Fully continuous biosimilar manufacturing framework: A case study
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)
RecordedJun 14 201868 mins
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Ken Wong, Deputy Director at Sanofi Pasteur and Diego Zurbriggen, Technical Account Manager at West Pharma
Title: Extractables and Leachables have been used interchangeablely for too long. Are we still confused?
Presenters: Ken Wong, Deputy Director at Sanofi Pasteur and Diego Zurbriggen, Technical Account Manager at West Pharma
Dr Xin Bu, Principal Scientist, Bristol-Myers Squibb
Dissolution is one of the critical quality attributes for solid oral dosage forms, typically tablets and capsules. In addition as a quality control (QC) test to release commercial products, dissolution is often used as a comparative test to 1) apply biowaiver for lower strength(s) when multiple strengths of one product with the same or similar formulation are marketed, or 2) support post approval changes. In these cases, in-vitro dissolution test is used in place of in-vivo bioequivalence study to establish equivalency between products of different strengths or pre- and post-change. Guidances provided by major regulatory agencies, the United States Food & Drug Administration (US FDA) and European Medicines Evaluation Agency (EU EMEA) are often followed by many countries around the world. However some countries/ regions, such as Australia, Japan, China, Taiwan and Korea have their own country specific guidances. The dissolution requirements by the FDA and EMEA are generally similar, and depend on the type and level of changes as outlined in the relevant guidances. The requirements from other mentioned countries are often significantly different from that of US and EU, and different from each other. For products marketed globally, it’s prudent to understand the differences amongst the different country requirements when applying post approval changes using dissolution to demonstrate equivalency. Several sets of comparative dissolution studies may have to be conducted in order to satisfy all regulatory agencies. This presentation compares differences in dissolution testing requirements among the listed countries and provide examples to illustrate how for conduct studies to comply with the relevant guidance(s).
Sekhar Reddy, DSP Lead for Biosimilars at Biocon MSAT
Downstream processing of Biosimilar Monoclonal Antibody utilises variety of raw materials that a critical for achieving the desired product quality. In this webinar, we would like to discuss the data from three cases of lot to lot variability namely Depth filtration, Chromatographic resin and buffer component used in downstream chromatography unit operations. Changes in lots of depth filter resulted in significant clogging and differences in Host cell impurity clearance. Similarly, changes in resin lots resulted in increased back pressure during processing and variability in buffer raw material lots resulted in undesirable colouring of resin upon contact. In each case, we will present the root cause investigation, impact on product quality profile and associated CAPAs to control the effects of variability to ensure manufacturing continuity.
Yasser Nashed-Samuel, Principal Scientist at Amgen
Attribute Sciences, Process Development, Amgen Biopharmaceuticals are drugs manufactured bygrowing genetically engineered cells in bioreactors to produce a therapeutic protein. Plastic single-use bioreactors are of interest to biopharmaceutical drug manufacturers due to their significant environmental and cost benefits and flexibility over stainless steel bioreactors. Effect of plastics on the biomanufacturing process is not yet completely understood. A case study on extractables from single-use bioreactors and impact on cell culture performance will be presented.
Lance Marquardt, Bristol-Myers Squibb & Sara Bell, Merck
By Lance Marquardt, Associate Director – Upstream Processing for Hopewell Clinical Manufacturing at Bristol-Myers Squibb and Sara Bell, Senior Marketing Manager for Mercks’s single-use product portfolio.
An overview of the current use of single use manufacturing within the Bristol-Myers Squibb manufacturing networks and planned future state. The challenges in implementing single use manufacturing for commercial production will be discussed. Comparisons will be made to the implementation of past improvements and the plans for future improvements, such as continuous processing.
Dr. Dakshesh Mehta, Associate Vice President and Head of Bioprocess Group at Biotech & Genomics division
In recent years, due to major advances in upstream process, therapeutic proteins can be produced at higher concentrations than ever before. For, these high-titer, high-cell density production, chromatography operations may be as perceived bottlenecks. Column size limitations, low dynamic capacity and buffer volume requirements are generally considered as contributing factors, apart from high resin costs.
