worldwide supply and demand of plasma and plasma- derived...

volume3 number 3 2011 111

Worldwide Supply and Demand of Plasma And Plasma-Derived Medicines

Patrick ROBERT, Ph.D. President of the Marketing Research Bureau, Inc., 284 Racebrook Road, USA,Phone: 001 203799-0298, Fax: 001 203 891-8855, Email: [email protected]

1) The Early Years of the Plasma IndustryIn the early 1940’s, Dr. E. Cohn dis-covered the plasma fractionation pro-cess in Boston (1). After it was found that albumin was an efficacious and safe drug, and could be produced in large quantities, several manufactur-ing plants were built in the United States. Pharmaceutical companies involved at the early stage of the fractionation industry included Parke Davis, which built a plant in Los An-geles (now operated by Grifols), Ar-mour near Chicago, now operated by CSL Behring, Cutter in Berkeley, and Baxter in Glendale, near Los Ange-les. Some public entities also built facilities to process human plasma, such as the Michigan Biological Laboratory. In Europe, fractionation plants were built in Germany (Behrin-gwerke, part of the Hoechst pharma-ceutical concern), Italy (Farma Biag-ini, Sclavo), France (Centre national de Transfusion Sanguine and Institut Merieux), Grifols in Spain, and the Swiss Red Cross Blood Transfusion Service in Switzerland (2). In Japan,

the Green Cross corporation built the first fractionation plant in Asia (3). These facilities began producing albumin, and some “normal” (poly-valent) or specific immune globulin preparations, such as anti-tetanus, anti-hepatitis B, anti-rabies immune globulin, and others. Rho(D) immune globulin was discovered in the late 1960’s, as were antihemophilic fac-tors vIII and IX.

2) Plasma Supply: Emergence of the “Source” Plasma Collection Sector in the United States

Initially, the Red Cross and other non-profit blood transfusion services supplied plasma, but they were soon unable to supply sufficient quan-tities for the fractionation plants, which were gradually expanded. As a result, a business sector focus-ing exclusively on collecting plasma for fractionation began to emerge in the United States, comprising a myriad of private plasma collection organizations. This sector’s growth was spurred by the fact that plasma

OrIGINAl ArTIClE

IRAnIAn JOURnAL OF BLOOD AnD CAnCER112

donors were allowed to donate rela-tively frequently: twice a week, with a two day interval (4), corresponding to about 65 liters per year, whereas the donation frequency authorized in most other countries was such that the maximum volume of plasma that could be donated by an individual was 15 to 18 liters of plasma per year (5).Until the mid-1980s, plasma was col-lected in bags and separated from whole blood by centrifugation. The introduction of automated plasma-pheresis machines in the 1980’s in-creased the donation process’ safety and efficiency (6). The plasma col-lected from these centers was called “source”, while the plasma obtained from whole blood was called “recov-ered plasma”. Outside the U.S., the supply of plasma remained mainly with the blood transfusion services. In Austria and Germany, legislation allowed more frequent donations.In the 1980’s, the AIDS crisis led to a complete transformation of the plasma collection sector and of the fractionation industry in the United States.In 1978, 5.4 million liters of “source” (apheresis) plasma were collected in the United States. This volume in-creased to almost 12 million in 1996, then declined to 9.6 million in 2000, due to, among others, the closing of some fractionation plants as a result

of the strict enforcement of “good Manufacturing Practices” (GMPs) by the U.S. regulatory authorities (Food and Drug Administration) (7). The volume of source plasma directly depended on the needs for finished products.

3) From Albumin to IVIG: the “Market Drivers”Until the 1970’s, the fractionation plants produced as much albumin as the market required, and they pur-chased the quantities of plasma they needed to meet the production re-quirements for this protein. Albumin was the market driver. When plasma-derived factor vIII began to be com-mercialized in the late 1970’s, it became the market driver because larger volumes of plasma were need-ed to meet the demand for it. By that time, the U.S. fractionators produced albumin, intramuscular immune globulin and coagulation factors for the domestic market as well as for export because the U.S. fractionation plants were significantly larger than those operating in other countries. At the beginning of the 1980’s, intrave-nous immune globulin (IvIG) was in-troduced in the United States. It be-came the market driver in the 1990’s when plasma-derived factor vIII, and soon, factor IX, were replaced by re-combinant products. The demand for albumin, factor vIII, and since the

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early 1990’s, IvIG, determine the vol-ume of source plasma collected. For this reason, the volume of plas-ma has shown wide variations over the years, while the fact that source plasma donors were compensated also contributed to these variations. In contrast, the quantity of recovered plasma for fractionation obtained from separation from whole blood remained remarkably flat over the years because its volume depended on the needs for labile blood compo-nents, in particular red cell concen-trates and, increasingly, platelets.Similar observations can be made in other regions: in Asia and Pacific, source plasma is mainly collected in China, where the quantity of plasma collected is also determined by the need of the domestic plasma indus-try. In 2005, some 4.5 million liters of plasma were collected in China. As the plasma industry was subjected to a strict enforcement of the good manufacturing practices by the reg-ulatory authorities (SFDA) following the discovery of contaminated prod-ucts, similar to events that occurred in the U.S. in the late 1990’s, the volume of source plasma collected dropped to 2.7 million liters in 2007, and climbed again to about 3.4 mil-lion liters in 2009. Recovered plasma cannot be used for fractionation in China. no other country in the region collected plasma for fractionation in

any significant quantities (8). In Europe, the quantity of source plas-ma for fractionation only increased in recent years, from less than a mil-lion liters to about 2.5 million liters in 2009. The commercial fractionators mainly processed source plasma im-ported from the U.S.

