Albrecht Gröner

The University of Edinburgh, Edinburgh, SCT, United Kingdom

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Publications (30)68.03 Total impact

  • Albrecht Gröner
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    ABSTRACT: Plasma-derived factor VIII (FVIII) concentrates have been used successfully to treat haemophilia A since the late 1960s. To ensure the pathogen safety of the plasma-derived FVIII concentrate, Beriate(®) (formerly Beriate(®) P), donors of blood/plasma are carefully selected and all donations are screened for hepatitis B virus surface antigen (HBsAg), antibodies against HIV types 1 and 2 (HIV-1/HIV-2) and hepatitis C virus (HCV), and genomic material of hepatitis A virus (HAV), hepatitis B virus (HBV), HCV, and for high titres of parvovirus B19 (B19V). As additional quality control, plasma pools for fractionation are only released for further processing when non-reactivity has been demonstrated in serological and genome amplification assays. The manufacturing process for Beriate(®) comprises dedicated virus reduction steps such as pasteurization and the recently introduced virus filtration step, resulting in effective inactivation of various enveloped and non-enveloped viruses and effective removal of viruses and prion material larger than the mean pore size of the virus filter (19nm). The effectiveness of these production steps has been demonstrated in virus and prion validation studies using a range of different viruses and prion preparations. The multiple precautionary measures inherent to the overall production process for Beriate(®) (and its predecessor Beriate(®) P) are reflected in an excellent safety record documented during 20years of clinical use with no proven record of virus transmission, even before the introduction of the virus filtration step. Continued improvement of safety measures according to scientific knowledge and regulatory guidance maintains and even enhances the excellent safety profile of Beriate(®).
    Thrombosis Research 04/2014; · 3.13 Impact Factor
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    Transfusion Medicine and Hemotherapy 02/2014; 41(1):60-72. · 1.59 Impact Factor
  • Transfusion Medicine and Hemotherapy 02/2014; 41(1):73-82. · 1.59 Impact Factor
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    ABSTRACT: Human prion diseases are a group of rare fatal neurodegenerative conditions with well-developed clinical and neuropathological diagnostic criteria. Recent observations have expanded the spectrum of prion diseases beyond the classically recognized forms. In the present study we report six patients with a novel, apparently sporadic disease characterised by thalamic degeneration and rapidly progressive dementia (duration of illness 2¿12 months; age at death: 55¿81 years). Light and electron microscopic immunostaining for the prion protein (PrP) revealed a peculiar intraneuritic distribution in neocortical regions. Proteinase K resistant PrP (PrPres) was undetectable by Western blotting in frontal cortex from the three cases with frozen tissue, even after enrichment for PrPres by centrifugation or by phosphotungstic acid precipitation. Conformation-dependent immunoassay analysis using a range of PK digestion conditions (and no PK digestion) produced only very limited evidence of meaningful D-N (denatured/native) values, indicative of the presence of disease-associated PrP (PrPSc) in these cases, when the results were compared with appropriate negative control groups. Our observation expands the spectrum of conditions associated with rapidly progressive dementia and may have implications for the understanding of the pathogenesis of prion diseases.
    Acta neuropathologica communications. 11/2013; 1(1):72.
  • Robert Klamroth, Albrecht Gröner, Toby L Simon
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    ABSTRACT: Pathogen safety is crucial for plasma-derived clotting factor concentrates used in the treatment of bleeding disorders. Plasma, the starting material for these products, is collected by plasmapheresis (source plasma) or derived from whole blood donations (recovered plasma). The primary measures regarding pathogen safety are selection of healthy donors donating in centers with appropriate epidemiologic data for the main blood-transmissible viruses, screening donations for the absence of relevant infectious blood-borne viruses, and release of plasma pools for further processing only if they are nonreactive for serologic markers and nucleic acids for these viruses. Despite this testing, pathogen inactivation and/or removal during the manufacturing process of plasma-derived clotting factor concentrates is required to ensure prevention of transmission of infectious agents. Historically, hepatitis viruses and human immunodeficiency virus have posed the greatest threat to patients receiving plasma-derived therapy for treatment of hemophilia or von Willebrand disease. Over the past 30 years, dedicated virus inactivation and removal steps have been integrated into factor concentrate production processes, essentially eliminating transmission of these viruses. Manufacturing steps used in the purification of factor concentrates have also proved to be successful in reducing potential prion infectivity. In this review, current techniques for inactivation and removal of pathogens from factor concentrates are discussed. Ideally, production processes should involve a combination of complementary steps for pathogen inactivation and/or removal to ensure product safety. Finally, potential batch-to-batch contamination is avoided by stringent cleaning and sanitization methods as part of the manufacturing process.
