Meeting Report: 2015 PDA Virus & TSE Safety Forum.

The report provides a summary of the presentations at the Virus & TSE Safety Forum 2015 organized by the Parenteral Drug Association (PDA) and held in Cascais, Portugal, from 9 to 11 June, 2015. As with previous conferences of this series, the PDA Virus & TSE Safety Forum 2015 provided an excellent forum for the exchange of information and opinions between the industry, research organizations, and regulatory bodies. Regulatory updates on virus and TSE safety aspects illustrating current topics of discussion at regulatory agencies in Europe and the United States were provided; the conference covered emerging viruses and new virus detection systems that may be used for the investigation of human pathogenic viruses as well as the virus safety of cell substrates and of raw material of ovine/caprine or human origin. Progress of development and use of next-generation sequencing methods was shown by several examples. Virus clearance data illustrating the effectiveness of inactivation or removal methods were presented and data provided giving insight into the mechanism of action of these technologies. In the transmissible spongiform encephalopathy (TSE) part of the conference, the epidemiology of variant Creutzfeldt-Jakob disease was reviewed and an overview about diagnostic tests provided; current thinking about the spread and propagation of prions was presented and the inactivation of prions by disinfection (equipment) and in production of bovine-derived reagents (heparin) shown. The current report provides an overview about the outcomes of the 2015 PDA Virus & TSE Safety Forum, a unique event in this field.

Meeting Report: 2013 PDA Virus & TSE Safety Forum.

The report provides a summary of the presentations and discussions at the Virus & TSE Safety Forum 2013 organized by the Parenteral Drug Association (PDA) and held in Berlin, Germany, from June 4 to 6, 2013. The conference was accompanied by a workshop, "Virus Spike Preparations and Virus Removal by Filtration: New Trends and Developments". The presentations and the discussion at the workshop are summarized in a separate report that will be published in this issue of the journal as well. As with previous conferences of this series, the PDA Virus & TSE Safety Forum 2013 provided again an excellent opportunity to exchange information and opinions between the industry, research organizations, and regulatory bodies. Updates on regulatory considerations related to virus and transmissible spongiform encephalopathy (TSE) safety of biopharmaceuticals were provided by agencies of the European Union (EU), the United States (US), and Singapore. The epidemiology and detection methods of new emerging pathogens like hepatitis E virus and parvovirus (PARV 4) were exemplified, and the risk of contamination of animal-derived raw materials like trypsin was considered in particular. The benefit of using new sequence-based virus detection methods was discussed. Events of bioreactor contaminations in the past drew the attention to root cause investigations and preventive actions, which were illustrated by several examples. Virus clearance data of specific unit operations were provided; the discussion focused on the mechanism of virus clearance and on the strategic concept of viral clearance integration. As in previous years, the virus safety section was followed by a TSE section that covered recent scientific findings that may influence the risk assessment of blood and cell substrates. These included the realization that interspecies transmission of TSE by blood components in sheep is greater than predicted by assays in transgenic mice. Also, the pathogenesis and possibility of productive TSE infection of cell substrates were considered, and cell-based assays that may be suitable for use in TSE clearance studies were discussed. The current report provides an overview about the outcomes of the 2013 PDA Virus & TSE Safety Forum, a unique event in this field.

Meeting report-workshop on spike characterizations and virus removal by filtration: trends and new developments.

This workshop was held on June 3, 2013, in Berlin, Germany, in conjunction with the PDA Virus & TSE Safety Forum 2013. A total of nine speakers presented on key considerations of virus filtration, including a historical overview and emerging trends in evaluating parvovirus filters. Several talks addressed understanding the mechanism of virus capture and breakthrough by filters, as well as addressing this risk by carefully controlling transmembrane pressure. Improvements to validation studies were proposed via the use of highly purified virus preparations, more relevant models such as Chinese Hamster Ovary retrovirus-like particles, as well as new assays for virus quantification. The workshop ended with a panel discussion covering a range of topics including virus breakthrough, up-stream media treatment, virus spike preparation quality control, and regulatory expectations.

Meeting Report: PDA Virus and TSE Safety Forum.

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.

Meeting report--workshop on virus removal by filtration: trends and new developments.

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.

Breakout session C summary: current virus detection methods.

CONFERENCE PROCEEDING Proceedings of the PDA/FDA Adventitious Viruses in Biologics: Detection and Mitigation Strategies Workshop in Bethesda, MD, USA; December 1-3, 2010 Guest Editors: Arifa Khan (Bethesda, MD), Patricia Hughes (Bethesda, MD) and Michael Wiebe (San Francisco, CA).