RXIX Session Topics

Chairs
Jennifer Pollard, Merck & Co
Todd Przybycien, Rensselaer Polytechnic Institute

The pace of innovation in downstream bioprocessing is accelerating, driven by new upstream capabilities, new modalities, new technologies, new computational tools, new competition, new encouragement from regulators and new thinking. We’ve advanced from interferons and insulins, to monoclonal antibodies and virus-like particles, and beyond to CAR-T cells and exosomes. A natural consequence is that techniques and methodologies have been evolving, being discarded or replaced by newer strategies as our process knowledge and understanding have grown. It is important to recognize, however, that many current innovations have roots in and draw motivation from the past. Earlier processes that have gone through multiple rounds of process innovation may provide insights for newer challenges. Previous technologies that were not applicable may now be utilized to greater benefit given the change in expression systems, modalities, and cell line productivities. A greater diversity of expression systems may be able to take advantage of work done in the early days of bioprocessing, exploiting higher cell densities and titer to provide opportunities to leverage non-chromatographic unit operations. The newer portfolio of non-mAb related modalities may be able to adopt the same workflows and techniques established by platform antibody processes or traditional vaccine manufacture.

This session seeks contributions from both industry and academia on novel strategies, workflows or techniques that draw inspiration from the past. These can be utilized for new modalities or applied to more traditional product formats. Case studies should describe the technical inspiration drawn from the past, including an explanation of the prior technology and usage in its historical context, as well as show the application of the technology in its new form with a line of sight to future applications.

Chairs
Anne Kantardjieff, bluebird bio
John Moscariello, Juno Therapeutics, a Celgene Company

Cellular and gene therapies have been described by many as the third pillar of medicine. A large subset of these therapies is considered by some to be personalized as they utilize or modify the patient’s owns cells for treatment, such as CAR-T technologies, or genomic sequencing of the patient’s tumor to generate a customized, or on-demand vaccine. In addition to these therapies which leverage starting material from the patient, there has been significant progress providing on-demand access to vaccines and biologics throughout the world by implementing regional manufacturing in developing nations. While the therapeutic benefit of these therapies has been well established, this session will focus on the significant challenges associated with these on-demand technologies. These challenges span clinical and commercial manufacturing, including decreasing the significant manufacturing costs and implementing technologies which enable scale-out of these therapies to serve expanding patient populations.

Specific to cellular and gene therapies, this session also aims to address the use of new technologies to improve the recovery and isolation of specific cellular types, challenges in establishing a quality target product profile (qTPP) and subsequent critical quality attributes (CQAs), the use of predictive models to correlate properties of the starting cellular material to manufacturing and/or clinical outcomes, challenges in supply chain management, including traceability and the patient interface, and the impact of cryopreservation on the quality of cellular products. Case studies that speak to any or more of these areas are welcome.

Chairs
Nooshafarin (Nooshie) Sanaie, Gilead
Andrew Ramelmeier, Sangamo Therapeutics

In recent years cell and gene therapy has gained considerable attention as a new wave of therapies addressing unmet needs for a wide array of diseases and with the potential for a cure. Recent approvals of cell and gene therapies has shifted the focus towards turning these therapies from costly personalized medicines to broader, more cost-effective and universal applications using gene therapy viral vectors and allogeneic cells.

Viral vectors, both as gene therapy agents as well as CAR gene enablers for cell therapies, require similar unit operations as developed for other biological products. They, however, present unique challenges due to the size and complexity of the biomolecules. These challenges impact the performance of filtration, chromatography and viral clearance steps and need to be redeveloped for this new breed of biomolecules. A cursory look at the allogeneic cell therapy process, on the other hand, reveals very different challenges to the design and development of these therapies compared to traditional biological products. Recovery and purification technologies play a significant role in the desired cell selection from the initial blood cell pool from a healthy donor to the final selection of the engineered cells. The manufacturing cost, time and required doses are among other factors which need to be considered in development of a universal therapy. The market need can vary significantly for a specific rare or large disease indication, which can demand different scales or processes for manufacturing of these therapies.

