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THE Industry Meeting Place to Exchange Real-World Solutions to Improve Speed, Cost and Quality
Conference: September 16-19, 2013 · Exhibition: September 17-19, 2013 ·
Cell Culture and Upstream Processing Agenda
Cell Culture and Upstream Processing Agenda
Cell Culture and Upstream Processing
Registration and Coffee
Chairwoman's Opening Remarks
Cynthia Hoy, Ph.D., Process Science Fellow, Life Technologies
CaseImpact of Single-Use Bioreactors on Upstream Processing
Thomas Ryll, Ph.D., Senior Director, Cell Culture Development, Biogen Idec
Cell Metabolism and Physiology - Impact on Production
Modulating Autophagy to Increase Protein Production in CHO Cell Fed-batch Processes
Autophagy is a cellular process that targets intracellular components for lysosomal degradation as part of a survival response to stress. This mechanism was found to be activated under fed-batch conditions along with a decrease in cell-specific productivity. Adding a chemical inhibitor of autophagy increased monoclonal antibody or tissue plasminogen activator production 2-fold or more, without impairing the protein glycosylation.
James Piret, Ph.D., Professor, Michael Smith Laboratories & Department of Chemical and Biological Engineering, University of British Columbia
Apoptosis of CHO Cells Monitored by a Novel Dielectrophoretic (DEP) Cytometer
A prototype dielectrophoretic (DEP) cytometer has been developed to measure the dielectric properties of individual cells. This can identify early apoptotic changes corresponding to changes in cellular polarizability. This offers a novel technology for monitoring mammalian cells based on their dielectric properties. There are several potential applications of the device as a low-cost, label-free, electronic monitor of physiological changes in cells.
Michael Butler, Ph.D., Professor, Department of Microbiology, University of Manitoba
Networking Refreshment Break
Osmotic Stress Responses in CHO Cells Producing Recombinant Monoclonal Antibodies
CHO cells have become the preferred source of recombinant monoclonal antibodies in the pharmaceutical industry. The addition of concentrated feeds and base in fed-batch processes can lead to increases in osmolarity, altering cell physiology and placing limitations on viable cell density and culture duration. Here we investigate cellular responses to osmotic stress, particularly intracellular and extracellular metabolite profiles.
Matthew DeSieno, Ph.D., Post-Doctoral Fellow, Pfizer and University at Albany
Overcoming Barriers in Fed-Batch Processes that Require High Nutrient Supplementation
Fed-batch processes have become standard to reach both high viable cell density as well as high protein productivity. In this presentation we will discuss a novel technology to address two key issues associated with fed-batch process development: inability to concentrate particular components to avoid culture dilution and the resulting use of extreme pH if concentration can be achieved.
Robin Ng, Ph.D., Process Science Fellow, Life Technologies
CaseCedex Bio and Bio HT - The Benefit of Using Next Generation Cell Culture Analysis
Roche Cedex Bio HT systems are based on photometric and ISE technologies resulting in accurate, precise, and sensitive substrate and metabolite analysis. A previously unpublished independent case study was performed comparing Cedex Bio HT to Nova Bioprofile 400, YSI, and ForteBio Octet. CHO-S IgG and DG 44 EPO cell lines were used to compare 22 conditions, run in duplicate, over a 17 day fermentation cycle. Glutamine, glutamate, IgG, and ammonia parameters showed the most variance between Cedex Bio HT and other methods.
Presented by Roche
Concurrent Technology Workshops
Toolbox Strategies for a Diversity of MAbs
High-titer feed-stocks and an increasing demand for separation of MAb variants (aggregates, fragments, charge variants, etc.) call for chromatography resins with new features. The focus here is to develop strategies for post Protein A polishing of various MAb purification challenges. New polishing resins, both ion-exchange and multi-modal resins, with high resolution will be compared regarding binding/elution conditions and ability to separate MAbs from impurities. Depending on the level of impurities, different processes including one or two polishing steps will be proposed.