The talk will cover how flexible manufacturing systems could help establish efficient downstream processes to overcome capacity bottleneck. Also how downstream footprint can be reduced whilst speeding up purification process. Is there anyway, one could eliminate chromatography operations with other technologies that may require less space and buffers and also may be more cost effective?
Dr. Joe X Zhou is the CEO Walvax Bio Group & Floris D Smet, Director of Field Marketing, Sarotrius China
Following patent cliffs for Erbitux, Rituxan, Sandosta_n and several big blockbusters, Herceptin, Avastin are now among the next biosimilar targets. This is creating huge potential for biosimilars, prompting innovators to shift their focus to target more emerging markets which remain untapped for many companies. In this presentation, Joe will be sharing with you his vision of the biosimilars market with a focus on China. He will also discuss key considerations for mAb and biologics therapeutic development, providing a broad overview of challenges and opportunities presenting in the market.
1. Landscape changes of mAb therapeutics
2. New targets and process/manufacturing innovation
3. Key consideration of mAb industry in China
4. Case study: Development strategies of PD-1 mAb as anti-tumor therapeutics in China for global market
Ben Jeyaretnam (Ph. D., MBA), E&L Analytics Lead, Sanofi, Swiftwater
Pharmaceutical industry has been increasingly using single use systems (SUS) for bioprocessing and storage of intermediate and final bulk material in addition to primary packaging. Before a SUS could be used in the manufacturing process, it needs to be qualified for use by a pre-determined process. This presentation will discuss a variety of challenges, both internal and external to the industry that the end use faces during the qualification process. Complexity of SUS, varying quality of vendor data, component change management, changing regulatory expectations, analytical data generation, logistical challenges during E&L study execution, analytical challenges, and the potential impact of unexpected E&L study results will be presented.
The pharmaceutical industry paradigm change is occurring and industry has taken an important leap towards formality of quality improvement using quality tools. Recent industry and regulatory support of ‘risk-based’ concepts and principles are leading to a ‘desired state’ of industry development and production of pharmaceuticals that have a higher level of consistency in meeting purity, safety and efficacy.
Microbiologists’ role as active partners in the pharmaceutical environment is to help transform industry to a routine Quality by Design paradigm. With the help of quality tools and using the concepts and principles of Quality by Design, a better understanding of how and where to implement microbiological control of processes can be developed, and microbiological purity can be built into products for all patient populations.
Yuyi Shen PhD, Principal Scientist, Grifols, John Cyganowski, Director of Manufacturing Sciences and Technologies Downstream
The desire for innovative technology that can eventually cause disruptive improvement remains high in the biotech pharmaceutical industry. The road between pursuing and developing that technology to genuine implementing is not a smooth ride. In this webinar, the presenter identifies key challenges of implementing innovative technologies and the major drive for implementing innovative technologies and process upgrades. The presenter will share some case studies of implementing successful innovation tools and provide comparative economic analysis based on the understanding the true value of innovation driven process design. The webinar also provide the insight of the balance needs for quality, cost and speed.
Vivek Halan Zumutor Biologics Pvt Ltd, Bangalore, India
This Webinar will discuss MMC in purifying biologics which includes monoclonal antibodies (mAbs), Bispecific antibodies (BsAbs), antibody fragments (Scfv,Fab) and other recombinant proåteins. My discussion is intended for audience from biopharmaceutical industry as well as active collaborators from academic institutes.
Dr Sourav Kundu, Senior Director at Teva Pharmaceuticals Global Biologics R&D and Adam Kaletski, Business Leader, Bioprocess
· Facility needs and characteristics for clinical manufacturing
· Single-use or stainless steel?
