Transfusion and Apheresis Science 28 (2003) 93–100 The Norwegian plasma fractionation project––a 12 year clinical and economic success story O. Flesland a,b,*, J. Seghatchian c, B.G. Solheim b a Blood Bank, Baerum Hospital, N-1306 Barum, Norway b Institute of Immunology, Rikshospitalet University Hospital, N-0027 Oslo, Norway c Blood Component Technology and Thrombosis/Haemostasis Consultancy, 50 Primeroe Hill Road, London NW3 3AA, UK The establishment of the Norwegian Fractionation Project (Project) was of major importance in preserving national self-sufficiency when plasma, cryoprecipitate and small batch factor IX-concentrates were replaced by virus inactivatedproducts in the last part of the 1980s. Fractionation was performed abroad by contract with Octapharma after tenderson the European market. All Norwegian blood banks (>50) participated in the Project. Total yearly production was50–60 tons of mainly recovered plasma. From 1993 solvent detergent (SD) treated plasma has replaced other plasma fortransfusion.
The blood banks paid for the fractionation and/or viral inactivation process, while the plasma remained the property of the blood banks and the final products were returned to the blood banks. The Project sold surplus products to otherNorwegian blood banks and the majority of the coagulation factor concentrates to The Institute of Haemophilia andRikshospitalet University Hospital. Both plasma and blood bank quality was improved by the Project. Clinical ex-perience with the products has been satisfactory and self-sufficiency has been achieved for all major plasma proteins andSD plasma, but a surplus exceeding 3 years consumption of albumin has accumulated due to decreasing clinical use.
The Project has secured high yields of the fractionated products and the net income from the produced products is NOK 1115 (140 € or US$) per litre plasma. An increasing surplus of albumin and the possibility of significant salesabroad of currently not fractionated IVIgG, could lead to a reorganisation of the Project from that of a co-ordinator toa national plasma handling unit. This unit could buy the plasma from the blood banks and have the plasma frac-tionated by contract after tender, before selling the products back for cost recovery. The small blood banks couldproduce plasma for products for the Norwegian market, while surplus products from the larger blood banks which arecertified for delivery of plasma for fractionation of products to be consumed in the European Community, could be soldon the international market.
Ó 2003 Elsevier Science Ltd. All rights reserved.
Abbreviations: HIV: human immunodeficiency virus; HAV: hepatitis A virus; HCV: hepatitis C virus; SD: solvent detergentKeywords: Blood; Plasma; Plasma fractionation; Self-sufficiency; Factor VIII; IVIgG; SD-plasma; Octaplasâ; Uniplasâ * Corresponding author. Address: Blood Bank, Baerum Hospital, N-1306 Barum, Norway. Tel.: +47-6780-9703; fax: Norway is a sparsely populated country with 4.5 million inhabitants. Blood donation is voluntary and non-remunerated, and all blood banks are 1473-0502/03/$ - see front matter Ó 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S1473-0502(02)00104-0 O. Flesland et al. / Transfusion and Apheresis Science 28 (2003) 93–100 hospital-associated. Self-sufficiency has been a na- fractionation in 1988, when the fractionation was tional goal since 1980. Norwegian blood banks performed at CRTS in Lille, France. All the frac- produce 50–60 tons of plasma per year, of which tionation products from the fractionation are re- approximately 90% has been recovered plasma.
This is not enough to establish a fractionationplant. The plasma is collected in more than 50 dif-ferent blood banks, making each individual blood bank commercially uninteresting to the interna-tional plasma fractionation industry. At the same As each blood bank is small, the time for col- time there is a demand for safe blood products.
lecting one full individual batch of plasma for In the first part of the 1980s, the policy of self- fractionation would be long. The Project ensures sufficiency and use of cryoprecipitates and factor that fresh frozen plasma (FFP) is shipped from XI prepared from small plasma pools ensured a several blood banks at a time, hence reducing high quality of life for Norwegian haemophiliacs storage time before fractionation. The Project also and secured a prevalence of anti-HIV of only 6% stores the returned fractionated products. Each for the whole haemophilia population [1]. Because blood bank orders from this store, when needed, of the human immunodeficiency virus (HIV) epi- ensuring that the oldest products are used first.
