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Viral Safety for Biologicals
CSS
Strategies, Technologies and Regulatory Perspectives for Detection, Prevention and Remediation in Upstream, Downstream and Manufacturing Operations
Alternate Language Options:
February 27 - 28, 2012 · Hilton San Diego Bayfront Hotel · San Diego, CA
Agenda
Monday | Tuesday
8:20
Chairperson's Welcome and Opening Remarks
Yuling Li, Ph.D., Fellow, Process Biochemistry, Biopharmaceutical Development, MedImmune
Yuling Li, Ph.D., Fellow, Process Biochemistry, Biopharmaceutical Development, MedImmune
Strategies and Solutions for Developing a Viral Safety Action Plan
8:30
Integrated Strategies for the Risk Mitigation of Adventitious Virus Contamination
Adventitious viral contamination is a high impact risk to any biopharmaceutical organization that produces products from mammalian cell lines. Although the biotech industry has an excellent viral safety record in supplying patients with recombinant protein products, rare events of viral contamination have caused severe impact to the companies on product supply, production facility downtime and significant business loss. This presentation discusses a proactive risk management strategy integrated throughout an entire organization from research and development to production operations with examples of associated opportunities and challenges.
Yuling Li, Ph.D., Fellow, Process Biochemistry, Biopharmaceutical Development, MedImmune
Adventitious viral contamination is a high impact risk to any biopharmaceutical organization that produces products from mammalian cell lines. Although the biotech industry has an excellent viral safety record in supplying patients with recombinant protein products, rare events of viral contamination have caused severe impact to the companies on product supply, production facility downtime and significant business loss. This presentation discusses a proactive risk management strategy integrated throughout an entire organization from research and development to production operations with examples of associated opportunities and challenges.
Yuling Li, Ph.D., Fellow, Process Biochemistry, Biopharmaceutical Development, MedImmune
9:00
Risk-Based Measures for Adventitious Agents in Developing Viral Vaccines
Roya Ravanbakhsh, Director, Quality Assurance, PaxVax, Inc.
Roya Ravanbakhsh, Director, Quality Assurance, PaxVax, Inc.
Regulatory Perspective
9:30
Ensuring Safety of Viral Vaccines - A Regulatory Perspective
Santosh Nanda, Ph.D., Microbiologist/Primary Reviewer, Division of Vaccines and Related Products Applications, Office of Vaccine Research and Review, CBER, US FDA
Santosh Nanda, Ph.D., Microbiologist/Primary Reviewer, Division of Vaccines and Related Products Applications, Office of Vaccine Research and Review, CBER, US FDA
10:00
Networking Refreshment Break and Opening of Exhibit & Poster Hall
Establishing Effective Viral Barriers: Emerging Technologies for Detection, Clearance, Characterization and Control
10:45
Microbial Detection Array for Product Safety and Public Health
DNA microarrays have emerged as a viable platform for detection of adventitious agents from vaccine products and cell substrates, and to detect pathogenic organisms in clinical and environmental samples. We designed a Lawrence Livermore Microbial Detection Array (LLMDA) that can detect any of the sequenced viruses or bacteria within 24 hours, have used the array to identify a contaminating pig virus from a rotavirus vaccine and have demonstrated that the LLMDA can achieve a similar level of sensitivity to massively parallel sequencing. We expect that microarrays such as the LLMDA will evolve during this decade to become the most cost-effective means for quality control of biological products and identifying known pathogens present in clinical samples.
Crystal Jaing, Ph.D., Group Leader, Applied Genomics, Lawrence Livermore National Laboratory
DNA microarrays have emerged as a viable platform for detection of adventitious agents from vaccine products and cell substrates, and to detect pathogenic organisms in clinical and environmental samples. We designed a Lawrence Livermore Microbial Detection Array (LLMDA) that can detect any of the sequenced viruses or bacteria within 24 hours, have used the array to identify a contaminating pig virus from a rotavirus vaccine and have demonstrated that the LLMDA can achieve a similar level of sensitivity to massively parallel sequencing. We expect that microarrays such as the LLMDA will evolve during this decade to become the most cost-effective means for quality control of biological products and identifying known pathogens present in clinical samples.
