Cambridge Healthtech Instituteの第9回年次会議
Intensified & Continuous Processing
2023年8月14 - 15日、EDT（米国東部標準時）
Registration and Morning Coffee8:00 am
PERFUSION AND PROCESS INTENSIFICATION APPROACHES
Which Program Is Not Accelerated? Increasing Efficiencies in Process Development for Speed, Quality, and Safety
Doing the right thing first time can be greatly informed by prior knowledge. Appropriate scientific assessments support the choice of the molecule that minimizes development effort. Process platforms allows for faster troubleshooting and produces related datasets, therefore increasing the predictive capability of process decisions. Taking smart risks, paralleling activities, appropriate prioritization, standardization and lean design of studies are all examples of tools to accelerate development. The talk will specifically discuss the reuse of columns during clinical production, as an example of a strategy that combines business and scientific arguments to support potential acceleration.
Implementation of N-1 Perfusion in Production of Biologics
The production of recombinant proteins using mammalian cell culture has become an increasingly important process in the biopharmaceutical industry. The N-1 perfusion method has emerged as a promising approach for improving protein yields and reducing production costs. The aim of this discussion is to explore the advantages and disadvantages of this method compared to traditional batch and fed-batch processes. However, this technology also presents other challenges compared to traditional bioprocessing. Therefore, we will also examine other aspects such as facility design, equipment design, and process reproducibility.
Scaled-Down Models of N-1 Perfusion Enable Screening and Development of Intensified Upstream Fed-Batch Processes
A high-seed density upstream fed-batch process was developed through the implementation of N-1 perfusion scale-down models in shake flasks and bench-scale bioreactors. A greater than 50% increase in harvest titer yields with comparable product quality was achieved as proof-of-concept for a bifunctional fusion protein using this intensified seed train process. By adding only a few additional days to the seed train duration, a significant gain in harvest titer can be achieved for increasing overall manufacturing throughput while also reducing the associated costs of goods
Session Break12:30 pm
MAXIMIZING YIELD AND IMPROVING PERFUSION PERFORMANCE
Optimisation of Commercial-Scale Intensified Cell Culture
Scaling up a bioprocess for manufacturing is complex and the impact of cell culture parameters influence manufacturing modalities. BioSolve Process incorporating Multi-objective Bayesian Optimization is used to analyse the complex design space to help identify optimal solutions. This case study identifies optimal configurations in terms of Fed Batch, Perfusion, or Intensified Fed Batch. The outcomes of the optimisation studies identify those factors that maximise economic, and sustainable benefits.
Maximizing Yield of Perfusion Cell Culture Processes: Evaluation and Scale-Up of Continuous Bleed Recycling
Bleed recycling is an innovative method to enhance yield in steady-state perfusion processes by concentrating process bleed, selectively removing biomass, and recycling the liquid fraction. This saves significant product otherwise wasted. Inclined gravity settling was compared to acoustic separation as bleed recycling technologies. With similar efficiency and no negative impact on cell viability, nutrient levels, or product quality, it emerged as the preferred technology due to its reduced complexity and scalability. A 3.5-fold bleed reduction with a 19% average harvest rate increase was achieved during a 42-day perfusion process, making it an attractive option to improve process sustainability and yield.
Networking Refreshment Break2:25 pm
Evaluating Filter Chemistry as a Lever for Improving Perfusion Performance
Sieving efficiency decline caused by foulants in therapeutic biologics production using continuous manufacturing (CM) is a significant challenge. It is undesirable to pass large quantities of foulants through the filter as it may complicate the downstream purification process. Moreover, membrane fouling may lead to filter failure and eventually batch failure. Adding expensive media additives to improve sieving efficiency might affect cell culture performance, increase cost of goods and may not be as effective across clones or programs. Here, we evaluated three commercially available, commonly utilized membrane chemistries from multiple manufacturers and compared their sieving efficiency performance.
