FOCUS ON... BUSINESSThe PlasmaFractionation IndustryNew Opportunities To Move Forward?John Curling and Christopher Bryant S hortly after the turn of the millennium, Australian fractionator CSL Ltd. acquired the Swiss plasma plant at ZLB, Bern (Central Laboratory of the Swiss Red Cross Blood Transfusion Service). Two years later, the US plasma fractionation industry entered the year 2003 with an announcement that the proposed merger between Aventis Behring and Bayer’s plasma operations would not happen. In August 2004, soon after CSL completed its acquisition of Aventis Behring, the newswires buzzed with speculation over Bayer’s long- awaited divestment of its plasma business in Clayton, NC. On 14 December 2004, Cerberus and Ampersand agreed to acquire that ANTHONY HERNANDEZ (WWW.ISTOCKPHOTO.COM) Bayer unit. Such movements seem COHN FRACTIONATION commonplace in an industry sector that has endured consent-The development of methods for plasma protein fractionation was driven by decrees, battled with producta need for human albumin in World War II and the requirement to isolate shortages of both plasma-deriveddiphtheria and tetanus antibodies from horse serum. and recombinant products, facedE. J. Cohn and his many coworkers published their landmark paper describing dramatic drops in product pricing,ethanol fractionation in 1946 (1). Their paper was 43rd in a series entitled and all but lost a market forStudies on Plasma Proteins from Harvard Medical School. The first use of albumin. Raw material (plasma)ethanol fractionated albumin was to treat casualties at Pearl Harbor in 1941. costs have risen significantly, andThe fractionation industry is now driven by the demand for IgG to treat processing costs rise with eachimmune deficiencies and recombinant as well as plasma-derived Factor VIII incremental addition of safetyfor hemophiliacs. Nonetheless, the industry standard backbone is still “Cohn measures such as inventory holdfractionation” with chromatography and membrane technologies, integratedwith viral inactivation, dominating side-stream fractionation. and plasma pool testing. However, CSL Ltd (www.csl.REFERENCE com), now the holding company for1 Cohn EJ, et al. Preparation and Properties of Serum and Plasma Proteins, IV: A System ZLB Behring and the world’s largestfor the Separation into Fractions of the Protein and Lipoprotein Components of BiologicalTissues and Fluids. J. Am. Chem. Soc. 62, 1946: 459–475. fractionator with a 25% market share18 BioProcess International MARCH 2005
(with operations in Switzerland, PLASMA INDUSTRY CHANGES 2003 AND 2004Germany, and the United States),reported net profit after tax of 13% 2003on revenues of US$1.65 billion for Bayer and Aventis halt plans for a merger of their plasma productsthe past financial year, ending 30 businesses.June 2004. Importantly, CSL’s cashflow increased significantly, and R&D CSL announces preliminary negotiations with Aventis concerning theexpenditure was up 11% to over acquisition of Aventis Behring.US$100 million. As anotherimportant industry indicator, Baxter announces plans to close 26 of its 120 plasma collection centers inapproval of new plasma products the United States as well a 700,000-L plant in Michigan. Plasma collectedindicates no lack of innovation. New, and fractionated will drop from 4.6 million liters to 4 million liters, andhigher yielding side-stream processes 800 jobs will be eliminated.also indicate innovation within limits, Probitas Pharma completes acquisition of assets of Alpha Therapeutic fromintended or not, frequently set by Mitsubishi Pharma.regulatory authorities. Octapharma completes acquisition of Mexican fractionator Probifasa SAINDUSTRY CONSOLIDATION de CV.Major structural changes of theNorth American–European plasma Aventis Bio-Services sells 21 of its 80 plasma collection centers tofractionation axis are shown in the International Bioresources.“Plasma Industry Changes 2003and 2004” box. Clearly, major Bayer initiates divestment of the plasma operations of its Biologicalchemical-pharmaceutical companies Products Division. Plasma product sales were €679 in 2002. Bayerare seeking to exit the business, employs 1350 people at its Clayton, NC, facility.whereas dedicated plasma companiessuch as CSL Ltd., which continues CSL and Aventis sign a definitive agreement, creating a new entity, ZLBto divest non-core business, and Behring, for US$925 million. Aventis Behring generated €1.068 billion inProbitas Pharma (Grifols) are eager sales in 2002 and employs 5800 people worldwide.to consolidate and strengthen their 2004positions. Increasingly, raw material Baxter further reduces fractionation capacity by around 13% (400,000 L(plasma) follows the laws of annually and closure