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Analytical Challenges for Gene Therapy

Presented by Clare Blue and Dr Saba Hussein

One of the biggest challenges for AAV gene therapy products is establishing an appropriate analytical strategy to support product manufacture, release, stability, comparability and characterization at different stages of development. This presentation will highlight some of the existing analytical challenges and provide guidance on development of an appropriate strategy to help overcome these.
Recorded Nov 3 2020 74 mins
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Presented by
Clare Blue at Biogen and Saba Hussein at Vironova
Presentation preview: Analytical Challenges for Gene Therapy
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  • Raw Material Sourcing and Qualification Recorded: Nov 23 2020 65 mins
    Scott R. Burger, MD, Principal of Advanced Cell & Gene Therapy, LLC
    Effective raw materials sourcing, testing, qualification and control are critical for product safety and quality to assure lot-to-lot consistency and functional activity in the manufacturing process. This is more challenging for biological raw materials, such as enzymes, sera, and cytokines, which often cannot be fully defined by testing, and may present risks related to animal or human source, or country of origin. These points can be addressed by sourcing and qualifying materials based on an evaluation of potential risk and desired functional characteristics, and defining supplier requirements, testing, specifications, and other control mechanisms accordingly. Raw material qualification becomes increasingly rigorous and comprehensive as clinical development progresses. This webinar will identify critical concerns, clarify regulatory requirements and outline how to develop robust systems for managing and qualifying raw materials.
  • In Depth Characterization with Mass Spectrometry and Orthogonal Methods of... Recorded: Nov 18 2020 33 mins
    Bruno Genet, Lab head Structural Analysis MS at Sanofi
    Full Title: In Depth Characterization with Mass Spectrometry and Orthogonal Methods of Conformers in a Trispecific HIV Antibody

    Presented by Bruno Genet, Lab head Structural Analysis MS at Sanofi

    The initial characterization of a trispecific anti-HIV antibody lead to an aberrant two-peaks size exclusion chromatography profile. In such case, a column interaction is suspected, but a possibility of actually having conformers was taken into consideration. We have used both analytical characterization, structural analysis and molecular dynamics to cross all the informations. The mass spectrometry toolbox has been largely used with native and denaturing MS, ion mobility and direct infusion to carefully study both the antibody and the antigens interactions.
  • Real Time Monitoring of Bioprocess and Beyond – A Process Analytical Perspective Recorded: Nov 16 2020 107 mins
    Dhanuka Wasalathanthri, And Julia Ding at Bristol Myers Squibb & Eric Carlson, Ph.D., President & CEO, Protein Metrics
    Presented by Dhanuka Wasalathanthri & Julia Ding at Bristol Myers Squibb

    A significant attention and interests have been granted towards developing an analytical paradigm with unprecedented capabilities of real time monitoring of process in biopharmaceutical development space in the past decade. The core requirement for real time analytics involves Process Analytical Technology (PAT), a system for designing, analyzing, and controlling manufacturing through real time monitoring of critical quality and performance attributes to ensure the final product quality. Regulatory agencies including U.S. Food and Drug Administration endorse the utility of PAT, and embrace the integration of novel analytical technologies for process monitoring. Our PAT landscape for process monitoring during biologics development features broad spectrum of technologies including chromatography, spectroscopy & chemometrics, sensors and mass spectrometry for inline and online analysis by integrating into upstream and downstream unit operations through automated aseptic sample preparation or proprietary flow cell sensors for real time acquisition of analytical data. The roadmap for successful implementation of PAT tools entails strategic identification of critical quality attributes, and critical control points of the bioprocess for efficient and smarter development with reliable understanding of the capabilities and limitations of the analytical technologies. Our vision includes the integration of automated-data processing, visualization, and feedback control capabilities for seamless process control. Mechanistic modeling, machine learning and deep learning techniques are utilized to deep-dive in to the analytical data, prediction and for more holistic understanding of the process. Accurate process understanding and control will enable the development of the process through quality by design (QbD) for more sustainable manufacturing of biopharmaceuticals.
  • Think Big, Start Small - Capability Implementation on the Path to Smart Manuf... Recorded: Nov 13 2020 118 mins
    Robert Guenard, at Biogen, Petter Moree, at OSIsoft,Mark Demesmaeker at Sartorius Stedim Data Analytics
    Full Title: Think Big, Start Small - Capability Implementation on the Path to Smart Manufacturing within Industry 4.0