Mats Gruvegard, Bioprocess Project Leader, GE Healthcare Life Sciences
The Smart Way to Optimize Virus Filtration Steps
Current biomanufacturing processes have reached a high degree of standardization and companies are working on the basis of proven technology platforms. While this helps to set up new purification trains in short timeframes, virus clearance concepts still require a thorough optimization to address economic challenges and product related characteristics. The tool box is getting bigger with different membrane types and features, different pre - filtration methods as well as product conditioning. This presentation will focus on different ways to optimize virus filtration to end up with a most efficient step.
Anika Meyer, Product Manager Virus Clearance, Sartorius Stedim Biotech GmbH, Germany
Luncheon Presentation (Space is limited)
Next-Generation Clarisolve Technology for Clarification of Recombinant Proteins from High Cell Density Mammalian Cell Culture Systems
Increasingly high cell density, high product titer cell cultures containing mammalian cells are being used for the production of recombinant proteins. These high productivity cultures are placing a larger burden on traditional downstream clarification and purification operations due to higher product and impurity levels. EMD Millipore aims to address this challenge by developing a proprietary Clarisolve technology to improve primary and secondary direct depth filtration of pre-treated high cell density mammalian cell cultures. Novel filter media designs with a deep gradient-density to provide a wide span of pore sizes, tuned to couple with particle sizes created by polymer flocculation or low pH precipitation techniques, have resulted in single stage clarification process for pre-treated cell culture suspensions.
Nripen Singh. Ph.D., Research Scientist III, EMD Millipore
Jonathan Romero, Ph.D., Associate Director, Biogen Idec, Inc.
Susan Casnocha, Ph.D., Research Fellow, BioTherapeutics Pharmaceutical Sciences, Pfizer
Fast Identification of Reliable Hosts for Targeted Cell Line Development from a Limited-Genome Screening Using Combined φC31 Integrase and CRE-Lox Technologies
We present a non-viral based approach for quickly identifying target integration hosts from a limited-genome screening. These TI hosts are reliable in producing diverse antibodies regardless of antibody subclass or prior traditional CLD performance. Moreover, a ~2-fold increase in titer (~2g/L) can be achieved in non-optimized fed-batch shake flask production by employing a strategy with an exchange vector carrying 2 units of the antibody gene.
Yongping Crawford, Ph.D., Scientist, Early Stage Cell Culture, Genentech, Inc.
CaseAccelerating the Cell Line Development Timeline and Incorporating Cell Lines QbD
To support preclinical program timelines, we continuously optimize our workflow for generating and selecting high titer CHO clones. Recent modifications to our approach include implementing an improved process for selection and sorting of transfected pools, enhanced imaging documentation of cell line clonality in 96-well plates, and reducing the timeframes for pool selection and clone expansion. These changes resulted in higher titer clones being identified sooner; in some cases, clonal cell lines were selected as development candidates in as few as 15 weeks from transfection. Once the first tier of candidate clones has been selected, clone quality assessments are performed to help narrow down the list of suitable cell line candidates. This cell line QbD, which includes RNA integrity, expression stability prediction, and product quality, is implemented at small scale which reduces resources and cost by eliminating cell lines with undesirable characteristics early in the development timeline. Case studies of work flow optimization and cell line QbD will be presented.
Christine DeMaria, Ph.D., Associate Director, Therapeutic Protein Expression, Genzyme, a Sanofi Company
CaseSite Directed Targeted Integration
Lin Zhang, Ph.D., Associate Research Fellow, Global Biologics, Worldwide Pharmaceutical Sciences, Pfizer Inc.
Rohin Mhatre, Ph.D., Vice President, BioPharma Development, Biogen Idec
Producing High Quality, Low Cost Biotherapeutics in the Century of Biology
Over the last 30 years there have been substantial advancements in the manufacture of protein therapeutics. For example, product titers have been increased by more than four orders of magnitude using mammalian expression systems. Today we have the capability of producing metric tons of relatively low cost complex biologics; enough to meet the most demanding therapeutic markets. While some believe our advancements in this field are reaching a plateau, the century of biology will provide the knowledge and tools for even greater innovation for those willing to invest.