of further collection centers).commodity markets as we witnessthe acquisitions and divestments ZLB Behring, formerly Aventis Behring, closes 35 collection centers,of collection centers across the reducing collection volume by one million liters and leaving 65 centersUnited States. in operation. Plasma throughput at the Kankakee, MI, facility will be Past and current chairs of the reduced, the Vienna plant closed, and production transferred to Marburg,Plasma Protein Therapeutics Germany. ZLB Bioplasma’s facility will implement improved use, and theAssociation (PPTA, www. combined capacity of CSL’s facilities will be reduced from 4.2 million toplasmatherapeutics.org) have 3.1 million liters. CSL expects to save US$100 million in operating costs.successfully differentiated the plasmaindustry from the pharmaceutical Probitas Pharma is forced to suspend its IPO because of weak investorindustry. For example, raw material demand. The company expects to double its sales from US$1.26 billioncosts account for around 45% of the in 2003 over five years, achieving a 10% global market share.units on an income statement in theplasma industry compared with 5% Bayer’s short list of bidders for its plasma fractionation business includesin the pharmaceutical industry (1). investment firms Bain Capital and Carlyle Group. Cerberus is alsoQuality plasma costs have risen 40% bidding, and the American Red Cross is reported to have an interest. Onover the past seven years, and 14 December, Cerberus Capital and Ampersand Ventures agreed to buynucleic-acid testing alone adds the business for over US$590 million. The new company thus created,US$5–15 per liter of plasma (2). NPS Biotherapeutics, Inc., will also incorporate Precision Pharma. Bayer’sAlthough recalls and withdrawals plasma products generated sales of US$739 million with a pretax loss ofhave declined dramatically, inventory US$426 million in 2003. Sales in FY2004 were €481 million.hold costs the industry anotherUS$33 million per year (2). The Finnish Red Cross, which decided to discontinue fractionation in In his 2004 analysis of the 2003, enters an agreement with Sanquin for the manufacture and supplyindustry, the PPTA Chair Peter of plasma products for Finland’s market. Intermediates will be producedTurner notes that “US and in the Belgian Red Cross fractionation facility and finished productsEuropean demand for IVIG processed in Amsterdam. MARCH 2005 BioProcess International 19
[intravenous immunoglobulin] Table 1: New, US, normal plasma and equivalent recombinant product approvals (BLA) in 2002–2004has been met, and prices have Manufacturer Claimed Benefit/fallen 20–25% in two years, the price Product Approval Date Indication Improvementof albumin has halved in three years, Aralast Alpha Therapeutic API deficiency and First alternative tosubstitution of recombinant Factor Alpha-1 Proteinase (now Baxter) evidence of Prolastin; patient choiceVIII for plasma-derived product Inhibitor (API) 23 December 2002 emphysemacontinues, and there is greater accessto alpha1-protease inhibitor” (3). Crosseal Omrix Hemostasis in Ease of preparation and In this climate, industry Fibrin Sealant (Distr.: American patients use Red Cross undergoing liverconsolidation and realignment are 21 March 2003 surgeryunderstandable, but widely disparateaccess to plasma protein therapies Zemaira Aventis Behring API deficiency and Purity (90%), safety, Alpha-1- 8 July 2003 evidence of efficacy, convenience;remains unaddressed across the Proteinase emphysema 15 min. infusion timeglobe. Among the PPTA models Inhibitor (API) (cf 30 mins for otherfor the future (3) are a products) • Broad portfolio of high Advate Baxter Healthcare Hemophilia A Recombinant, no plasmayielding products rFactor 25 July 2003 products used in MAb • Global plasma reach selling VIII Plasma/ production or asthree–four products/liter of plasma Albumin Free additives; no prion risk; • Efficient scale and competitive Method tolerability, hemostatic efficacy; low inhibitorcost structure. rate; easy to useMORE PRODUCTS Gamunex Bayer Primary immune Unprecedented primary IVIG, 10% by 27 August 2003 deficiency and ITP immune deficiency (PID)PER LITER OF PLASMA Chromatography clinical results; anti-Blood plasma is the most complex Process infective efficacy; newhuman-derived proteome. It safety paradigmcontains 55–60% albumin and offers Flebogamma Instituto Grifols Primary immune Liquid, ready-to-usean exceptional dynamic abundance IVIG (Probitas Pharma) deficiencyrange (10 orders of magnitude) — 15 December 2003from picograms/mL of interleukins Octagam Octapharma Primary immune Only liquid and doubleup to 35–50 g/L range for albumin. IVIG 21 May 2004 deficiency virus inactivated