Crystal Jaing, Ph.D., Group Leader, Applied Genomics, Lawrence Livermore National Laboratory
11:15
Viral Risk Mitigation Strategy: In-Process Monitoring of Rodent Parvovirus in CHO Manufacturing Process Using Real-Time PCR
Genentech's experience with two large-scale manufacturing contamination events by Mouse Minute Virus (MMV) did not definitively identify a specific root cause. However, the experience led to successful implementation of viral barrier approaches such as HTST (high temperature short time) heat treatment of cell culture medium. Because HTST is not applicable to all raw materials, and virus culture for detection is a lengthy method, an In-Process monitoring PCR assay for rodent parvoviruses was implemented for rapid detection of viral genomic material during manufacturing. This assay serves as an early warning system for detecting potential rodent parvovirus contamination in the large scale product manufacturing and also as a hold step prior to further downstream processing. The characteristics of this assay will be presented along with the overall viral safety program.
Serge Monpoeho, Ph.D., Senior Manager, QC Virology & Mycoplasma, Genentech, Inc.
Genentech's experience with two large-scale manufacturing contamination events by Mouse Minute Virus (MMV) did not definitively identify a specific root cause. However, the experience led to successful implementation of viral barrier approaches such as HTST (high temperature short time) heat treatment of cell culture medium. Because HTST is not applicable to all raw materials, and virus culture for detection is a lengthy method, an In-Process monitoring PCR assay for rodent parvoviruses was implemented for rapid detection of viral genomic material during manufacturing. This assay serves as an early warning system for detecting potential rodent parvovirus contamination in the large scale product manufacturing and also as a hold step prior to further downstream processing. The characteristics of this assay will be presented along with the overall viral safety program.
Serge Monpoeho, Ph.D., Senior Manager, QC Virology & Mycoplasma, Genentech, Inc.
11:45
Effective Prefiltration - The Smart Way to Robust Virus Filter Performance
Anika Meyer, Product Manager, Viral Clearance, Sartorius Stedim Biotech GmbH, Germany
Anika Meyer, Product Manager, Viral Clearance, Sartorius Stedim Biotech GmbH, Germany
12:15
Electrospray Differential Mobility Analysis (ES-DMA): An Emerging Technology for Viral Identification, Characterization and Clearance
Here we describe an emerging technology for viral detection, identification, characterization, and clearance, known as electrospray differential mobility analysis (ES-DMA). This technique is a label free platform that measures both the size and concentration of viruses, virus like particles, and vaccines with sufficient resolution to differentiate and quantify individual proteins, capsomers, viruses and viral aggregates. The talk highlights our efforts to validate this technique according to ICH Q2 guidelines with the FDA, select a bacteriophage of choice for classification of small virus-retentive filters with the Parenteral Drug Association's (PDA's) Virus Filtration Task Force, and evaluate the thermal and pH induced degradation of viruses using ES-DMA. In general, we have been systematically preparing this technique to serve as a process analytical technology (PAT). We also describe nanotechnology based approaches to identifying viruses and compare ES-DMA to other routinely used techniques.
Leonard Pease, Ph.D., Professor, Departments of Chemical Engineering, Pharmaceutics & Pharmaceutical Chemistry and Internal Medicine, University of Utah
Here we describe an emerging technology for viral detection, identification, characterization, and clearance, known as electrospray differential mobility analysis (ES-DMA). This technique is a label free platform that measures both the size and concentration of viruses, virus like particles, and vaccines with sufficient resolution to differentiate and quantify individual proteins, capsomers, viruses and viral aggregates. The talk highlights our efforts to validate this technique according to ICH Q2 guidelines with the FDA, select a bacteriophage of choice for classification of small virus-retentive filters with the Parenteral Drug Association's (PDA's) Virus Filtration Task Force, and evaluate the thermal and pH induced degradation of viruses using ES-DMA. In general, we have been systematically preparing this technique to serve as a process analytical technology (PAT). We also describe nanotechnology based approaches to identifying viruses and compare ES-DMA to other routinely used techniques.
