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PROGRAM CHAIRS:
Robert R. Boulanger, PhD - CRB
Jeffery N. Odum - NNE

Christoph Herwig, PhD
Head Biochemical Engineering, Technische Universität Wien
Multi-Parametric Control Strategies for Enabling Continuous Biomanufacturing

Abstract

The goal of bioprocessing is to optimize process variables, such as product quantity and quality in a reproducible, scalable, and transferable manner. However, bioprocesses are highly complex. A large number of process parameters and raw material attributes exist, which are highly interactive and may vary from batch to batch. Those interactions need to be understood, and the source of variance must be identified and controlled. Currently, mechanistic models, which are based on mechanistic links and first principles, are the focus of development. They are perceived to allow transferability and scalability because mechanistics can be extrapolated. Moreover, the models deliver a large range of hardly measureable states and physiological parameters. Furthermore, models need to be deployed in the control context: bioprocesses need to be controlled on the one hand by different parameters simultaneously (e.g. constant precursor concentration and specific growth rate), and on the other hand may have different objective functions (maximum productivity and correct product quality). Hence, novel solutions and case studies for multiple input and output controls need to be developed, as they already exist in other market segments. The presentation will display current solutions and case studies of mechanistic model development and its deployment for multi-parametric control of bioprocesses. The following elements, for example, will be covered:
• Workflows: how mechanistic models can be developed and calibrated in terms of identifiability, sensitivity, and observability
• Models as process analytical technology (PAT) tools: demonstrations of cases in which models are a solution to measure less
• Observer solutions for real-time parameter optimization
• Multiparametric control and event prediction

Biography

Christoph Herwig, bioprocess engineer, graduated from the process engineering department, RWTH Aachen University in 1994. He worked in industry in the design and commissioning of large chemical facilities prior to entering his interdisciplinary PhD studies at the Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland in the field of bioprocess identification. Subsequently he positioned himself at the interface between bioprocess development and design of biopharmaceutical facilities through his work at different companies from process development and engineering services to biopharmaceutical production. Since 2008, he has been a full professor of biochemical engineering at the Vienna University of Technology (TU Wien). His research area focuses on the development of methods for integrated, science-based, and efficient bioprocess development along PAT and QbD principles. The product fields are circular economy and biopharmaceuticals within industry-driven projects.

Gilad Langer, PhD
Director, Automation & MIS, NNE
Breaking Down the Walls – Integrated Process and
Automation Design with Concurrent Engineering

Abstract

Engineering and design of a pharmaceutical facility requires extensive collaboration and communication between many engineering disciplines. Yet in the pharma industry, it is still common practice to engineer and design in disciplinary silos. Compared to other industries, the pharma engineering practices are laggards from this perspective. Thirty years ago in the advent of the lean manufacturing movement, a similar observation brought about the concept of Concurrent Engineering. The observation was that performing engineering in silos where design was "tossed over the wall" between disciplines was inherently wasteful. Concurrent Engineering, sometimes also called Integrated Design, presents a method in which engineering activities are performed in parallel with simultaneous activities leading to a higher quality process design and a more effective engineering process. The benefits include the ability to achieve specific design goals such as flexibility, configurability for multi-product processes, discovering errors and redesigns early, integrated quality, more effective qualification, and much more. We are addressing a specific issue within our industry in which we are lagging behind. Concurrent Engineering practices have been around for over 30 years and yet we still have a practice of engineering in silos. We need to find a way to capitalize on the benefits of this well proven concept and make it the mainstream way to engineer and design facilities and processes starting with concurrently engineering the process and automation systems.

Biography

Dr. Gilad Langer is an accomplished business leader with broad technical knowledge and strategic perspective in the manufacturing systems domain. His experience spans over 25 years in different roles in complex engineering projects including project management, implementation, team building, strategy development, research, and support of mission critical operations. His experience spans a multitude of domains in the biopharmaceutical, pharmaceutical, life sciences, automotive and semi-conductor industries, including: manufacturing business systems (i.e. manufacturing execution systems [MES], manufacturing intelligence [MI/EMI], quality management systems [QMS], etc.) and interoperability with both automation and enterprise systems; all aspects of engineering and integration services operations, strategy, management and sales; as well as industrial and academic research by way of a doctorate degree focused on adopting the characteristics of social systems in software architectures for manufacturing systems. Specialties include manufacturing systems, MES, QMS, MI, manufacturing quality, lean manufacturing, manufacturing operation, software modeling, software development, product strategy, product management, product marketing, business analysis, strategic planning, business intelligence, business process interoperability, pragmatic marketing, agile management, and team building.