IVIGDespite the plethora of true plasma that can be stored atproteins (secreted from solid tissues room temperature (2–and immunoglobulins), tissue- 25 °C) up to 24 months; free from stabilizersleakage products, and temporaryplasma passengers, only 289 proteinshave been documented; about 100 It also appears that the established (6). Despite lower pricing for IVIG,are used in diagnostic assays and industry is focused on highly this product is likely to remain anfewer than 20 as plasma competitive markets in which industry driver, but added revenuestherapeutics, with three proteins products are differentiated by from plasma-derived Factor VIIIaccounting for 80% of the revenue manufacturers and distributors and alpha1-protease inhibitor are(4). Assessing opportunities for the rather than by therapeutic effect. mandatory for an industry thatfuture, Over (5) found only five new (That is changing, but on “benefit- needs to invest in both plant andproducts in clinical trials in 2002. to-patient” attributes such as ease R&D. Net revenues (after the costHowever, 2003 was an exceptional of use, infusion time, shelf-life, and of plasma) from existing productsyear for new approvals by CBER storage conditions.) The industry per liter of plasma dropped from an(www.fda.gov/cber/products.htm), still tends to differentiate on safety, all-time high of about US$220 inas shown in Table 1. advocating added or improved viral 1999 to barely over US$100 in It is striking that all those clearance or prion safety as well as 2003 (3). Among the variousproducts are new variants of new manufacturing techniques. measures triggered by such a lossestablished products and that they A quick review of a plasma has to be the development of trulywere launched in the US market as product distributor site — www. new products from plasma, not justan attempt to expand market share, blooddiagnostics.com — illustrates incremental improvements tocompeting against existing products. the competitive nature of the market existing ones. This involves aSignificantly, products new to the as well as the product offerings. paradigm shift and a new era ofmarket are absent from the list of Such an environment leads to price innovation that Christensenapprovals — such as plasmin, pressures and loss of revenue/liter describes as a “disruptivefibronectin, and apolipoprotein A-1. of plasma as described by Rankin technology” path (7).20 BioProcess International MARCH 2005
HIGH-YIELDING PROCESSES Table 2: Average process yields per liter of plasma from existing “Cohn” fractionation facilities.The Cohn backbone process wasdeveloped for albumin, so it is not Yield Yield Industry Industry Target Protein Cohn trunk (%) Cohn total (%) Average (1) Average (2)surprising that this protein isobtained in high yield. Processes for Factor VIII by 40 18 140–270 IU ~200 IU cryoprecipitationother plasma proteins have beendeveloped either by addition of Factor IX — — — ~350 IU(cryo-)precipitation or adsorptivetechnologies before using ethanol Immunoglobulin G 66 53 3–4 g ~3.5 gfractionation or by mainlychromatographic processing of Alpha1-protease 23 15 — ~0.2 gfractions of the Cohn system, as inhibitorin methods developed for alpha1-antitrypsin. These processes are Albumin 95 86 22–28 g ~25 ggenerally low yielding. Particularly, Yield figures in % are calculated from industry sources. The “Industry average (1)” figures are fromthe low yield of IVIG caused “Contract Fractionation”, World Federation of Haemophilia (reference 16). Industry average (2) estimates(previously) major players Baxter are from the PPTA (reference 17).and Bayer to implement significantimprovement to purification from Affinity Chromatography: NewFraction II + III. Considering the chromatography. This recently technologies, which break thedata in Table 2, there should be reviewed (8) technique is already “S-curve” (7) development scheme,considerable room for improvement, used in many established process: are unlikely to use differentialbut that would necessitate a radical in the purification of coagulation solubility as the driver of separation.change of processing technology, factors, for example, and in new They are far more likely to usenot generally attractive to an processes such as that for plasmin. discerning technologies,established industry bound by Such technologies allow for commonplace in downstreamexisting product licenses in the sequential adsorption, not bioprocesses, such as affinityUnited States and around the world. precipitation, from the main FDA GUIDANCE FOR INDUSTRY: SCREENING MATERIALS FOR HUMAN DONORS OF BLOOD AND BLOOD COMPONENTS by James ReillyIn 2000, the American Association of Blood Banks Questionnaire.” The outcome of the task force