Leonard Pease, Ph.D., Professor, Departments of Chemical Engineering, Pharmaceutics & Pharmaceutical Chemistry and Internal Medicine, University of Utah
12:45
Networking Luncheon in Exhibit & Poster Hall
1:55
Chairperson's Remarks
Nathan J. Roth, Ph.D., Director, Virology & TSE, Pathogen Safety, Grifols, Inc.
Nathan J. Roth, Ph.D., Director, Virology & TSE, Pathogen Safety, Grifols, Inc.
Nanofiltration and Pre-Filtration
2:00
Case
Study
Nanofiltration Robustness - Use of Prefilters and Optimizing Rinsing Strategies to Maintain Effective Virus Retention and Maximize Product RecoveryStudy
Nathan J. Roth, Ph.D., Director, Virology & TSE, Pathogen Safety, Grifols, Inc.
2:30
Intelligent Process Design for Reducing Parvovirus Filter Costs
This presentation will discuss: 1) methods for enhancing parvovirus filter capacity including isolating, preventing, and neutralizing foulants; 2) antibody variability, which can sometimes lead to unpredictable performance using proven methods; and 3) how enabling various methods can have synergistic effects on the multiple types of foulants that are likely present.
Jerome Bill Jr., Engineer II, Purification Development, Genentech, Inc.
This presentation will discuss: 1) methods for enhancing parvovirus filter capacity including isolating, preventing, and neutralizing foulants; 2) antibody variability, which can sometimes lead to unpredictable performance using proven methods; and 3) how enabling various methods can have synergistic effects on the multiple types of foulants that are likely present.
Jerome Bill Jr., Engineer II, Purification Development, Genentech, Inc.
3:00
Implementation and Validation Considerations for a Virus Prefilter
Improvements in upstream process development often generate complex, high titer process streams, placing considerable demands on downstream processing steps. Given that protein aggregates in these feeds influence hydraulic performance of virus filters significantly impacting process economics, the adoption of prefiltration in front of a virus filter is increasing. This presentation will discuss the prefilters typically implemented , mode of operation, impact on process development and virus filter validation, including considerations for virus spiking.
Navid Z. Khan, Ph.D., NA Field Manager, Viral Clearance, EMD Millipore
Improvements in upstream process development often generate complex, high titer process streams, placing considerable demands on downstream processing steps. Given that protein aggregates in these feeds influence hydraulic performance of virus filters significantly impacting process economics, the adoption of prefiltration in front of a virus filter is increasing. This presentation will discuss the prefilters typically implemented , mode of operation, impact on process development and virus filter validation, including considerations for virus spiking.
Navid Z. Khan, Ph.D., NA Field Manager, Viral Clearance, EMD Millipore
3:30
Networking Refreshment Break in Exhibit & Poster Hall
4:00
Identification and Characterization of the Critical Factors for Enhancing the Viral Filtration Performance of Nanofilters for Hydrophobic Monoclonal Antibodies
Several commercial viral removal filters were instantly clogged when a generic load condition was used for two hydrophobic therapeutic mAb. The effect of viral filtration load pH, conductivity, and mAb concentration on the filtration throughput were studied using design of experiment and all these factors at lower levels were found to be critical for enhancing the viral filtration performance. The self-association of the hydrophobic mAb was proposed to be responsible for the viral filter clogging under the non-optimal conditions.
Guihang Zhang, Ph.D., Purification Group Leader, Process Sciences, Agensys, Inc.
Several commercial viral removal filters were instantly clogged when a generic load condition was used for two hydrophobic therapeutic mAb. The effect of viral filtration load pH, conductivity, and mAb concentration on the filtration throughput were studied using design of experiment and all these factors at lower levels were found to be critical for enhancing the viral filtration performance. The self-association of the hydrophobic mAb was proposed to be responsible for the viral filter clogging under the non-optimal conditions.
Guihang Zhang, Ph.D., Purification Group Leader, Process Sciences, Agensys, Inc.
4:30
Enhancing Viral Spikes for Nanofiltration Studies with Different Viral Purification Techniques and QC Characterization Including DLS - Particle Analysis
We have refined a multi-step purification process for parvoviruses which demonstrates significantly improved nanofiltration performance using a few viral grades on three companies' filters and different MABs. Dynamic light scattering (DLS) analyses is proving to be a useful QC tool along with total protein and DNA for predicting viral spike performance for nanofiltration and other process steps.