James Thomas, Ph.D., Vice President, Process and Product Development and WA Site Head, Amgen, Inc.
A Systems Approach to Managing Biomanufacturing Complexity - Genzyme's Allston Plant Case Study
Sandra Poole, Senior Vice President Biologics Operations, Genzyme
Transforming the Development of Biotechnology Drugs for the 21st Century: A CEO's Perspective from a Small Biotech Company
In these times of growing unmet medical need driven innovation in drug development is needed more than ever. Rapid translation of ideas into high value drugs that move rapidly from the bench to the bedside requires the perfect blending of science, medicine, policy and capital. While efficacy and safety will continue to be the key drivers of value, other factors driving healthcare impact, outcomes and cost will have to be more proactively integrated into drug discovery and drug development. The small biotech company will continue to be a critical component of the solution to these challenges.
Abbie Celniker, Ph.D., CEO, Eleven Biotherapeutic
Technology Workshop with Light Continental Breakfast
Implementing Disposable Chromatography: Technology Fit in Downstream Purification
While single-use and disposable technologies are prevalent in many areas within upstream and downstream processing, up until now there has not been a broadly applicable solution for chromatography steps. In this presentation, best practices for implementing pre-packed disposable columns in clinical manufacturing will evaluated, and a case study from a recent GMP manufacturing implementation will be presented.
Stephen Tingley, Vice President, Bioprocessing, RepliGen
Chairwoman's Opening Remarks
Kathie Fritchman, Scientific & Applications Manager, BD Biosciences-Advanced Bioprocessing
Consistency Through Control of Raw Materials and Media Optimization
CaseControlling Process Variability due to Raw Material Variability
Dave Kolwyck, M.S., MBA, Principal Scientist, Material Science, Amgen Inc.
CaseDetection of Vesivirus 2117 in Bovine Serum Using a Validated RT-PCR Limit Test
Animal-derived components such as bovine serum are potential sources of adventitious agents in biopharmaceutical manufacturing. Genzyme developed and validated an RT-PCR limit test for the detection of Vesivirus 2117 in bovine serum. This test was implemented as a Quality Control release assay for this raw material. Assay development, validation and transfer to Quality Control will be discussed.
Francis Poulin, Ph.D., Staff Scientist Analytical Development, Genzyme, A Sanofi Company
CaseA Scale Down Model to Test Raw Material Variability
During a tech transfer across sites at similar scale, an unusual drop in cell growth and viability was observed in the production stage, while the typical small scale model showed normal cell culture performance. After investigation, several raw materials were identified as leading suspects including the shear protectant. Following a switch in respective raw material lots, the culture performance returned to the expected range supporting the hypothesis. Subsequently, a specific scale down model was developed and tailored for raw material screening. Additionally, the mechanism causing underperformance was investigated in conjunction with the application of various analytical methods to study lot-to-lot variation.
Haofan (Eric) Peng, Senior Engineer I, Cell Culture development, Biogen Idec
CaseChemically Defined Media Optimization: Challenges and Solutions
In recent years, biopharmaceutical manufacturers have achieved significant improvements in performance and productivity through process and medium optimization. However, the optimization of a high performance CD medium is an arduous process involving the adjustment of numerous interacting components to their optimal levels based on cell and process specific requirements. Here, we present case studies addressing key challenges of CD media optimization.
James Brooks, Ph.D., R&D Manager, BD Biosciences-Advanced Bioprocessing
Methods and Strategies to Maximize Throughput of Higher Titer Processes and Culture Intensification
How to Introduce Perfusion into a Fed-Batch Manufacturing Environment
Bruno Figueroa, Ph.D., Senior Principal Scientist, Bioprocess R&D, Pfizer Inc.
