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Facts On Quality And Safety Characteristics Of Fresh Frozen Plasma Single Donations And octaplasLG ® Jürgen Römisch, Ph.D. Senior Vice President R&D Plasma.

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Presentation on theme: "Facts On Quality And Safety Characteristics Of Fresh Frozen Plasma Single Donations And octaplasLG ® Jürgen Römisch, Ph.D. Senior Vice President R&D Plasma."— Presentation transcript:

1 Facts On Quality And Safety Characteristics Of Fresh Frozen Plasma Single Donations And octaplasLG ® Jürgen Römisch, Ph.D. Senior Vice President R&D Plasma Octapharma PPGmbH Vienna, Austria BPAC Meeting, Rockville, MD September 20, 2012

2 Table of Contents Quality and Safety Aspects of Fresh Frozen Plasma Single Donations Plasma Transfusion Related Adverse Events (TRALI): Biochemical / cellular background octaplasLG ® - Manufacturing Process octaplasLG ® - Pathogen Safety octaplasLG ® - Plasma Quality / Biochemical Profile 2

3 Quality and Safety Aspects of FFP Single Donations Donor screening requirements in USA for fresh frozen plasma 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 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] Guidance for Industry: Implementation of acceptable full-length donor history questionnaire and accompanying materials for use in screening donors of blood and blood components.FDA, October 2006 [2] [3] 3

4 Transfusion Related Acute Lung Injury has emerged as the leading cause of fatalities after blood/plasma transfusion Incidence (TRALI Study Group) [4] : /10,000 transfused units ( ) Typical presentation of TRALI is development of dyspnea, hypoxemia, hypotension and fever 6 hrs after transfusion (bilateral pulmonary infiltrates) [5] –Immune-mediated TRALI is usually caused by antibodies of the blood/plasma donor transferred to the recipient Reactive antibodies to Human Leukocyte Antigens (HLA) or Human Neutrophil Antigens (HNA) cause complement and cell activation and aggregation Release of cytokines and induction of pro-inflammatory reactions Damage of vascular endothelium and exudation of fluid across the pulmonary basement membrane Edema and associated/subsequent events TRALI Plasma Transfusion Related Adverse Events (TRALI) Biochemical/cellular background [4] Transfusion Related Acute Lung Injury Letter; October 19, [5] Toy P et al. For the TRALI Study Group. Transfusion-related lung injury: incidence and risk factors. Blood 2012; 119:

5 octaplasLG ® Manufacturing Process Overview: FFP pooling Pooling of individual donations (630-1,520 FFP units) facilitates Dilution and immune neutralization of - allergens - pathogenic antibodies - infectious agents Leveling out individual heterogeneity, thus reducing variability of contents of plasma components resulting in a consistent product quality Individual antibody specificities of different donations Individual antigen structures contained in single FFP units Cell fragments Antibodies to WBCs were detected in a certain number of FFPs, but not in Octaplas ® batches tested [6a,6b,7] [6a] Sachs U. et al. Transfusion 2005; 45: [6b] Barz D. et al. Anaesthesiol. Reanimate 1994; 156: [7] Sinnott P. et al. Eur. J. Immunogen. 2004; 31:

6 octaplasLG ® Manufacturing Process Overview: safety measures: pathogen safety Antibodies to WBCs (TRALI) Non-Enveloped Viruses ADRs related to cells and fragments Lipid-Enveloped Viruses Bacteria & Parasites Safety against Infectious Prions Fast thawing and pooling of single FFP units Removal of cells, fragments and aggregates by 1.0 µm filtration Full quality control and release of final product Castor oil extraction of TNBP, clear filtration and solid phase extraction of Octoxynol Addition of glycine Affinity chromatography for PrP sc capture Sterile filtration (0.45 µm and 0.2 µm) Aseptic filling, sealing of bags and fast freezing (≤ -60°C) and storage (≤ -30°C) S/D treatment (1% TNBP & 1% Octoxynol for hrs at +30°C ± 1°C) Pooling of individual donations (630-1,520 FFP units) facilitates Dilution and immune neutralization of - allergens - pathogenic antibodies - infectious agents Leveling out of individual heterogeneity and reducing variability of contents of plasma components, resulting in a consistent product quality 6

