Multiple Dedicated Measures Result in a Plasma-Derived FVIII Concentrate with High Margin of Safety Regarding Pathogen Transmission

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4355-4355
Author(s):  
Albrecht Groener ◽  
Thomas Nowak ◽  
Birgit Popp ◽  
Wolfram Schäfer
Keyword(s):  
Heat Treatment ◽  
Production Process ◽  
Manufacturing Process ◽  
Specific Model ◽  
Enveloped Viruses ◽  
Margin Of Safety ◽  
Virus Filtration ◽  
Reduction Capacity ◽  
Very High ◽  
Reduction Factors

Abstract Abstract 4355 A minimal load of infectious virus, if any, in human plasma, the starting material for the production of a FVIII concentrate, is achieved by selecting donor centers and donors, by testing donations for viral markers and genomic material of HAV, HBV, HCV, HIV-1 and high titers of parvovirus B19 (B19V), and by releasing plasma pools for fractionation when non-reactive for these blood-borne viruses. Two dedicated virus reduction steps and further steps of the manufacturing process of this FVIII concentrate [Beriate] were investigated: heat treatment in aqueous, stabilized solution (“pasteurization”), virus filtration (filter with a mean pore size of approx. 19 nm (Planova 20N)), and a chromatography step. The virus and prion reduction capacity of the manufacturing process of this FVIII concentrate was evaluated in in vitro studies. Product intermediates from selected steps of the manufacturing process for the FVIII concentrate, derived from different production lots, were spiked with enveloped and non-enveloped viruses of diverse physico-chemical characteristics and processed according to a scaled-down, validated manufacturing process. The virus panel employed in these studies consisted of HIV, BVDV (bovine viral diarrhea virus, a specific model virus for HCV and WNV), HAV, parvoviruses (B19V and CPV (canine parvovirus)) and PRV (pseudorabies virus, a non-specific enveloped DNA virus). The prion reduction capacity was studied by spiking cryoprecipitate with two different spike preparations and performing the whole manufacturing process including the virus filtration according to a valid down scaled process. Pasteurization (heat treatment) inactivates all blood-borne viruses or their specific model viruses effectively, i.e. HIV, BVDV, HAV and B19V were inactivated in the order of 4 log10 or more. Virus filtration removed effectively all enveloped viruses and HAV and removed CPV, a small non-enveloped virus, to a very high degree. Further manufacturing steps reliably contribute to the overall virus reduction capacity of the manufacturing process of this FVIII concentrate. Two different prion preparations prepared from brain homogenate of 263K infected hamsters were used in prion evaluation studies: a membrane-associated preparation of prion material (microsomes) and a PrPSc preparation without membranes (purified PrPSc) were used to evaluate the prion reduction capacity of the FVIII production process. Studying the whole manufacturing process in a combined step approach documented the removal of both spike preparations below the limit of detection. Prion material in the different fractions was quantified using a biochemical/serological method, the Conformation-Dependent Immunoassay (CDI). Spiking different manufacturing steps independently and adding the individual reduction factors to the overall prion reduction factor was considered not appropriate as conditioning of the spiked prion material by the production process may impact the reduction capacity. The pathogen reduction capacity for the FVIII concentrate Beriate is shown in the following table: Based on the epidemiology in the donor population and donation frequency, the sensitivity of the NAT assay, the amount of plasma needed to produce one vial of FVIII concentrate and the virus reduction factors demonstrated, it can be concluded that the measures taken result in a FVIII concentrate [Beriate] with a very high margin of safety for a wide range of viruses and other pathogens. Disclosures: Groener: CSL Behring: Employment. Nowak:CSL Behring: Employment. Popp:CSL Behring: Employment. Schäfer:CSL Behring: Employment.