CaseStrategies to Optimize a Perfusion Cell Culture Process for the Production of a Monoclonal Antibody
Hang Zhou, Ph.D., Process Engineer II, Commercial Cell Culture Development, Genzyme, A Sanofi Company
Perfusion of IgG Producing Chinese Hamster Ovary Cells by Alternating Tangential Flow Filter at Very High Cell Density
The increasing success of Alternating Tangential Flow (ATF) in industry has lately contributed to higher focus on perfusion technology. We reproducibly obtained cell densities larger than 100 x 1E6 cells/mL by ATF microfiltration or ATF ultrafiltration with a comparable cellular production. Using tangential flow filtration perfusion, allowed us to understand the impact of the cell density viscosity at very high density up to 200 x 1E6 cells/mL, contributing to hollow filter design.
Veronique Chotteau, Ph.D., Principal Investigator, KTH - Royal Institute of Technology, Sweden
Concurrent Technology Workshops
Efficient and Intelligent Process Control for Animal Cell Culture
With an increased focus on process efficiency and quality, once considered basic cell culture processes are under further scrutiny. The presentation will outline how improved process control, automation and smart sensors can maximize efficiency while increasing quality and repeatability. Once considered basic operations such as seed train and cell banking will be examined.
Richard Ferraro, Business Leader WAVE Products Group, GE Healthcare
Impact of Disposable Technology on the Bio-manufacturing Landscape
One of the key trends in bio-manufacturing is the move from the production of small molecule drugs to biologics and cellular therapies. In this environment, single-use technology platforms are a key enabler for increasing productivity and reducing costs. Here we discuss the benefits of disposable solutions, including novel scale-up vessels with specialized surfaces and custom media formulations.
Richard M. Eglen, Ph.D., Vice President & General Manager, Corning Life Sciences
Networking Luncheon in Poster and Exhibit Hall
Susan Dana Jones, Ph.D., Vice President and Senior Consultant, BioProcess Technology Consultants, Inc.
Implementing Flexible Manufacturing in Upstream Processing
CaseDisposable and Stainless Steel Hybrid Technique Used for the Implementation of a New Process
Fitting a broad variety of process formats in an existing multi-product facility and still being efficient is quite a challenge. When transferring a phase III product to a CMO for commercial manufacturing, comparability and timelines are critical, too. Combining disposables and stainless steel is one option to face these requirements. We will present a case study showing how this hybrid operating mode strategy was implemented by integrating disposables into an existing stainless steel facility.
Lars Dreesmann, Ph.D., Director, Upstream Manufacturing, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Developing a Robust Process Platform with Flexibility for Implementation at Multiple Manufacturing Sites
Susan Casnocha, Ph.D., Research Fellow, Bioprocess R&D, Culture Process Development, BioTherapeutics Pharmaceutical Sciences, Pfizer
CaseNovel Process Technologies - Producing More Product from Smaller Bioreactors
Sourav Kundu, Ph.D., Director, Biopharmaceutical Development, Teva Biophramaceutical USA
Joanne T. Beck, Ph.D., Vice President, Process Development, Shire Human Genetic Therapies
Biologics Manufacturing in a Rapidly Changing Environment
The environment for Biopharmaceutical manufacturing is rapidly changing. While the overall market is still growing rapidly, challenges in development coupled with increasing yields have resulted in significant overcapacity in manufacturing. At the same time disposable manufacturing approaches have made significant advances, while new biologics entering the market have seen slow adoption due to pricing/reimbursement issues and conservative prescribing by physicians. Dr. Moesta will discuss Bristol-Myers Squibb's portfolio of Biologics and the positioning of its manufacturing network in this dynamic environment.
Peter Moesta, Ph.D., Senior Vice President, Biologics Manufacturing & Process Development, Bristol-Myers Squibb Co.
Eliminating Interfaces: Process Development Lessons from Aggressive Platform Development
Platform approaches have yielded dramatic gains in speed and savings in the business of process development, most notably for antibody products. And it doesn't end there: increasingly we see platforms driving change in the organizational and scientific domain, up to and including a re-definition of the role of the process scientist itself. But how marry the core drivers of platform success - standardization and templating - with the needs of tomorrow's increasingly diverse pipelines?
