Jürgen Römisch , Ph.D. Senior Vice President R&D Plasma Octapharma PPGmbH Vienna, Austria

1. Facts On Quality AndSafetyCharacteristicsOfFreshFrozen Plasma Single DonationsAndoctaplasLG® JürgenRömisch, Ph.D. Senior Vice President R&D Plasma Octapharma PPGmbH Vienna, Austria BPAC Meeting, Rockville, MD September 20, 2012

2. Table of Contents Quality andSafetyAspectsofFreshFrozen Plasma Single Donations Plasma Transfusion RelatedAdverse Events (TRALI): Biochemical / cellularbackground octaplasLG® - Manufacturing Process octaplasLG® - Pathogen Safety octaplasLG® - Plasma Quality / Biochemical Profile

3. Quality andSafetyAspectsof FFP Single Donations Donorscreeningrequirements in USA forfreshfrozenplasma Unique donor identification and registration in a validated computer system Deferral check (history of donor) Donor questionnaire (preferably electronic); completed prior to each donation[1] Education on blood borne diseases and transmission risks Physical donor assessment by a health professional Exclusion of donors who do not meet the established acceptance criteria (defined in 21 CFR 640.3 and other guidance documents)[2, 3] Individual donations are tested on several parameters such as on the absence of HBsAg and antibodies against HIV, HCV and Syphilis [1] GuidanceforIndustry: Implementationofacceptablefull-lengthdonorhistoryquestionnaireandaccompanyingmaterialsforuse in screeningdonorsofbloodandblood components.FDA, October 2006 [2] http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=640.63 [3] http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=640.3

4. Plasma Transfusion RelatedAdverse Events (TRALI) Transfusion RelatedAcute LungInjuryhasemergedastheleadingcauseoffatalities after blood/plasmatransfusion Incidence(TRALI Study Group)[4]: 2.57-0.81/10,000 transfusedunits (2006-2009) Typicalpresentationof TRALI isdevelopmentofdyspnea, hypoxemia, hypotensionandfever 6 hrs after transfusion (bilateral pulmonaryinfiltrates)[5] • Immune-mediated TRALI isusuallycausedbyantibodiesoftheblood/plasmadonortransferredtotherecipient Biochemical/cellularbackground ReactiveantibodiestoHuman Leukocyte Antigens (HLA) or Human Neutrophil Antigens (HNA) causecomplementandcellactivationandaggregation Release ofcytokinesandinductionofpro-inflammatoryreactions Damageofvascularendotheliumandexudationoffluid acrossthepulmonarybasementmembrane Edemaandassociated/subsequent events TRALI [4] Transfusion RelatedAcute Lung Injury Letter; October 19, 2001 http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ucm105850.htm [5] Toy P et al. Forthe TRALI Study Group. Transfusion-relatedlunginjury: incidenceandriskfactors. Blood 2012; 119:1757-1767

5. octaplasLG® Manufacturing Process Overview: FFP pooling Antibodies to WBCs were detected in a certain number of FFPs, but not in Octaplas® batches tested [6a,6b,7] Y Individual antibodyspecificitiesof different donations Individual antigenstructurescontained in single FFP units Pooling of individual donations (630-1,520 FFP units) facilitates Dilution and immune neutralizationof - allergens - pathogenicantibodies - infectiousagents Leveling out individual heterogeneity, thusreducingvariabilityofcontentsofplasmacomponents resulting in a consistentproductquality Y Y Y Y Y Y Y Y Y Y Cellfragments [6a] Sachs U. et al. Transfusion 2005; 45:1628-1631 [6b] Barz D. et al. Anaesthesiol. Reanimate 1994; 156: 155-158 [7] Sinnott P. et al. Eur. J. Immunogen. 2004; 31:271-274

6. octaplasLG® Manufacturing Process Overview: safetymeasures: pathogen safety Safety against Fast thawingandpoolingofsingle FFP units Pooling of individual donations (630-1,520 FFP units) facilitates Dilution and immune neutralizationof - allergens - pathogenicantibodies - infectiousagents Leveling out of individual heterogeneityandreducingvariabilityofcontentsofplasmacomponents, resulting in a consistentproductquality Antibodies to WBCs (TRALI) Non-Enveloped Viruses ADRs related to cells and fragments Removalofcells, fragmentsandaggregates by 1.0 µm filtration S/D treatment (1% TNBP & 1% Octoxynolfor 1-1.5 hrsat +30°C ± 1°C) Lipid-Enveloped Viruses Castor oilextractionof TNBP, clearfiltrationand solid phaseextractionofOctoxynol Addition ofglycine AffinitychromatographyforPrPsccapture Infectious Prions Sterile filtration (0.45 µm and 0.2 µm) Bacteria & Parasites Asepticfilling, sealingofbagsand fast freezing (≤ -60°C) andstorage (≤ -30°C) Fullqualitycontrolandreleaseof final product