High Margin of Pathogen Safety for a Plasma-Derived FXIII Concentrate for the Treatment of Congenital FXIII Deficiency

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4655-4655
Author(s):  
Albrecht Groener ◽  
Thomas Nowak ◽  
Birgit Popp ◽  
Wolfram Schäfer
Keyword(s):  
Heat Treatment ◽  
Manufacturing Process ◽  
Specific Model ◽  
Reduction Factor ◽  
Published Data ◽  
Wide Range ◽  
Virus Filtration ◽  
Reduction Capacity ◽  
Fxiii Deficiency ◽  
Genomic Material

Abstract Abstract 4655 Congenital Factor XIII (FXIII) deficiency is an extremely rare, serious, and life-threatening condition, especially due to intracranial haemorrhage, which can be treated by a plasma-derived FXIII concentrate. The pathogen safety of this plasma-derived protein is achieved by the complementary measures (i) selecting and testing the starting material, human plasma, (ii) releasing the plasma pool for fractionation when non-reactive for viral markers and genomic material of blood-borne viruses, and (iii) ensuring adequate capacity of the production process to reduce a wide range of viruses as well as prions. Virus validation and prion evaluation studies were performed to assess the reduction capacity of the manufacturing process of this FXIII concentrate. A minimal load of infectious virus, if any, in human plasma, the starting material for the production of a FXIII concentrate, is achieved by selecting donor centers and donors, by testing donations for viral markers and genomic material of HAV, HBV, HCV, HIV-1 and high titers of parvovirus B19 (B19V), and by releasing plasma pools for fractionation when non-reactive for these blood-borne viruses. Two dedicated virus reduction steps and further steps of the manufacturing process of the FXIII concentrate were investigated: heat treatment in aqueous, stabilized solution (“pasteurization”), virus filtration (two filters in series with mean pore sizes of approx. 19 nm (20N/20N)), and partitioning steps. The virus and prion reduction capacity of the manufacturing process of this FXIII concentrate was evaluated in in vitro studies. Product intermediates from selected steps of the manufacturing process for the FXIII concentrate, derived from different production lots, were spiked with enveloped and non-enveloped viruses of diverse physico-chemical characteristics and processed according to a scaled-down, validated manufacturing process. The virus panel employed in these studies consisted of HIV, BVDV (bovine viral diarrhea virus, a specific model virus for HCV and WNV), WNV, HAV, parvoviruses (B19V and CPV (canine parvovirus)) and PRV (pseudorabies virus, a non-specific enveloped DNA virus). Prion reduction capacity was currently assessed by studying one manufacturing process step with two different spike preparations and based on data for other products from CSL Behring or published data. Pasteurization (heat treatment) inactivates all blood-borne viruses or their specific model viruses effectively, i.e. HIV, BVDV, WNV, HAV and B19V were inactivated in the order of 4 log10 or more. Virus filtration removed effectively all viruses studied. Further manufacturing steps reliably contribute to the overall virus reduction capacity of the manufacturing process of this FXIII concentrate. Two different prion preparations prepared from brain homogenate of 263K infected hamsters were used in the prion evaluation study: a membrane-associated preparation of prion material (microsomes) and a PrPSc preparation without membranes (purified PrPSc). Both spike preparations were removed equally by the manufacturing step Al(OH)3 adsorption / defibrination. Prion material in the different fractions was quantified using a biochemical/serological method, the Conformation-Dependent Immunoassay (CDI). The pathogen reduction capacity for this FXIII concentrate is shown in the following table:Pathogen Reduction Factor [log10]Manufacturing stepsHIVBVDVWNVPRVHAVCPVB19VPrionsMicrosomespurified PrPScpublished dataCryoprecipitation8% ethanol pptAl(OH)3 adsorption/ defibrination7.02.62.7Ion exchange chromatography5.03.4≥6.53.43.73.0*Heat treatment (Pasteurization)≥7.7≥8.1≥7.44.31.0≥4.0Ammonium sulphate precipitation20N/20N virus filtration≥6.1≥5.0≥6.4≥5.66.04.0*Formulation/sterile filtration/ lyophilizationOverall Reduction≥18.8≥16.5N/A≥19.913.310.7N/A9.69.7*based on preliminary data (for other plasma proteins from CSL Behring) or published data, included in the overall prion reduction factor. Based on the epidemiology in the donor population and donation frequency, the sensitivity of the NAT assay, the amount of plasma needed to produce one vial of FXIII concentrate and the virus reduction factors demonstrated, it can be concluded that the measures taken result in a FXIII concentrate with a very high margin of safety for a wide range of viruses and other pathogens. Disclosures: Groener: CSL Behring: Employment. Nowak:CSL Behring: Employment. Popp:CSL Behring: Employment. Schäfer:CSL Behring: Employment.