demic, the Norwegian Health Authorities decided Most of the coagulation factors are sold to the in 1985 that plasma, cryoprecipitate and factor IX National Institute of Haemophilia and Rikshos- should be replaced by virus inactivated plasma pitalet University Hospital. Factor VIII is made products prepared from Norwegian plasma by from all of the plasma. Also, until recently albu- 1988. A pilot project for contract fractionation was min has been made from all of the plasma. The initiated by the Red Cross and National Hospital Project ensures that enough, but not too much, of Blood Centre in 1986. After an increasing number other plasma products are produced. Initially this of blood banks joined the project during 1987–88, was factor IX and prothrombin complex (factors the Norwegian Plasma Fractionation Project was II, VII, IX and X). Later, intravenous immuno- established and took over co-ordination of con- globulin (IVIgG) and solvent detergent (SD) tract fractionation as of January 1989. The con- treated plasma and cryoprecipitate were intro- tract fractionation initiative, the postponement of elective orthopedic surgery in haemophiliacs, anda special grant by the Norwegian Parliament forequipment for freezing and storage of plasma, en- abled the transition to virally inactivated plasmaproducts with the retention of self-sufficiency [2].
The Project helped to improve the quality of the The Project collects plasma from all blood blood banks and the plasma. In order to secure banks in the country. Based on tenders on the high yields of factor VIII, product quality became a point of interest for the blood bank community Switzerland) has fractionated and/or virus inacti- from the start, resulting in standardised proce- vated the plasma since 1988 according to contract.
dures being introduced. FFP which amounted to On behalf of the blood banks and the Norwegian 95% of the plasma, was generally produced by counties, the National Institute of Health issued separation of whole blood within 4 h after collec- tenders and was the formal contract partner in tion and promptly snap frozen (core temperature relation to Octapharma. With respect to the Pro- <)28 °C within 35 min for 300 ml bags). Norwe- ject, the Blood Bank Council (appointed by the gian GMP guidelines were written and inspection Directorate of Health) was the professional ad- by pharmacists from the Surgeon GeneralÕs office viser to the Institute. Production has been carried were started largely because of this project [3]. ISO out at OctapharmaÕs plant in Vienna, Austria, certification and accreditation is now the next step except for the first eight months of 1989 and test for several blood banks. Another issue will be O. Flesland et al. / Transfusion and Apheresis Science 28 (2003) 93–100 certification of larger blood banks for delivery of high amounts of anti-Parvovirus B19 IgG. When plasma for commercial fractionation of products analysing patients at risk for Parvovirus B19 in- to be consumed in the European Community.
fection one out of nine patients transfused with Virus inactivation by SD treatment has been the only SD-plasma and 8 out of 14 patients trans- standard procedure for the plasma products. Since fused with SD-plasma and cellular components, 1998 an additional step of dry-heat treatment or seroconverted and developed anti-Parvovirus B19 nanofiltration has been added for the coagulation antibody positive status, however none of them developed clinical symptoms of disease.
Tests for antibodies directed against HIV and A study on fractionated albumin [14] demon- hepatitis C virus (HCV) were introduced in Nor- strates blocking of transport sites on albumin due way promptly after they were commercially avail- to stabilisers added (sodiumcaprylate and acetyl- able. Due to low HCV prevalence [4], introduction tryptophan) during pasteurisation of the product, of NAT test for HCV was delayed until April 2000, while albumin in SD-plasma is not affected. These when a small pool test (24 samples) was introduced transport sites are essential for the binding to al- for all blood and plasma collections. However, bumin of such drugs as Naproxen, Warfarin and according to European guidelines, Octapharma introduced NAT testing for HCV on all plasmabatches from July 1999. The delay in introductionof small pool NAT-testing in Norway led to the loss of products from two batches of plasma (onefor fractionation and one for SD-plasma produc- A successful clinical study with SD-plasma was tion) due to positive NAT tests for HCV in the final performed at the Rikshospitalet, University Hos- production pools. This demonstrated that small pital, in 1992 [8]. In 1993, Norway was the first pool testing, even if expensive, is cheaper than country to introduce SD-plasma as the sole plasma losing whole batches of plasma and corresponding for transfusion. The documentation for Methylene products. From April 2000, small pool HCV NAT blue treatment of plasma was evaluated as insuf- testing also became a requirement for the release of cellular products. We have not yet introduced do- nor exclusion of people who have spent time in the plasma (Octaplasâ) differs from the method ap- UK. This may delay commercialisation further.