7. Pathogen Safety Safetymeasures Beyond the basis precautionary safety measures ensured for FFP, such as donor screening and look-back procedures, the followingoctaplasLG® process steps add to the pathogen safety profile • Plasma pooltesting(HIV, HBsAG, HAV, HBV, HCV, HEV and Parvovirus B19) • Solvent / Detergent (S/D) treatmentfortheinactivationofthemosthazardoustransfusionrelatedenvelopedviruses such as HIV, HBV, HCV and WNV • andotherpotentiallyemerginglipid-envelopedviruses • Immune neutralizationby specificantibodies in theplasmapool and the final product such as HAV, Parvovirus B19 and HEV • Pooling of on average 1,000 plasmadonationsensuresthepresenceofthoseantibodies • Respectiveminimumantibodytitersarespecifiedand must bemetforproductrelease • Micro-filtrationminimizestheriskofbacteriaandparasitespresence • Specificaffinitychromatographywith a highbindingcapacitycanremovepotentiallypresentinfectiousprionprotein, whichis not inactivatedorsufficientlyremovedbyothermanufacturingsteps

8. Pathogen Safety Plasma pooltesting The plasma pool for octaplasLG® (630-1,520 FFP units) is tested for: * under FDA review ** tested in IP sample 1 • # Implementation Nov. 2012

9. Pathogen Safety S/D treatment Solvent / Detergent (S/D) treatmentcausesdisruptionofthelipidenvelopesof LEV resulting in complete, fast and robust virusinactivation[8,9] Red line —= kinetics – Blue square = below limit of detection (LOD) ≥ 5.47 log10 At 85% S/D concentration (robustness) ≥ 5.09 log10 ≥ 5.24 log10 ≥ 5.99 log10 At 85% S/D concentration (robustness) Total inactivation  4 log10 to LOD within 1 minute, i.e.  98.9% time-safety-margin for 1 hours S/D PRV: model virus for HBV; BVDV: model virus for HCV [8] Dichtelmüller H.O. et al. Transfusion 2009; 49:1931-1943 [9] Hellstern P. et al. Transfus. Med. Hemother. 2011: 38:65-70

10. Pathogen Safety Immune neutralization Immune neutralizationdepends on thevirusload and thespecificantibodycontentoftheplasmapool and the final container For non-envelopedviruses, whichare not inactivatedby S/D treatment, minimumtitersofneutralisingantibodieswerespecified, thus must bepresent HAV: Hepatitis A Virus B19: Parvovirus B19 HEV: Hepatitis E Virus

11. Pathogen Safety Micro-Filtration Filtration stepsat different stagesofthemanufacturingprocessminimizetheriskof a bacterialorparasitetransfection • 1.0 µm filtration subsequent to FFP pooling • 0.45 µm and 0.2 µm sterile filtrationspriortoasepticfilling

12. Pathogen Safety Global virusreductionfactorsduringoctaplasLG®manufacturing PCR of HAV, B19, HBV, HCV, and HIV genomesareperformed on plasmapoollevel; HEV PCR isbeingimplemented Anti- HAV (pool and product), HBsAg (pool), anti HIV 1/2 (pool), anti-B19 (product) and anti-HEV (product) antibodytitersaretested and must complywiththedefinedspecifications Lipid-envelopedvirusesNon-envelopedviruses HIV: Human Immunodeficiency Virus Type 1 PRV: Pseudorabies Virus; model for Herpes Virus SBV: Sindbis Virus; model for Hepatitis C Virus BVDV: Bovine Viral Diarrhea Virus; model for Hepatitis C Virus WNV: West Nile Virus VACV: Vaccinia Virus HSV-1. Herpes Simplex Virus Type 1 HAV: Hepatitis A Virus COX-B6: Coxsackie Virus B6 POL-1: Poliovirus type 1 OctaplasLG. Biological LicenceApplication (STN 125416/0). 3.2.A.2.4.3 SummaryTablesof Virus Validation Factors.

13. Pathogen Safety PrPScAffinityChromatography A sensitive and robust assaytodetecteventuallypresentinfectiousprionprotein in bloodandplasmadonationsis not yetavailable The affinitychromatographywith a specificimmobilizedligandhas a highcapacitytoadsorbinfectiousprionprotein, thusreducestheriskoftransfusionrelated Creutzfeldt-Jakob Disease • Prion removal capacity (PrPSc) of octaplasLG® was confirmed in animal bioassay studies[10] •  5.64 log10 ID50 / ml gel [10] Heger A. et al. Vox Sang 2012; 104:294-301.