In this session we would like to hear contributions addressing the role of recovery on the industrialization of universal cell and gene therapies, which can include the following topics:

• What roles can purification and recovery sciences play in cell selection, enrichment, depletion and its automation and scale up?
• What are the current challenges in viral vector production, scale up, impurity removal and downstream processes? How can these challenges be addressed using conventional technologies? What new approaches will need to come to bear to meet this need?
• What are some unique considerations for cGMP manufacturing of gene and cell therapies (e.g. designing of multi-product facilities, automation and equipment design, scale-up/scale-out of processes)?
• Can high throughout techniques get employed in the development and analytical aspects of the cell therapy and vector production?
• What strategies can be implemented to improve throughput, process efficiency and reduce cost of goods (COG)?

Chairs
Jayme Franklin, Genentech
Michaela Wendeler, AstraZeneca

Chemical synthesis steps are an integral part of the manufacturing process for a wide diversity of established and emergent classes of biologics, including antibody-drug conjugates, peptide and nucleic-acid based therapeutics, Fc-fusions, protein-polymer conjugates, synthetic polypeptides, and derivatized nanoparticles. The number of these modalities has grown considerably over the past years, and we must consider the unique challenges for clinical and commercial development in terms of impurity clearance, control of product homogeneity, and process consistency. Development of therapeutics containing both small and large molecule moieties requires a blending of development and manufacturing knowledge from both small and large molecule classes. In addition, as more of these molecules move into commercial process development, an integrated control strategy needs to be defined that links quality attributes of small molecule and biologics components to ensure that established quality attribute targets are met. Along with the broadening portfolio, the advancement of fully synthetic production routes for increasingly large molecules, as well as the adoption of cell free synthesis to generate complex biologics more rapidly and cost-efficiently require novel downstream approaches.

For this session, we invite contributions that explore the impact of a chemical synthesis step on downstream processing, as well as the scientific, regulatory, and business decisions that lead to the implementation of a robust process. We welcome case studies that address advanced control strategies, illustrate process evolution from early stage through commercial development, or address challenges associated with the synthetic production of larger molecules and the influence on purification processes and CQAs.

In addition, key questions to be addressed in this session include:

• What downstream strategies are successful to control conjugate homogeneity and impurity clearance following a chemical synthesis step?
• What downstream approaches are required for biologics produced fully synthetically or by cell-free synthesis? How do these operations impact CQAs, and how must we interface with the QbD paradigm for process optimization and characterization?
• Which processes benefit from approaches that leverage both small and large molecule attributes for challenging separations?
• What tools and technologies are uniquely enabling for efficient manufacturing of conjugated biotherapeutics and for process monitoring and control?

Chairs
Hong Li, Merck & Co
Juergen Hubbuch, Karlsruhe Institute of Technology

Diverse and complex biologics, vaccines, cells and vectors for gene therapy comprise a significant and growing category for the treatment of human diseases. Early manufacturability assessment of these therapeutic candidates has been one of the critical aspects in selecting modalities that can be manufactured with a robust and cost-effective process, whilst at the same time meeting the expected quality target product profile.

Key elements in manufacturability assessment include among others the ability to produce the modality as such, the respective process productivity, facility fit and finally its stability during production, formulation and storage. Stability evaluation centers on the product’s physical stability, the propensity for aggregation, chemical stability & PTMs, and pre-formulation. Stability issues can occur at different stages of the overall manufacturing process and during scale-up, which can impact not only the yield and cost of the manufacturing but also the target product profile, drug delivery, and potential patient safety.