Yaling Shi, PhD
Senior Manager, Emerging Technology, Lonza Walkersville, Inc.
Automated Manufacturing Solutions for Patient-Scale Therapies

Abstract

Cell therapies have been in clinical development to attempt to treat an array of human diseases. Researchers around the globe are evaluating the effectiveness of cell therapy as a form of replacement or regeneration of cells for the treatment of numerous organ diseases or injuries. However, the current manufacturing costs of these therapies are too labor intensive and expensive. The commercialization of cell therapy processes will thus require automated and closed manufacturing processes which are cost effective, robust, and efficient. Octane Cocoon is an integrated manufacturing solution for all patient-scale therapies (Precision Medicine) in an automated, scalable, and closed system. Cocoon can not only be used for suspension cells such as CAR T-cells, but also for adherent cells such as mesenchymal stem cells (MSCs) and chondrocytes. This presentation will highlight both the CAR T and MSC process using Cocoon to maximize final product yield. We will also identify common bottlenecks and challenges in automated cell therapy design and explore potential solutions for the optimization of cell-based products.

Biography

Dr. Shi leads autologous cell therapy platform development at Lonza. She has a proven track record of developing cell-based technologies from concept, to scale-up, to commercialization, and through sales and marketing. She has commercialized two cellular products AlloStem® (a stem-cell based bone growth substitute for spinal fusion, non-union, and foot and ankle, etc.) and ProChondrix® (a chondrocytes-based live cartilage product).

William G. Whitford
Strategic Solutions Leader, BioProcess, Life Sciences, GE Healthcare
Developments in Digital Biomanufacturing

Abstract

The concept of digital biomanufacturing (DB) is changing the way we view biopharmaceutical manufacturing. Keys to this initiative include increased monitoring, connectivity, information integration, computing power, control algorithms, and automation. DB is part of an evolution: one further step in the application of such technologies as multiplexed reactor monitoring, industrial internet of things (IIoT), and cloud computing. Powerful algorithms employ disparate data from new sensors and at-line analytics, along with such other high value information as process history records, to better understand the current state of operations and provide advanced model-based process control. More than instruments becoming interconnected, DB denotes high levels of data analysis, information management, and dynamic simulation in a “process network”. Such initiatives support the implementation of such new manufacturing modes as continuous biomanufacturing and such new products as targeted exosomes. By this, manufacturers gain actionable intelligence, transformative insights, and more effective plant control. Supported by DB, EMS designs will move beyond highly automated to become nearly autonomous sources of centralized integrated control of the distributed pools of metadata in such arenas as supply chain, manufacturing process control, and customer relationship management.

Biography

Bill Whitford is the Strategic Solutions Leader at GE Healthcare in Logan, Utah with over 20 years' experience in biotechnology product and process development. He joined the company as an R&D leader developing products supporting protein, biological, and vaccine production in mammalian and invertebrate cell lines. Products he has commercialized include defined hybridoma and perfusion cell culture media, fed-batch supplements, and aqueous lipid dispersions. An invited lecturer at international conferences, Bill has published over 250 articles, book chapters, and patents in the bioproduction arena. He now enjoys such activities as serving on the Editorial Advisory Board for Bioprocess International and the European Medical Journal.

Marissa Nasshan
Director, Business Development US, Ovizio Imaging Systems NV/SA
In-Line, Automated Monitoring with Viral Detection, A Case Study

Abstract

Finding process analytical technology (PAT) solutions for in-line and automated cell culture monitoring during infection processes is now acheivable with the iLine F Monitoring System. In 2017, we conducted several experiments that resulted in viral load detection, offering an accurate read-out and percentage of infected cells alongside viability and density measurements. Pushing our proprietary software to new depths by recording 74 cellular parameters, we can now add viral detection and visualization of protein expression to the growing list of measured data.