    Transfusion 09/2013; · 3.53 Impact Factor
  • Transfusion Medicine and Hemotherapy 08/2013; 40(4):265-84. · 1.59 Impact Factor
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    ABSTRACT: The report provides a summary of the presentations and discussions of the Virus & TSE (transmissible spongiform encephalopathy) Safety Forum 2011 that was organized by the Parenteral Drug Association and held in Barcelona, Spain, on 28-30 June, 2011. The conference was accompanied by a workshop named "Virus Removal by Filtration: Trends and New Developments." A summary of the workshop is provided as a separate report and will be published in this journal as well. The risk of virus contamination and mitigation strategies for medicinal products, sequence-based methods for virus detection, and virus reduction studies that characterize the capacity of specific unit operations for virus removal/inactivation were reported during the Virus Safety Forum. The application of the design of experiment concept to virus safety studies, and the extensive work performed to understand the mechanism of action and to identify critical process parameters for virus removal/inactivation, have produced considerable data. They were provided during the conference and discussed. This report summarized not only the presented data; it also provides a summary of the panel discussion, which included representatives of regulatory agencies from different areas (USA, Europe, Japan) as well as experts from universities and industry. The TSE Safety Forum provided first an overview of the scientific data considering the occurrence of TSEs and the epidemiological situation in different areas. For production of cell-derived medicinal products, the risk of contamination occurs from bovine-derived raw materials like fetal bovine serum or from other raw materials produced with animal-derived components. The current risk of plasma-derived medicinal products from contamination of plasma with the variant Creutzfeldt-Jakob disease agent was considered, and gaps in knowledge and interpretation of TSE studies were discussed from the regulatory standpoint. Current understanding and gaps were intensively discussed by a panel of experts from universities, regulatory agencies and industries; they are summarized in this report. LAY ABSTRACT: The report provides a summary of the presentations and discussions on the Virus & TSE (transmissible spongiform encephalopathy) Safety Forum 2011 that was organized by the Parenteral Drug Association and held in Barcelona, Spain, on 28-30 June, 2011. The conference was accompanied by a workshop named "Virus Removal by Filtration: Trends and New Developments." A summary of the workshop will be published separately in this journal. The risk of virus contamination and mitigation strategies for medicinal products, sequence-based methods for virus detection, and results of virus reduction studies were reported during the Virus Safety Forum. The application of the design of experiment concept to virus safety studies and data identifying critical process parameters for virus removal/inactivation were discussed. This report summarises the presentations and the panel discussion, which included representatives of regulatory agencies from different areas (USA, Europe, Japan) as well as experts from universities and industry. The TSE Safety Forum considered the occurrence of TSEs in different areas. The TSE risk from raw materials and the risk of contamination with the variant Creutzfeldt-Jakob disease agent from human plasma were considered, and gaps in knowledge and interpretation of TSE studies were discussed from the regulatory standpoint. The results of the conference were discussed by a panel of experts. They are summarized in this report.
    PDA journal of pharmaceutical science and technology / PDA. 03/2013; 67(2):81-97.