Efficient Reduction of Prions by the Manufacturing Process of a VWF/FVIII Product

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 995-995
Author(s):  
Albrecht Groener ◽  
Martin Groschup ◽  
Wolfram Schäfer
Keyword(s):  
Manufacturing Process ◽  
Reduction Factor ◽  
Scale Model ◽  
Spongiform Encephalopathy ◽  
Microsomal Preparation ◽  
Biochemical Methods ◽  
Sterile Filtration ◽  
The Impact ◽  
Reduction Capacity ◽  
Reduction Factors

Abstract Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disease acquired through infection with prions which cause bovine spongiform encephalopathy (BSE) by consumption of beef products from infected cattle. Presumptive transfusion transmitted cases of vCJD have been reported in the UK increasing the concern that medicinal products manufactured from plasma might also pose a risk of vCJD transmission. Therefore, investigational studies were performed to assess the prion reduction capacity of the manufacturing process of a VWF/FVIII product (Haemate® P / Humate-P®). In these studies hamster brain derived prion material in the form of a microsomal preparation were used to spike plasma product intermediates. As the purification process of a desired plasma protein may impact the physico-chemical form of the spiked prion protein, the addition of reduction factors from single step studies possibly might not reflect the true prion reduction of the full process; in particular where the spike material is heterogeneous, one fraction, i.e. gross aggregates of prion material could be preferentially removed by one step and the same subfraction by a subsequent step. Therefore, we employed a combined step study approach and not a single spike step approach to address that issue of the impact of heterogeneous spike fractions regarding the overall reduction factor. The manufacturing process of the VWF/FVIII product was divided in two parts which were studied independently twice: Pooled plasma donations (4,500 ml) were spiked and processed covering cryoprecipitation, Al(OH)3 adsorption and subsequent precipitations by glycine and NaCl. The second part of the VWF/FVIII manufacturing process was studied starting with spiked dissolved NaCl precipitate (154 ml) and processed further by pasteurization, second NaCl precipitation, dialysis, ultracentrifugation and sterile filtration. The prion spiked starting material and product intermediate were processed according to the manufacturing conditions based on a valid down-scale model. The prion reduction factors were determined as the difference of the prion load in the spiked starting materials and in the respective final samples using a biochemical assay (Conformation-Dependent Immunoassay (CDI)) or a bioassay in hamsters for quantification of PrPSc (dose dependent incubation period measurement). The results of these investigational studies for the two prion quantification methods are shown below PrionReduction Factors [log10] demonstrated by Manufacturing steps biochemical methods (CDI) bioassay (incubation time) Cryo precipitation / Al(OH)3adsorption / Glycine precipitation 3.2 ± 0.1 2.8 ± 0.3 Pasteurization / NaCl precipitation / Dialysis / Ultracentrifugation / Sterile filtration 2.9 ± 0.2 3.1 ± 0.1 Filling / Lyophilization n.d. n.d. Overall Prion Reduction Factor 6.1 ± 0.2 5.9 ± 0.3 These results demonstrate (i) comparable prion reduction factors quantified either by biochemical methods or by a bioassay and (ii) an appropriate overall prion reduction capacity of the manufacturing process of Haemate® P / Humate-P®. Based on complementary safety procedures, i.e., collection of plasma by stringent donor selection due to geographic donor deferral policy and the overall prion reduction factor of approximately 6 log10, which clearly exceeds a potential prion load in the manufacturing pool, a risk assessment results in an extremely remote risk of prion transmission by the VWF / FVIII product Haemate® P / Humate-P®.

“In vitro” and in Animal Model Studies on a Double Virus- Inactivated Factor VIII Concentrate

1995 ◽  
Vol 74 (03) ◽  
pp. 868-873 ◽  
Author(s):  
Silvana Arrighi ◽  
Roberta Rossi ◽  
Maria Giuseppina Borri ◽  
Vladimir Lesnikov ◽  
Marina Lesnikov ◽  
...  
Keyword(s):  
Heat Treatment ◽  
Animal Model ◽  
Factor Viii ◽  
Hepatitis A ◽  
Hepatitis A Virus ◽  
Virus Inactivation ◽  
Enveloped Viruses ◽  
Model Studies ◽  
Heat Treated

SummaryTo improve the safety of plasma derived factor VIII (FVIII) concentrate, we introduced a final super heat treatment (100° C for 30 min) as additional virus inactivation step applied to a lyophilized, highly purified FVIII concentrate (100 IU/mg of proteins) already virus inactivated using the solvent/detergent (SID) method during the manufacturing process.The efficiency of the super heat treatment was demonstrated in inactivating two non-lipid enveloped viruses (Hepatitis A virus and Poliovirus 1). The loss of FVIII procoagulant activity during the super heat treatment was of about 15%, estimated both by clotting and chromogenic assays. No substantial changes were observed in physical, biochemical and immunological characteristics of the heat treated FVIII concentrate in comparison with those of the FVIII before heat treatment.

