Tuesday, September 24, 2024 - Day One of Main ConferenceTuesday, 24 September 2024 - ET (Eastern Time, GMT-05:00)

• Confidently identifying ultra-low-abundance Host Cell Proteins in therapeutic proteins
• A recursive LC-MS/MS method for data-dependent acquisition that includes an automated, iterative exclusion list
• A benchmark host cell protein library for various commercially available monoclonal antibody standards

Autologous induced pluripotent stem cells (iPSCs) enable replacement cells/ tissues to be manufactured from a person’s own blood, enabling treatment of chronic degenerative diseases without immunosuppression or donor matching. However, current manufacturing requires manual labor, qualitative human decision-making, and open systems- resulting in high variability, low scalability, and high cost ($800k/dose per Huang et al., 2019). Here we present an AI (artificial intelligence)-driven optical biomanufacturing platform for consistent, scalable production of autologous iPSC-derived therapies. Cells are imaged, AI-driven algorithms analyze images to quantify cell/ colony characteristics, and laser-generated bubbles selectively remove cells as needed.

Here we present several cell culture processes that have been replaced by AI-driven optical bioprocesses, including: estimation of well confluence, clonalization of a stem cell population, and passage-free culture of proliferating cells. We demonstrate that the cells resulting from the optical bioprocesses maintain important characteristics.

The optical bioprocesses shown here are compatible with closed biomanufacturing, which is necessary to enable parallelization while minimizing the risk of cross-contamination. We present prototypes of fluidic cassettes for closed cell culture, including demonstrations of key processes, such as: cell seeding, cell growth, and laser-based cell removal.

Together, this work enables scalable and consistent manufacturing of personalized regenerative medicines.

This presentation will provide insight into the bit.bio team's recent work to scale-up from 2-D adherent culture to 3-D suspension culture of iPSC-derived cell therapies and commercial research products. The unique characteristics of bit.bio's foundational opti-ox technology allow for precise control of homogenous 3-D suspension cultures.

Here, we summarize the development and optimization of the scale down model for the BEAM-201 manufacturing process. The BEAM-201 clinical manufacturing process makes about 15x10⁹ edited allogeneic CAR-T cells to treat T-cell acute lymphoblastic leukemia (TALL). The large-scale (LS) process uses the cells from healthy donors that are selected based on the pre-defined donor screening tests. As part of the donor screening effort, the cell culture performance gets evaluated as small-scale in process development lab. Therefore, it is relevant to use a scale-down model (SDM) that performs comparably to the manufacturing process.

The BEAM-201 process consists of eight steps from isolating the cells to preparing the final drug product. Among these steps, the isolation was identified as the main source of variability across the two scales. By changing the isolation magnetic beads, columns, and reagents, we were able to obtain comparable process outcomes such as cell population doubling, purity, viability, and editing efficiency. We also report the addition of the TCRαβ depletion step to the SDM that could reliably predict the process performance at the manufacturing scale.

Cell therapies have emerged as a groundbreaking approach in the treatment of various diseases. However, the production process for these therapies is intricate and necessitates precise monitoring to ensure both safety and efficacy. Analytical assays that are commercially available have become essential tools in this process, seamlessly integrating into the workflows of researchers and manufacturers. These assays offer the capability to measure critical parameters such as safety, potency, and quality. During our discussion, we will explore the commonly used types of assays and demonstrate how these techniques can be applied to different stages of the production process. Additionally, we will introduce our latest solutions, including rapid sterility testing of samples, rapid mycoplasma detection, and assay kits that utilize digital PCR. Ultimately, this presentation aims to provide attendees with a comprehensive understanding of the significance of analytical kits in cell therapy production. Furthermore, we will highlight how leveraging these kits can improve the efficiency of manufacturing these life-changing therapies, reducing both the time and resources required. For Research Use Only. Not for use in diagnostic procedures.

• Roadmap on how to navigate the complex path of an AAV drug product clinical development from R&D to BLA
• Current trends on various Vector designs, Manufacturing platforms, PD and AD, assays for release and characterization from Phase I – BLA drug products
• Adapting to the evolving regulatory guidance for successful IND and BLA filing with the impact on CMC changes and comparability studies

Many cell & gene therapy companies struggle to find the right balance between screening a number of novel viral vector construct designs and moving quickly through development. Often the transition from R&D to Process development (PD) can be bumpy and may result in delayed timelines or, even worse, an underperforming candidate that does not meet critical quality metrics. Building in key manufacturability and quality metrics early on in R&D helps define a successful candidate. This involves employing advanced analytics and characterization testing at an earlier stage in R&D, including cell-based functionality, to help detect any red flags that may not have been found until later in development. Additionally, aligning protocols across R&D and PD early on helps simplify the coordination and allows for more streamlined interpretation of the data. The combination of these aligned workflows result in improved characterization and allows for more viral vector designs to be evaluated in parallel. The ability to screen and characterize more sequence designs helps to understand the impact of different designs improvements such as codon optimization, promoter variants and other sequence elements. We will demonstrate lentiviral vector and AAV workflows with representative data to help highlight a streamlined workflow for accelerated development.