Biography

Marissa Nasshan joined the Ovizio team in 2016. As the Director of Business Development, Marissa is the permanent presence and first point of contact to expand the Ovizio brand and line of products in the US. Marissa received a Bachelor’s and Master’s Degree in Cell and Molecular Biology from Central Connecticut State University. She gained six years of experience working for a company specializing in vaccine development and protein production, first as a Research Scientist in Upstream Process Development Cell Culture, and later as Manager of Commercial Operations. She then became Director of Operations for a privately held government research startup firm before joining Ovizio. Other experiences include molecular imaging, bioprocessing, commercialization, manufacturing, and marketing and sales. Outside of work Marissa is a Board Member for a non-profit organization that empowers young women to enter into professions in STEM.

Ravi Shankar
Life Science Industry Manager, Endress+Hauser Inc.
Continuous Process Verification — Asset Health and Performance

Abstract

Critical processes in the pharmaceutical and biosciences industries often require frequent calibration of temperature instrumentation to insure proper sterilization has occurred and there is no risk of cross contamination. In most cases the calibration cycle is a statistical calculation based upon the risk of excessive drift of the sensor occurring based upon an evaluation of risk vs. downtime, lost production, and the expense of conducting manual calibration. Recent developments in instrumentation simplify and promote greater calibration process efficiency, reduce the risk and need for frequent, unnecessary calibrations, and provide better reliability. This presentation will explore asset health and performance monitoring that gives reliable data on process impact factors related to corrosion, coating or build up, and entrained gas and present metrology-based techniques to verify measurement quality by a traceable and attested means.

Biography

Ravi Shankar is the Life Sciences Industry Manager at Endress+Hauser USA in Greenwood, Indiana. Based in the San Francisco Bay area, he joined Endress+Hauser in May 2011. He has worked with process instrumentation for 21 years and been associated with the life sciences industry for the last 13 years in various roles. He is also active with the ASME BPE subcommittee on process instrumentation as a member in developing guidelines for the industry. He holds a BE in instrumentation technology from Bangalore University, India. His interests include smart instrumentation and single use sensors and systems.

Mark F. Witcher, PhD
Senior Specialist, Process Operations,
Strategic Manufacturing Concept Group (SMCG), NNE
Developing Control Strategies for Maintaining Cleanroom Environments by Using
a System Risk Structure (SRS) for a Quality Risk Management (QRM) Analysis

Abstract

Controlling cleanroom contamination risks remains a challenge for designing and operating manufacturing areas. This presentation describes how these risks can be described, evaluated, and controlled by an SME (subject matter expert) team performing a quality risk management (QRM) analysis using a system risk structure (SRS). The SRS approach will be presented in more detail at a prior workshop at the conference and was recently published in Bioprocessing Journal. The SRS approach assists the SME team with designing an appropriate operating space that meets the environmental needs of the process such that contamination risks are appropriately evaluated, controlled, and accepted. The appropriate environmental control strategies for the specific situation being considered depend on identifying and evaluating both the risk threats and process design elements using the SRS. Some of the process design elements include: single pass air, air flow characteristics, equipment types including closed disposable systems, types of process unit operations, organism being used in the area, personnel factors, and a variety of other environmental and operational considerations. The SRS provides a mechanism for identifying and describing the uncertainty of the various threats and how they can be controlled to an acceptable level using the process design factors based on the SME team’s experience and judgement.

