Transcript Document 7152852

REVIEW OF PLASMA
PRODUCTS FOR TRANSFUSION
March 17, 2005
Mark Weinstein, Ph.D.
Office of Blood Research and Review
CBER, FDA
Issue
FDA seeks advice from the Committee on the
extent to which the available scientific data may
support:
• Changes to further standardize processing of
plasma products for transfusion
• The need for additional scientific studies that
would be helpful to resolve current areas of
uncertainty.
Background
• Currently, plasma products for transfusion are poorly defined and
characterized in the CFR and the AABB Circular of Information.
• 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 to consider the possible development of minimal standards
for these products that would further ensure their clinically relevant
safety, purity and potency.
• 2004 FDA workshop on plasma standards identified multiple
parameters that can affect the composition and potentially the quality
of plasma products for transfusion
– time and temperature of separation of plasma from cells
– the anticoagulant used
– freezing, storage, thawing, and post thawing conditions
• This session will consist of a review of the key literature on plasma
processing and a presentation on the clinical use of plasma products.
Topics
•
•
•
•
•
Issue
Safety and quality of products
Plasma products and their uses
Potential areas of improvement
Focus on temperature-related issues of
preparing plasma transfusion products
What’s the Problem?
• Current standards may not reflect current scientific
knowledge.
• Side effects and hazards of plasma for transfusion products
(AABB circular)
– Immediate immunologic complications: febrile nonhemolytic
reactions, allergic reactions, anaphylactoid reactions, transfusionrelated acute lung injury (TRALI)
– Delayed immunologic complications: alloimmunization to antigens
of red cells, white cells, platelets, or plasma proteins.
– Transmission of infectious agents: virus, bacteria, prions
– Circulatory overload, hypothermia, or metabolic complications.
• Plasma products may not be made in a way that will
minimize risks and exposure to product.
What’s the Current Situation?
Product Definitions (CFR, AABB Circular):
Fresh Frozen Plasma
• [21 CFR 640.32 (a)] When whole blood is intended for Plasma,
Fresh Frozen Plasma, and Liquid Plasma, it shall be maintained at a
temperature between 1 and 6 oC until the plasma is removed. [Note:
FFP can also be made from plasma separated within 8 h of
collection from Whole Blood that has been maintained at room
temperature “Eight-Hour Hold; Blood and Plasma Inspectors – memo 11/13/89” ]
• [21 CFR 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
• [AABB Circular] 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
Factors that Could Affect
Plasma Quality
• Time, temperature of plasma contact
with cells
• Anticoagulant
• Residual cellular content
• Rate of freezing (affected by the
following)
– Volume of plasma to be frozen
– Shape of container
– Freezing device, e.g., freezer, cold room, blast
freezer
Definition of Other Plasma Transfusable Products
(AABB Circular)
• Cryoprecipitate: Prepared by thawing FFP between 1-6 oC and
recovering the precipitate. Each unit should contain > 80 IU FVIII and
>150 mg fibrinogen in approximately 15ml plasma
• 21 CFR 640.54 (a) (3) (b) “…AHF shall be separated from the plasma
by a procedure that has been shown to produce an average of no less
than 80 units of antihemophilic factor per final container”
• Plasma, Cryoprecipitate Reduced: is prepared from FFP that is
thawed and centrifuged, with the cryoprecipitate removed by
centrifugation.
• Thawed Plasma is derived from FFP prepared in a way that ensures
sterility (closed system), thawed at 30-37 oC, and maintained at 1-6 oC
for 1-5 days. A product not in the CFR, not a licensed product.
• Liquid Plasma is separated no later than 5 days after the expiration
date of the Whole Blood. Plasma may be stored at <-18 oC. Liquid
plasma is stored at refrigerator temperature 1-6 oC.
• Plasma frozen within 24 hours after phlebotomy: must be separated
and placed at <-18 oC within 24 hours of whole blood collection.
Labeled Uses of FFP (AABB)
• Management of preoperative or bleeding patients who require
replacement of multiple plasma coagulation factors (e.g., liver
disease).
• Patients on warfarin who are bleeding or need to undergo an
invasive procedure…
• Patients with massive transfusion who have clinically significant
coagulation deficiencies
• For transfusion or plasma exchange in patients with thrombotic
thrombocytopenic purpura (TTP)
• Manage coagulation factor deficiencies, congenital or acquired,
for which no specific coagulation concentrates are available
• Manage rare specific plasma protein deficiencies, such as C-1esterase inhibitor and FV.
• Source material for Cryoprecipitate, Cryopoor plasma, and
thawed plasma
Labeled Uses of Other Transfusable
Plasma Products (AABB circular)
• 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.