plied by Vitex in the US for Plasâ þ SD. Twomajor differences for Octaplasâ are a smaller batchsize (200–380 l versus 600–1500 l) and that a final ultrafiltration/concentration step performed byVitex is omitted. In addition stabilisation of co- A research fund of NOK 0.75 million estab- agulation factors and final citrate concentration lished by the Project, supports scientific activities differs for the two products. Pool size increases the within transfusion medicine. In addition, Octa- process time, which can affect labile proteins and pharma has sponsored clinical studies, which have loss of activity due to absorbtion, while ultrafil- been carried out as agreed to with hospital re- tration could influence the good haemostatic bal- search organisations. These agreements ensure the ance observed between the coagulation factors investigatorsÕ rights to publish the study results.
and coagulation inhibitors in Octaplasâ [15]. This The studies on IVIgG [5–7] and SD-plasma [8– may explain problems recently observed with 12] have demonstrated good product quality and Plasâ þ SD and not with Octaplasâ. In addition interesting clinical results. A study performed by a2-antiplasmin activity has been reported lacking us demonstrated that antibodies directed against in the US produced SD-plasma [16] while it is re- Parvovirus B19 in SD-plasma, neutralise Parvo- duced at the most by 76% in Octaplas [15,17–20].
virus B19 in the product [10,13]. Out of 25 plasma Because a2-antiplasmin is a liver synthesised acute batches tested, all contained Parvovirus B19 and phase serine protease inhibitor of plasmin [21], this O. Flesland et al. / Transfusion and Apheresis Science 28 (2003) 93–100 could result in fibrinolysis in patients with severe All haemophilia patients are regularly tested for liver failure. It should therefore be considered to viral disease transmission. For enveloped viruses, administrate serine protease inhibitor (i.e. Apro- which are inactivated by SD the treatment, only tinin) when transfusing Octaplasâ to patients with one seroconversion for HCV has been observed.
severe liver failure (including liver transplants) or No other patients treated with products from the with high risk of fibrinolysis. Due to the ultrafil- same batches seroconverted, nor were any irregu- tration/concentration process the concentration larities found with the batches. The conclusion was of plasma proteins is in general unchanged in the therefore that the seroconversion was not related US produced SD-plasma, while a 10% decrease is to coagulation factor treatment. With respect to transmission of non-enveloped viruses, which are After SD-plasma was introduced in Norway, not affected by SD treatment, four haemophilia the number of units consumed has increased by patients were infected with hepatitis A virus 78% to 7.9 units/1000 inhabitants. However, the (HAV) by highly purified factor VIII in 1998. The introduction of SD-plasma reduced the unit vol- batch involved in the HAV transmissions was ume from 270 to 200 ml, thus the consumed FFP shown to contain plasma from a donor with vire- mia in connection with HAV infection. We have not observed any HAV transmission with cryo- development and clinical testing of an universal precipitate or intermediate purity factor VIII SD-plasma (Uniplasâ) which can be transfused concentrates [21], but it is documented that the irrespective of a patients ABO type. In a pro- content of antibodies against HAV is too low in spective, randomised study which recently was the highly purified factor VIII to neutralise the concluded at Rikshospitalet University Hospital, HAV [13,22,23]. As a consequence, double viral Uniplasâ was found to be efficient, well tolerated inactivation has since been introduced for all pu- rified coagulation factors and no further viral A SD treated cryoprecipitate has been produced by Octapharma for use in Norway in the very few Since 1993 the SD-plasma, Octpaplasâ, has re- von Willebrand factor (vWF) deficient patients not placed FFP and other plasma for transfusion in responding adequately to the standard factor VIII Norway. More than 250,000 units have been product (Octa V.I.â, Octaviâ and Octanateâ).
transfused to all types of patients, including neo- These are products with a high content of vWF.
nates and 208 liver transplants. Aprotinin has The SD treated cryoprecipitate also represents a generally only been used in complicated repeat cardiac surgery and patients with severe liver fail-ure undergoing liver transplantation. Neithertransmission of viral disease, nor thrombotic/ fibrinolytic complications or TRALI, have beenreported, related to the transfusion of Octaplasâ.
The coagulation factor concentrates are well The only serious adverse event reported after Oct- tolerated and the haemophilia patients have ex- aplasâ transfusion, was due to the misuse of 4 units pressed satisfaction with the introduction of highly of Octaplasâ as an acute volume substitution. This purified factor VIII and IX concentrates which are resulted in cardiac arrest due to a citrate induced easier to dissolve and cause less side-effects than rapid fall in ionised calcium in an elderly patient low purity concentrates or cryoprecipitate. Only who, however, was successfully resuscitated.