Biography

Mark is a Sr. Specialist, Process Operation in NNE’s Strategic Manufacturing Concept Group in Durham, North Carolina. Prior to joining NNE, he worked on feasibility and conceptual design studies for advanced biopharmaceutical manufacturing facilities. Prior to working for engineering companies, Mark was an independent consultant in the biopharmaceutical industry for 15 years on operational issues related to: process development, product development, strategic business development, clinical and commercial manufacturing planning, tech transfer, and facility design and construction. For many years, he taught courses on process validation for the International Society for Pharmaceutical Engineering (ISPE). He was previously the Sr. Vice President, Manufacturing Operations for a contract manufacturing organization (CMO), Covance Biotechnology Services (formerly Corning Bio, Inc.). At Covance, he was responsible for the design, construction, start-up, and operation of Covance's $50 MM contract manufacturing facility. Prior to joining Covance in 1995, he was Vice President of Manufacturing for Amgen, Inc. Mark was with Amgen for nine years and held positions as Engineering Manager, Plant Manager, and Director of EPOGEN® Manufacturing. Mark received his PhD in Chemical Engineering from the University of Massachusetts.

Sheldon E. Broedel Jr., PhD
Chief Executive and Science Officer, Athena Environmental Sciences, Inc.
Counter-Current Chromatography and Its Use in Bioprocessing

Abstract

Multi-column chromatography systems permit the development of continuous purification schemes that are more efficient than batch chromatography. Counter-current simulated moving bed techniques in capture steps using high concentration feed streams and high capacity resins have resulted in 30% to 60% reductions in operating and resin costs. Counter-current chromatography can also be applied to more challenging separations in the polishing steps. Three such techniques, multi-column solvent gradient purification (MCSGP), integrated batch chromatography (IBC) and N-Rich, when applied to a twin column system, have been shown to yield recovery and purity of >95%. MCSGP is designed to increase the resolution of separations without sacrificing yield. In traditional single column chromatography with complex feeds, only a portion of the product is collected corresponding to the purest portion of the chromatograph peak. Impure side fractions containing product are discarded as purity is chosen at the expense of yield. With MCSGP, the step recoveries are increased by recycling the overlapping contaminated fractions. IBC performs sequential chromatographic separations without the need for collecting and reserving intermediate fractions. Cycling of the process steps automates the separation, reduces resin usage, increases process efficiency and permits semi-continuous production. Combining a simulated moving bed (SMB) capture step, such as CaptureSMB®, with an SMB polishing step permits the design of a continuous manufacturing process. In one iteration, the effluent from a perfusion cell culture system producing a Mab was fed continuously to a protein A capture step followed by polishing on a cation and anion exchange. Stable production of Mab was achieved over 25 days.

Biography

Dr. Broedel is a founder of Athena Environmental Sciences, Inc. and has served as CEO/CSO since the company’s inception in 1994. He also holds a position as the Associate Graduate Program Director and Adjunct Professor for the Master’s of Professional Studies (MPS) in Biotechnology at University of Maryland, Baltimore County (UMBC) and an Adjunct Professor with the Department of Microbiology and Immunology at Georgetown University School of Medicine. Dr. Broedel has served on several boards including as founding Chairman of the science advisory board for the College of Natural and Mathematical Sciences at UMBC (2007–2009), board member of the science advisory board to Stevenson University (2009–present), advisory board member of the MPS in Biotechnology Program UMBC (2007–present), and on scientific advisory boards for Applied Cell Sciences, Inc. (2007–2009), Plasmonix (2014–2016), and GlycoPure (2016–present). Dr. Broedel received his doctoral and master's degrees from UMBC in Microbial and Molecular Genetics and his BS degree in Biology from the State University of New York at Geneseo. He has 30 years of industrial experience, which included positions with Martin Marietta Laboratories, Dorlin Pharmaceuticals, Inc. (formerly ChekTec Corporation), and Athena Environmental Sciences, Inc. as well as eight years of post-graduate academic research experience. In 2005, Dr. Broedel received UMBC’s Outstanding Alumni of the Year Award. Dr. Broedel has a diverse range of scientific publications, holds several issued patents, and has designed, reduced to practice, and launched more than 160 products ranging from life science research tools to consumer products. He and his development teams have received eleven Small Business Innovation Research (SBIR) grant awards for their work with infectious diseases, bioprocessing, and diagnostic tests. His technical expertise and experience includes microbiology, genetics, molecular biology, immunochemistry, biochemistry and enzymology, drug discovery and high throughput screening, fermentation and process development, and GLP/GMP manufacturing of biologics.