7 Pathogen Safety Safety measures Beyond the basis precautionary safety measures ensured for FFP, such as donor screening and look-back procedures, the following octaplasLG ® process steps add to the pathogen safety profile –Plasma pool testing (HIV, HBsAG, HAV, HBV, HCV, HEV and Parvovirus B19) –Solvent / Detergent (S/D) treatment for the inactivation of the most hazardous transfusion related enveloped viruses such as HIV, HBV, HCV and WNV –and other potentially emerging lipid-enveloped viruses –Immune neutralization by specific antibodies in the plasma pool and the final product such as HAV, Parvovirus B19 and HEV –Pooling of on average 1,000 plasma donations ensures the presence of those antibodies –Respective minimum antibody titers are specified and must be met for product release –Micro-filtration minimizes the risk of bacteria and parasites presence –Specific affinity chromatography with a high binding capacity can remove potentially present infectious prion protein, which is not inactivated or sufficiently removed by other manufacturing steps 7

8 Plasma pool testing Pathogen Safety Parameter*Limit Plasma Pool* anti-HIV 1/2negative HBsAg negative anti-HAV**≥ 1 IU/ml HAV-PCR negative HBV-PCR negative HCV-PCR negative HEV-PCR # negative HIV-PCR negative Parvo B19 PCR≤ 10.0 IU / µl The plasma pool for octaplasLG ® (630-1,520 FFP units) is tested for: * under FDA review ** tested in IP sample 1 # Implementation Nov

9 Pathogen Safety S/D treatment Solvent / Detergent (S/D) treatment causes disruption of the lipid envelopes of LEV resulting in complete, fast and robust virus inactivation [8,9] PRV: model virus for HBV; BVDV: model virus for HCV [8] Dichtelmüller H.O. et al. Transfusion 2009; 49: [9] Hellstern P. et al. Transfus. Med. Hemother. 2011: 38:65-70 Red line — = kinetics – Blue square  = below limit of detection (LOD) ≥ 5.09 log 10 ≥ 5.24 log 10 ≥ 5.99 log 10 At 85% S/D concentration (robustness) ≥ 5.47 log 10 At 85% S/D concentration (robustness) Total inactivation  4 log 10 to LOD within 1 minute, i.e.  98.9% time-safety-margin for 1 hours S/D 9

10 Pathogen Safety Immune neutralization Immune neutralization depends on the virus load and the specific antibody content of the plasma pool and the final container For non-enveloped viruses, which are not inactivated by S/D treatment, minimum titers of neutralising antibodies were specified, thus must be present VirusPlasma pooloctaplasLG ® HAV PCR anti-HAV IgG negative ≥ 1 IU/ml B19 PCR anti-B19 IgG ≤ 10.0 IU/µl ≥ 11 IU/ml HEV PCR anti-HEV IgG Implementation Nov ≥ 0.2 IU/ml HAV: Hepatitis A Virus B19: Parvovirus B19 HEV: Hepatitis E Virus 10

11 Pathogen Safety Micro-Filtration Filtration steps at different stages of the manufacturing process minimize the risk of a bacterial or parasite transfection –1.0 µm filtration subsequent to FFP pooling –0.45 µm and 0.2 µm sterile filtrations prior to aseptic filling 11