10% of the patients with a severe deficit of factorVIII have developed an inhibitor to factor VIII (A.
Glomstein, personal communication). Due to a high content of vWF, the factor VIII concentrateshave also given satisfactory treatment results in The Project has secured Norwegian self-suffi- ciency. It allowed a smooth transition from cryo- O. Flesland et al. / Transfusion and Apheresis Science 28 (2003) 93–100 Fig. 1. Plasma and albumin consumption in Norway from 1985–2001.
precipitate and low purity factor XI to high purity possibility of commercialisation. This is illustrated products. In addition, self-sufficiency has been es- by the consumption of albumin and IVIgG in tablished for prothrombin complex (factors II, Norwegian hospitals. After a peak in 1989, when VII, IX and X), albumin and IVIgG. The amount we used 332.9 kg albumin/million inhabitants, the of factor VIII produced has declined due to the consumption has constantly declined (Fig. 1). The increased purity of factor VIII, double virus inac- Cochrane report in 1998 [24] led to a further re- tivation and the reduced plasma volume (and duction in albumin use, which in 2001 was only content of factor VIII) caused by the production 121.5 kg/million inhabitants. By that time we of A and AB SD-plasma. However, after 1995 a had a surplus of more than three years production gradual change has taken place in the factor VIII of albumin so, to avoid outdating, Octapharma treatment of children with the substitution of started to store the albumin paste. The use of plasma derived factor VIII with recombinant fac- IVIgG has been low in Norway and IVIgG was tor VIII. This change also prevented a potential only produced from 30% of our plasma in 2001.
product shortage by covering the increased factor Because albumin and, in particular IVIgG, are in VIII needs when treatment in children in the same short supply on the international market, Octa- period was changed from ‘‘on demand’’ adminis- pharma suggested possible sale of surplus albumin tration to prophylactic treatment. This policy and IVIgG outside Norway as early as 1994. This change was a major reason for the consumption option was included in the contract from 1998, but increase from 2 to 3.5 million IU factor VIII/mil- the Project did not respond to this idea until 2001.
lion inhabitants from 1995 to 2001. However, due The delayed response was partly due to the blood to the loss of more than 2 million IU Factor VIII banks resistance to introduce ALT-testing, which due to positive HCV NAT tests, 2 million IU was required for commercialisation. Another factor VIII from Swedish plasma were imported to problem was the lack of certification of the blood ensure the plasma derived factor VIII supply in banks for delivery of plasma for commercial frac- 2001. Plasma derived factor VIII is currently pri- tionation of products to be consumed in the Euro- marily used in adult patients with haemophilia-A 8. Internationalisation and commercialisation During production, around 0.3% of the plasma Since the goal of the project was to ensure self- has been discarded due to excessive haemolysis sufficiency, too little focus has been put on the or labelling irregularities. Except for three small O. Flesland et al. / Transfusion and Apheresis Science 28 (2003) 93–100 batches of factor VIII, which had to be discarded The Project is based on the fact that the blood during pilot production in 1988, there have been bank that produces the plasma pays for the frac- no product losses due to production errors.
tionation of this plasma and then owns the prod- In 1992 three batches of SD-plasma (2580 units) ucts from fractionation. Input–output from the were lost when a trailer sank due to a ferry Project is given in Table 1. Over all, the cost of wreckage. The loss caused a delay of several fractionation has been less than the profit from months in the introduction of SD-plasma in Nor- the factor VIII sold by the blood banks to the way, but due to insurance it did not represent an National Institute of Haemophilia (which has the economic loss to the Project. Since this incident, responsibility for home treatment) or Rikshospi- however, no more than one batch (a monthÕs talet University Hospital (where treatment of production) is returned in the same transport.
