Anurag Khetan
Advances In Cell Line Development And Process Development To Speed Mab And Non Mab Assets Faster To Clinic
Bristol-Myers Squibb
Susan Burke, Ph.D.
Digitization of Raw Material Data and The Application of Data Analytics to Better Understand and Control Variation
Amgen
Coffee and Registration
Chairperson’s Opening Remarks
Advances In Cell Line Development And Process Development To Speed Mab And Non Mab Assets Faster To Clinic
Streamlining Early Cell Line Development to Increase Speed and Efficiency
Optimizing Cell Line Development with Beacon®: On-Chip Cloning Technology To Improve Performance And Reduce Timelines
The cell line development process - specifically single cell cloning and clone assessment - requires lengthy, labor-intensive processes to identify a highly productive and stable lead clone. While the probability of identifying such clones increases as the number of clones screened increases, there is a limit on traditional cloning and screening capacity. Berkeley Lights, Inc. (BLI) has developed a novel microchip system capable of generating and screening thousands of individual clones while shortening development timelines. The Beacon® platform was directly compared to the Biogen platform development process, producing high-quality clonal cell lines with improved titers. A comprehensive data package will be presented to highlight the benefits and challenges of transitioning to microchip technology for optimized, expedited cell line development.
Chairperson’s Opening Remarks
Overview of BioPhorum Raw Material Variability (RMV) Workstream
Presenting the vision, value, and achievements of BioPhorum Raw Material Variability (RMV) workstream. This workstream provides an effective forum for biopharmaceutical manufacturers and raw material suppliers to collaborate, to enable data and information sharing and benchmarking, and to explore practical solutions and mitigation strategies. Progress and results from subteams working on various topics will be highlighted.
Digitization of Raw Material Data and The Application of Data Analytics to Better Understand and Control Variation
This talk will review the challenges and opportunities associated with the digitization of Raw Material related data and how access to that data can then be used to understand and potentially control the impact of Raw Material variation on process and product variation during the manufacture of biopharmaceutical products.
Understanding and Controlling the Impact of Elemental Impurities in Cell Culture
Unexpected variation of trace elements in cell culture raw materials has historically posed a problem for commercial biopharmaceutical operations. Variations lead to shifts in cellular metabolism, decreased cell growth, lowered productivity, unexpected shifts in product quality and the loss of whole batches. This presentation explores the mapping of elemental variability from key raw materials to their impact on the bioreactor, coupled with a detailed analytical characterization of common raw materials and their historical elemental impurity profiles. We show how elemental mapping and proper process design can minimize the impact of unavoidable raw material impurity variation.
Chairperson’s Opening Remarks
Annex 1 Draft/Preventing Contamination and Cross Contamination during Aseptic Fill-Finish
During aseptic fill-finish the cleaning and decontamination should be validated to avoid microbiological contamination. Furthermore, every second new developed Biopharmaceutical Product is considered as highly potent or toxic. Those kinds of products require also cleaning and cross contamination requirements. What limits for cleaning should be considered for aseptic fill finish and the non-product contact surfaces close to open containers like Vials or Syringes.
Mitigating Particle Problems During Biopharmaceutical Formulation, Storage, and Use
Particle formation remains a challenge in biopharmaceutical drug development and can occur during manufacturing, storage, or drug product administration. The causes vary and there are examples related to protein instability, surfactant degradation, and glass delamination. This presentation includes case studies in which challenges related to these issues occurred and strategies were implemented to mitigate them.
Chairperson's opening Remarks
Investigating USP & DSP Tools For Analysis: Round Table:
Table 1: In The Bioreactor (30 minutes)
Speaker: Ting-Kuo, Senior Engineer, Genentech
Table 2: For Protein Purification (30 minutes)
Using Raman Spectroscopy for Monitor and Control of Critical Quality Attributes in Ultrafiltration/Diafiltration of Biotherapeutics
To support process intensification for the downstream production of biotherapeutics, process analytical technology (PAT) is essential for rapid process monitoring and process control. Raman Spectroscopy (Raman) can be implemented at key points in the purification process as a PAT strategy. Regeneron Pharmaceuticals has developed tools to incorporate Raman and predictive model generation for the control and automation of the ultrafiltration/diafiltration (UF/DF) unit operation. This study experimentally characterizes chemometric models developed from Raman spectra for real-time monitoring and control of critical quality attributes such as protein concentration and buffer excipient levels.
