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Controlling variability to increase accuracy in the BET Assay

Karen McCullough’s presentation will look at the many sources of variability in the Bacterial Endotoxins Test. While a certain level of variability is expected from the biological reagent prepared from the lysed amebocytes of the horseshoe crab, additional variability in the testing laboratory can significantly affect the performance of the test. This discussion focuses on the laboratory, and highlights some of the controls that should be considered to assure consistency and accuracy of reported test results.
Recorded Jun 5 2013 51 mins
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Presented by
Karen McCullough and Alan Baines
Presentation preview: Controlling variability to increase accuracy in the BET Assay
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  • Lifecycle management of single use technologies Jul 25 2018 12:00 pm UTC 75 mins
    Francis Verhoeye, Director Single Use Technologies, GSK Vaccines
    Single-use technologies (SUTs) are one of the key drivers in the biopharmaceutical industry today and are changing the way we are operating and qualifying our bioprocesses, offering more flexibility and increasing efficiency. However, the extended use of those technologies in commercial operations requires a robust and specific lifecycle management approach. In this context, we have built an improved technical lifecycle management approach involving close partnership with key suppliers, enhanced standardization, early involvement of global manufacturing functions and full compliance with item creation process in order to ensure business continuity and value creation.
  • Key components of a comprehensive program for the management of single use techn Jul 18 2018 2:00 pm UTC 75 mins
    John Maguire, Shire
    As a result of the increased adoption of single-use technologies (SUTs) in biotech manufacturing, companies need to develop and implement programmatic approaches for the management of these systems under regulatory compliance. This webinar discusses the key aspects of such programs, with emphasis on collaboration with suppliers, cost management, as well as practical insights about the use of SUTs.
  • Development and Manufacturing of Recombinant Nanoparticle Vaccines Jul 12 2018 9:30 am UTC 75 mins
    Atin Tomar, CPL Biologicals
    A recombinant vaccine technology platform based on highly purified, properly-folded protein antigens in stable well-defined Nanoparticles, enabling efficient and safe manufacture of vaccines against highly pathogenic targets. Nanoparticles are intrinsically immunogenic, producing both durable neutralizing antibodies and cellular immunity. The platform can be utilized for rapid response to potential pandemics as the time from identification of relevant viral gene sequence to final GMP drug product ready for human studies has been demonstrated to take less than 4 months for multiple vaccines.
    The GMP drug substance manufacturing process for the platform largely utilizes single-use technologies. Single-use-technologies and recombinant platform enables the utilization of same manufacturing facility for multiple products with rapid change-over.
  • Raman spectroscopy measurements during Bioprocessing Jul 11 2018 2:00 pm UTC 75 mins
    Nobel Vale, Research Scientist II, Bristol-Myers Squibb
    Raman spectroscopy has been seen as spectroscopic tool used in bioprocessing to monitor and control cell metabolism to optimize quality and yield of titer. This is due to Raman’s insensitivity to water and ability to analyze samples without manipulation. However there are certain challenges for Raman when analyzing a complex and dynamic sample such as a cell culture. This article will describe the different challenges in analyzing in-line Raman data and how to mitigate changes in samples that include changes in fluorescence background, presence of cells/debris in samples, and spectral interference.
  • Strategies to overcome Low Endotoxin Recovery using the conventional LAL assay Jun 28 2018 2:00 pm UTC 75 mins
    Dr. Ruth Daniels, Janssen & Kevin L. Williams, BIOMÉRIEUX USA, Inc.
    Title: Strategies to overcome Low Endotoxin Recovery using the conventional LAL assay
    Presenter: Dr. Ruth Daniels, Janssen
    This 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