Lars Pampel, Ph.D., Group Head, Early Phase Process Development, Novartis Pharma AG, Switzerland
Charles Sardonini, Ph.D., Associate Director, Process Engineering/Development, Genzyme, a Sanofi Company
Innovation at the Interface of Upstream and Downstream Processing
Integrated and Fully Continuous Processing of Recombinant Therapeutic Proteins
Our data reveal that an integrated fully continuous process results in a dramatic increase in the process throughput, decrease in the equipment footprint, elimination of several non-value added unit operations, elimination of hold steps and reduced the number of unit operations to minimum. These findings also demonstrate the potential of integrated fully continuous bioprocessing as a universal platform for the manufacture of various kinds of therapeutic proteins.
Veena Warikoo, Ph.D., Department Head, Purification Development, Late Stage Process Development, Genzyme, A Sanofi Company
CaseHead-to-Head Comparison of the Disc Stack and Fluidized Bed Centrifuges to Clarify a Biopharmaceutical Product
This presentation is a comparison of Disc Stack Centrifuge and Fluidized Bed Centrifuge technologies to clarify a biopharmaceutical product. The DSC and FBC will be evaluated based on harvest parameters such as clarification efficiency and product recovery, along with an analysis of the impact of each technology on cell health due to shear within the system. Cost and equipment turnaround are also compared.
Jason Condon, M.S., Scientist, Pharmaceutical Development & Manufacturing Sciences, Janssen Research & Development
CaseClarification of Recombinant Proteins from High Cell Density Mammalian Cell Cultures Systems using Disposable Technologies
To address the challenges of processing high cell density mammalian cell cultures systems from batch processes, disposable clarification technologies such as Depth filtration, Tangential flow filtration, and fluidized bed centrifugation are compared for harvesting of untreated and flocculated high cell density feeds. Results will highlight the benefits and limitations of these technologies both from a processing performance perspective and an operational and economical Cost model analysis. A framework will be presented for optimizing disposable clarification technology and cost during scale-up into a GMP setting.
Jonathan Romero, Ph.D., Associate Director, Global Manufacturing Engineering, Biogen Idec
CaseDevelopment of Novel and Efficient Cell Culture Flocculation Process Using a Stimulus Responsive Polymer to Streamline Antibody Purification Process
Kenneth Kang, Ph.D., Principal Scientist, Head of Purification Team, BioProcess Sciences, ImClone Systems, A wholly-owned subsidiary of Eli Lilly and Company
Beyond Antibodies - Production of New Modalities
Production of Homogeneous Best-In-Class Antibody Drug Conjugates by Cell-Free Protein Expression
Sutro has developed a robust, scalable and controllable cell-free protein synthesis platform for the efficient production of homogeneous therapeutic proteins, including full length IgGs and ADCs, bispecific antibodies, cystine-knot peptides and proteins. Many variants can be expressed in hours and rapidly assessed for function. Within days, production of chosen variants can be scaled using the same platform to generate material for GLP-tox studies and clinical studies. The platform brings speed to molecular design, process development and manufacture and could enable pre-clinical timelines to be reduced by 18-24 months from concept to clinic.
Trevor J. Hallum, Ph.D., Chief Scientific Officer, Sutro Biopharma, Inc.
The Challenges of Developing Processes for New Protein Formats
New protein formats often do not fit in established development platform processes. An integrated development approach from format selection to drug product stability is recommended to reduce timelines and costs of development.
Kurt Lang, Ph.D., Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Germany
Concurrent Technology Workshops
Downstream Applications for the Emphaze™ Hybrid Purifier
This session will focus on downstream applications for the Emphaze™ Hybrid Purifier , a new bioprocess purification platform that integrates anion exchange hydrogel chromatography and size exclusion membrane into a single-use, scalable device format.