Simon J. Saxby
Chief Executive Officer, Stratophase Ltd.
Adaptive Process Control Techniques for Next Generation Biologics
and Biomanufacturing of the Future

Abstract

Biologics are becoming increasingly complex in terms of therapeutic properties and the conditions required to manufacture them. The diversifying pipelines within the biologics industry present a significant challenge during process development through into biomanufacturing. A game-changing solution to such challenges is the adoption of adaptive process control techniques, enabled by big data approaches to process characterization and next generation real-time monitoring and control technologies. Adaptive process control techniques enable processes to be dynamically tracked, and the process parameters required to maintain the quality of the process and product adjusted in real time. The ability to adapt to, and compensate for, in-process variation is of particular benefit to cell culture processes where subtle differences in the environment can have a profound effect on product yield and quality, both in terms of a single batch but also with respect to batch-to-batch consistency. Adaptive process control will also be essential for continuous manufacturing processes to become a reality in biomanufacturing. A review of the techniques and technologies being applied to adaptive process control will cover the application of ‘big data’ and real-time monitoring approaches, including; statistical techniques such as Design of Experiments (DOE) and Multivariate Data Analysis (MVA) used to generate greater process understanding during process development and into manufacturing; real-time monitoring techniques used to implement novel control strategies such as Raman spectroscopy, soft-sensors, and probing control. A number of case studies will be presented showing adaptive process control being applied to rapid cell culture optimization during process development, and dynamic feeding control for enabling complex and multi-component feeding strategies during upstream biomanufacturing. The emergence of adaptive process control techniques has the potential to minimise process development timelines and increase process robustness during manufacturing. These advanced control strategies are expected to have a profound impact on the manufacture of next generation biologics and are potentially enabling for the advanced therapies industry.

Biography

Simon Saxby is the Chief Executive Officer of Stratophase Ltd and has over thirty years' global international experience in life sciences, including CEO roles in both public and private companies, and over 25 years of board experience. Simon’s international experience includes five years in the United States and over four years in Malaysia. Prior to his role at Stratophase, Simon was the Project Director for the design and build of the UK government’s 7,200 m2 Cell and Gene Therapy Catapult commercial scale GMP Manufacturing Centre in Stevenage. His educational background includes Savio College in Cape Town, South Africa, William Ellis Grammar School in London, and Swansea University in the UK, earning a 2:1 BSc (Honors) in Zoology. He has also served as visiting lecturer in Industrial Biotechnology at Vienna Medical and Technical University, visiting lecturer to the Masters in Biotechnology Enterprise (MBE) programme at Cambridge University, and as a course student advisor at Boston University Questrom School of Business.

Aditya Bhat, PhD
Director of Technology, Aber Instruments Ltd.
Monitoring and Controlling Viable Biomass in Bioprocesses
Using Dielectric Spectroscopy for PAT Control

Abstract

The radio frequency impedance method for real time detection of viable biomass, typically also known as capacitance measurement, is established in biopharmaceutical applications. This method provides real time information on live biomass and is not only used extensively to monitor bioprocesses, but also to control critical events during the culture. The presentation will aim to cover the principle behind the trusted capacitance technology, the need for this technology today in view of the PAT initiative, and interesting applications of capacitance measurement with different end goals across processes, making it a robust PAT tool. Sophisticated multifrequency scanning measurements, models, and their benefits will also be discussed.

Biography

Dr. Bhat has been associated with dielectric spectroscopy in bioprocesses for over 10 years. He started his journey with Aber Instruments as a Research Scientist. He now heads Aber's US subsidiary Aber Instruments Inc as Director of Technology. He is widely seen as an expert in Aber's products and technology, and has written several publications for Aber around dielectric spectroscopy for various applications. The experience of having travelled around the world visiting premier sites using Aber technology has put him in a unique position to observe and influence the direction in which the technology goes forward.