Accurate Biomass Soft-Sensor Using 2-D Fluorescence and MARS Modeling
Chairperson’s Opening Remarks
Development of Tissue Therapies as compared to the Development of Cell and Gene Therapies: A Look Back, A Look Ahead
Raw Materials/Starting Materials
Cell Culture and Expansion
Chairperson's Opening Remarks
Single-Use Technologies for Cell & Gene Therapies
An Introduction to Single-Use Technologies and the specific attributes and quality needs when implementing Single-Use Technologies in Cell and Gene Therapy Manufacturing. BPI’s training workshop will focus on the importance and the implementation of Single-Use technologies in production of manufacturing facilities. The format of the course includes valuable and unbiased classroom instruction by industry expert James Dean Vogel, P.E. With Mr. Vogel’s assistance, course participants will experience the latest Single-Use products first hand during the lab portion of the course.
Topics include:
Attendees range from end-users, suppliers, sales and regulatory personnel who have a general understanding of the SUT industry and want to experience Single-Use products hands on!
Data Science Tools for Accelerated Product Life Cycle
Course Objective
Hands-on learning of basic principles and best practices performing data analytics and data management for integrated bioprocesses. Designed for the biopharmaceutical and industrial biotech industry. The course topics include
Primary Audience
This course is designed for all individuals who are involved in bioprocess development & manufacturing as well as process validation. This includes bioprocess development scientists, engineers, manufacturing and quality supervisors, and management. No statistical or mathematical background is required. Interactive seminar Bring your own laptop. You will perform exercises on bioprocess data management and analytics using the web-based educational software tool inCyght®.
Course Outline
Networking Refreshment Break
Anticipating Cell Lines Challenges for CMC Readiness
In an organization focused on novel immuno-oncology targets, the development of CHO production cell lines must account for occasional off-platform approaches: novel molecule formats, alternative antibody isotypes, product quality characteristics and their implication for the mechanism of action of a drug. Concurrently, the fundamental requirements of high titer, robust growth and stability determine the late stage manufacturing strategy. In this talk, relevant examples will be discussed.
Challenges On Stable Cell Line Development Using Horizon CHO GS Knock Out System
The stable cell line for antibody production was developed using Horizon CHO GS knockout system through optimization of transfection, and culture medium during cloning steps. The electroporation transfection procedure with Lonza system was developed based on different programs and buffers, cuvette size, host cell health, DNA quality and quantity. To increase transfection efficiency and protein expression, FACS method was also introduced to verify targeted product expression and quality during cloning selection.
Consistently Delivering Outperforming Cell Lines Leveraging Extensive CLD Expertise and Innovative Seeding Platform
Breakthrough biologics of tomorrow seldom reach their potential due to inefficiencies in the development of high performing cell lines. Industry leading biosolutions provider Celonic and cutting edge platform developer Solentim joined hands to collaborate on development of a robust workflow with an objective of consistently delivering outperforming cell lines. The scope of this collaboration was to design and assess the most optimal seeding and growth conditions to ensure a robust clone selection workflow and generating rich, high quality supporting data for regulatory submissions.
Media Raw Material Variability: Case Studies in Different Stages of Product Lifecycle
Advancement in Raw Material Management and Control
A Representative from Boehringer Ingelheim
Spotlight Presentation
Syringe Filling of a High-Concentration mAb Formulation: Issues and Mitigation Strategies
Successful large-scale manufacturing by an automated syringe filling machine is a challenging task. Clogging of filling needles during syringe filling of high-concentration mAb formulations by an automated filling machine is a major hurdle for successful large-scale manufacturing. Preventing needle clogging is essential to ensure minimal fill weight variation, product waste and manufacturing down-time. Understanding the factors that influence the propensity for filling needle clogging is essential to develop mitigation strategies for large-scale manufacturing. This presentation summarizes the issues faced during syringe filling process and mitigation strategies. Learnings of this work can be leveraged for the development of syringe filling process for other high-concentration mAb products or to mitigate the needle clogging issue.