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    ABSTRACT: The workshop was held on 27 June 2011 in Barcelona, in conjunction with the PDA Virus & TSE (transmissible spongiform encephalopathy) Safety Forum 2011. Virus-retentive filters are important tools to assure a high virus safety level of biological medicinal products. Important parameters such as properties of virus spike preparations, mechanism of virus retention by different filter brands, use of prefilters to improve the filtration performance, and, finally, strategies to select the most appropriate filter for a specific product were discussed on the workshop. The panel discussion at the end of the workshop that involved speakers and regulators from different global areas came to following conclusions: The major mechanism of virus retention is size exclusion; filtration, however, is complex and protein and virus can interact with the membrane in multiple ways. Pressure interruption during filtration resulted in enhanced virus passage. It has never been reported that murine leukemia virus (MuLV) passes a parvovirus filter. It makes sense that a small virus can be used to provide a claim for a large virus like MuLV. This relies on the assumption that there is no aggregation or interaction of the model parvovirus with proteins leading to aggregates larger than retroviruses. Several prefilters are under investigation to improve flow rate and throughput of filtration in large-scale manufacture. It was discussed whether the prefilter and the virus-retentive filter can be viewed as one unit operation so that virus retention by both can be claimed as the viral clearance capacity of this manufacturing step. This question engendered some controversy: whereas some saw the combination as a correct reflection of manufacturing conditions, others discussed the different mechanisms of virus retention, which need to be studied separately. All together, the workshop was seen as a valuable forum for the discussion between regulators and industry; it was proposed that such forum should be provided again if possible in connection with one of the next PDA Virus & TSE Safety Conferences. LAY ABSTRACT: The workshop was held on 27 June 2011 in Barcelona, in conjunction with the PDA Virus & TSE (transmissible spongiform encephalopathy) Safety Forum 2011. Virus-retentive filters are important tools to assure a high virus safety level of biological medicinal products. Important parameters such as properties of virus spike preparations, mechanism of virus retention by different filter brands, use of prefilters to improve the filtration performance and, finally, strategies to select the most appropriate filter for a specific product were discussed on the workshop. At the end of the workshop, aspects of the discussion were summarized by the following: The major mechanism of virus retention is size exclusion, but interactions are complex. Pressure interruption during filtration resulted in enhanced virus passage. It has never been reported that murine leukemia virus (MuLV) passes a parvovirus filter, and thus the parvovirus may provide a claim for a large virus like MuLV. Combination of prefilter and the virus-retentive filter are seen by some panelists as a correct reflection of manufacturing conditions; others discussed the different mechanisms of virus retention, which need to be studied separately. All together, the workshop was seen as a valuable forum for the discussion between regulators and industry.
    PDA journal of pharmaceutical science and technology / PDA. 03/2013; 67(2):98-104.
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    Transfusion Medicine and Hemotherapy 02/2013; 40(1):50-62. · 1.59 Impact Factor
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    ABSTRACT: BACKGROUND: The variant Creutzfeldt-Jakob disease incidence peaked a decade ago and has since declined. Based on epidemiologic evidence, the causative agent, pathogenic prion, has not constituted a tangible contamination threat to large-scale manufacturing of human plasma-derived proteins. Nonetheless, manufacturers have studied the prion removal capabilities of various manufacturing steps to better understand product safety. Collectively analyzing the results could reveal experimental reproducibility and detect trends and mechanisms driving prion removal. STUDY DESIGN AND METHODS: Plasma Protein Therapeutics Association member companies collected more than 200 prion removal studies on plasma protein manufacturing steps, including precipitation, adsorption, chromatography, and filtration, as well as combined steps. The studies used a range of model spiking agents and bench-scale process replicas. The results were grouped based on key manufacturing variables to identify factors impacting removal. The log reduction values of a group are presented for comparison. RESULTS: Overall prion removal capacities evaluated by independent groups were in good agreement. The removal capacity evaluated using biochemical assays was consistent with prion infectivity removal measured by animal bioassays. Similar reduction values were observed for a given step using various spiking agents, except highly purified prion protein in some circumstances. Comparison between combined and single-step studies revealed complementary or overlapping removal mechanisms. Steps with high removal capacities represent the conditions where the physiochemical differences between prions and therapeutic proteins are most significant. CONCLUSION: The results support the intrinsic ability of certain plasma protein manufacturing steps to remove prions in case of an unlikely contamination, providing a safeguard to products.