Marc Pelletier, PhD
Director of Process Technology, CRB
Importance of Facility Fitness in Aging Facilities

Abstract

The biopharmaceutical industry is currently evaluating future and flexible facility concepts, closed bioprocessing, single-use systems, plug and play drug manufacturing, etc. It may also be time to look back at our traditional stainless steel factories. These aging facilities have been the workhorse of the industry for large-scale manufacturing for decades. Are these facilities ready to face the next few decades in an efficient and cost-effective way? Many cost of goods studies have shown that stainless steel facilities can be the better low cost option in the long term. However system failures resulting in production interruptions can be extremely costly and may even result in drug supply issues. A proactive approach is required to ensure the drug manufacturing facility is operating in its validated state and that it will manufacture the desired product in an uninterrupted and repeatable and reproducible fashion. Evaluating, monitoring, and maintaining a Fit Facility is key to a successful operation.

This presentation looks at the fundamentals in good bioprocessing equipment design that conforms to the ASME BPE Standard and offers suggestions for how one may evaluate an existing facility and equipment for its ability to perform in the way it was intended. Design features within new and traditional facilities will be presented in graphic fashion, highlighting basic design flaws that are currently in evidence in many biopharmaceutical facilities. These flaws will result in system and operational failures if they are not rectified in a timely way. The Fit Facility is a state that must be achieved, maintained, and validated. This presentation is designed to be interactive, provoking biopharmaceutical manufacturers to re-evaluate their operations and to share their opinions.

Biography

Marc is Director of Process Technology at CRB. His roles include strategic planning, conceptual design, process engineering, risk assessments, compliance, and validation for the life technologies sector. He has been with CRB for 11 years of his 30+ year career in biotech. Marc was the former Vice Chair of the American Society of Mechanical Engineers BioProcessing Equipment (ASME BPE). He is also the author of the Closed Processing and Risk Assessment chapters of the new ISPE Baseline Guideline on Biopharmaceutical Manufacturing Facilities. He is a contributor on the BPOG Room (de)Classification Team. Marc has served as adjunct professor at the University of Manitoba, Canada and Bemidji State University, Minnesota. He is a frequent lecturer for ASME, IBC, ISPE, and now ISBioTech.

Sebastijan Peljhan, PhD
Head of Process Analytics Development, BIA Separations
Process Analytics for Gene Therapy Vector Production

Abstract

Process analytical technology (PAT) is a useful instrument to design, control, and analyse manufacturing processes through measurement of critical process parameters. Compared to traditional chemical and pharmaceutical industries, where PAT has been used for decades to ensure process reproducibility, implementation of PAT in biopharmaceutical manufacturing is much more challenging due to the complexity of biomolecules and batch to batch variability resulting from slight process variations during production. Methods able to provide nearly real-time data about the production process are highly desired for efficient process monitoring. Since traditional biological assays for analytics of biopharmaceuticals are usually labour intensive and time consuming, chromatographic analytical methods are an excellent alternative due to their speed, accuracy, and reliability. HPLC columns that would be able to handle samples from different feed streams and determine the amount of the target molecule and impurity profile in nearly real time should be highly efficient and selective for large biomolecules and nanoparticles.

High complexity of the samples also reflects in complex chromatograms what makes their analysis particularly challenging. Modern computational algorithms enable us to overcome the obstacles of analysing complex sets of data efficiently and enable us to extract the patterns which are intricately masked in the abundance of chromatographic fingerprints. In this presentation, examples of fingerprint analysis by utilizing inCyght software on simple and complex examples of adeno-associated virus, lentivirus, and flu virus will be presented.

Biography

Dr. Sebastijan Peljhan completed his PhD in theoretical physical chemistry at University of Ljubljana, Faculty of Chemistry and Chemical Technology and Jožef Stefan Institute, Ljubljana, Slovenia in 2012. In the same year he joined the application department of BIA Separations where he was in charge of downstream processes and analytical method development of biomolecules on monolithic chromatographic supports. Currently, his main focus is development of process analytical technologies supported by advanced data manipulation used in upstream and downstream biotechnological processes. He is currently head of process analytics development at BIA Separations.

Matthew T. McRae
Biotechnology Product Line Manager, Nova Biomedical
Rapid Process Development for a Miniature-Scale Culture System
Tod Canty
Engineer, JM Canty, Inc.
Novel Process Analytical Technology (PAT) Applications
Using Advanced Imaging Technology


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