· When to use single-use equipment
· Hybrid manufacturing facilities – best of both worlds
· Teva’s clinical manufacturing facility – attributes, layout, construction, qualification, choice of equipment
· Final thoughts
John Duguid, Senior Director, at Vericel Corporation in Cambridge, and Nicola Reid, Senior Product Manager at Charles River
Title:Regulatory Approval of Three Rapid Microbiological Methods for MACI Product Release
Rapid detection of contaminants is essential for cell therapy products with short shelf lives. Integrating quality into the process through lot segregation, raw material qualification, environmental control, personnel training, and detailed procedures is critical because final results for conventional microbiological tests may not be available prior to product release or patient administration. EMA approval of the MACI MAA in 2013 followed by US FDA BLA approval in 2016 included three RMM product release assays for sterility, endotoxin, and mycoplasma.
This webinar reviews the constraints and complexities of vaccine product development and manufacture.
The evolution of bioprocess and analytics innovation and technologies to overcome these challenges are discussed.
The strategy and leveraging of innovation and technology for rapid product development and accelerating timelines is described.
Case studies to illustrate the advances in vaccine development and manufacture are illustrated.
A look into the future with state of the art technologies.
Dhaval Tapiawala, Pfizer and Satish Kumar Mohanvelu Life Sciences Management Professional at MilliporeSigma
• Understanding extractables and leachables for better adoption of single use systems
• Ensuring safety of drug through determining the level of leachables throughout product life cycle
• Case Study of implementation of standardized testing protocol
Brian O’ Mara, Senior Research Scientist I, Bristol-Myers Squibb and Alexei Voloshin, Global Application Strategy Specialist
Title:Impact of Depth Filtration on Disulfide Bond Reduction during Downstream Processing of Monoclonal Antibodies from CHO Cell Cultures
Presenters: Brian O'mara, Senior Research Scientist I, Bristol-Myers Squibb and Alexei Voloshin, Global Application Strategy Specialist
• Understand disposable depth filtration technology used in the recovery of antibodies from CHO cell cultures as a unit operation leading to cellular lysis under particular operational conditions • Study how cellular lysis occurring during depth filtration releases endogenous REDOX regulating enzymes and co-factors into the clarified harvest, resulting in the reduction of antibody interchain disulfide bonds • Classify critical process parameters and quality attributes of the clarified harvest to be monitored during filtration development • Discuss risk mitigation strategies to control antibody reduction when using single-use disposable technologies in the recovery of antibodies from CHO cells
Dr Anita Krishnan, Lupinand -Dr. Annu Uppal, Global Demo Lead and Advanced Workflow Specialist at SCIEX
Biotechnological products are so complex, that manufacturing biologics which are both cost-effective and with best product quality, is a technical challenge. In the context of biosimilar manufacturing at each step, the sponsor should evaluate the extent to which there is residual uncertainty about the biosimilarity of the proposed product. Often there is remnant quality difference beyond the capability of process to address. In such instances, in-depth understanding of the process, impurities, analytical methods, the mechanism of action (MOA) of the drug substance and clinical relevance of any observed structural differences, will help in implementing novel CMC strategies. This talk will examine the elements of biopharmaceutical development that lead to successful licensure of biotherapeutics.
Thorsten Lorenz, Team Head Developability Assessment Biologics, Novartis and Beate Kern, Product Manager, NanoTemper
Title: Developability Assessment of Therapeutic Proteins – A Toolbox for Tackling Increasing Complexity
Presenter: Thorsten Lorenz, Team Head Developability Assessment Biologics, Novartis
Early lead selection of biotherapeutics during preclinical development requires careful characterization of a variety of molecule properties to reduce the risk for encountering unexpected obstacles during technical development. The diversity and increasing complexity of new protein formats requires a change from former platform approaches often applied for antibodies, to project specific strategies. The developability assessment concept applied at Novartis combines information addressing various technical areas, such as expression, aggregation propensity, process fit, stability, physicochemical properties, etc. This integrated concept prior to lead selection provides a thorough, yet resource efficient approach to select suitable candidates.
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Fully continuous biosimilar manufacturing framework: A case studySamir Varma, Head of Manufacturing, Enzene Biosciences and Lotta Molander, Global Product Manager, GE Healthcare[[ webcastStartDate * 1000 | amDateFormat: 'MMM D YYYY h:mm a' ]]68 mins