    Transfusion 12/2012; · 3.53 Impact Factor
  • Albrecht Gröner, Thomas Nowak, Wolfram Schäfer
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    ABSTRACT: BACKGROUND: Human plasma-derived products-such as C1 esterase inhibitor (C1-INH) concentrate, used to treat hereditary angioedema-carry with them the risk of transmitting blood-borne viruses and, theoretically, prion proteins. To minimize this risk, three complementary approaches are implemented: selection and testing of plasma donations for the absence of pathogenic blood-borne viruses, similarly testing and releasing the plasma pool for fractionation, and ensuring that the manufacturing process includes validated steps for pathogen inactivation and removal. STUDY DESIGN AND METHODS: This article describes the selection of plasma for the production of C1-INH and the studies used to confirm the pathogen reduction capacity of the manufacturing process: three independent virus reduction steps-pasteurization, hydrophobic interaction chromatography (HIC), and virus filtration-and two prion reduction steps. Samples of product intermediates from the manufacturing steps were spiked with a panel of enveloped and nonenveloped viruses and two prion preparations and subjected to a valid scaled-down version of the respective manufacturing steps resulting in the quantification of the pathogen reduction factors. RESULTS: Validation studies demonstrated overall virus reduction factors for all viruses of more than 15 log, considerably exceeding the potential amount of virus present in a plasma pool for fractionation. Prion proteins were also efficiently removed by the manufacturing process, as currently determined in evaluating the prion removal capacity of the ammonium sulfate precipitation and HIC steps. CONCLUSION: The pathogen reduction capacity demonstrated here indicates that the manufacturing process of the C1-INH Berinert is highly effective for reducing enveloped and nonenveloped viruses and prion proteins.
    Transfusion 03/2012; · 3.53 Impact Factor
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    ABSTRACT: Disease-associated prion protein (PrP(Sc)) can be distinguished from the cellular isoform (PrP(C)) by conformation-dependent immunoassay (CDI). This technique exploits the presence of an epitope, accessible in PrP(C), but only unmasked by denaturation in PrP(Sc). In this study, we investigated PrP(Sc) in different brain regions in variant and sporadic Creutzfeldt-Jakob disease (CJD) by using CDI, and directly compared the results with those obtained using the more commonly employed protease digestion and Western blotting. In general, there was good agreement between the results, although there were certain discrepancies in relative abundance when the regional distribution in variant CJD cases was considered. The results largely confirmed the previously described targeting of different brain regions by variant and sporadic CJD. Additionally, the combination of protease digestion and CDI detection demonstrated, for the first time, the presence of PrP(Sc) in variant CJD brains that is susceptible to proteolysis under standard conditions.
    Journal of General Virology 03/2011; 92(Pt 3):727-32. · 3.13 Impact Factor
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    ABSTRACT: Virus removal by partitioning into different fractions during cold ethanol fractionation has been described by several authors, demonstrating that cold ethanol fractionation can provide significant contribution to virus removal, even in those cases where virus removal is limited and must be supported by additional measures for virus inactivation during further processing. Plasma Protein Therapeutics Association (PPTA) member companies collected and evaluated 615 studies on virus removal by the steps of the cold ethanol fractionation process. The studies describe the precipitation and separation of Fraction (F)III or FI/III in the immunoglobulin fractionation process and precipitation and separation of FII/III, FI/II/III, and FIV/IV in the albumin fractionation process. The data indicate a significant contribution of cold ethanol fractionation to the overall clearance of a broad spectrum of viruses, at varied process variables such as pH, temperature, and alcohol concentration and demonstrate the robustness of virus removal by the cold ethanol fractionation process. The data presented here support the importance of the partitioning steps for virus safety for immunoglobulins and albumin. However, virus removal by cold ethanol fractionation alone cannot provide viral safety of human albumin and immunoglobulins and therefore must be completed by other virus inactivation and removal procedures.