Michael Wang, Ph.D., Advanced Technical Specialist, 3M Purification Inc.
ambr™: An Advanced Tool for Automated Optimization of Cell Culture for Biotherapeutics
Challenges in cell line development include: how to explore sufficient cell lines to identify clones with optimal protein expression; how to perform Design of Experiment (DoE) analyses with suitable power to identify relevant culture parameters; and how to explore more cell line candidates and culture conditions to enable better, faster decision making. This session is an overview of TAP Biosystems' advanced microbioreactor (ambr™) technology, with industry derived data that demonstrate ambr's suitability for cell culture optimization, in the context of biotherapeutics development.
Barney Zoro, Product Manager, TAP Biosystems, United Kingdom
Novel Protein A Affinity Chromatography Resin for Efficient mAb Purification Applications
Protein A affinity chromatography continues to be the workhorse in the purification of therapeutic monoclonal antibodies (mAb). The highly specific interaction between Protein A and an antibody's Fc region provides high product yield while also ensuring that more than 99% of impurities from clarified cell culture are removed. EMD Millipore introduces a novel Protein A chromatography resin that delivers high performance stability under extreme pH conditions. Additionally, this new resin is distinct from current commercially available Protein A resins in its unique ability to remove high molecular weight (HMW) species from a mAb feed. The added benefits of this new resin are delivered along with the high dynamic binding capacity and impurity removal capabilities expected from a modern Protein A resin.
Nanying Bian, Ph.D., EMD Millipore
Networking Luncheon and Last Chance for Exhibit and Poster Viewing in Poster and Exhibit Hall
Pranhitha Reddy, Ph.D., Director, Process Development, Seattle Genetics
Control of Process and Product Quality
CaseApplication of Multivariate Predictive Monitoring and Control of Cell Culture Processes
Tony Wang, M.S., Senior Engineer, Digital Development, Amgen Inc.
CaseDeveloping an Adaptive Manufacturing Process to Ensure Product Quality using QbD and PAT
As described in ICH Q8, product and process understanding, in combination with QRM, can be used to develop a manufacturing process so that variability can be compensated for in an adaptable manner to deliver consistent product quality. Using this approach, an alternative manufacturing paradigm was developed where the variability of a cell culture process was less tightly constrained, while PAT and an adaptive process step was included to ensure consistent product quality.
Jose M. Gomes, Principal Scientist, Culture Process Development, Pfizer Inc.
Use of Flow Cytometry for Prediction and/or Conformation of Instability in Cell Lines Expressing Recombinant Antibodies
One significant problem in the manufacturing of a therapeutic protein is the phenomenon of cell line instability where a cell line loses productivity during culture expansion to bioreactor production. This presentation will focus on the application of flow cytometry for predicting cell line instability early in the cell line development process for selection of the most stable manufacturing clones.
Susanne Corisdeo, M.S., Scientist, Biotechnology Center of Excellence, Janssen Research & Development, LLC
Networking Refreshment Break
Models for Perfusion and Fed Batch Processes
CaseMathematical Modeling of Perfusion Fermentation Processes and Impacts on Manufacturing and Downstream
Rick Johnston, Ph.D., Principal, Bioproduction Group, Executive Director, CELDI Center at University of California at Berkeley
CaseDevelopment of Qualified Scale-Down Models for Fed-Batch Processes
Small-scale models are used during both commercial process development and process characterization to facilitate scale-up and technology transfer of monoclonal antibody (MAb) manufacturing processes. In this work, we will discuss both the development and application of a production bioreactor small-scale model for a MAb process that exhibited variable process performance during clinical manufacturing. Small-scale model development included controlling cell age and raw materials, aligning the pH control strategy with clinical manufacturing, and aligning dissolved carbon dioxide profiles. Once the small scale model was qualified, it was used to identify process sensitivities to raw materials and for process characterization. The final result was a robust process characterization data package supporting process variability similar to that observed for other processes.
Sara Gall, M.S., Senior Associate Scientist, Amgen Inc.
CaseFrom Bioreactors to Shake Flasks to Mini-Bioreactors: Minimizing the Scale in Fed Batch Mammalian Cell Culture
Vijay Janakiraman, Ph.D., Senior Engineer II, Cell Culture Development, Biogen Idec
Close of BioProcess International™ Conference & Exhibition 2013