    Title: Addressing Low Endotoxin Recovery at the root with ENDO-RS® product-specific demasking strategies - Case studies
    Presenter: Kevin L. Williams, BIOMÉRIEUX
    Scientific studies have demonstrated that biologics typically containing protein in high concentrations and non-ionic surfactants, are likely to change the aggregate state of endotoxin in such a way that it is no longer accessible for detection with Factor C-based endotoxin detection methods (LAL and rFC). The ENDO-RS® endotoxin recovery method developed by Hyglos - a bioMérieux company, is a unique toolbox of dedicated reagents for demasking (recovering) endotoxin prior to detection, also for conventional LAL. This presentation covers the mechanism of LER, work principle of ENDO-RS as well as data from concluded protocol development projects on biologics from leading manufacturers.
  • Challenges in the Development of Continuous Processes for Vaccines Jun 27 2018 3:00 pm UTC 75 mins
    Danny Vellom
    The development and application of continuous manufacturing processes for vaccines presents both great opportunity as well as significant challenges, both technical and cultural, for the global industry. The key drivers are manufacturing capacity and flexibility, speed to market, and improved quality through the application of Quality-by-Design and Process Analytical Technology (QbD/PAT). Given the diversity of immunogens (toxoids, conjugate and subunit vaccines, live-attenuated and inactivated viruses, VLPs, etc.), and the variety of unique processes currently utilized to produce either single- or multi-component vaccines, it is unlikely that the transition to continuous processing will happen overnight. Additionally, cultural challenges are faced whenever a new mode of operation appears to some as “too different”, especially in a traditionally conservative sector like the developed-world vaccine industry. That said, market forces, global climate change, and Nature’s propensity to fill unoccupied niches with emerging infectious diseases will undoubtedly induce a first round of pioneers to explore this exciting new design space, ultimately leading to a more nimble industry and more and better opportunities for protection for the global population.
  • Platform tech development for biosimilar upscaling Jun 21 2018 8:00 am UTC 75 mins
    Dr Hung Fai Poon, President, QuaCell Biotech Ltd
    Discover strategies to move candidate molecules through development
    Building consistent, straightforward processes with low variability
    Exploring the possibility of using single use, high throughput bioreactors in the upscaling process
  • Manufacturing strategies for Biosimilar: A case of continuous capture Jun 15 2018 8:30 am UTC 75 mins
    Solomon Alva, Biocon & Presented by Yvan Ruland, PhD, Technology Director, Asia/Pacific operations, Novasep Asia
    Continuous manufacturing is an emerging technology in biopharmaceutical industry. The focus of this webinar is a case-study on the benefits of continuous Protein A capture on productivity, capacity utilization and buffer consumption. The potential challenges of adopting the technology such as its integration with cell culture and low pH incubation step has been discussed. There is promise of this technology as an effective platform, and potential of additional savings when considering new generation Protein A resins and in-line concentration technologies.
  • Fully continuous biosimilar manufacturing framework: A case study Jun 14 2018 8:30 am UTC 75 mins
    Samir Varma, Head of Manufacturing, Enzene Biosciences and Lotta Molander, Global Product Manager, GE Healthcare
    Biologics manufacturing has traditionally been in fed batch mode for the last 2 decades. During the early stages of biologics manufacturing, lower cell line productivity and product instability necessitated the usage of perfusion technology. As productivity increased and mabs became more stable, perfusion was replaced by fedbatch technology, as they were simpler to scale up. However, during the past 2-3 years, the perfusion technology is making a comeback due to the novel continuous chromatography technology. Connecting the perfusion bioreactor to the continuous chromatography system creates a continuous flow of drug substance and promises the following advantages

    The facility footprint for a continuous manufacturing plant would be substantially lower. Our calculations show that a 10-fold reduction in bioreactor size is possible with continuous bioprocessing. So the capacity of a 2000L Fed batch Bioreactor can be achieved by a 200L continuous bioreactor. This reduces the capex by about five fold.
    Consumption of media per amount of DS produced is the same for fedbatch and perfusion, although the cost per liter might be lower for perfusion as it could be a more diluted version of the fedbatch media ,
    Another major cost in bioprocessing is the Protein A resin. A significantly smaller Protein A column could be used in the continuous process and the utilization could be maximized by this strategy.
    As the process is more dynamic in continuous, automation and in-line analytical tools are essential for the successful implementation.
    Enzene Biosciences is on the forefront of the development of the continuous bioprocessing. We are in the processing of building a cGMP plant that would have a fully integrated continuous bioprocess. We have already complete a proof of concept studies in pilot scale (50L)
  • Preview of USP’s Informational Chapter , Guidelines on the Endotoxins Test Jun 11 2018 2:00 pm UTC 75 mins
    Karen Zink McCullough of MMI Associates & Kevin L. Williams of BioMérieux
    Title: Preview of USP’s Informational Chapter, Guidelines on the Endotoxins Test
    Presenter: Karen Zink McCullough, MMI Associates
    The retirement of FDA’s 1987 Guideline on LAL testing left a number of gaps in the written body of knowledge
    on LAL testing. Some of these gaps include: Guidance on RSE:CSE standardization, Guidance on Training,
    Guidance on OOS test results, and Calculation of Endotoxin Limits. The proposed chapter, that will appear in the
    July/August issue of Pharmacopeial Forum, provides information and recommendations on these topics and
    more. This Webinar will provide an overview of the contents of this new informational chapter.