    Over the years there have been many frames of reference on the use of process analytical technology including monitoring, closed loop control, quality control/real time release, advanced process control, quality by design, Industry 4.0, etc. With each evolution of framing, the context we view process analysis of manufacturing processes is trending towards expanded scope and context from unit operation, to production train and plant level up through manufacturing network, supply chain and value chain to customer. In this talk we will present how we at Biogen are applying technology capabilities on a pathway towards realization of Smart Manufacturing by keeping the greater context in mind and delivering value added process analytics capabilities.
  • Smart machine learning solution to master industry 4.0 in biopharma Recorded: Nov 11 2020 42 mins
    Moritz von Stosch, PhD
    In the biopharmaceutical industry the utilization of miniaturized and parallelized high throughput techniques, continuous bioprocessing and continuous data acquisition as well as the utilization of data- and knowledge-driven tools for process analysis, forecasting, monitoring, control and digital twin creation are now becoming more common. In order to eventually enter fully in the industry 4.0 era, these methodologies and technologies must be further developed so that they can be fully rolled-out across the biopharmaceutical process industry.

    Throughout the past years, several digital solutions for the analysis, modelling and interpretation of cell culture processes based on advanced engineering statistics, hybrid modelling approaches and advanced spectral data processing methods have emerged. We show how they can successfully be integrated into upstream and downstream process development workflows in several collaboration projects with the biopharmaceutical industry. Based on these industrial collaborations we will share our insights into central challenges in digitalization and data analytics in biopharma. We will demonstrate the potential to provide systematically technological and business value through integration of smart technologies as digital twins into the work stream of upstream and downstream development and tech transfer.
  • Designer Sterile Filtration in Aseptic Processing Using Single Use Technology Recorded: Nov 10 2020 94 mins
    Alan Kelly, Project Engineer at Sanofi and Terri Love, Senior BioManufacturing at Merck
    Alan Kelly is a Project Engineer who has been employed within the pharma/biopharma industry in Ireland for the past 25 years and is currently in his 18th year at Sanofi Waterford. Previous employers include Leo Pharma and Elan. During his current tenure at Sanofi Alan has held several engineering roles, including Project Lead on two high speed aseptic vial-filling isolator technology lines integrated with industrial scale freeze dryers and as Process Engineering Manager during start-up of fill finish. Alan has worked in the Technical Services Department at Sanofi responsible for technical expertise input into front-end studies for new aseptic filling lines with isolator technology. In his most recent role in MSAT, Alan is responsible for next generation product transfers, identifying innovative technology including: real time microbial monitoring, drone vial studies to assess aseptic filling line set-ups and multi-purpose PAT technology for detection of trace silicone oil, leak detection and primary/secondary drying functionality for freeze dryers. Alan has successfully led cross functional teams in the qualification of high speed automatic visual inspection technology for cartridges and manual visual inspection of syringes. Alan has presented at international conferences including ISPE (Case study on VHP Cycle Development and Qualification of large scale aseptic Filling Isolator technology, European Compliance Agency (ECA) on “Case study on Manual Visual Inspection of syringes”, Alan is an active member of PDA Ireland Chapter and lead organiser for recent events including Annex 1 Conference (Revision of the EU GMP Guideline) May 2019 and Advances in Aseptic Processing with a focus on Media Fill simulations Oct 2018
  • Innovation in Biomanufacturing Plants Recorded: Nov 10 2020 91 mins
    Hang Zhou, Ph.D., Vice President at WuXi Biologics and Earl Pineda, Senior Manager, Field Applications, at Repligen, Europe
    Presented by Hang Zhou, Ph.D., Vice President, Head of Cell Culture Process Development Biologics and Bioprocess Dept. at WuXi Biologics

    Biopharmaceutical plants will look different in the future. Agility and flexibility for rapidly changing product portfolios, single-use technologies, continuous manufacturing, small batch manufacturing, personalised medicine manufacturing will not only change the face of a plant but will also require other logistics models. Chris will explain WuXi Biologics’ approach to biological facilities of the future.
  • Next Generation Manufacturing at Biogen – PAT as an Enabler for Enhanced Process Recorded: Nov 6 2020 121 mins
    Oliver Steinhof PAT Scientist at Biogen and Martin Gadsby Owner, Optimal Industrial Automation LTD
    Biogen is among the first biopharmaceutical companies to employ PAT in an active role in manufacturing of biologicals. The implementation of in-process Raman for glucose control, biocapacitance for in-line cell growth monitoring as well as in-line refractive index and other univariate techniques for automatic in-line release of process solutions is being discussed. GMP-specific considerations such as risk assessment, data integrity and qualification strategy are presented as well.