4) recovered Plasma: An Un-tapped Source of life-Saving MedicinesIn the blood collection sector, the priority given to the procurement of adequate quantities of labile compo-nents, notably red cells and platelets, tends to relegate plasma to a low pri-ority. The term of “recovered” plasma is in itself rather diminishing, as if it was a by-product – which it is many blood centers. Yet, recovered plasma is just as good as source plasma to produce therapeutic proteins, if not better in the case of some of them. From one liter of plasma, whether source or recovered, a fractionation plant can produce, according to gen-erally agreed production yields (9):- 25 to 28 grams of albumin,- 150 to 200 international units of factor vIII (possibly more in the case of source plasma which is frozen im-mediately after collection),- 250 to 300 international units of factor IX- 3 to 5 grams of intravenous immune globulin (possibly more in the case of

Worldwide Supply And Demand...


recovered plasma)- 250 international units of anti-thrombin III- 0.20 grams of alpha-1 antitrypsin, and- various quantities of hyperimmune globulin products, assuming that an adequate antibody titer is present in the plasmaIn a number of countries, in particu-lar in developing countries, the blood centers’ focus on supplying hospitals with labile components has turned plasma into a “forgotten” commodity. The need for red cells and platelets requires the blood centers to collect a certain number of blood units to cover hospitals’ needs. The quantity of whole blood collected is such that some plasma, generally fresh frozen, remains unused. Some units of fresh frozen plasma are delivered to hospi-tals to treat patients with coagulopa-thies and other conditions, but the leftover plasma units are stored and eventually jettisoned. This plasma could well be sent to a fractionator, whether domestic of foreign, to man-ufacture life-saving plasma-derived medicines.In some parts of the world, espe-cially in emerging countries, the collection standards do not match those required by the fractionators. As they are under the obligation to follow strict rules and regulations regarding the quality of their opera-

tions, starting with the quality of the raw material, the fractionators must be very selective about the plasma they use. For instance, the European health authorities (10) require that the plasma pool for fractionation be tested for HIv, Hepatitis A, B and C, and Parvovirus B 19. The blood col-lected by many centers around the world is often unable to comply with these regulations, causing some re-covered plasma to be unused. Other problems include logistics, includ-ing the storage of the plasma and its shipment to a fractionation facil-ity. These obstacles are not insur-mountable, as illustrated by the con-tract fractionation between private or public fractionators and blood transfusion services in Brazil, Iran, Hong Kong, Singapore, Taiwan, and Tunisia, to name but a few. This re-quires the blood centers to upgrade their collection standards, which is a worthwhile endeavor consider-ing the clinical and financial value of recovered plasma. Furthermore, this is also owed to the donors, who deserve that their donation be fully used without waste. In Colombia, a country where the collection stan-dards are among the top in the re-gion, approximately two thirds of the recovered plasma is not used. This represents close to 90,000 liters of plasma per year, the value of which may be estimated at roughly $12 mil-

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lion. The fractionation of this quantity of plasma would have a market value in excess of $24 million (11).

5) Worldwide Demand for Fin-ished Plasma-Derived MedicinesIn 2009, the worldwide demand for plasma-derived medicine was esti-mated at $11.8 billion, IvIG repre-senting 46% of the total, albumin 10% and factor VIII, 9% (Chart 1)(12). Plasma-derived medicines are pri-marily used in the industrialized countries, due to the comparatively high cost of therapy. For example, the European market, which only had 11% of the world population, repre-sented close to 36% of the world mar-ket, while the Asian & Pacific market represented 15%, with 58% of the world population (Charts 2 and 3). These discrepancies are illustrated by wide variations in per capita us-age (Charts 4 and 5).In the case of polyvalent intrave-nous immune globulin (IvIG), such variations are caused by product availability, financial access to ther-apy or insurance coverage, price, authorization to prescribe for certain non-approved indications, product awareness, and more importantly, diagnosis of the conditions for which IvIG is indicated. As for coagulation factors, it is often a function of gov-ernment’s ability and willingness to

cover hemophilia care. Lobbying ac-tivities by patients groups play an im-portant role in this regard.