and(AABB) convened an Interorganizational Uniform workshop proceedings was a series of donor-historyDonor History Questionnaire Task Force at the request questionnaire (DHQ) documents, which whenof the US Food and Drug Administration. The Task implemented in their entirety effectively represent aForce included a wide spectrum of constituents comprehensive donor history screening system.including blood center staff, survey design experts, In April 2004 the FDA published a draft guidance titledan ethicist, and a statistician, as well as organizational Acceptable Full-Length Donor History Questionnairemembers from AABB, America’s Blood Centers, and Accompanying Materials for Use in ScreeningAmerican Red Cross, Plasma Protein Therapeutics Human Donors of Blood and Blood Components,Association, US Department of Defense, and liaisons which fully incorporated the DHQ documentsfrom the FDA, Centers for Disease Control and includingPrevention, and Canadian Blood Services. The goalsof the task force were to • Blood Donor Educational Materials • Full-Length Donor History Questionnaire• Provide major improvement in blood donor • Medication Deferral Listscreening • Donor History Questionnaire• Make the process more effective in capturing • User Brochure (including glossary, flow charts, andrelevant blood-donor qualifying information references).• Simplify the screening process• Enhance recruitment and retention without AABB DHQ DOCUMENTSsacrificing the safety of transfusion recipients. Several important points need to be made regardingIn October 2000, the FDA and AABB cosponsored a the DHQ documents and the FDA draft guidance.workshop on “Streamlining the Blood Donor History (continued)22 BioProcess International MARCH 2005
stream and the design of a 91% of the world’s production of is a highly complex issue. Thebackbone that targets the most pharmaceuticals (9). Plasma product InterAcademy Council (IAC,needed plasma products. use is no exception to this. In 2000, www.interacademycouncil.net) the Americas and Europe consumed notes that “the global reality isGLOBAL ACCESS 83% of the plasma-derived Factor that many innovations fail to accrueTO PLASMA PRODUCTS VIII and almost all the world’s to those who need them most.”With a supply crisis for IVIG an issue recombinant products (10). In the Furthermore, “stronger scienceof the past, the overproduction of same report, Europe and North and technology capacity in thealbumin, and the availability of new- America accounted for about three developing nations is not a luxury,generation Factor VIII presentations quarters of the IVIG. For all but an absolute necessity if theseand alternative alpha1-protease products, the use of plasma nations are to participate as fullinhibitor (API) products, the derivatives in Africa is only about partners in the world’s fast-forming,majority of patients in North 1% of the total. With the current knowledge-based society” (13).America, Europe, and other worldwide market for plasma- The debate attempting to resolvedeveloped countries generally receive derived products stable at US$5.8 issues related to plasma fractionationthe products they need. Exceptions billion, North America accounts for is not new with advocates of “self-are that many hemophiliacs have yet 37% and Europe for 30% (11). In sufficiency” (those who advocateto be on prophylactic treatment, and contrast, North America accounts local or national fractionation oraccording to the Alpha-1 Foundation for 6.7% and Europe for 12% of the contract fractionation at a distant-(www.alphaone.org), at least 90% of world population of just over six but-established fractionator). Thethe 100,000 API-deficient patients in billion. Although the United States December 1997 Transfusion Todaythe United States remain exports over 6.5 million liters of contains six short articles on theundiagnosed and untreated — plasma (12), that is largely to subject (14), and the Gordian knotindicating a market opportunity if facilities in Europe that either lack has not been untied over almost tworeimbursement policies would allow. sufficient collection structures or are decades. Central to the ability to However, a very much larger and mandated not to use domestic produce safe and reliable plasmamore global issue must be tackled. sources because of possible vCJD products is the existence of anThe World Health Organization risk (as in the United Kingdom). adequate infrastructure for plasma(www.who.int) estimates that 15% The state of science and collection, recently discussed byof the world’s population consumes technology in developing countries Farrugia (15). This is a necessity FDA GUIDANCE FOR INDUSTRY (CONTINUED)Blood Donor Educational Materials: This document