Evaluation of a Single-Use Small-Scale Continuous Centrifuge as a Scale-Down Model for Future Manufacturing Continuous Disc Centrifuge
Continuous centrifugation is commonly used as the initial clarifying stage in the recovery of biopharmaceuticals from cell culture. The benefit of a low shear environment and suitability for manufacturing scale makes the technology a great choice over other methods like depth filtration. However, lack of a proper scale-down model make the implementation of continuous centrifugation usually a try-and-error operation directly at large scale. In this study, with the intention to develop a proper scale down model, we side-by-side compared a single-use pilot-scale centrifuge to a bench-top centrifuge. Turbidity, lactate dehydrogenase (LDH), and host cell protein were all evaluated for comparison. Successful harvesting was accomplished with high yield, great filterability, and low additional cell lysis. The process will be scaled up to a stainless steel continuous centrifuge at manufacturing scale based on the outcomes of the pilot scale conditions.
Session Break and Transition to Plenary Keynote Session3:40 pm
PLENARY KEYNOTE: SOLVING TODAY'S CHALLENGES
Overcoming the Challenges of Bioprocesses: The Future of Biomanufacturing
Novel therapies and technologies are emerging to meet the needs of patients; however, the manufacturing of biopharmaceuticals remains a complex and challenging process. As demand for biopharmaceuticals grows, the industry faces new challenges in terms of scalability, cost, and process robustness. The implementation of innovative technologies to improve process efficiency and the importance of process control and data analytics in ensuring process robustness are key levers to meet these challenges.
Commercializing Gene Therapies - The Combined Power of Patient Advocacy and Cost-Effective Manufacturing
There is only a very small handful of FDA-approved gene therapies. This presentation will examine the development of an FDA-approved gene therapy where patient advocacy played a critical role resulting in the first-ever clinical use of a lentiviral vector. Although manufacturing continues to represent a significant challenge throughout the entire R&D journey, there are opportunities for advocacy and manufacturing communities to seek alignment and combine their collective powers to achieve the common goal of increasing patient access to transformative medicines.
Welcome Reception in the Exhibit Hall with Poster Viewing5:30 pm
Close of Day6:30 pm
Registration and Morning Coffee7:30 am
DIGITALIZATION AND MECHANISTIC MODELING FOR CONTINUOUS PROCESSING
End-to-End Mechanistic Models of Integrated and Continuous Biomanufacturing Processes
We will describe examples of how Siemens customers are building and applying dynamic end-to-end mechanistic models of integrated and continuous biomanufacturing processes (ICB) to determine the impact of expected disturbances, deviations, and uncertainties on product quality. We will show practical examples where these models can generate value by performing tasks that are not possible experimentally due to the prohibitive material requirements and complexity of building end-to-end processes in the lab.
Moving towards Advanced Automation of Continuous Processing
In the Integrated Continuous Biomanufacturing project, CPI and its partners have produced an end-to-end continuous mAb production and purification system that demonstrates the possibilities of Advanced Process Control, where CQAs are measured in real-time and controlled in a flexible process. The system also utilises a flexible digital architecture to enable model-based control while maintaining robustness, and a novel flow-balancing architecture to greatly simplify continuous processing.
A Spiking-Augmentation Method to Improve the Prediction Performance of FTIR-Titer Model on New Molecules
Intensified and continuous processes require fast and robust methods for in-line titer monitoring. FTIR and chemometric-based multivariate modeling are promising tools for real time titer monitoring. This presentation demonstrates an adaptive modeling strategy: the model was initially built using a calibration set of available CB samples and then updated by augmenting spiking samples of the new molecules to the calibration set to improve the model robustness.
Coffee Break in the Exhibit Hall with Poster Viewing10:00 am
Breakout discussions provide an opportunity to discuss a focused topic with peers from around the world in an open, collegial setting. Select from the list of topics available and join the moderated discussion to share ideas, gain insights, establish collaborations or commiserate about persistent challenges. Please visit the breakout discussions page on the conference website for a complete listing of topics and descriptions.