• 24 h Plasma; thawed plasma; Liquid plasma:
Serve as a source of defective or deficient plasma
proteins except for FV and FVIII. Indications same
as for FFP except not to be a source of FV or FVIII.
Factors Affecting Quality of
Transfusable Plasma Products
Blood drawing technique; adequate mixing of anticoagulant
with plasma Appropriate technique is needed to avoid
activation of coagulation and other proteins
Anticoagulant: CPD or ACD Literature is mixed on whether
collection in ACD results in less FVIII than CPD.
Anticoagulant-related differences in plasma protein activity
occur over time in plasma stored at 6 oC.
Residual cells in plasma Cells and cellular components in
plasma have the potential of causing immunological
reactions and release of proteolytic enzymes, that could
lead to some side effects seen in plasma product
transfusions. There are no standards on cellular content
of plasma products, but plasma products must be ABO
compatible. Plasma separation techniques vary widely.
Factors Affecting Quality of
Transfusable Plasma Products
Time, Temperature from draw to freezing Allowable times
and temperatures vary among different regulatory
bodies with varying degrees of scientific justification.
Conditions optimal for plasma quality may not be
optimal for cellular preservation.
Plasma contact with cellular components – Temperature
effects Cold activation of the coagulation and plasma
kinin system is of concern. FVIII and vWF can be
reduced by significant amounts
Rate of freezing plasma, thaw and post thaw conditions
Plasma Contact with Cellular Components:
Cold Activation [Favaloro, 2004]
• Experiment: 39 donors, Whole Blood into 3.2% NaCit tubes
–
–
–
–
Aliquot centrifuged immediately, plasma frozen –80 oC
Aliquot whole blood held at 4oC, 3.5 h
Aliquot whole blood held at 22oC, 3.5 h
Separate plasma; test for FII, V, VII, VIII, IX, X, XI, XII, vWF:Ag,
vWF:CB
• Result: No effect of temperature on FII, V, VII, IX, X, XI, XII
• For plasma from WB kept at 4oC, 3.5 h:
– 25% loss of FVIII
– 50% loss of vWF:Ag (Non-O blood)
– 60% loss of vWF:CB (Non-O blood)
• True for plasma from blood collected in CPD or ACD?
• Should the time and temperature of WB before plasma
separation be more narrowly defined?
Anticoagulant Affects Activity of Proteins in
Stored Plasma
Blomback, 1984
Focus on Freezing Plasma
• FDA sponsored a workshop on
August 31-September 1, 2004 to
– review scientific data,
– regulatory requirements,
– current industry practices
regarding the freezing, storage,
and shipping of plasma.
• Purposes:
– help develop regulatory standards for recovered
plasma
– examine the potential of harmonizing regulations
with Europe
Plasma
Product
US FFP
COE Plasma for
Transfusion
Collection
method
Whole blood or
Plasmapheresis
Whole blood
plasma
aphaeresis
Time from draw
to start
freezing
<8 hrs
<18 hrs, (< 6
hrs optimal)
if +20 – 24 C,
then <24 hrs
< 6 hrs
Freezing
conditions,
temperature
At <-18 C
To < -30 C within 1 hr
Storage,
expiration
<-18 C, 1 yr
If -18 C to -25 C, 3 months
If <-25 C, 24 months
Shipping
temperature
<-18 C
-18 C to -25 C, or <-25 C (see
above)
Allowable
deviation
none
none
if +20 – 24 C,
then <24 hrs
Comparison of US and COE
Standards and Recommendations:
Issues to Consider
• What is the scientific basis for differences
in freezing conditions between US and
COE?
• What are the advantages and
disadvantages of rapid freezing?
• Product use?
• Product need?
• Practical implications?
Parameters Affecting Plasma Quality
Plasma Separation
from WB
Method
Time
Temperature
Cell content
Whole Blood
ACD,
CPD?
Plasma unit
Thaw Method
Rate of
Freezing
Storage time, temperature
Cryoppt
FFP
Cryosup
recovered plasma
“thawed plasma”
Time to Freeze 700 ml, 1500 ml Plasma
Under Varying Conditions
Carlebjork, 1986
Factor VIII Recovery in FFP Affected by Freezing Rate
Carlebjork, 1986
FVIII Activity in FFP After “Slow” and “Rapid” Freeze
Akerblom, 1992
Samples: 200ml, N = 10, prepared within 2 hr of blood draw
Rapid freeze: -40 oC, <40 min
Slow freeze: place in -40 oC or -20 oC cabinet freezer; time to freeze
not reported
Effect of Freezing of on FFP
Akerblom, et al, 1992
• Rapid freeze (-40 oC, <40 min): loss of about 8%
FVIII from pre to post freeze; 9% increase in betaTG (platelet lysis) but not statistically significant
• Slow freeze, (-20 oC): 20% loss FVIII; 8% loss FV;
14% increase in beta-TG
• Slow freeze, (-40 oC): 14% loss FVIII; freeze rate
more important than final temperature
• No difference between fast and slow freeze in
FVII, vWF, soluble fibrin, TAT complex, C1esterase inhibitor
Parameters Affecting Plasma Quality
Plasma Separation
from WB
Method
Time
Temperature
Cell content
Cryoppt
Thaw
Method
Whole Blood
ACD,
CPD?