Medication Deferral List: The most significantprovides a first layer of safety by familiarizing donors improvement to this component of the donor screeningwith the donation process and risks that result in process was combining the various FDA-requireddeferral from donation. The document emphasizes the permanent and temporary deferrals for medications.importance of accuracy and honesty in responses to The document includes a rationale for the deferral,screening questions. written in terms that donors can understand, and defines the period that a donor would be ineligible toFull-Length Donor History Questionnaire: The donate. This approach allowed the replacement ofquestionnaire is significantly different from previous multiple questions with a single question aboutquestionnaires and is designed to be either donor self- medications in DHQ documents after review of theadministered or administered by direct oral screening, list. Facilities, at their option, can supplement the listor computer-assisted screening. However, staff must be with additional medications that have been identifiedreadily available to help donors in all cases. The DHQ as a result of local medical policies.uses “capture” questions that require additional actionwhen a donor gives an unacceptable answer. Donor History Questionnaire User Brochure: The brochure provides detailed instructions to facility screeningThe questionnaire allows for addition of facility- personnel regarding how to administer the overallspecific questions to meet local regulatory documents and system. The glossary, flow charts, andrequirements and questions that respond to temporary references provide follow-up questions to the “capture”situations — such as those about severe acute questions and explain the process.respiratory syndrome (SARS). The DHQ documentsincorporate screening questions based on cancer; DHQ Document Evaluation and Review: The first donor-organ, tissue, or bone marrow transplants; bone or skin screening questionnaire was developed in 1953.grafts, and pregnancy (1). These go beyond the FDA (continued)requirements in 21 CFR Part 640.24 BioProcess International MARCH 2005
independent of the volume of Handed down from the UN center responsible for the commercialplasma made available for Millennium Development Goals production of plasma products.fractionation and independent of (www.un.org) and embedded in If the gap between “have” andwhere fractionation is carried out. WHO thinking are ambitious targets “have-not” nations is to beHowever, another side of the coin is for maternal and child health, narrowed, the technology for suchthat it must be possible within the infectious disease control, and an industry needs to embracehealthcare system to diagnose, access to essential medicines. Many current, best biopharmaceuticalreach, and treat patients in need. mechanisms for achieving those goals practice and embrace high yielding,Additionally, there needs to be depend on partnerships that serve to competitive, and economicallypolitical will and a regulatory narrow the ever-widening gap beneficial processes. In plasmaenvironment to support provision between developing and developed product manufacturing, this isof plasma products. nations. The IAC Report provides unlikely to be based on Cohn Import of finished products, strong arguments and a framework fractionation technology, but to relyalthough a possible short-term for local development (13). In on the standard unit operations ofnecessity, is neither a long-term, countries that benefit from the bioprocessing: chromatography andsustainable solution nor an realization that supply of plasma membrane separations together witheconomically satisfactory resolution products is a biopharmaceutical the most recent and proven meansfor making plasma products endeavor rather than an “altruistic” of viral inactivation. R&D effortsavailable. The pros and cons of branch of blood transfusion, there will, therefore, probably be sharedcontract fractionation available in is every reason to investigate between the technology providersdeveloping countries are well establishing a national and the local, transfer recipients.discussed in a World Federation nongovernmental organization When product development occursof Haemophilia document (16). (NGO) or independent industrial at the local (national) level, patientNeither solution encourages the venture. Creating world-class centers needs can be targeted in the settingdevelopment and establishment of of excellence in biotechnology and where the products are to be used.biopharmaceutical processing at a bioprocessing can embracelocal level. establishing a plasma biotechnology FDA GUIDANCE FOR INDUSTRY (CONCLUDED)Since that time, donor