Feasibility of Frozen BDS Storage Of Ultra-High Concentration mAbs
One of the biggest challenges in formulation development of ultra-high concentration mAbs is the concentration dependent degradation route associated with aggregation. Conventional approach to extend shelf life for biotherapeutics in liquid formulations to mitigate degradation, such as aggregation, involves BDS storage at subzero temperatures. However, potential cryoconcentation may be a larger risk for ultra-high concentration mAbs. Careful design of small scale frozen storage feasibility studies and selection of current frozen storage technologies makes frozen BDS storage of ultra-high concentration mAbs possible.
The Effect of Surfactant Excipients on the Stabilization of Proteins during Mechanical, Oxidative and Thermal Stress
Non-ionic surfactants are often used to stabilize biologics, and while the underlying mechanisms of degradation have been considerably reviewed, the influences of individual surfactants, both positive and negative remain an unmet challenge. In this work, a multitude of surfactant excipients including common polysorbates with innovative excipients like polyoxyl 15 hydroxystearate are evaluated for model protein stability under mechanical, thermal and oxidative stress.
Real-time titer measurement methods to control Protein A column loading during continuous antibody production - a technology overview
Evaluation of PAT Co-Laboratory Process Development Model
Spotlight Presentation
Cell Harvest
Scaffold Fabrication - 3D Printing
Scaffold Fabrication
Single-Use Technologies for Cell & Gene Therapies
An Introduction to Single-Use Technologies and the specific attributes and quality needs when implementing Single-Use Technologies in Cell and Gene Therapy Manufacturing. BPI’s training workshop will focus on the importance and the implementation of Single-Use technologies in production of manufacturing facilities. The format of the course includes valuable and unbiased classroom instruction by industry expert James Dean Vogel, P.E. With Mr. Vogel’s assistance, course participants will experience the latest Single-Use products first hand during the lab portion of the course.
Topics include:
Attendees range from end-users, suppliers, sales and regulatory personnel who have a general understanding of the SUT industry and want to experience Single-Use products hands on!
Data Science Tools for Accelerated Product Life Cycle - Cont'd
Course Objective
Hands-on learning of basic principles and best practices performing data analytics and data management for integrated bioprocesses. Designed for the biopharmaceutical and industrial biotech industry. The course topics include
Primary Audience
This course is designed for all individuals who are involved in bioprocess development & manufacturing as well as process validation. This includes bioprocess development scientists, engineers, manufacturing and quality supervisors, and management. No statistical or mathematical background is required. Interactive seminar Bring your own laptop. You will perform exercises on bioprocess data management and analytics using the web-based educational software tool inCyght®.
Course Outline
Networking Luncheon
Accelerating Timelines through Implementation of TLA Sequencing in Cell Line Selection
Cell line stability studies is a rate limiting step in the selection of recombinant protein production cell lines. This case study demonstrates the utility of TLA sequencing prior to cell line stability studies to accelerate production timelines. Early identification of lead cell lines enables cell culture process development in parallel with confirmatory cell line stability studies. The benefits and limitations of TLA data in driving cell line selection is presented, as well as its potential to facilitate workflows that further reduce cell line development timelines.
Further Streamlining CLD: Combining Single Cell Cloning and Enrichment using FACS into Semi-Solid Media
The development and selection of high titer recombinant cell lines can be a long and arduous process. To better meet rising patient demand amidst the competitive biologics landscape, we seek to improve out methodologies to identify more highly productive cell lines while reducing timelines. Our legacy workflow utilizes independent enrichment and monoclonality steps based on imaging technologies that leverage fluorescence to identify robust cell lines and ensure regulatory compliance. We have recently developed a method that overlays these two functional steps. With modifications to the cell culture matrix, we have enabled Fluorescence Activated Cell Sorting (FACS) directly into a microscopy based monoclonality identification step that is coupled to additional enrichment, all without major reductions in cell line outgrowth. FACS gating for rare events has enabled identification of more highly productive clones while reducing the overall screening burden. This new method additionally reduces our cell line development timeline by three weeks, while enhancing the ability to generate high titer clones.