12 Pathogen Safety Global virus reduction factors during octaplasLG ® manufacturing OctaplasLG. Biological Licence Application (STN /0). 3.2.A Summary Tables of Virus Validation Factors. PCR of HAV, B19, HBV, HCV, and HIV genomes are performed on plasma pool level; HEV PCR is being implemented Anti- HAV (pool and product), HBsAg (pool), anti HIV 1/2 (pool), anti-B19 (product) and anti- HEV (product) antibody titers are tested and must comply with the defined specifications Step HIV-1PRVSBV BVDVWNVVACVHSV-1HAVCOX-B6POL-1 Immune neutralisation (log 10 ) n.a.n.a ≥ 11.1 (pool) ≥ 10.0 (pool) ≥ 8.6 (pool) ≥ 10.9 (pool) S/D treatment (log 10 ) ≥ 6.18≥ 5.03≥ 5.31≥ 5.12≥ 5.63≥ 5.00n.a Global reduction factor (log 10 ) ≥ 6.18≥ 5.03≥ 5.31≥ 5.12≥ 5.63≥ 5.00 ≥ 11.1 (pool) ≥ 10.0 (pool) ≥ 8.6 (pool) ≥ 10.9 (pool) Lipid-enveloped viruses Non-enveloped viruses HIV: Human Immunodeficiency Virus Type 1PRV: Pseudorabies Virus; model for Herpes Virus SBV: Sindbis Virus; model for Hepatitis C VirusBVDV: Bovine Viral Diarrhea Virus; model for Hepatitis C Virus WNV: West Nile Virus VACV: Vaccinia Virus HSV-1. Herpes Simplex Virus Type 1HAV: Hepatitis A Virus COX-B6: Coxsackie Virus B6POL-1: Poliovirus type 1 12

13 Pathogen Safety PrP Sc Affinity Chromatography A sensitive and robust assay to detect eventually present infectious prion protein in blood and plasma donations is not yet available The affinity chromatography with a specific immobilized ligand has a high capacity to adsorb infectious prion protein, thus reduces the risk of transfusion related Creutzfeldt-Jakob Disease –Prion removal capacity (PrP Sc ) of octaplasLG ® was confirmed in animal bioassay studies [10] –  5.64 log 10 ID 50 / ml gel [10] Heger A. et al. Vox Sang 2012; 104:

14 Plasma Quality & Biochemical Profile QC release parameters For product release each octaplasLG ® batch is tested on a number of parameters (following slides) in the Quality Control department Specifications for these parameters have been set and some of them were revised for US for octaplasLG ®, also taking into consideration the history in US of a first generation S/D treated plasma product from another manufacturer [11] These specifications must be met for release of each batch to safeguard the presence of physiologically relevant concentrations of the tested plasma components, in particular –Balance of coagulation factors and their haemostasis regulating proteins (inhibitors) [11] Coignard P. et al. Hepatology 2002; 36 (4): Pt.2 BPAC 102 nd Meeting May, 2012: Evaluation of potential new plasma products manufactured following storage at room temparature for up to 24 hours 14

15 Plasma Quality & Biochemical Profile Protein S and Plasmin Inhibitor In the course of the implementation of the Ligand Gel chromatography the S/D treatment exposure time was shortened –maintaining a sufficient safety margin for complete inactivation of lipid- enveloped viruses –but facilitating an improved plasmin inhibitor in-vitro recovery [12,13] [13] [12] Heger A. et al. Vox Sang 2012; 103:30 [13] Heger A. et al. Vox. Sang. 2009; 96:225 15

16 Plasma Quality & Biochemical Profile Protease inhibitors and cofactors Parameters FFP (n=12) [14] Final Product Specification octaplasLG ® USA # octaplasLG ® (n=33) [12] Antithrombin [IU/ml]1.06 ( )n.s.0.92 ( ) Heparin cofactor II [IU/ml]0.95 ( )n.s.1.06 ( ) Protein C [IU/ml]0.89 ( )≥ ( ) Protein S [IU/ml]1.03 ( )≥ ( ) Plasmin inhibitor [IU/ml]1.04 ( )≥ ( ) α 1 -Antitrypsin [mg/ml]*1.57 ( )n.s.1.29 ( ) C1-inhibitor [IU/ml]0.87 ( )n.s.0.89 ( ) n.s., not specified *different test methods used for FFP (kinetic nephelometry) and octaplasLG ® (ELISA) # under review by FDA [12] Heger A. et al. Vox. Sang. 2012; 103:130 [14] Beeck H. et al. Vox. Sang. 1998; 74:

17 Plasma Quality & Biochemical Profile Coagulation factors and proteins of the haemostatic system Parameters FFP (n=12) [14] Final Product Specification octaplasLG ® USA octaplasLG ® (n=33) [12] Fibrinogen [mg/ml]2.6 ( ) ( ) Factor II [IU/ml]0.88 ( )≥ ( ) Factor V [IU/ml]0.90 ( )≥ ( ) Factor VII [IU/ml]0.95 ( )≥ ( ) Factor VIII [IU/ml]0.76 ( )≥ ( ) Factor IX [IU/ml]1.02 ( )n.s.0.94 ( ) Factor X [IU/ml]0.79 ( )≥ ( ) Factor XI [IU/ml]1.13 ( )≥ ( ) Factor XII [IU/ml]0.82 ( )n.s.1.00 ( ) Factor XIII [IU/ml]1.06 ( )n.s.1.01 ( ) VWF:RCo [IU/ml]0.89 ( )n.s.0.88 ( ) ADAMTS13 [IU/ml] [15] 1.24 ( )≥ ( ) Plasminogen [IU/ml]0.98 ( )n.s.0.91 ( ) n.s.: not specified [12] Heger A. et al. Vox. Sang. 2012; 103:130 [14] Beeck H. et al. Vox. Sang.1998; 74: [15] Heger A. et al. Vox. Sang. 2007; 92: (Octaplas, n=18) 17

18 Plasma Quality & Biochemical Profile Ranges of plasma protein concentrations in octaplasLG ® batches and FFPs are equivalent [12] Heger A. et al. Vox. Sang. 2012; 103:130 [14] Beeck H. et al. Vox. Sang. 1998; 74:

19 The Thrombin Generation Assay demonstrated the overall coagulation potential of octaplasLG ®, comparable to the range measured in FFPs Plasma Quality Global coagulation assays and specific assays [12] Heger A. et al. Vox Sang. 2012; 103:130 [16] Pock K. et al..Transfusion Apher. Sci, 2007; 37: OctaplasLG ® (US plasma, n=12) [12,16] Parameters FFP (n=18) [16] octaplasLG ® (n=33) [12] Peak thrombin [nM]331 ( )396 ( ) Lag phase [min]14.6 ( )12.2 ( ) 19

20 ADAMTS13 levels and von Willebrand Factor multimeric structures are equivalent in octaplas ® batches and in FFP [15,17] Plasma Quality Global coagulation assays and specific assays octaplas ® Normal Plasma Ref. Standard ADAMTS13 VWF VWF multimer structure: densitometry FFP octaplas ® [15] Heger A. et al. Vox Sang. 2007; 92: [17] Heger A. et al. Haemophilia. 2006; 12 (2):05PO125 20

21 Summary In addition to the basic safeguarding measures for FFP with respect to a potential transfusion related infection, the octaplasLG ® manufacturing process adds S/D treatment, micro-filtrations and a dedicated PrP Sc adsorption step (LG); immune neutralization of non-enveloped viruses and PCR testing in the plasma pool are ensured for each octaplasLG ® batch FFP pooling of (on average 1,000 donations) results in neutralization of pathogenic antibodies and substances (minimization TRALI risk) The overall biochemical profiles of FFPs and octaplasLG ® are comparable –Reduction of S/D exposure period increased the plasmin inhibitor in-vitro recovery in octaplasLG ® –Balanced coagulation factor and inhibitor contents are ensured by product release specifications (several inhibitor activities) for each octaplasLG ® batch 21

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


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