Joseph Hughes, Ph.D., Chief Scientist of Virology and VP of Service Development, Wuxi Apptec
We have refined a multi-step purification process for parvoviruses which demonstrates significantly improved nanofiltration performance using a few viral grades on three companies' filters and different MABs. Dynamic light scattering (DLS) analyses is proving to be a useful QC tool along with total protein and DNA for predicting viral spike performance for nanofiltration and other process steps.
Joseph Hughes, Ph.D., Chief Scientist of Virology and VP of Service Development, Wuxi Apptec
5:00
Case
Study
Streamlining Nanofiltration Clearance Studies for Early Phase Clinical Development by Claiming Modular Retrovirus Clearance for Parvovirus Filters - A Data Driven Case StudyStudy
The nanofiltration unit operation is a dedicated virus clearance step in Eli Lilly and Company's downstream purification processes for biologicals produced in mammalian cell culture. The unit operation removes viruses by the mechanism of size exclusion. Parvovirus filters (~20 nm) are used to ensure that the unit operation can remove viruses with broad size ranges. While parvovirus breakthrough is often detected, retrovirus (~100 nm) breakthrough across parvovirus filters has not been observed either at Lilly or across the industry. By co-spiking of both parvovirus and retrovirus, we have demonstrated that Planova 20N filters can consistently and reliably achieve ≥ 6.0 logs of retrovirus clearance even when parvovirus breakthrough is taking place. Based on (i) the size exclusion mechanism of parvovirus filters, (ii) the fact that retrovirus breakthrough has never occurred with parvovirus filters, and (iii) results from co-spiking studies, we propose to claim modular clearance of ≥ 6.0 logs for retrovirus clearance in the future to support clinical development when Planova 20N is used in our downstream purification process. The risk and benefit of this approach will be discussed based on regulatory expectations for viral safety in support of clinical development.
Dayue Chen, Ph.D., Research Advisor, Process Development, Eli Lilly & Co.
5:30
Cocktail Reception in Exhibit & Poster Hall
Monday | Tuesday
8:20
Chairperson's Remarks
Horst Ruppach, Ph.D., Global Manager of Viral Clearance and Global Coordinator Virology, Charles River Biopharmaceutical Services, Germany
Horst Ruppach, Ph.D., Global Manager of Viral Clearance and Global Coordinator Virology, Charles River Biopharmaceutical Services, Germany
Mitigating Risk of Raw Material Contamination by Adventitious Agents
Session Sponsor:
8:30
Risk Assessment and Management for Adventitious Agents in Raw Materials Used in the Biopharmaceutical Industry
Conducting a risk assessment for adventitious agent contamination (viruses, mycoplasmas, bacteria and fungi) in raw materials used in the biopharmaceutical process requires a science based approach to risk assignment. Just like in the insurance business, actuary tables can be developed to aid in determining risk for adventitious agent contamination of raw materials. This presentation will provide a basis for developing such tables to aid in determining the risk of adventitious agent contamination in the biopharmaceutical industry.
Barbara J. Potts, Ph.D., Senior Consultant, Potts and Nelson Consulting, LLC
Conducting a risk assessment for adventitious agent contamination (viruses, mycoplasmas, bacteria and fungi) in raw materials used in the biopharmaceutical process requires a science based approach to risk assignment. Just like in the insurance business, actuary tables can be developed to aid in determining risk for adventitious agent contamination of raw materials. This presentation will provide a basis for developing such tables to aid in determining the risk of adventitious agent contamination in the biopharmaceutical industry.
Barbara J. Potts, Ph.D., Senior Consultant, Potts and Nelson Consulting, LLC
9:00
A Holistic Approach for Mitigating Risk of Adventitious Agents in Raw Materials
Ivar J. Kljavin, Ph.D., Associate Director, QC Virus, Mycoplasma and Adventitious Agent Management, Genentech, Inc.
Ivar J. Kljavin, Ph.D., Associate Director, QC Virus, Mycoplasma and Adventitious Agent Management, Genentech, Inc.