    Title: Regulatory Compliance of Alternative Methods
    Presenter: Kevin L. Williams, BIOMÉRIEUX
    Recombinant Horseshoe Crab Factor C (rFC) tests are endotoxin-specific alternatives to Limulus Amebocyte Lyste
    (LAL). The United States Food and Drug Administration included rFC in their Guidance for Industry in 2012 and in
    2016 the European Pharmacopoeia followed suit. Recently, the Japanese Pharmaceutical and Medical Device
    Agency published a collaborative study demonstrating equivalence between rFC and LAL. This presentation will
    provide an overview of how alternative method validation of rFC methods is conducted in accordance to USP
    chapters < 1225 > and < 85 >.
  • Finding the Common Road to Quality for Single Use Materials Jun 6 2018 4:00 pm UTC 75 mins
    Dr Trishna Ray-Chaudhuri, Genentech & Dr Hélène Pora & Dr James Hathcock of Pall Biotech |
    - GMP requirements touch every single use assembly used in clinical studies to commercial manufacturing.  The drug product produced in clinical studies are given to patients.

    - GMP practices followed in producing the single use assemblies will ensure that there is no risk to patients in clinical trials and future commercial products. 

    IF WE CAN”T PROVE GMP WHAT HAPPENS?

    -Single use assemblies will not be accepted by regulatory agencies and internal quality departments as an alternative to stainless steel tanks.

    -The perception will continue that there is inadequate quality controls on single use assemblies as GMP practices are not adequately followed.

    - Implementation of single will be inhibited
  • Extractable Study Design & Data Evaluation of Polymeric Product Contact Material Jun 5 2018 2:00 pm UTC 75 mins
    Dr. Ping Wang, Principal Scientist, Janssen R&D & Dr Nixdorf, SGS Group
    Concerns over the safety and drug product qualities due to extractables and leachables (E&L) from polymeric Product Contact Materials (PCM), especially single use systems, in the manufacturing, packaging and delivery of biologics have increased in recent years. Based on surveys and author’s experience, almost all major regulatory agencies require the E&L risk assessment of PCM for new biologics license applications (BLA). To ensure the E&L data are suitable for the assessment of intended application of the PCM, the health authorities are paying close attention to the study design, analytical assays employed, and how the extractable data being used to conduct a safety risk assessment of the materials. The key to the success is to ensure the study design and data interpretation is product and process specific. The lack of relevant E&L data from suppliers presents end-users a great challenge. Strategies of developing relevant extractable data and applying that in the toxicological evaluation will be discussed.
  • Current USP Perspectives on a Rapid Sterility Test May 30 2018 1:00 pm UTC 75 mins
    Dr David Roesti, Novartis/USP and Erin Patton, Charles River
    The current growth-based Sterility Tests with at least 14-days incubation is not suitable for short-lived products. An expert panel was formed under the USP General Chapters– Microbiology Expert Committee to provide recommendations on user requirements specifications and candidate technologies based on the URS in the area of rapid sterility tests. Based on the evaluation of the URS, the expert panel made recommendations for appropriate modern/rapid technologies available from multiple vendors. The next step would be to recruit collaborating labs to conduct the proof-of-concept studies that would support drafting of a rapid sterility test chapter in the USP.
  • Integration of Disposable Components into Traditional Stainless-steel Facilities Recorded: May 22 2018 81 mins
    Ron Bates, Bristol-Myers Squibb and Miriam Monge, Sartorius Stedim
    This presentation will analyse the benefits and limitations associated with the implementation of single-use technology at a large-scale, multi-product commercial manufacturing facility. By integrating single-use components into a stainless steel facility, a hybrid equipment approach enhances manufacturing flexibility while enabling an accelerated manufacturing cadence.
  • Implementation Strategies and Challenges for SUT at Commercial scale Recorded: May 17 2018 73 mins
    Adam Goldstein, Roche/Genentech & Jacob McNeil, Thermo Fisher Scientific
    For over 10 years, single-use technology (SUT) has been a growing buzzword in the biomanufacturing industry for its advantages in speed, flexibility, and cost. A recent 2015 BioPlan Associates, Inc. industry survey of biopharmaceutical manufacturers, contract manufacturing organizations, industry vendors, and direct material suppliers identified the ‘Top Concerns’ for why biopharmaceutical manufacturers are choosing to increase their use of disposables. The top three reasons were (i) Eliminates cleaning requirements, (ii) Reduces time to get facility up and running, and (iii) Reduces capital investment in facility & equipment. These reasons are no surprise, as elimination of steam in place (SIP) and clean in place (CIP) allows for a reduction of required piping and controls, which in turn significantly decreases capital costs, design engineering, and field installation times.