This session will focus on early biophysical characterization such as biomolecular modeling, surrogate/high throughput analytics and other approaches – both experimentally and in silico – that can be applied to evaluate, predict and improve the manufacturability of complex biotherapeutic modalities. Case studies where these tools have been successfully utilized to predict and mitigate development / manufacturing risks are encouraged, especially those with some surprising/novel elements.

Scopes of interest include, but are not limited to:

• How can we accelerate traditional workflows? Strategic workflow, best practices and novel technologies applied in manufacturability assessment and risk mitigations, especially hard-to-predict biologics (for example, utilizing Quality by design approach, developing critical manufacturability assessment acceptance criteria);
• What can be done in silico? Computational algorithms to predict aggregation propensity and chemical instability, as well as the correlation/predictability of these liabilities to productivity, and process yield; Structural modeling to accurately predict the surface properties of biologics, for example hydrophobicity and charge, assessing not only their solution behaviors, but also chromatography ligand interactions;
• What experimental or analytical methods are there and how do we assess / analyze the data obtained? Novel experimental methodologies used in candidate formulation assessment and pre-formulation screening; empirically measured biochemical and biophysical characteristics that can provide prediction of accelerated and long-term stability behaviors.

Chairs
Sophie Karkov, Novo Nordisk
Giorgio Carta, University of Virginia

Accelerating bioprocess development is critical to speeding up the rate at which new biologics move from the lab to the clinic and to assess early on the manufacturability of new therapeutic entities. Several tools exist to accelerate process development while new tools are being investigated to address the challenges of the increasingly lean environment in which new bioprocesses are being developed. High-throughput process development (HTPD) is a well-established tool for generating process-relevant data. However, handling the large amount of data accumulated and transforming the data into effective processes remains challenging. Hybrid approaches of combining HTPD techniques with mechanistic or statistical modeling for real-world process predictions are emerging. Moreover, integration of process analytical technologies (PAT) may facilitate process monitoring and adaptive control to further accelerate bioprocess development.

This session will address advances in HTPD and other tools for integrated process development across upstream, downstream and formulation. Predictive modeling of downstream processes supplementing HTPD data, tools that could potentially avoid the need for bench-scale experimentation and enable moving directly from HTPD to large-scale manufacturing as well as multidimensional monitoring of quality attributes for fast process development will be emphasized.

For this session, we invite contributions that address rapid process development in the following areas:

• Current challenges and opportunities in bioprocess development
• Tools to accelerate bioprocess development
• Smart paths from HTPD to manufacturing scale
• On-line multidimensional monitoring of quality attributes in process streams
• Collection and use of on-line and real-time data
• Adaptive manufacturing and control
• Integrated automation
• Intelligent automation control
• PAT and QbD

Chairs
Dorothee Ambrosius, Boehringer Ingelheim Pharma GmbH & Co. KG
Steven Cramer, Rensselaer Polytechnic Institute

The implementation of Big Data Analytics for biomanufacturing is having a significant impact on the way we carry out process research for biologics, development, and manufacturing as well as throughout product life cycle management. This has been due to advances in hardware and software for storing, processing and analyzing vast amounts of data as well as our need to address the challenges of distributed manufacturing and to define quality by design in a global setting. In order to fully employ data analytics in downstream processing we must have proper access to and use of data from research, development and manufacturing. It will also be important for our community to create a common “vocabulary” to describe our unit operations and processes. We will also need to create better understanding of our processes through integrated statistical evaluations and establish sufficient platform knowledge for justifications of CQAs and Process ranges (CPP). This session will examine the state-of-the-art of Big Data Analytics and hybrid modeling approaches as they are being employed to develop, predict, diagnose and control downstream processes. We are looking for "real and executed" case studies from research, development or manufacturing that demonstrate the experience, risk and benefit of implementing the use of big data. Contributions that address the topics mentioned above as well as fundamental investigations and case studies in the following areas are encouraged:

• State-of-the-art examples of creation and utilization of data lakes.
• Advances in machine learning and AI and potential paths forward for their utilization in downstream bioprocessing.
• Harnessing digital twins of unit operations and processes through the use of machine learning, hybrid modeling or novel AI approaches.
• Using digital twins in concert with screening tools to expedite process development.
• Improved data analytics based predictive tools for molecule properties and behavior throughout the purification trains.
• Developing workflow analysis systems that will enable data analysts to include rich contextual and linking information.
• Using big data as a basis for linking product knowledge and process understanding to improve process control and reduce deviations.
• Use of data from existing processes and manufacturing facilities to support trouble shooting and to improve productivity during life cycle management.