9:30
Testing Raw Materials for Adventitious Agents Prior to Use in Manufacturing
Sridhar Pennathur, Ph.D., Senior Director, Biosafety Testing, Department of Quality Control, MedImmune, Inc.
Sridhar Pennathur, Ph.D., Senior Director, Biosafety Testing, Department of Quality Control, MedImmune, Inc.
10:00
Networking Refreshment Break in Exhibit & Poster Hall
10:45
Methods for the Identification and Reduction of Adventitious Agent Risks in Raw Materials for Live Virus Vaccine Manufacturing
Adventitious agents in vaccine and biological products have been an area of concern to regulatory agencies, manufacturers, and public health officials since the issue first arose in the early 1900s. While vaccines and the raw materials used during vaccine production are manufactured and tested in compliance with current regulations; quality control tests are broad, non-specific, and may not be capable of detecting novel or emerging adventitious agents. The possibility of adventitious agent contaminations of licensed products has recently been brought to light through the use of new analytical technologies. Such non-biased, highly sensitive technologies have been able to detect adventitious agent contaminations where conventional methods have failed to detect them. In response to these events, vaccine manufacturers have had to re-evaluate adventitious agent risks in their manufacturing processes. Legacy live virus vaccine processes are dependent on animal derived raw materials; removing animal derived raw materials from these processes, if possible, can take >10 years to realize. As such, Merck & Co. has developed a systematic approach to evaluate adventitious agent risks associated with the use of animal derived raw materials in live virus vaccine manufacturing. This approach includes the combination of FMEA and the development of a novel raw material screening program to identify adventitious agent risks in animal derived raw materials. Potential strategies for remediating the identified adventitious agent risks are also presented.
Tara Tagmyer, Ph.D., Process Scientist, Vaccine Manufacturing Sciences & Commercialization, Merck & Co.
Adventitious agents in vaccine and biological products have been an area of concern to regulatory agencies, manufacturers, and public health officials since the issue first arose in the early 1900s. While vaccines and the raw materials used during vaccine production are manufactured and tested in compliance with current regulations; quality control tests are broad, non-specific, and may not be capable of detecting novel or emerging adventitious agents. The possibility of adventitious agent contaminations of licensed products has recently been brought to light through the use of new analytical technologies. Such non-biased, highly sensitive technologies have been able to detect adventitious agent contaminations where conventional methods have failed to detect them. In response to these events, vaccine manufacturers have had to re-evaluate adventitious agent risks in their manufacturing processes. Legacy live virus vaccine processes are dependent on animal derived raw materials; removing animal derived raw materials from these processes, if possible, can take >10 years to realize. As such, Merck & Co. has developed a systematic approach to evaluate adventitious agent risks associated with the use of animal derived raw materials in live virus vaccine manufacturing. This approach includes the combination of FMEA and the development of a novel raw material screening program to identify adventitious agent risks in animal derived raw materials. Potential strategies for remediating the identified adventitious agent risks are also presented.
Tara Tagmyer, Ph.D., Process Scientist, Vaccine Manufacturing Sciences & Commercialization, Merck & Co.
11:15
Overview of Regulations, Strategies and Methods Used to Minimize the Risk of Virus Contamination of Biopharmaceutical Processes and Products through Raw Materials
The risk of virus contamination through raw materials highly depends on the nature of raw material used in the production process of biopharmaceuticals. Different guidelines address different raw materials typically used in the production of vaccines, cell derived products and other human or animal derived products. These guidelines will be shortly outlined and summarized. Testing and physical or chemical treatment of raw material should provide significant virus safety. However, both testing and treatment provides safety to different degree. In this presentation the value and the limitations of testing methods and treatment procedures are discussed. Their impact must be considered adequately to define the total virus risk assessment of the biopharmaceutical product.
Horst Ruppach, Ph.D., Global Manager of Viral Clearance and Global Coordinator Virology, Charles River Biopharmaceutical Services, Germany
The risk of virus contamination through raw materials highly depends on the nature of raw material used in the production process of biopharmaceuticals. Different guidelines address different raw materials typically used in the production of vaccines, cell derived products and other human or animal derived products. These guidelines will be shortly outlined and summarized. Testing and physical or chemical treatment of raw material should provide significant virus safety. However, both testing and treatment provides safety to different degree. In this presentation the value and the limitations of testing methods and treatment procedures are discussed. Their impact must be considered adequately to define the total virus risk assessment of the biopharmaceutical product.