Intensified & Continuous Processing
- Lessons learned from mAb intensified and continuous process, pros and cons
- What are your opinions to adopt this technology to other modalities such as vaccines, AAV, and plasmid purification process development?
- ICH5QA (R2) addressed viral clearance for continuous manufacturing. What are current and future industrial approaches to align with regulatory requirements?
TOWARD COMMERCIAL-SCALE AND SUSTAINABLE BIOMANUFACTURING
Intensification Strategies: Moving from Lab-Scale to Clinical- and Commercial-Scale
Processes can be intensified at all scales and at all dimensions. However, that requires implementing approaches to achieve “more, with less efforts, faster” already at the beginning. This presentation gives a comprehensive overview on strategies how to integrate process intensification through the whole product life cycle and when you switch scales and facilities. The opportunities from early development to continuous process improvements will be summarized in this talk.
Sustainable Biologics Manufacturing - Current State and Future Outlook
Sustainability of biologics manufacturing processes is critical in ensuring the efficient production of these life-saving therapies in a resource constrained world. This presentation will provide an overview of the current state of biologics sustainability for different modalities and discuss the findings from process mass intensity (PMI) and life cycle assessments (LCA). The work highlights the need for a comprehensive metric(s) that will drive innovations in sustainability of biologics manufacturing. Future directions to assess and improve the sustainability of biologics manufacturing will be discussed.
Refreshment Break in the Exhibit Hall with Poster Viewing1:30 pm
DOWNSTREAM PROCESS INTENSIFICATION
Ultrafiltration of Adeno-Associated Virus Clarified Cell Lysate for Downstream Process Intensification
Affinity Chromatography operational time is directly related to affinity load volume. Implementing an ultrafiltration step to concentrate AAV Clarified Cell Lysate (CCL) prior to Affinity loading can reduce overall operational time, maintain product quality, reduce cost of goods, and simplify the manufacturing procedure. Three commercially available membranes were evaluated over a range of conditions to show proof of concept, reproducibility, scalability, maintained or improved product quality and high product recovery.
Development of a Simplified Scaled-Down Model for Characterization of a Multi-Column Continuous Protein A Operation
Continuous manufacturing for mAbs, involving multi-column capture, has demonstrably improved productivity. Process characterization of multi-column ProA, requires substantially large volumes of material, long run duration to achieve steady state, and operational complexity of a closed, sterile system. This talk will explore the opportunities of utilizing a single column as a scale-down model for continuous chromatography process characterization of a multi-column capture step, and share the lessons learned using this approach.
Optimizing Continuous Chromatography through MPC and EKF: A Novel Approach to Address Resin Aging
The aging of chromatography columns impacts process economics intensively, including productivity, resin utilization, and buffer consumption. Our online optimization approach employs a residence time gradient during the loading step to balance these demands. Using an extended Kalman filter and model predictive controller, the approach can forecast optimal conditions to maximize productivity and resin utilization. Results showed a savings of up to 43% in buffer consumption and increased productivity and resin utilization beyond the feasible range with classic chromatography.
Refreshment Break in the Exhibit Hall with Poster Viewing3:45 pm
INTENSIFIED PROCESSES FOR NOVEL & EMERGING BIOLOGICS
A highly concentrated and purified stock solution of CHO-derived Retrovirus Like Particles (RVLP's) has been used as a BSL-1 compatible spiking agent for viral clearance studies. In this presentation we will compare the Log Reduction Values derived from RVLP's vs XMuLV over multiple modes of separation, including; Protein A, virus filtration, CEX, AEX and Mixed Mode chromatography.
Intensified Processing for Novel Modalities - mRNAs, AAVs, EVs, and More: Hype vs. Reality
- Potential for efficiency and cost improvements with process intensification
- What modalities have the most to benefit from intensification?
- What are the key technology and skill gaps impeding progress?
Close of Intensified & Continuous Processing Conference5:30 pm