14. Plasma Quality & Biochemical Profile QC releaseparameters ForproductreleaseeachoctaplasLG®batchistested on a numberofparameters (followingslides) in the Quality Controldepartment Specificationsfortheseparametershavebeenset and someofthemwererevisedfor US foroctaplasLG®, also takingintoconsiderationthehistory in US of a firstgeneration S/D treatedplasmaproductfromanothermanufacturer[11] These specifications must bemetforreleaseofeachbatchtosafeguardthepresenceofphysiologically relevant concentrationsofthetestedplasmacomponents, in particular • Balance ofcoagulationfactors and theirhaemostasisregulatingproteins (inhibitors) [11] Coignard P. et al. Hepatology 2002; 36 (4): Pt.2 BPAC 102nd Meeting May, 2012: Evaluation of potential newplasmaproductsmanufactured followingstorageatroomtemparatureforupto 24 hours

15. Plasma Quality & Biochemical Profile Protein S andPlasmin Inhibitor In thecourseoftheimplementationofthe Ligand Gel chromatographythe S/D treatmentexposure time was shortened • maintaining a sufficientsafetymarginforcompleteinactivationoflipid-envelopedviruses • but facilitating an improvedplasmininhibitorin-vitrorecovery[12,13] [13] [12] Heger A. et al. Vox Sang 2012; 103:30 [13] Heger A. et al. Vox. Sang. 2009; 96:225

16. Plasma Quality & Biochemical Profile Proteaseinhibitorsandcofactors n.s., not specified *different testmethodsusedfor FFP (kineticnephelometry) andoctaplasLG® (ELISA) # underreviewby FDA [12] Heger A. et al. Vox. Sang. 2012; 103:130 [14] Beeck H. et al. Vox. Sang. 1998; 74:219-223

17. Plasma Quality & Biochemical Profile Coagulationfactorsandproteinsofthehaemostaticsystem n.s.: not specified [12] Heger A. et al. Vox. Sang. 2012; 103:130 [14] Beeck H. et al. Vox. Sang.1998; 74:219-223 [15] Heger A. et al. Vox. Sang. 2007; 92:206-212 (Octaplas, n=18)

18. Plasma Quality & Biochemical Profile Ranges ofplasmaproteinconcentrations in octaplasLG®batchesand FFPs areequivalent [12] Heger A. et al. Vox. Sang. 2012; 103:130 [14] Beeck H. et al. Vox. Sang. 1998; 74:219-223

19. Plasma Quality The Thrombin Generation Assay demonstratedtheoverallcoagulation potential ofoctaplasLG®, comparabletotherangemeasured in FFPs Global coagulationassaysandspecificassays [12,16] OctaplasLG® (US plasma, n=12) [12] Heger A. et al. Vox Sang. 2012; 103:130 [16] Pock K. et al..Transfusion Apher. Sci, 2007; 37:223-231

20. Plasma Quality ADAMTS13 levelsand von Willebrand Factormultimericstructuresareequivalent in octaplas®batchesand in FFP [15,17] Global coagulationassaysandspecificassays ADAMTS13 octaplas® VWF multimerstructure: densitometry FFP octaplas® VWF Normal Plasma Ref. Standard [15] Heger A. et al. Vox Sang. 2007; 92:206-212 [17] Heger A. et al. Haemophilia. 2006; 12 (2):05PO125

21. Summary In additiontothebasicsafeguardingmeasuresfor FFP withrespectto a potential transfusionrelatedinfection, theoctaplasLG®manufacturingprocessadds S/D treatment, micro-filtrations and a dedicatedPrPScadsorptionstep (LG); immune neutralizationof non-envelopedviruses and PCR testing in theplasmapoolareensuredforeachoctaplasLG®batch FFP poolingof (on average 1,000 donations) results in neutralizationofpathogenicantibodies and substances (minimization TRALI risk) The overallbiochemicalprofilesof FFPs andoctaplasLG®arecomparable • Reductionof S/D exposureperiodincreasedtheplasmininhibitorin-vitrorecovery in octaplasLG® • Balancedcoagulationfactor and inhibitorcontentsareensured by productreleasespecifications (severalinhibitoractivities) foreachoctaplasLG®batch

22. Acknowledgements Andrea Heger Simone Meindl Andrea Neisser-Svae Barbara Rangetiner Torben Schmidt Tor-Einar Svae Michael Szkutta