As monoclonal antibody (mAb) platforms evolved, the roles for each tangential flow filtration (TFF) format settled into place. In upstream applications we take advantage of the low shear environment in hollow fibers to recirculate cells without impacting product quality. Flat sheet cassettes are typically used in downstream applications, as their higher turbulence enables faster processing in smaller footprints. However, platform processes for viral vector-based gene therapies are still in their infancy, and the roles for TFF technologies have yet to be defined. Interestingly, we have seen many examples of innovators using different technologies in the same application. These new modalities carry with them unique product and process requirements compared to mAb’s. For example, lower product stability may push us towards faster and gentler processing. And more challenging adventitious agent clearance may increase the need for closed processing. With these requirements in mind, is there an ‘optimal’ TFF option? Here we aim to address this question with a comparison of TFF technology formats: hollow fibers versus flat sheets. The work focuses on adeno-associated virus (AAV) and includes data from several common serotypes and multiple locations along the downstream process. We will share technical data comparing key performance outputs such as flux, purity, and yield. Included in that work we attempt to define flow and pressure limits based on product quality (i.e., shear sensitivity of the viral vector). Finally, our comparison will cover manufacturing considerations including footprint, process economy, scalability, and options for closed processing.

Resolution Therapeutics is a clinical-stage biopharmaceutical company pioneering macrophage cell therapy for transformative outcomes in inflammatory organ diseases. The Company leverages its proprietary platform to engineer autologous macrophages with distinct pro-regenerative properties as cell therapy medicines capable of delivering superior patient outcomes across the spectrum of inflammatory organ disease. Resolution’s initial focus is on developing RTX001, its lead product candidate with first-in-class potential supported by preclinical data demonstrating anti-fibrotic and anti-inflammatory advantages relative to non-engineered macrophages, for patients diagnosed with end-stage liver disease. The Company is also advancing efforts to expand the potential of its platform beyond the liver into indications where engineered macrophages have therapeutic potential. Resolution Therapeutics is a UK based Biotech.

• Navigating the complex grey area of manufacturing for Phase 1 and 2 trials
• Keeping efficiency while complying with limited guidance
• Need conversation between regulators and developers
• Lessons learnt and case studies from companies moving between clinical phases
• Therapeutic Developer/CDMO dynamics in the phase 1 and beyond
• How to best leverage CDMO expertise and capital efficiency

• Reducing wait times and logistical magnitude to reduce overhead costs
• Increasing accessibility, distributing to multiple locations closer to patient populations and remove transportation cost barriers
• How QC release testing and material kitting and management will be handled for POC manufacturing in this ecosystem.
• Establishing harmonized regulatory standards across different regions
• Implementing robust oversight mechanisms to ensure compliance with regulatory requirements and maintain product in a distributed manufacturing model.
• EMA vs FDA approach

Technology Transfer of Cell Therapy products into Good Manufacturing Practice (GMP) operations is a critical step in the commercialization of advanced therapeutic products. The process involves meticulous planning and coordination across multiple departments including development, Manufacturing Operations (including Quality Control), Quality Assurance and Regulatory-CMC. Herein we will discuss elements regarding facility set-up, documentation, process and analytical transfer strategies whilst considering project management do’s and don’ts form the viewpoint of ATMPs. Consideration will be also taken for both early and late phase products not only as a transferring site but as a CMO partner whilst considering various health authority requirements.

Plasmids play a crucial role in the production of Adeno-Associated Viruses (AAV) and significantly impact the quality of the final product. This talk will focus on three strategic plasmid optimization methods developed at Alexion Pharmaceuticals that have significantly enhanced both AAV yield and quality.

Recombinant adenovirus associated virus (rAAV) is the most widely used viral vector for in vivo gene therapy with over 200 ongoing clinical trials across the world. A manufacturing process that is sufficiently productive with the requisite product quality is critically important for commercialization success. The Ultragenyx production system for rAAVs is based on our proprietary Pinnacle producer cell line (PCL^TM) platform that leverages stably transfected cell lines with integrated AAV and helper genes, which are induced through infection with wild type Ad5. The production platform already generates a high rAAV yield with sufficiently high quality for various rare disease therapeutic targets. To better understand whether further improvements are possible at the cell line level, as well as to better understand the intracellular dynamics of rAAV assembly and secretion, we developed a mechanistic model, and used it to simulate rAAV expression and Ad5 replication. The model was trained with empirical scale-down production data. Sensitivity analysis and non-linear optimization were used to identify bottlenecks and provide insights into the critical cellular processes that contribute to high yield and high percentage of full rAAV particles. Analysis was conducted to assess the competition between rAAV and Ad5 production. Additional improvements to the Pinnacle PCL™ expression system were to identified based on model predictions which will provide a guide for our next-generation cell line engineering efforts.