    While these are some of SUT’s core drivers, their validity among that of many additional drivers have already been analyzed and proven at length. Perhaps the more interesting reasons for the continued focus on SUT are the growing industry trends towards modular flexible facilities and lean manufacturing.

    In order to adapt towards more targeted therapies for niche populations, biopharmaceutical manufacturers will need to produce multiple high potency products, with greater changeovers, and at smaller batch sizes.4 By significantly reducing capital outlay, disposable modular facilities allow for both product and geographical manufacturing flexibility. Production is thus enabled at a lowered associated risk wherever assets are best utilized and production costs minimized, such as in emergent markets.
  • End User Perspective on Setting in-Process in Endotoxin Limits Recorded: May 15 2018 41 mins
    Dr Friedrich von Wintzingerode, Roche/Genentech
    There is a lack of detailed guidance for setting endotoxin in process limits (alert levels and action limits) for biologics. This webinar will present a concept for setting in-process  limits and a case study which allows to understand the underlying rationales and challenges. 
  • Current Progress in Approaches for The Safety Assessment of E&L Recorded: Apr 6 2018 75 mins
    Kim Li, PhD, DABT, MPH, Amgen Inc.& Erica J. Tullo, Technology Manager, E&L – Analytical Labs, West Pharmaceutical Service
    Title: Current Progress in Approaches for The Safety Assessment of E&L
    Presenter: Kim Li, PhD, DABT, MPH, Amgen Inc
    Summary: This Webinar will review the current progress in the risk management of extractables and leachables (E&L) impurities with focus on protein therapeutics. While toxicology assessments of E&L impurities are maturing toward best practices, their potential impact to product quality requires new approaches from the toxicologist toolbox. This webinar will discuss the in silico prediction of chemical functional groups that pose high risk of covalent binding, potentially leading to structural modifications of proteins and impact to quality attributes.


    Title: A Practical Approach to Extractables and Leachables
    Presenter: Erica J. Tullo, Technology Manager, E&L – Analytical Labs, West Pharmaceutical Service
    Summary: While many realize that regulatory agencies require extractable and leachable (E&L) information, many may not have knowledge of how to design an appropriate extractables study that will lead to proper selection of targets in leachables testing. During the extractables study, it is important to choose the most appropriate solvents and extraction conditions for the type of packaging components under evaluation. It is also important to consider a simulation study in which the entire system is assessed. Since leachables are typically a subset of extractables, the design of the extractables and simulation studies can significantly impact the subsequent leachables method development and monitoring. This presentation will highlight different considerations of each phase of E&L testing.
  • SUS Leachable Testing: Leachable Study Design for Single-Use Components Recorded: Mar 20 2018 69 mins
    Kathryn McGohan
    The BPOG Leachables Working Group has recently published a Best Practice Guide for Leachables. The Best Practice Guide was developed to help Biopharmaceutical and Vaccines Manufacturers to develop science-based, robust, and efficient approaches to handling the risk of leachable compounds that is associated with increasing use of Single-Use Systems in manufacturing processes. The Best Practice Guide is composed of three parts: the risk assessment model, leachable study design, and analytical methods. This article provides insight into the application of the Best Practices for Leachables Study Design by end users and will include a case study to highlight the importance of the study design.
  • Process analytical Technology for Upstream Bioprocessing Recorded: Mar 5 2018 71 mins
    Erica Fratz-Berilla & LCDR Agarabi
    In commercial cell culture bioprocessing, consistent high quality protein is a fundamental goal that is typically accomplished during development through product and process engineering of bioreactor parameters. The FDA’s Center for Drug Evaluation and Research (CDER)’s Office of Biotechnology Products’ upstream bioprocessing laboratory, a part of the Office of Pharmaceutical Quality’s Center of Excellence (COE) in Manufacturing Science and Innovation, studies Process Analytical Technology (PAT) for upstream bioprocessing, focusing on the production of monoclonal antibodies. These capabilities are being leveraged to study continuous bioreactor cell culture production and compatible PAT tools. Case studies are presented that illustrate collaborative laboratory research being conducted on PAT tools for upstream bioprocessing to support regulatory decision making.
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  • Title: Controlling variability to increase accuracy in the BET Assay
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  • Presented by: Karen McCullough and Alan Baines
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