Plasma unit
Rate of
Freezing
Storage time, temperature
FFP
Cryopoor
recovered plasma
“thawed plasma”
Effect of Freezing Rate of FFP on
Cryoprecipitate/supernatant Production
Samples: 200 ml, N=6, prepared within 3 hr of donation, thaw
siphon process to make cryoppt
Slow freeze: -40 oC freezer, -0.33 oC/min
Rapid freeze: - 70 oC Liquid N2/ ETOH, -5 oC/min
Note: VIIIR:Ag = vWF
Farrugia, 1985
Effect of Freezing of on FFP, Cryoppt
Farrugia, et al, 1985
• Total recoverable FVIII activity, (cryosupernatant plus
cryoprecipitate) not significantly different between slow
and fast freeze. This suggests that the FVIII activity in
FFP might not differ significantly between the two
freezing rates.
• More FVIII (25%), vWF (24%), and fibrinogen (13%)
were in cryoprecipitate made from fast frozen than from
slow frozen plasma, using the thaw siphon methodology
to prepare cryoprecipitate.
• Potentially, under these fast freeze conditions, less
cryoppt and cryopoor plasma would be needed to
achieve the desired outcome
FVIII in FFP: Fast and Slow Freeze
Interpret Data with Caution!
Slow freeze
Fast
freeze
Sample: 200ml plasma, n = 10
Fast: -30oC, fluorocarbon bath
Slow:
-30oC,
cold room
Thaw 37 oC, store 22 oC
Farrugia, 1992
Under Certain Conditions, “Fast” and “Slow”
Freeze of FFP has Little Effect on FVIII, vWF,
and Fibrinogen in Cryoprecipitate
Farrugia, 1992
Considerations
• Need to define “fast” and “slow” freeze
conditions.
• Increasing the rate of freezing plasma
decreases the loss of FVIII activity up to a point,
beyond which the rate has little effect.
• The amount of FVIII, vWF, and fibrinogen in
cryoprecipitate is highly dependent on the thaw
method as well as the freezing rate.
• Under defined conditions there is little
advantage in freezing to -30 oC within 1 h
compared to 2 h.
Parameters Affecting Plasma Quality
Plasma Separation
from WB
Method
Time
Temperature
Cell content
Whole Blood
ACD,
CPD?
Plasma unit
Thaw Method
Cryoppt
Rate of Freezing
Storage time,
temperature
FFP
Cryopoor
recovered plasma
“thawed plasma”
No Change in FVIII and Other Proteins in FFP
Stored at –20 oC vs – 40 oC for 36 Months
Kotitschke, 2000
Effect of Storage Temperatures on FVIII
-74oC
5 ml aliquots of plasmapheresis plasma
- 24 oC
Frozen and stored at -74oC (x)
Frozen and stored at - 24 oC (o)
Woodhams, 2001
Effect of Temperature Cycling of Plasma
on Fibrinogen
Content
in
Cryoprecipitate
CRYOPRECIPITATE
QUALITY
PLASMA STORAGE
EFFECT OF TEMPERATURE INSULT
TEMPERATURE CYCLING
Farrugia & Prowse 1985
Farrugia & Prowse 1985
PLASMA
CORE OC
10
5
0
-5
-10
-20
-30
-40
Plasma temperature
cycling
ONE CYCLE
TWO CYCLES
STEADY
CONDITIONS
2000
1800
1600
1400
1200
1000
800
600
400
200
0
STEADY
ONE CYCLE
TWO CYCLES
FVIII
1
2
3
4
5
6
FIBRINOGEN
7 DAYS
Farrugia, 1985
Considerations
• Most, but not all studies suggest that rapidly
frozen FFP can be stored at –20 oC for more than
one year without significant changes in the activity
of certain proteins, including FVIII. Current
standards specify one year storage for FFP.
• Temperature fluctuations in frozen FFP can affect
cryoprecipitate composition. Current regulations
for FFP do not permit deviations above –18 oC.
• Should these standards be reconsidered?
Challenges in Evaluating Data
• Comparison of study results is
complicated because of differences in
measured parameters, and assay
techniques
• Laboratory studies may not reflect
practically achievable conditions
• Conditions optimal for production of one
product may not be optimal for others
Requests to 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 excursions,
cellular content.
• What additional scientific studies are needed?
• What recommendations do you have for the next
steps forward?