Raw Material Control Strategies: From User Requirements to Design of Specifications
Raw materials may be effectively managed through end-to-end control strategies that focus on thoughtful determination of User Requirements, defining associated raw material attributes and implementing appropriate control strategies through a combination of meaningful supplier engagement and manufacturer’s internal testing. This presentation will describe such an approach and associated efforts to manage raw materials for biologics manufacturing at Amgen.
Development of A Holistic Approach to Raw Material Risk Assessments Through Industry Collaboration
Spotlight Presentation
Challenges and Strategies for Low-Dose Drug Product Development During In-Use Administration Studies
Establishing stability, safety and efficacy of a biological drug product during in-use administration studies is crucial for clinical and commercial success of drug product. Regulatory guidelines require manufactures to demonstrate compatibility of biologics with diluents and dosage delivery devices. It is highly critical and challenging to evaluate if the complete dose is administered to the patient especially when the target dose is extremely low (concentrations ranging from ng/mL to ug/mL). Additionally, dose escalation studies during first-in-human studies further demand the dose to be further reduced. In these scenarios, the in-use developmental activities pose analytical challenges for low dose drug product characterization. This presentation will focus on case studies to discuss in-use developmental challenges especially for low dose drug products and strategies for their successful clinical administration
In Pursuit of Robust Drug Product Manufacturing Process for mAbs
Drug product manufacturing is a critical segment in a biopharmaceutical product’s roadmap starting from cell line development leading up to commercial launch and beyond. This presentation will review and evaluate fill-finish manufacturing processes, discuss a few operational challenges and assess their impact on drug product quality. The application of single use disposable commodities in mAb based drug product manufacturing will be highlighted.
Enhancing Process Optimization Using Advanced Analytical and Data Handling
There is Industrial interest in the use of new technology for optimizing process operations - which includes continuous processing. Regulatory initiatives such as PAT and Quality by Design (QbD) have encouraged approaches to process intensification and process optimization. These have allowed for better process understanding, which leads to developing the operational design space for the process. Process control systems can then be improved using sensor inputs.
PAT in Freeze drying - Measurement of Residual Moisture Content by Non-Invasive Methods
Spotlight Presentation
Single-Use Technologies for Cell & Gene Therapies
An Introduction to Single-Use Technologies and the specific attributes and quality needs when implementing Single-Use Technologies in Cell and Gene Therapy Manufacturing. BPI’s training workshop will focus on the importance and the implementation of Single-Use technologies in production of manufacturing facilities. The format of the course includes valuable and unbiased classroom instruction by industry expert James Dean Vogel, P.E. With Mr. Vogel’s assistance, course participants will experience the latest Single-Use products first hand during the lab portion of the course.
Topics include:
Attendees range from end-users, suppliers, sales and regulatory personnel who have a general understanding of the SUT industry and want to experience Single-Use products hands on!
Data Science Tools for Accelerated Product Life Cycle - Cont'd
Course Objective
Hands-on learning of basic principles and best practices performing data analytics and data management for integrated bioprocesses. Designed for the biopharmaceutical and industrial biotech industry. The course topics include
Primary Audience
This course is designed for all individuals who are involved in bioprocess development & manufacturing as well as process validation. This includes bioprocess development scientists, engineers, manufacturing and quality supervisors, and management. No statistical or mathematical background is required. Interactive seminar Bring your own laptop. You will perform exercises on bioprocess data management and analytics using the web-based educational software tool inCyght®.
Course Outline
Networking Refreshment Break
Engineering CHO Cells: How to Herd Cats
Engineering complex process performance characteristics such as cell growth and productivity is an unpredictable challenge made more difficult by the inherent variability of CHO cells, protein products and production processes. There is no one-size-fits-all solution. However, most companies engineer cells to produce a specific recombinant product using a generic vector, host cell line and medium. Constraints are built in from the start, and this can be a particular problem for difficult-to-express proteins. As a new paradigm for cell line development we are developing a hyper-variable design space for mammalian cell factory engineering that utilises directed and synthetic variation of chemical, genetic and cellular input components as a core strategy to optimize cell functional performance beyond natural limits.