Chairs
Lisa Connell-Crowley, Just Biotherapeutics
Victor Goetz, Eli Lilly and Company

The biologics industry has entered an era of rapid transformation that is fueling a divergent evolution of commercial production facilities. At one end, traditional mAb manufacturing is maturing towards highly automated, intensified processing in response to ever increasing cost/productivity pressures. At the other end, an explosion of new modalities and small-batch, personalized therapeutics require innovative new processes and facility designs. This session wishes to highlight the facility design concepts that define this transformation – from integrated, continuous bioprocesses, single-use technologies, ballroom designs, to modular, micro- and/or mobile facilities for on-demand or regional manufacture of patient-specific treatments.

In this session, we invite contributions across a broad range of modalities from mAbs and other therapeutic proteins to peptides, cell and gene therapies, exosomes, and vaccines that address topics such as:

• What business drivers are considered in the design and building of new facilities, or renovation of existing facilities?
• What facility design strategies are being implemented for new modalities and how do they differ from traditional mAb manufacturing?
• What modalities demand entirely new facilities vs adapting existing facilities?
• What are the regulatory challenges for future facilities and how can they be overcome?
• Does a closed system operating in a ballroom environment alleviate pre-/post-viral segregation requirements?
• How is multiproduct segregation assured when every patient is a distinct raw material as well as a distinct product?
• Do micro/mobile facilities have their own unique regulatory and operational challenges?
• Is it feasible to fully automate a micro facility at patient bedside such that a nurse could introduce a blood sample at one end and obtain a cell therapeutic at the other end?
• What are the arguments for central vs regional vs mobile facilities for patient-specific therapies?
• How can innovations such as PAT, advanced automation, comprehensive data collection, and AI, be used in future facilities?
• How can sustainability be included as part of facility design and operation?

Chairs
Jean Bender, Visterra, Inc.
Ranga Godavarti, Pfizer

The last two decades have seen the emergence of monoclonal antibodies as the leading modality of choice for the majority of biopharmaceutical companies. Chinese Hamster Ovary (CHO) based production systems have been the dominant expression system and major advances in production platforms have been made. Continued usage of mammalian systems (in particular, CHO), is expected to be high due to existing infrastructure, significant history of safety and ongoing development of technologies aimed at simplifying and improving CHO-based operations. However, the product portfolios for most biopharmaceutical companies are becoming increasingly diverse with the inclusion of multiple modalities beyond just monoclonal antibodies. These modalities cover a wide spectrum of molecules and therapies such as bispecific/trispecific antibodies, recombinant and conjugate vaccines, viruses, virus-like particles, mRNA, and gene therapy (including plasmids/viral vectors). Production of novel modalities requires systems that extend beyond CHO expression. In fact, alternative expression systems such as bacteria, yeast, and hybridoma were used to manufacture some the earliest approved biopharmaceuticals. The diversity of expression systems ranges from mammalian expression such as Human embryonic kidney (HEK) cells to non-mammalian microbial systems such as E. coli or native organisms for production of vaccines to more non-conventional systems such as yeast, algae, plant, baculovirus or even cell-free synthesis. The breadth and diversity of the expression systems and production platforms brings unique and exciting challenges to bioprocessing.