Norwegian haemophiliacs is centralised). Sale of The major loss of products was due to two factor IX, prothrombin complex, SD-treated plasma batches which tested positive for HCV by cryoprecipitate and IVIgG to the same units pro- NAT in 1999 and to look back procedures. The vided an income of NOK 153 million (19 million € losses due to look back procedures were increased or US$). In addition, the blood banks consumed by the authorities demand to discard products albumin and SD-plasma worth NOK 461 million containing plasma collected from a donor one year (57.5 million € or US$) produced from their own prior to seroconversion, if the blood bank could plasma. At the end of 2001, the Project had a stock not provide samples from the previous dona- of coagulation factors, albumin, IVIgG and SD tions which demonstrated negative serological and plasma worth NOK 62.1 million (7.8 million € or NAT-testing results. This led to a policy of 100% US$), and paste worth NOK 10.1 million (1.3 collection and storage of retention samples from million € or US$), based on international spot The cost of scrapped products has been divided On a national scale this has been a very sound by the blood banks according to the total amount project. Each blood bank has received the prod- of plasma delivered to date, and represents NOK ucts they needed, plus their part of the profit. The 36.5 million (4.6 million (€) or US$) or 2.6% of the profit has been greater than the costs involved. The blood banks could look at it two ways; they couldsay that the value of each litre of FFP they pro-duced was approximately NOK 1115 (€ or US$140), or they could say that the plasma products they used were in fact free of charge. This is mostfavourable, taking into account that only first class Prices have been set yearly. The Project has apheresis plasma from licensed blood banks costs priced its products at, or below, the present in- € or US$ 80–90 on the international market, and ternational market price for each product. The that about 90% of the Norwegian plasma was the products have not been subjected to government less valued recovered plasma. With the reduced consumption of albumin, this is changing. Hospi-tals using little or no fractionated plasma productspay for fractionation, receive payment for coagu- lation factors and IVIgG, but have little interest inthe albumin they receive. As albumin presently Over a period of 12 years the project has ob- cannot be sold outside Norway, it may appear to tained a high yield of albumin (26.5g/l plasma) and be better for the blood bank to sell its FFP to the factor VIII (212 IU/l plasma) in addition of se- highest bidder. However, so far no Norwegian curing the Norwegian needs for factor IX, pro- blood banks are GMP-certified to deliver plasma trombin complex (factors II, VII, IX and X), for fractionation of products to be consumed in SD-cryoprecipitate, IVIgG and SD-plasma.
the European Community. For blood banks using O. Flesland et al. / Transfusion and Apheresis Science 28 (2003) 93–100 Table 1The Norwegian Plasma Fractionation Project: plasma income-products outcome 1989–2001 (include transport,storage and admin-istration) 92.5 (total, subtracted scrapped products) From a total of 663,638 l of plasma, 599,375 l were fractionated and 64,263 l were used for the production of SD-plasma.
a Included albumin paste worth 0.8.
b IU Factor VII.
c IU Factor VIII.
d Included IVIgG paste worth 0.5.
e Unit volume 200 ml.
their entire production of albumin, participation in The price could be calculated to provide cost re- the Project is still very lucrative.
covery for the blood banks that supplied FFP,while all surplus products would be sold for themarket price. This would ensure continued na- tional self-sufficiency and give excellent resultseconomically both for each blood bank and on a As the Project has been a success for the supply of safe blood products based on a self-sufficiencyconcept and has generated a significant income tothe blood banks over a long period, it should not be terminated lightly. At the same time the voicesobjecting to the present situation need to be heard, The strong support of Director Bodolf Hareide, since the project is based on all blood banks CEO National Institute of Health, and the pro- sharing common interests. One way forward may fessional guidance by the Blood Bank Council be to change the role of the Project, from that of a have been essential for the Project. Tor-Einar co-ordinator, to a national plasma handling unit.
Svae, Octapharma, initially established the Pro- This unit could then buy the plasma from the jects efficient logistics for collection and transport blood banks and have the plasma fractionated by of plasma/return and distribution of final prod- contract after tender, before selling the products ucts. Jan Erik Orn has been responsible these tasks back. The small blood banks could produce plas- ma for products for the Norwegian market, whilesurplus products from the larger blood banks certified for delivery of plasma for fractionation ofproducts to be consumed in the European Com- [1] Evensen SA, Ulstrup J, Skaug K, Fr€ munity could be sold on the international market.
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June 2009 Newsletter First Responders by Doug Brown How To Detect A Heart Attack Dizziness can be an early symptom of heart attack Cardiac chest pain is often vague, or dull, and may be described as a pressure or band-like sensation, squeezing, heaviness, or other discomfort. Pain is Not Always a Symptom of Heart Attack A heart attack often starts with mild symptoms that may not be

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