Horst Ruppach, Ph.D., Global Manager of Viral Clearance and Global Coordinator Virology, Charles River Biopharmaceutical Services, Germany
Panel Discussion
11:45
Raw Materials and Adventitious Agents
- Has the value/impact of raw material testing been measured?
- What new technologies and strategies are emerging?
- What are the current regulatory expectations and experiences?
- How to evaluate safety of raw materials from vendors?
Technology Workshop
12:15
This case study will show the relationship between manufacturing impacting the availability of various raw materials for biopharmaceutical companies, and the risk-mitigating steps we have encouraged our customers to take. This analysis is part of Doe & Ingalls' MOR™ (Management of Risk) program, in which we monitor the markets of key raw materials used in biotech production and make customers aware of market changes that can impact supply. A discussion of biopharmaceutical raw material variability, and associated issues, will also be included.
Charlotte Hicks, Management of Risk (MORTM ) Program Manager, Doe & Ingalls
12:45
Networking Luncheon in Exhibit & Poster Hall
1:55
Chairperson's Remarks
Sam Yaghmour, Senior Associate Scientist, Product & Process Development, Amgen, Inc.
Sam Yaghmour, Senior Associate Scientist, Product & Process Development, Amgen, Inc.
Strategies and Technologies to Prevent Contaminations in Upstream and Downstream Development
2:00
Risk Mitigation for Adventitious Agent Contamination in Bioprocesses: New Approach for Seed-Train Expansion of Mammalian Cells
Sam Yaghmour, Senior Associate Scientist, Product & Process Development, Amgen, Inc.
Sam Yaghmour, Senior Associate Scientist, Product & Process Development, Amgen, Inc.
2:45
Speeding up Early Stage Biologics Development by Employing Generic Virus Clearance Platform Technologies
Wensheng Wang, Ph.D., Senior Staff Development Scientist, Pathogen Safety - Global Biologics Development, Bayer HealthCare LLC
Wensheng Wang, Ph.D., Senior Staff Development Scientist, Pathogen Safety - Global Biologics Development, Bayer HealthCare LLC
3:30
Networking Refreshment Break and Last Chance for Exhibit & Poster Viewing
Case Studies and Strategies for Manufacturing Facility Control, Protection and Remediation
4:00
Approaches to Mitigation of Viral Contamination Risk
James Gilbert, Ph.D., Associate Director, Global QC Virology, Biogen Idec, Inc.
James Gilbert, Ph.D., Associate Director, Global QC Virology, Biogen Idec, Inc.
4:30
Case
Study
Applying a Risk-based Product Protection Strategy to a New Mammalian Cell Culture Bioprocessing FacilityStudy
A case study for a newly commissioned bioprocessing facility, IE42, Kinsale will be presented. This discussion will focus on creating design and segregation strategies for a new multiproduct facility to reduce risk of contamination. The review will also assess decisions on introduction of rapid methods for early contamination detection, and proactive remediation plans for facility contamination responses.
Marie Murphy, Ph.D., Microbiologist, Biotechnology Operations, Eli Lilly, Ireland
5:00
Case
Study
MMV Contamination: Detection, Root Cause Determination, and Corrective ActionsStudy
MMV contamination poses a threat to CHO cell based production of biologic drugs. This virus can come from many sources - including non-animal derived media components. Compounding the hazard, the contamination may be "silent", with no impact on cell viability and eluding detection in in vitro virus assays. In our experience, direct testing of raw materials could not identify the contamination source. However, when suspect raw materials were tested in an experiment that mimicked upstream production culture conditions, the contaminating virus replicated to detectable levels and permitted identification of the contamination source. The execution of a corrective and preventative action (CAPA) plan that included disposal of contaminated materials, decontamination of the facility, and replacement of the contaminated raw material with a new lower risk source allowed Merrimack to resume of MMV-free production.
Mark D. Moody, Ph.D., Vice President of Analytical Services, Merrimack Pharmaceuticals
5:30
Close of Conference
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