**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
[\<]{.underline}-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 [\<]{.underline}-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 [\>]{.underline} 80
IU FVIII and the Circular, but not the CFR, also indicates that the
product should contain [\>]{.underline}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 [\<]{.underline}-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
[\<]{.underline}-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]{.underline}: 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]{.underline}. 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]{.underline} 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]{.underline} 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]{.underline} 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**
[\<]{.underline}-30 °C within 1 hour. This is in contrast to the CFR
requirement that such plasma be frozen, stored and shipped at
[\<]{.underline}-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]{.underline} 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 [\<]{.underline}-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
[\<]{.underline}-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**

![](media/image1.wmf)

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References

References 11/13/2023

1.  **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,]{.underline} 283-287

2.  **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,]{.underline}
    246-259

3.  **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]{.underline}, 433-437

4.  **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]{.underline}, 686-692

5.  **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]{.underline},
    492-497

6.  **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]{.underline}, 76

7.  **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]{.underline}, 174-180

8.  **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]{.underline}, Dordrecht, 203-213

9.  **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,]{.underline} 145-150

10. **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]{.underline}, 229-236