Wage-setting Mechanisms in the Russian Industry

2004 ◽  
pp. 66-90 ◽  
Author(s):  
R. Kapelyushnikov
Keyword(s):  
Special Section ◽  
Close Correlation ◽  
Specific Model ◽  
Wage Determination ◽  
Collective Agreement ◽  
Wage Setting ◽  
Industrial Enterprises ◽  
Subsistence Minimum ◽  
Competitive Model ◽  
Very High

The paper examines a specific model of wage-setting evolved in Russia under transition. Using new survey data author reveals paradoxical characteristics of wage-setting mechanisms at Russian industrial enterprises: very high union and collective agreement coverage; nearly unilateral control of managers over wage determination; close correlation between earnings and enterprises' performance; voluntary utilization of wage standards established by the state. The special section explores effects of fulfilling a new provision stipulated for by the recently adopted Labor Code to raise minimum wage to the subsistence minimum level. The author concludes that wage-setting in the Russian labor market is at odds with a textbook competitive model and poorly fits into many other sophisticated theoretical schemes (such as labor-managed firms, bargaining models etc.).

UNS A97075

Alloy Digest ◽  
1986 ◽  
Vol 35 (7) ◽  
Keyword(s):  
Mechanical Properties ◽  
Heat Treatment ◽  
Aluminum Alloy ◽  
High Strength ◽  
Heat Treating ◽  
Good Resistance ◽  
Temperature Performance ◽  
Structural Applications ◽  
Structural Parts ◽  
Very High

Abstract UNS No. A97075 is a wrought precipitation-hardenable aluminum alloy. It has excellent mechanical properties, workability and response to heat treatment and refrigeration. Its typical uses comprise aircraft structural parts and other highly stressed structural applications where very high strength and good resistance to corrosion are required. This datasheet provides information on composition, physical properties, hardness, elasticity, tensile properties, and shear strength as well as fatigue. It also includes information on low temperature performance as well as forming, heat treating, and machining. Filing Code: Al-269. Producer or source: Various aluminum companies.

Analysis of the information management system in the manufacturing process of cigarette enterprises using fuzzy AHP

2021 ◽  
pp. 1-11
Author(s):  
Song Gang ◽  
Wang Xiaoming ◽  
Wu Junfeng ◽  
Li Shufang ◽  
Liu Zhuowen ◽  
...  
Keyword(s):  
Quality Control ◽  
Production Process ◽  
Information Management ◽  
Manufacturing Process ◽  
Management System ◽  
Fuzzy Ahp ◽  
Control Process ◽  
Information Management System ◽  
Manufacturing Execution System ◽  
Quality Control Process

In view of the production quality management of filter rods in the manufacturing and execution process of cigarette enterprises, this paper analyzes the necessity of implementing the manufacturing execution system (MES) in the production process of filter rods. In this paper, the filter rod quality system of cigarette enterprise based on MES is fully studied, and the constructive information management system demand analysis, cigarette quality control process, system function module design, implementation and test effect are given. This paper utilizes the Fuzzy analytic hierarchy process to find the optimal system for processing the manufacturing of cigarette. The implementation of MSE based filter rod quality information management system for a cigarette enterprise ensures the quality control in the cigarette production process. Through visualization, real-time and dynamic way, the information management of cigarette production is completed, which greatly improves the quality of cigarette enterprise manufacturing process.

ELASTIC SCATTERING WITH THE LIPATOV POMERON

1992 ◽  
Vol 07 (26) ◽  
pp. 2415-2421 ◽  
Author(s):  
A. P. CONTOGOURIS ◽  
F. LEBESSIS
Keyword(s):  
Asymptotic Behavior ◽  
Elastic Scattering ◽  
Specific Model ◽  
Scattering Data ◽  
High Energies ◽  
Very High

First a unitarization procedure for an amplitude with the asymptotic behavior of the Lipatov Pomeron is presented; it amounts to its iteration along the s-channel. Next, based on this procedure, a specific model is considered and applied to the description of elastic scattering data at very high energies; it is shown that it leads to a fair description of them.