    The application of PAT in an active role as part of the control strategy in commercial production in a cGMP compliant environment is not yet done very frequently in the biopharmaceutical industry. This is due to a combination of risk factors which typically involve regulatory challenges, technology maturity and economic benefit. Biogen decided to employ PAT at large scale mammalian cell culture at its new manufacturing site at Solothurn, Switzerland. Biogen’s Aducanumab process has shown to benefit significantly from direct PAT control. Inline Raman spectroscopy and inline biocapacitance are used to actively control feed of glucose and nutrients to the production bioreactor. The glucose concentration is predicted using a validated PLS model and is used as input for a closed loop control device that is controlling the addition of glucose solution to the bioreactor in a virtually continuous manner
  • Case Study: Biomanufacturing for Tomorrow Recorded: Nov 5 2020 52 mins
    Marc Pompiati, Principal Scientist at Roche Diagnostics GmbH
    ·Gain insight of a combined USP/DSP line (SUB + 1. column) using disposables and automated systems, and a connected process

    ·Uncover the link from early research to phase I to market manufacturing

    ·Understand why it is essential to address BM4T in early research and development
  • Analytical Challenges for Gene Therapy Recorded: Nov 3 2020 74 mins
    Clare Blue at Biogen and Saba Hussein at Vironova
    Presented by Clare Blue and Dr Saba Hussein

    One of the biggest challenges for AAV gene therapy products is establishing an appropriate analytical strategy to support product manufacture, release, stability, comparability and characterization at different stages of development. This presentation will highlight some of the existing analytical challenges and provide guidance on development of an appropriate strategy to help overcome these.
  • Moving the Implementation of Digital Technologies in Pharmaceutical Manufactu.. Recorded: Oct 30 2020 109 mins
    Thomas O’Connor, Scientist at FDA, Mark Demesmaeker and Chris McCready at Sartorius
    Full Title: Moving the Implementation of Digital Technologies in Pharmaceutical Manufacturing Forward

    Presented by Thomas O’Connor, Scientist at FDA

    Industry 4.0 encompasses a wide range of technologies including industrial internet of things (IIOT), artificial intelligence (AI), and digital twins that have the potential to significantly increase the efficiency and robustness of pharmaceutical manufacturing. The implementation of Industry 4.0 technologies within the context of pharmaceutical manufacturing especially for applications that impact the control of the process or quality decision making may be subject to additional uncertainty in determining how the technologies fits within existing regulatory approaches. The presentation will describe FDA’s manufacturing science research programs that aim to proactively address such regulatory uncertainties. Case studies on the application of digital twins and advanced process control will be highlighted.
  • Next Generation Bioprocess Facility Design - A Case Study From Samsung Biologics Recorded: Oct 26 2020 97 mins
    Ken Green, Ph.D, Science and Technology at Samsung Biologics. John Bonham-Carter. Product Line Leader, Repligen
    A case study be presented describing initiatives and bioprocessing approaches to maximize capacity utilization within a new large scale (12x 15kL) drug substance biologics manufacturing facility at Samsung Biologics. Facility design, manufacturing and validation strategies utilizing two harvest and purification suites with regards to cadence and product changeover (PCO) will be discussed and an overview of Samsung’s experience with advanced technologies, including (N-1) perfusion, application of single use technologies will be presented. The webinar will also describe how activities are coordinated to ensure successful tech transfers to support clinical and commercial programs, including facility fit and gap assessments to ensure manufacturing processes are adequately transferred to support successful cGMP manufacture of biologics. The webinar will highlight initiatives and working practices at Samsung Biologics to ensure our biologic manufacturing operations are cost effective, flexible and responsive to the needs and demands of our clients and can adapt to a rapidly to accommodate a diverse pipeline of antibody biotherapeutics.
  • Mapping of PAT Tools for Enabling Integrated DSP in Continuous Biomanufacturing Recorded: Oct 23 2020 86 mins
    Dejan Arzenšek, Principal Scientist at Novartis and Maryann Cuellar, Life Science Product Manager at Kaiser Optical Systems,
    Presented by Dejan Arzenšek, Principal Scientist at Novartis
    Followed by an industry perspective presented by Maryann Cuellar, Life Science Product Manager at Kaiser Optical Systems, Inc.