Designing a production facility for gene therapy reagents requires meticulous planning to meet the quality and customization demands. Few facilities support the flexibility required nor meet the GMP standards for the small-scale manufacture of made-to-order products where sterility, process flow, and layout are critical. Learn how Teknova built their new, modular ISO 13485-certified facility to meet the rigorous demands of GMP-grade reagents for gene therapy development and commercialization.

• Raman spectroscopy, an optical method, shows particular promise for quantification of multiple critical quality attributes (CQAs) in a single measurement.
• Appropriate design of experiments early during the method development is key to ensure success in developing QC capability. Challenges that may be encountered during manufacturing, including those related to the life cycle management of the method, will be discussed.
• Regulators have demonstrated openness about the adoption of multi-attribute Raman spectroscopy. Key regulatory considerations and feedback will be discussed.

• Grab a 'Cloud Spritz' (Aperol Spritz)
  • Culture Bioscience's booth (328)
• Grab a SmartLabs 75 (French 75)
  • SmartLabs Booth (1824)

The success of CGT development and patient access hinges on effective collaboration between vendors, developers, and end-users. Proactive planning is crucial throughout the entire journey, from early-stage development to product delivery and beyond.

• Partner Selection & Collaboration:
  • Beyond expertise, prioritize alignment with patient needs, supply chain reliability, and scalability and healthcare implementation.
  • Selecting the right CDMOs: expertise and cultural fit. Will the Bio Secure Act have an effect?
• Quality & Compliance:
  • Robust safety systems, minimize errors, meet regulatory requirements throughout entire development and manufacturing process.
  • Making delivery of therapy to patients fit for purpose.
• From Start-up to Market:
  • Develop a long-term plan, keeping patients in mind, considering delivery practicalities, securing funding, and navigating the regulatory landscape.
  • Having a solid business plan to be ‘investor ready’.
  • Considerations across multiple markets/regions.
• The Patient Journey:
  • From manufacturing decisions to product delivery - keep patients in mind to ensure therapies meet real-world needs.
  • Engaging with patient organisations and shaping your clinical trials early on.

• Grab a 'Cloud Spritz' (Aperol Spritz)
  • Culture Bioscience's booth (328)
• Grab a SmartLabs 75 (French 75)
  • SmartLabs Booth (1824)

The traditional drug discovery process is known for its lengthy timelines and high costs, relying on animal models that often don’t accurately predict human responses. DART for animal-free testing introduces a novel approach by employing human stem cells and advanced AI algorithms to develop testing models that closely mimic human physiology. This session will explore how DART’s integration of predictive analytics and stem cell technology could offer a more precise and potentially faster alternative to conventional methods. By better simulating human biological processes, DART may help identify promising drug candidates earlier in the development pipeline, reducing the risk of late-stage failures. Join us to explore how DART for animal-free testing can reshape the future of drug discovery, opening up new avenues for innovation while upholding ethical standards.

Based on client feedback, the most important challenge companies face when adopting CRISPR technology for commercial cell line engineering is the complex landscape of intellectual property (IP). Multiple ownership of CRISPR/Cas9 patents has created uncertainty regarding commercial freedom to operate (FTO). This presentation will showcase how Demeetra has combined its own Cas-CLOVER IP with the CVC, key holders of foundational CRISPR IP, clearing the path for our clients to obtain straightforward commercial licenses with undeniable FTO.

It is essential to select perfusion clones during cell line development (CLD) that thrive in the unique environment of intensified bioprocesses. Such clones have high specific productivity (qP), moderate growth rates, and high volumetric titer and yield. Traditional fed-batch CLD selects for clones that perform well in fed-batch, but this performance may not translate to a perfusion process. Here, we highlight the advantage of adopting a perfusion-specific CLD process to create more productive clones and provide an integrated solution for intensified processing using the CHOZN GS-/- cell line, a suite of best-in-class media, and the Mobius Breez Microbioreactor system.

Bruker's Beacon® platform offers comprehensive single-cell analysis by integrating light-directed Optoelectronic Positioning (OEP) and microfluidics, enabling deep interrogation of cell colonies through sophisticated assays and automated workflows. This accelerates cell line development by facilitating early evaluation of productivity, quality, and stability, streamlining clone selection in CLD campaigns.

• Grab a 'Cloud Spritz' (Aperol Spritz)
  • Culture Bioscience's booth (328)
• Grab a SmartLabs 75 (French 75)
  • SmartLabs Booth (1824)