    Transfusion 01/2011; 51(7):1412-30. · 3.53 Impact Factor
  • A. Gröner, M. Konrad
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    ABSTRACT: Plasmaderivate sind gereinigte und in ihrer Konzentration standardisierte Proteine aus Plasma, dem zellfreien Bestandteil des menschlichen Blutes. Es gibt Menschen, denen diese Proteine aufgrund eines genetischen oder erworbenen Mangels in ausreichender Menge fehlen, was zu klinischen Symptomen bis hin zu lebensgefährlichen Erkrankungen führt. Solchen Patienten müssen diese Plasmaderivate infundiert werden. Die wichtigsten Proteine, die therapeutisch angewandt werden, sind in Tab. 19.1 zusammengestellt.
    12/2010: pages 271-286;
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    ABSTRACT: The phenotypic and strain-related properties of human prion diseases are, according to the prion hypothesis, proposed to reside in the physicochemical properties of the conformationally altered, disease-associated isoform of the prion protein (PrP(Sc)), which accumulates in the brains of patients suffering from Creutzfeldt-Jakob disease and related conditions, such as Gerstmann-Straussler-Scheinker disease. Molecular strain typing of human prion diseases has focused extensively on differences in the fragment size and glycosylation site occupancy of the protease-resistant prion protein (PrP(res)) in conjunction with the presence of mutations and polymorphisms in the prion protein gene (PRNP). Here we report the results of employing an alternative strategy that specifically addresses the conformational stability of PrP(Sc) and that has been used previously to characterize animal prion strains transmitted to rodents. The results show that there are at least two distinct conformation stability states in human prion diseases, neither of which appears to correlate fully with the PrP(res) type, as judged by fragment size or glycosylation, the PRNP codon 129 status, or the presence or absence of mutations in PRNP. These results suggest that conformational stability represents a further dimension to a complete description of potentially phenotype-related properties of PrP(Sc) in human prion diseases.
    Journal of Virology 11/2010; 84(22):12030-8. · 5.08 Impact Factor
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    ABSTRACT: The vacuolation, neuronal loss and gliosis that characterize human prion disease pathology are accompanied by the accumulation of an aggregated, insoluble and protease-resistant form (termed PrP(Sc)) of the host-encoded normal cellular prion protein (PrP(C)). In variant Creutzfeldt-Jakob disease the frontal cortex and cerebellum exhibit intense vacuolation and the accumulation of PrP(Sc) in the form of amyloid plaques and plaque-like structures. In contrast the posterior thalamus is characterized by intense gliosis and neuronal loss, but PrP(Sc) plaques are rare and vacuolation is patchy. We have used sucrose density gradient centrifugation coupled with conformation dependent immunoassay to examine the biochemical properties of the PrP(Sc) that accumulates in these different brain regions. The results show a greater degree of PrP(Sc) polydisperal in thalamus compared with frontal cortex or cerebellum, including a subpopulation PrP(Sc) molecules in the thalamus that have sedimentation properties resembling those of PrP(C). Much effort has focused on identifying aspects of PrP(Sc) biochemistry that distinguish between different forms of human prion disease and contribute to differential diagnosis. Here we show that PrP(Sc) sedimentation properties, which can depend on aggregation state, correlate with, and may underlie the distinct neurodegenerative processes occurring in different regions of the variant Creutzfeldt-Jakob disease brain.
    Brain Pathology 09/2010; 21(3):298-307. · 4.74 Impact Factor
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    Transfusion Medicine and Hemotherapy 01/2010; 37(6):339-350. · 1.59 Impact Factor
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    Transfusion Medicine and Hemotherapy 01/2010; 37(6):365-375. · 1.59 Impact Factor
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    Transfusion Medicine and Hemotherapy 01/2010; 37(6):351-364. · 1.59 Impact Factor
  • Biologicals 08/2009; 37(5):345-54. · 1.62 Impact Factor

Publication Stats

180 Citations
68.03 Total Impact Points

Institutions

  • 2010–2011
    • The University of Edinburgh
      • School of Clinical Sciences and Community Health
      Edinburgh, SCT, United Kingdom
    • Western General Hospital
      Edinburgh, Scotland, United Kingdom
  • 2009–2010
    • CSL Behring
      King of Prussia, Pennsylvania, United States
    • National Institute for Biological Standards and Control
      Potters Bar, England, United Kingdom