    The discussion will be focused around the exploration of multiple techniques and their possibilities to secure tight control of the major critical quality attributes (CQA) and different PAT tools for measuring different attributes in (near) real-time. A feasibility study of PAT tools covered in this talk demonstrates the technology for in-line measurements in fed-batch process steps and potential of their use in a continuous process.
  • Considerations on Impact of Raw Material Variability in Gene Therapy Recorded: Oct 22 2020 83 mins
    Aaron Mack,Greg Stromberg and Dr Lisa Dixon

    As the number of cell and gene therapy products grow it is important to consider aspects of gene therapy production process robustness, and one key characteristic is the variability of incoming raw materials. Understanding and controlling raw material variability is an important aspect of process development, characterization and commercialization. In the recent history of therapeutic protein production with cell cultures, many problems caused by raw material variability were only discovered post-commercialization, and failure to understand and address key raw material variability during process development led to costly underperformance and batch failure. In this article, we consider some known sources of raw material variability and specifically, those that have been known to impact cell culture production processes. Trace element impurity variation, particularly iron, copper, manganese and zinc, are candidates for high process impact risk. Compositional variation of undefined material (i.e., fetal bovine serum [FBS]) is another important potential failure mode. This includes known nutrient components, such as amino acids and cholesterol, as well as unidentified components, such as growth factors. Cell and gene therapy processes also include relatively new materials for cell culture, such as plasmid DNA and the transfection agent polyethyleneimine, the understanding of the variability of which must be considered.
  • Establish Early Development Strategies For Therapeutics Proteins Recorded: Oct 21 2020 92 mins
    Sorina Morar-Mitrica, Principal Fellow at Novartis and Bernardo Cordovez, PhD, Chief Science Officer & Founder, Halo Labs
    Presented by Sorina Morar-Mitrica, Principal Fellow Sr Drug Product Lead Early Phase Biologics at Novartis

    The protein therapeutics field has expanded considerably in number and diversity of protein formats. Along come higher expectations for patient-centric products. And the clinical and regulatory landscapes are ever-evolving. All these have significant implications for the early CMC development strategies for protein products.

    In this webinar we explore early-phase development strategies, covering both fundamentals (successful approaches such as platforms) and specialized considerations (what to consider when faced with novel constructs) as follows:

    drivers for the early-phase development strategy, and challenges typically encountered at this stage
    previously-established successful strategies for early-phase development
    desirable tools and expertise to enable early-phase development
    transforming our perceptions of early-phase risks into innovation opportunities

    Follolwed by an Industry perspective presented by Bernardo Cordovez, PhD, Chief Science Officer & Founder, Halo Labs
  • High-Resolution Optical and Dielectric Methods Monitoring Cells in Bioprocesses Recorded: Oct 19 2020 76 mins
    Michael Butler, PhD, Professor and Principal Investigator, National Institute for Bioprocessing Research and Training (NIBRT)
    Presented by Michael Butler, PhD, Professor and Principal Investigator, National Institute for Bioprocessing Research and Training (NIBRT)

    The metabolic state of mammalian cells in a bioprocess can be monitored by high-resolution optical systems or by changes in dielectric properties. Each method can determine a metabolic inflection points just prior to loss of cell viability. Such changes can be observed up to 20h before cells stain with trypan blue. We have established a threshold of cytoplasmic conductivity below which cells cannot be recovered from apoptosis. This point occurs at a time when there are observable changes in the cell membrane that can be detected by high-resolution optics. This early detection of metabolic changes allows dielectrics and high-resolution optics to be offered as a means of monitoring a bioprocess and maintaining cell viability over prolonged time periods.
  • Viral Safety by Design for Cell and Gene Therapy Products Recorded: Oct 16 2020 75 mins
    Mark Plavsic, Chief Technology Officer at Lysogene & Dr. Magali Roche, Sales Manager, PathoQuest, Biologics Genomic Service
    Presented by Mark Plavsic, Chief Technology Officer at Lysogene

