standards workshop. [Slide sets and a transcript of the workshop are available at
http://www.fda.gov/cber/summaries.htm, and
http://www.fda.gov/cber/minutes/workshop-min.htm respectively.]
Results
from the workshop and review of the literature suggest the following:
Time and temperature from
collection until freezing affects yield of labile products. FVIII is the most labile protein, and
changes in its activity may reflect unmeasured changes in other labile
factors. FVIII activity may be better
preserved in blood held at 20°C than at 4 °C before
separation [Over, 1990]
Labile
factors, particularly FVIII, are preserved better if plasma is frozen rapidly
compared to plasma frozen more slowly.
The Council of Europe has recommended that plasma for transfusion be
frozen to <-30 °C within 1
hour. This is in contrast to the CFR
requirement that such plasma be frozen, stored and shipped at <-18 °C. (see tables
below).
While
the data shows that rapid freezing preserves more factor VIII than slower
freezing, the magnitude of this effect depends on the details of the processing
conditions and may have more effect on cryoprecipitate than FFP. One study concluded that there was little
difference in FVIII activity in FFP between slow and fast frozen plasma,
[Farrugia, 1985], while
another [Akerblom ,1992] did
find a difference.
Higher
concentrations of FVIII, fibrinogen and vWF were present in cryoprecipitate
prepared from rapidly frozen plasma and correspondingly less in
cryosupernatant [Farrugia, 1985].
This may be advantageous when using Cryoprecipitate Reduced plasma to
treat thrombotic thrombocytopenic purpura.
These results may or may not be generalized to other methods of
preparing cryoprecipitate.
Some studies report that
little if any loss of clotting factor activity occurs when quick frozen plasma
is stored at <-20°C for 3 years [Kotitschke, 2000; Koerner, 1982]. Other investigators [Woodhams, 2001]
have reported losses.
Fluctuations in the storage
temperature of frozen plasma can alter yield of some proteins in
cryoprecipitate, such as fibrinogen. [[Farrugia, 1985]
While slow freezing reduces
the efficacy of FFP reflected in FVIII activity, the effect on safety is
unknown.
Plasma for transfusion in
the US is regularly shipped at <-20 °C according to meeting
participants.
In
evaluating scientific evidence that might support potential modifications of
existing standards, such as extending the dating period of FFP beyond 1 year,
care should be taken to examine the experimental details supporting the data,
especially in cases where results differ among studies. Laboratory conditions might not reflect
those achievable in blood processing centers.
It is also important to consider that parameters optimal for production
of one product may not be the best for others.
Questions for the Committee:
•Please discuss the
extent to which the available literature on plasma processing may support
changes to improve the clinically relevant safety, purity, potency or
consistency of various plasma products for use in transfusion, e.g. time to
plasma separation, time from collection or separation to freezing, freezing
rate and target temperature, storage temperature, allowed temperature
variations during shipping and storage, cellular content.
•What additional scientific
studies are needed?
•What recommendations do you
have for the next steps forward?
Summary of European Plasma Standards
- Akerblom, O, Bremme, K., Dackland, A.-L., Fatah, K.,
Suontaka, A.-M., and Blomback, M. (1992): Freezing technique and quality
of fresh frozen plasma, Infusiontherapie, 19, 283-287
- Allain, J.P., Friedli, J., Morgenthaler, J.,
Pflugshaupt, R., Gunson, H.H., Lane, R.S., Rock, G.A., Schorr, J.B.,
Menache-Aronson, D., Stryker, M.H., Woods, K.R., (1983): What are the critical factors in the production and
quality control of frozen plasma intended for direct transfusion or for
fractionation to provide medically labile coagulation factors? Vox Sang 44, 246-259
- Farrugia, A. and Prowse, C. (1985): Studies on the procurement of blood
coagulation factor VIII: effects of plasma freezing rate and storage
conditions on cryoprecipitate quality, J Clin Pathol 38, 433-437
- Favaloro, E.J., Soltani S., McDonald, J., (2004): Potential laboratory
misdiagnosis of hemophilia and von Willebrand disorder owing to cold activation
of blood samples for testing, Am J Clin Pathol, 122, 686-692
- Hogman, C.F., Knutson, F., Loof, H.,(1998) Storage of
whole blood before separation: the effect of temperature on red cell 2, 3
DPG and the accumulation of lactate, Transfusion, 39, 492-497
- Koerner, K. and Stampe, D. (1982):
Stability of factors of the coagulation system in fresh frozen plasma
during storage at –40 °C and -20
°C. Blut 45, 76
- Kotitschke, R., Morfeld, F., Kirchmaier, C.-M., Koerner,
K., and Kohler, M. (2000); –20 °C Stability of fresh frozen plasma:
results of 36-month storage at –20 °C,
–30 °C, and –40 °C, Infus
Ther Transfus Med 27, 174-180
- Over, J., and Loos, J.A. (1990) Preservation and
storage of human blood plasma proteins, in
Smit Sibinga, C.Th., Das, P.C., and Meryman, H.T. ed., Cryopreservation
and Low Temperature Biology in Blood Transfusion, in Developments in Hematology and
Immunology 24, Dordrecht, 203-213
- Pietersz, R.N.I., de Korte, D., Reesink, H.W., Dekker,
W.J.A., van den Ende, A., and Loos, J.A. (1989): Storage of whole blood
for up to 24 hours at ambient temperature prior to component preparation,
Vox Sang 56, 145-150
- Woodhams, B., Girardot, O., Blanco, M.-J., Colesse, G.,
and Gourmelin, Y. (2001): Stability of coagulation proteins in frozen
plasma, Blood Coagulation and Fibrinolysis 12, 229-236