Panel Discussion: Integrating New Engineering and Cell Line Development Technologies into Established Workflows
Developing an Accurate and Efficient Technical Raw Material Risk Assessment Process
In order to continually improve the reliability of Amgen’s manufacturing operations, we have recently developed a new raw material risk assessment process. The process is flexible to accommodate a wide range of materials (from chemicals to single-use systems) and modalities (from small molecules to cell therapies). Guiding principles include building and maintaining a library of raw material risks and mitigations to promote efficiency and consistency; assessing groups of similar materials rather than every material individually; and triaging out low-risk materials quickly to focus on potentially higher risks. The new process ensures that all new materials are evaluated for technical risks prior to introduction in the manufacturing network, and emphasizes communication of existing risks and mitigations across different products and manufacturing sites. Outcomes include a single, searchable source of truth for raw material risks and mitigations, and a ~60% reduction in time required to perform a new risk assessment for a product.
Qualification of Raw Material for Clinical Trials
My presentation will include examples of how to qualify raw materials for use in clinical trials Phase 1, 2 and 3 using a risk-based approach.
Further my presentation will include examples of which documentation could be established during qualification. Examples of challenges and mitigations during qualification will also be addressed.
From Sequence to Product in Hours - Cell Free Expression for Next-Generation Therapeutics
Technical advances are making personalised healthcare a reality. This poses a challenge to conventional production approaches, but for which cell-free expression (CFE) could be the solution. CFE has historically been utilised for production of small quantities of product, due to its rapid setup, short duration and flexibility. Its application to clinical manufacture is restricted by its high cost and low yields. The raw materials, particularly the cell lysate, are responsible for significant variability in performance and their lack of a consistent source continues to prevent effective yield improvement. Overcoming this variability would permit rapid optimisation of cell-free yields and support routine robust reaction performance and its implementation for manufacture of therapeutics. This talk will explore methods for reproducible production of the raw materials required for CFE and their application to high-throughput optimisation of yield, using our own work as a case study. Through applying cGMP manufacture principles to lysate production, we were able to develop a scalable and robust E. coli lysate generation process, identify quality control parameters and thereby resolve issues with batch-batch variability between lysates. This consistent lysate was subsequently used to support the development of a high-throughput platform for optimisation of CFE at microscale, through use of an automated liquid handling system in tandem with design of experiment statistical design. With the standardisation of raw material components, our work demonstrates how efficiently cell-free reactions can be optimised to drive up yields. This, in combination with the linear nature of cell-free scale up, should enable CFE to meet the demands of small batch manufacture and therefore should be considered when assessing methods of production for the next generation of therapeutics.
Panel Discussion: Latest Strategies to Overcome Challenges in Drug Product, Fill Finish & Formulation
Translating Data Into Decisions: Multivariate Data Analysis
Smart Data Analytics for Biomanufacturing Process Modeling and Advanced Process Control
Single-Use Technologies for Cell & Gene Therapies
An Introduction to Single-Use Technologies and the specific attributes and quality needs when implementing Single-Use Technologies in Cell and Gene Therapy Manufacturing. BPI’s training workshop will focus on the importance and the implementation of Single-Use technologies in production of manufacturing facilities. The format of the course includes valuable and unbiased classroom instruction by industry expert James Dean Vogel, P.E. With Mr. Vogel’s assistance, course participants will experience the latest Single-Use products first hand during the lab portion of the course.
Topics include:
Attendees range from end-users, suppliers, sales and regulatory personnel who have a general understanding of the SUT industry and want to experience Single-Use products hands on!
Data Science Tools for Accelerated Product Life Cycle - Cont'd
Course Objective
Hands-on learning of basic principles and best practices performing data analytics and data management for integrated bioprocesses. Designed for the biopharmaceutical and industrial biotech industry. The course topics include
Primary Audience
This course is designed for all individuals who are involved in bioprocess development & manufacturing as well as process validation. This includes bioprocess development scientists, engineers, manufacturing and quality supervisors, and management. No statistical or mathematical background is required. Interactive seminar Bring your own laptop. You will perform exercises on bioprocess data management and analytics using the web-based educational software tool inCyght®.
Course Outline
End of Pre-Conference Symposia
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