    Together with product efficacy, product safety is an essential characteristic of any medicinal product including cell and gene therapy (C&GT) biologics. Adventitious agents (viruses, bacteria, mycoplasma, prions, etc) pose constant risk to these biologics, and, as such they may impact directly product and patient safety. It is therefore of supreme importance to intentionally (by design) employ effective measures across the whole C&GT product manufacturing process to mitigate risk of adventitious agents. This presentation will review various interconnected steps throughout the manufacturing process, from the raw materials to the fill and finish, that would, in concert, help mitigate the risk while providing a high degree of product safety by design.
    Presented by Dr. Magali Roche, Sales Manager, PathoQuest, Biologics Genomic Service
  • Quantification and Control of Amorphous contents by Raman, Application and Case Recorded: Oct 2 2020 79 mins
    Michelle Raikes, M.S., Scientist IV and Dr. Fredrik Nordstrom, Sr Research Fellow at Boehringer Ingelheim
    Full Title: Quantification and Control of Amorphous contents by Raman, Application and Case Studies in Pharmaceutical Processing

    Presented by Michelle Raikes, M.S., Scientist IV and Dr. Fredrik Nordstrom, Sr Research Fellow at Boehringer Ingelheim

    Amorphous regions in crystalline material can have significant impact on bioavailability, processability and stability. Conversely, crystalline material can act as nuclei for recrystallization and resulting in instability of amorphous systems. Raman spectroscopy is sensitive to polymorphic differences and amorphous content in pharmaceutical materials. This make Raman spectroscopy a powerful process analytical technology (PAT), when combined with multivariate modelling, to control the amorphous content in a pharmaceutical process. We will present pharmaceutical case studies showing process-induced amorphization of crystalline drugs across the DS and DP processing steps. In addition, we will compare the kinetics of crystallization of amorphous material when stored at various relative humidity and temperature conditions. The results clearly demonstrate that Raman spectroscopic techniques combined with multivariate methods is a powerful and effective tool for quantitation of amorphous content in crystalline material with applications ranging from API isolation, milling and to multiple unit operations in DP manufacturing. The information generated was critical to determine the root-causes and outline appropriate mitigation measures
  • Digital Innovation and Transformation Lead, Biologics Business Excellence Recorded: Oct 1 2020 77 mins
    Robert Dimitri, Associate Director, Digital and Data Sciences Lead at Takeda + Toni Manzano Chief Science Officer, Aizon
    A walkthrough of the journey towards Digital Transformation for Takeda's Massachusetts Biologics Operations Site. This presentation shares the journey towards enhancing the site's digital and analytics capabilities and bringing it closer to a digital world and the progress and processes taken thus far.

    Presented by Robert Dimitri

    Robert Dimitri is a Director in Takeda’s Business Excellence group for the Biologics Operating Unit as the Digital Transformation and Innovation Lead. Previously he led the Digital and Data Sciences group in Manufacturing Sciences at Takeda’s Massachusetts Biologics Site leading a team for the implementation of digital tools used for the analysis of internal manufacturing operations data, used to support the production of biologic drugs to treat rare diseases. He has over 15 years of experience in this field, having worked previously as a process engineer and developing software to perform process data analytics. Robert has a B.S. degree in Chemistry and Computer Science, an M.S. in Computer Science, and an M.B.A.

    Followed by an Industry Perspective by Toni Monzano CTO and co-founder, Aizon Formerly Bigfinite
  • Strategies to Overcome Low Endotoxin Recovery Using the Conventional LAL Assay Recorded: Sep 28 2020 68 mins
    Ruth Daniels, Senior Scientist, Microbiology Expert, Janssen and Kevin Williams Microbiological Test Development, bioMérieux
    Presented by Dr. Ruth Daniels, Senior Scientist - Microbiology Expert at Janssen

    This webinar presentation will discuss:

    • Endotoxin hold time studies to identify LER
    • In silico assessment of interfering factors and associated LER mitigation strategies
    • Case study: optimization of product-specific LAL assay to overcome LER

    Followed By A Presentation From Kevin L. Williams, Microbiological Test Development at bioMérieux
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  • Title: Analytical Challenges for Gene Therapy
  • Live at: Nov 3 2020 3:00 pm
  • Presented by: Clare Blue at Biogen and Saba Hussein at Vironova
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