screening has become A SIGNIFICANT ADVANCEMENTsignificantly more complex and time consuming. The Donor screening is one of the pillars of transfusionDHQ documents represent a significant redesign and medicine and related biological therapies safety. Themodified process. They were evaluated and modified FDA DHQ documents, when implemented in theiras a result of testing that used a series of focus groups entirety, represent a significant advance in donorand one-on-one cognitive interviews (2). screening systems. Additional information and the DHQ documents canREGULATORY REQUIREMENTS be found at www.aabb.org, click on “Pressroom, AABBThe FDA draft guidance allows facilities to implement Donor History Questionnaire.” The complete FDADHQ documents — if adopted in their entirety — with Draft Guidance document can be found at www.fda.notice to the FDA only as a part of their annual report. gov/cber/guidelines.htm.There are two exceptions: Facilities choosing to modifythe DHQ (except for deletion of certain questions not REFERENCEScurrently part of FDA requirements) must notify the 1 Blood Bank Transfusion Service Standards Program Unit.FDA using the “Prior Approval Supplement” Standards for Blood Banks and Transfusion Services, 22nd edition.submission process; and those wishing to use the AABB: Bethesda, MD, 2003.computer-assisted interactive interview procedure 2 Orton SL, Virvos VJ, and Williams AE. Validation of Selected Comprehension. Transfusion 40(11) 2000: 1407–1413. should consider this a “moderate change” and use Donor-Screening Questions: Structure, Content, andthe “Changes Being Effective in 30 Days (CBE30)”notice process. (Additional information on FDA James Reilly is the director of Global Development, AABBreporting can be obtained at www.fda.gov/cbergdlns/ Consulting Services, 8101 Glenbrook Rd. Bethesda, MDdonorhistques.pdf). 20814; firstname.lastname@example.org BioProcess International MARCH 2005
7 Christensen CM. The Innovator’s 15 Farrugia A. Plasma for Fractionation:REFERENCES Dilemma. Harper Business: Boston, MA, Safety and Quality Issues. Haemophilia 10 1 Waeger R. The Future of Plasma 1997. 2004: 334–340.Protein Therapies. Presented at PlasmaForum 2003, 11– 13 June 2003 (Washington, 8 Curling JM. Affinity Chromatography: 16 Contract Fractionation: Facts andDC). PPTA: www.pptaglobal.org. From Textile Dyes to Synthetic Ligands By Figures. Monograph Series No. 5, World Design. Intl. BioPharm 17(7) 2004: 34–42; Federation of Haemophilia, September 1998. 2 Rankin PJ. Perilous Economics of the and Intl. BioPharm 17(8) 2004: 60-66. Accessed at www.wfh.orgIndustry. The Source (PPTA), September/November 2003: 5–10. 9 The World Health Report 2003: 17 Gustafson M. Overview of Plasma Shaping the Future. World Health Fractionation Practices. Presented at FDA’s 3 Turner P. Current Trends in the www.fda.gov/cber/summaries.htm#plasma. Organisation: Geneva, 2003; p. 30. Plasma Standards Workshop, 31 August 2004;Plasma Therapeutics Industry. Presented atInternational Plasma Protein Congress (IPPC) 10 Robert P. Access to Therapy.2004, 9-10 March 2004 (Brussels, Belgium). Presented at Plasma Forum 2002, 11–12PPTA: www.pptaglobal.org. June 2002, Arlington, VA. PPTA: www.pptaglobal.org Corresponding author John Curling is 4 Anderson NL, Anderson NG. The 11 Robert P. Personal communication, senior scientist and consultant, ProMeticHuman Plasma Proteome: History, Character The Marketing Research Bureau, BioSciences Ltd. 211 Cambridgeand Diagnostic Prospects. Mol. CellsProteomics 1(11) 2002: 845–867. August 2004. Science Park, Cambridge CB4 OZA, 12 International Blood Plasma News, email@example.com. Christopher 5 Over J. Plasma Protein Products,Opportunities for the Future. Downstream April 2003, p 128. http://home.earthlink. Bryant is program director, PlasmaPPB ´03 Extended Reports. Amersham net/~mrb_ibpn/home2.htm. Protein Purification, ProMeticBiosciences, 2004; http://bioprocess. 13 Inventing a Better Future: A Strategy BioSciences Inc., USA, 3155 Toulouseapbiotech.com/Applic/upp00738.nsf/ for Building Worldwide Capacities in Science Bourbonnais, IL 60914, chris.4A6F5FFC1256E97003EF794/ and Technology. InterAcademy Council, 2004; firstname.lastname@example.org. For further$file/18117706.pdf. www.interacademycouncil.net; report can be information please contact ProMetic accesssed at www.interacademycouncil.net/ 6 Rankin PJ. Economics of the Plasma BioSciences Ltd. at enquiries@prometic.Products Industry. Presented at International Object.File/Master/6/720/0.pdf. co.uk.Plasma Protein Congress (IPPC), 9–10 14 Boukef K, et al. Transfusion Today,March 2004 (Brussels, Belgium). PPTA: December 1997. International Societies forwww.pptaglobal.org. Blood Transfusion.