6) Matching the Demand for Fin-ished Plasma-Derived Medicines and the Supply of PlasmaOver the past few decades, the plas-ma industry has been able to supply the worldwide markets for plasma-derived drugs in most industrialized countries. Financial constraints have caused the low usage level recorded in the other countries, rather than limitations in the availability of plas-ma (source or recovered) or in frac-tionation capacity. Recent surveys show that the latter is sufficient to meet the needs in the coming years, as the fractionators can react rela-tively easily and quickly to a demand surge. As for the plasma, experience has shown that it is possible to in-crease the collection levels of source plasma in the United States relatively easily, provided that the necessary funding is available. In 2010, 78 fractionation plants were operating in the world, 25 of which were in China (which in fact has 35 li-censed plants – some of which oper-ate only sporadically), 26 in Europe, and 8 in the United States, the latter fractionation plants being of a larger size than those operating in other re-gions. The global fractionation capacity was


IRAnIAn JOURnAL OF BLOOD AnD CAnCER

about 48.4 million liters, and the re-corded volume of plasma fraction-ated (source and recovered), 33.6 million liters, including 29.1 million liters processed by the commercial sector, and 4.5 million liters by non-profit organizations. In the past de-cades, the fractionation industry has undergone three major trends: priva-tization (there are more commercial fractionators than ever), increase in processing volume (higher fraction-ation capacity) and increased pro-ductivity through higher yields.

7) Conclusion: Improving Global Access to Plasma Derived Medi-cines Plasma-derived medicines produced today are safe, efficacious and avail-able in large quantities. The cost of therapy remains the main barrier for access to these drugs in the emerg-ing countries. The use of recovered plasma which is currently destroyed by many blood centers could allevi-ate some of these barriers in some countries.

THE WOR L DWIDE PL AS MA FR ACTIONS MAR K E T B Y PR ODUCT - 2009

All Others29.4%

Factor IX (Plasma Derived) 1.8%

Hyperimmunes (IM & IV) 4.5%

Factor VIII (Plasma Derived)

8.6%

Polyvalent IVIG46.0%

Albumin9.7%

WITHOUT R E COMB INANT FACTOR S

Total Market $11,778.8 Million

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Figure1

The Marketing Research Bureau, Inc.

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Figure 2

World P opulation by R egion - 2010

E urope10.8%

As ia & P acific58.1%

North America5.0%

S outh America8.7%

Middle E as t & Africa17.4%

The Marketing Research Bureau, Inc


THE WOR L DWIDE P L AS MA F R AC TIONS MAR K E T B Y R E G ION - 2009

S outh America 5.7%

North America 36.7%

Africa 0.9%

Asia & P acific15.3%

Middle-E ast2.6%

E urope 36.2%

Oceania 2.6%

WITHOUT R E C OMB INANT F AC TOR S

T otal Market $11,778.8 Million

Figure 3


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The Marketing Research Bureau, Inc.

Figure 4

IV IG C O N S U M P T IO N P E R C A P IT A IN S E L E C T E D C O U N T R IE S - 2 0 0 7 -2 0 0 9(K ilo g ra m s p e r M ill io n In h a b ita n t)

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F A C T O R V II I C O N S U M P T IO N P E R C A P IT A IN S E L E C T E D C O U N T R IE SR E C O M B IN A N T & P L A S M A -D E R IV E D 2 0 0 7 -2 0 0 9

(In te r n a tio n a l U n its p e r In h a b ita n t)

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Figure 5

The Marketing Research Bureau, Inc

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references1. Surgenor David, Edwin J. Cohn, and the Development of Protein Chemistry, Harvard University Press 20022. Starr, Douglas, Blood, an Epic History of Medicine and Commerce, Alfred Knopf, New York, 19993. The Plasma Fractions Market in Japan 2009, in The Plasma Fractions Market in Asia & Pacific – 2009, The Marketing Re-search Bureau, Orange, Connecticut, 20114. Plasmapheresis, U.S. Code of Federal Regulations (CFR) 640.65, 108, 2001 and Volume Limits for Automated Collection of Source Plasma, Memorandum from Direc-tor of the Center for Biologics Evaluation and Research to All Blood Establishments, Bethesda, November 4, 19925. Guide to the Preparation, use and Quality Assurance of Blood Components, 12th Edi-tion, Council of Europe, Strasbourg 20066. The Plasma Fractions Market in the Unit-ed States - 2009, The Marketing Research Bureau, Orange, Connecticut, 2010, p 457. Ibid, p 678. The Plasma Fractions Market in China 2009, Ibid p. 1189. Plasma Proteins Manufacturing, Plasma Proteins Therapeutics Association (PPTA), www ppta org. Washington DC, 200810.Control Authority Batch Release of Vaccines and Blood Products, European

Union’s Administrative Procedure for Of-ficial Authority Batch Release, European Directorate for the Quality of Medicine and HealthCare, Council of Europe, Strasbourg, 201011. Separación en Componentes, Compo-nentes transfundidos, y Descarte de Com-ponentes 2009, Cuadros VIII-X, Coordina-cion Nacional de Sangre, Instituto Nacional de Salud, Bogota, 2010, p. 13-1512. The Worldwide Plasma Fractions Market – 2008, The Marketing Research Bureau, Orange, Connecticut, 201013. International Directory of Plasma Fractionators – 2010, The Marketing Re-search Bureau, Orange, Connecticut, 2011


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