Experimental Assessment of Roughness Changes in the Cutting Surface and Microhardness Changes of the Material S 355 J2 G3 after Being Cut by Non-Conventional Technologies

2011 ◽  
Vol 314-316 ◽  
pp. 1944-1947 ◽  
Author(s):  
Jozef Maščeník ◽  
Stefan Gaspar
Keyword(s):  
Mechanical Properties ◽  
Production Process ◽  
Laser Plasma ◽  
Manufacturing Process ◽  
Production Quality ◽  
Water Jet ◽  
Cutting Edge ◽  
Experimental Assessment ◽  
Cutting Surface ◽  
The Impact

Production of components, necessary for the construction of the machine resp. or device is a demanding manufacturing process. One of the possibilities of increasing efficiency and production quality is the introduction of unconventional technologies to the production process. Knowing the dependence of the impact of non-conventional technologies on the mechanical properties of products and their subsequent verification is an important aspect when designing and manufacturing them. The article deals with the impact of used unconventional technology, that means laser, plasma and water jet on the roughness of a cutting edge and microhardness of material S 355 J2 G3.

Effect of Heat Treatment on Very High Cycle Fatigue Properties of TC4

2021 ◽  
Vol 881 ◽  
pp. 3-11
Author(s):  
Bo Han Wang ◽  
Li Cheng ◽  
Xun Chun Bao
Keyword(s):  
Heat Treatment ◽  
High Cycle Fatigue ◽  
Treatment Method ◽  
Fatigue Performance ◽  
Fatigue Properties ◽  
Cycle Fatigue ◽  
Α Phase ◽  
Very High Cycle Fatigue ◽  
Significant Difference ◽  
Very High

The bimodal, equiaxed and Widmanstatten microstructures of TC4 titanium alloy were obtained through different heat treatment processes. The content of primary α phase in the bimodal and equiaxed microstructures was measured to be about 40% and 90%, and the average size was about 9.4μm and 7.9 μm. Three types of microstructure fatigue S-N curves are obtained, which are successively descending type, single-platform descending type and infinite life type. The order of very high cycle fatigue performance is Widmanstatten>equiaxed>bimodal, but the anti-fretting fatigue performance of Widmanstatten is the worst. The grain refinement makes the fatigue performance of the equiaxed better than that of the bimodal. The second process is determined as the best heat treatment method. There is no significant difference in the life of the crack propagation stage. The very high cycle fatigue life mainly depends on the crack initiation stage. In the bimodal and the equiaxed, the crack initiates in the primary α phase of the subsurface, and the crack in the Widmanstatten initiates in the coarse α 'grain boundary of the subsurface.

scholarly journals Mechanical Properties and Very High Cycle Fatigue Behavior of Peak-Aged AA7021 Alloy

Metals ◽  
2018 ◽  
Vol 8 (12) ◽  
pp. 1023 ◽  
Author(s):  
Byung-Hoon Lee ◽  
Sung-Woo Park ◽  
Soong-Keun Hyun ◽  
In-Sik Cho ◽  
Kyung-Taek Kim
Keyword(s):  
Mechanical Properties ◽  
Heat Treatment ◽  
Tensile Strength ◽  
High Cycle Fatigue ◽  
Fatigue Behavior ◽  
Cycle Fatigue ◽  
Solution Treated ◽  
Very High Cycle Fatigue ◽  
Peak Aged ◽  
Very High

The effect of heat treatment condition on non-Cu AA7021 alloy was investigated with respect to mechanical properties and very high cycle fatigue behavior. With a focus on the influence of heat treatment, AA7021 alloy was solution heat-treated at 470 °C for 4 h and aged at 124 °C. Comparing the results of solution-treated and peak-aged AA7021 alloy shows a significant increase in Vickers hardness and tensile strength. The hardness of AA7021 alloy was increased by 65% after aging treatment, and both tensile strength and yield strength were increased by 50~80 MPa in each case. In particular, this paper investigated the very high cycle fatigue behavior of AA7021 alloy with the ultrasonic fatigue testing method using a resonance frequency of 20 kHz. The fatigue results showed that the stress amplitude of peak-aged AA7021 alloy was about 50 MPa higher than the solution-treated alloy at the same fatigue cycles. Furthermore, it was confirmed that the size of the crack initiation site was larger after peak aging than after solution treatment.

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