In this session, we would like to explore the impact of diverse expression systems on purification strategies for the above-mentioned therapeutic modalities. In-process control methods and analytical strategies may also be discussed. The scope of the session includes the entire spectrum from early phase process development to late stage process characterization, technology transfer, and regulatory filing.

We are specifically interested in case studies that address:

• What are drivers to evaluate alternative expression systems e.g. alternatives to CHO for mAbs?
• What are some unique challenges of biologics production using diverse expression systems e.g. related to size, heterogeneity, multi-component complexity, novel impurities or others?
• What novel technology solutions have been employed to overcome those challenges?
• Any examples of development of fit for purpose control strategies and robust analytics?
• Other than the challenge of developing recovery processes, what are barriers to wider employment of these expression systems? Does this depend on class of molecules? What technology gaps need to be filled for developing ‘platforms’?

We invite the submission of abstracts that address these questions comprehensively, i.e. as case studies that highlight the problem, the science behind the solution, and the implementation into practice.

Chairs
Raquel Orozco, Boehringer Ingelheim
Abraham Lenhoff, University of Delaware

In this session, we are interested in exploring the directions that companies and academic researchers are pursuing to meet future demands and enable manufacturing strategies. As the biologics industry continues to evolve and the market for mature products such as mAbs and vaccines becomes more competitive, companies are looking for ways to decrease cost and increase flexibility and efficiency while maintaining high quality. Additionally, non-mAb formats and new modalities such as cell and gene therapies have created new challenges that are not always readily solved with existing purification technologies and/or chemistries.

This session will evaluate the strengths of new purification technologies and will highlight the technologies required to enable future implementation to address business, scientific, technological or unmet medical needs. Innovations in any relevant unit operations are appropriate, including harvest, chromatography, and membrane or other non-chromatographic processes including new ligand and surface chemistries. Our goal is to assemble a session that spans diverse topical areas, ranging from, for instance, new downstream processing formats to design of novel separation materials by the versatile exploitation of molecular properties, with particular interest in enabling capabilities that have the potential to be as transformative and disruptive as Protein A ligand has been in monoclonal antibody downstream processing or crystallization has been for insulins.

Chairs
Jan Griesbach, Roche
Nigel Titchener-Hooker, University College London

Over the next decades, new modalities and new variants of existing drug formats will need to be brought to market successfully. This will create new challenges and opportunities for bioprocess engineers. These issues we wish to explore from a series of angles in this session. We seek contributions that address a number of questions as set out below with industrially-relevant case studies which illustrate the ingenuity of our community so do not be limited by our imagination!

• Cost of Goods (COG): How can modelling be used to help drive down yet further the cost of existing modalities, and for emerging areas such as cell and gene therapies what can we see as the cost drivers and our best ways to address these?
• Sustainability analysis: Increasingly our design and operating philosophies will be driven by concerns with achieving robust, resilient processes with improved levels of sustainability. What metrics can we use to capture both the quality of designs and their environment impact; from concept to completion?
• Facility models: In an age of digital twins, machine learning and Industry 4.0, what insights can be gained through modelling of facilities? How can we use increasingly sophisticated facility models to aid decision making? How far can we rely on them and where might they let us down?
• Supply chain management: Many newer modalities will require more advanced logistics if they are to realise their potential as biologics. What new approaches to supply chain design are needed and, for example, can we learn from other industries where “just in time” philosophies have been adopted?
• The journey to commercialisation: Can we envisage ways to bring new modalities forward, safely, rapidly and at costs that make the approaches available at a truly global scale? What process modifications may be needed to enable next generation purification to be implemented in either existing infrastructure or in facility designs of the future?

We seek submissions that articulate the opportunities for bioprocess engineers, that illustrate the needs and which showcase the benefits of impactful approaches. Above all we want to provoke a debate that informs thinking in this critical area based upon real-life examples and experiences.

Chairs
Ana Azevedo, Instituto Superior Tecnico
Glen Bolton, Amgen
Charles Haynes, University of British Columbia