Myriam Armant view bio | back to agenda
Director, TransLab, Boston Children’s Hospital

Sustainable Development of Cell & Gene Therapy: Perspective from an Academic Translational Lab

The field of cell and gene therapy has been revitalized in recent years following several publications of clinical trial data showing therapeutic benefit combined with an excellent safety profile. This encouraging data is fueling a rapidly growing ecosystem of biotech and pharmaceutical companies that are investing to bring some of these therapies to market. As industry is developing approaches to commercialize these more established therapies, one needs to think about the future of the field. This presentation will zoom in on the role that academic translational labs can have in providing a long-term sustainable pipeline of novel cell and gene therapies.

Chris Ballas view bio | back to agenda
Associate Director, Gene Mediated Cell Therapies, WuXi Apptec

The Rise of Gene Therapy: Managing the Practical Challenges of Success in a CAR-T Product Case Study

The recent clinical success of CAR T cell immunotherapies has resulted in practical difficulties moving programs towards commercial readiness, in part by putting a strain on available manufacturing capacity. The unique challenges facing program leaders as they seek to meet the manufacturing needs of their rapidly advancing therapies will be discussed. Attendees will benefit from a better understanding of manufacturing options, timelines, bottlenecks, and critical decision points as these specialized projects move out of academic, R&D or early clinical studies to be scaled up for larger trials and commercial programs.

Dominic Clarke view bio | back to agenda
Global Product Manager for Cellular Therapy and Bioprocessing, Charter Medical

Addressing the Risks: Particulates, Extractables & Leachables in Cell Therapy

The cell therapy industry is currently engaged in over 1,900 clinical trials around the world. This includes more than 300 clinical trials being sponsored by approximately 250 companies developing commercial products for almost every imaginable disease or condition. Cells have been used as a standard of care for decades in the medical practice of hematology and oncology with stem cell transplants being a staple of cancer treatment since their inception in the late 1960s. The current pipeline of cell-based therapies however represents a maturation of the science surrounding these products. As such, the next generation of products carries with them enhanced expectations of quality, safety, efficacy and commercial viability.

For cell therapies, the cell is the product and therefore anything used as part of the manufacturing process impacts the product and remains a part of the final product. With the advancement of the products and the industry as a whole, it is becoming increasingly important to recognize the potential impact that items like particulates or extractables/leachables pose to the quality, safety and efficacy. So consequently, suppliers and companies developing commercial cell therapy products need to consider the potential risks and work together to better understand and control the components and manufacturing steps inherent to each product. Compared to the first generation of cell therapies, the products currently in clinical development must be better characterized and understood. And as many of these products are administered intravenously, developers involved with these products must work to improve their manufacturing quality and reduce the potential risk of harm to patients.

John Duguid view bio | back to agenda
Director, Process Development, Vericel Corporation

Validation and Implementation of Rapid Microbiological Methods for Cell and Gene Therapy Products

Rapid detection of contaminants is essential for cell and gene 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 test results for conventional microbiological tests may not be available prior to product release or patient administration. Developing, validating, and implementing rapid microbiological methods enables real-time release of these products, however. Application of a risk-based approach during development mitigates most issues prior to validation and facilitates successful implementation. Proactively removing these obstacles provides convincing evidence that the advantages of rapid methods outweigh the limitations, garnering support from regulators for implementation as routine product release tests.

Gary C. du Moulin view bio | back to agenda | back to panel
Associate Professor of Drug Regulatory Affairs, Massachusetts College of Pharmacy and Health Sciences University

Manufacture of Cell Therapy Products: A Look Back Through 26 Years of Development, Regulatory Challenges and Lessons Learned

This presentation summarizes a twenty six year career in cell therapy quality system and product development in two commercial organizations. During this time, eight cell based therapeutic modalities were produced for clinical applications including such unmet medical needs as catastrophic burns, Parkinson’s Disease, and renal cell carcinoma. The time frame included a period when such products were unregulated but which ultimately lead to a basic understanding of the need to develop robust quality systems in order to minimize variability, reduce risk, and optimize the therapeutic value of these therapies. The advent of modern Pharmaceutical Quality Systems (PQS) through global acceptance of the harmonization efforts by the International Council for Harmonization (ICH) provides developers with algorithms to ensure that quality is built into the product through a systematic understanding of the manufacturing process. Elements of Good Manufacturing Practice relating to cell based products to achieve and sustain quality will be discussed and summarized.

Denise Gavin view bio | back to agenda
Chief, Gene Therapy Branch, Division of Cell and Gene Therapy, United States Food and Drug Administration

Transitioning from Late Phase to Commercial Manufacturing of Gene Therapy Products

Brian Hawkins view bio | back to agenda
Senior Application Scientist, BioLife Solutions

Biopreservation Challenges in Cell Therapy Manufacturing

Cellular therapies are cell and tissue products sourced from biological material that are employed as ‘living drugs’. However, such ‘living drugs’ require specialized biological support, namely biopreservation, to ensure structural integrity and viability during ex vivo processing and handling. Successful biopreservation ensures optimal recovery, viability, and a return to function of cells post-preservation to deliver clinical and commercial efficacy. Unfortunately, traditional isotonic/extracellular-like home-brew cocktails (which may contain serum) are not compatible within a GMP (Good Manufacturing Practices) clinical manufacturing process. This presentation will address the incorporation of biopreservation best practices into a cell manufacturing process, including the evaluation, selection, and qualification of appropriate reagents, Quality/Regulatory considerations, and the transportation and storage of source material and final product.

Eileen Higham view bio | back to agenda
Associate Director/Product Development Team Leader - Adoptive Cellular Therapy, MedImmune

Leveraging CMC Capabilities with Biologics to Deliver Novel Cellular Therapies

Clinical trials using chimeric antigen receptor (CAR)-T cells targeting CD19 have generated encouraging clinical responses in patients with hematologic malignancies, demonstrating the exciting potential of CAR-T platforms for treating cancer. Most CAR-T products are autologous (individualized) with complex composition, so robust CMC strategies will be needed to broaden and accelerate patient access to these promising therapies. Production processes for CAR-T products have many potential variables that could impact product quality, including variables associated with the source and composition of starting cells, the strategy used for genetic engineering, the expansion conditions/duration and the formulation. However, the fundamental principles of cell culture engineering that have enabled the development of robust, well-controlled and scalable cell culture processes to produce biologics can be adapted and applied to such complex cellular therapies to help consistently deliver safe and efficacious products. This talk will outline how core CMC capabilities in a biologics organization can be leveraged for current and next generation process development for complex cellular therapies, while also highlighting potential gaps.

Joseph Hughes view bio | back to agenda
Vice President, Technology Development and Chief Scientist, WuXi AppTec

Challenges for QC Testing of Cell and Gene Therapy Products: Technical and Logistical Issues

Analytical, bio-safety and logistical issues provide numerous challenges to establish and maintain raw material, in-process and final product testing for most cell and gene therapy products. A few of the common issues will be described for raw material release programs that fall into the categories of potential biosafety issues, testing complex materials, and material release at pre-market/commercial stages. General outlines of in process and final product testing programs for autologous, allogeneic and vector production will be described. From the perspective of a contract testing and manufacturing company some of the common QC issues include the necessity for bringing on many semi-custom and custom assays for each product, and the corresponding need for reference materials used for verifying and validating the assays. A few examples of QC tests will be described where different technologies are being introduced to enhance the sensitivity and turn-around times. Examples will also be provided for dealing with potential residual contaminants with QC tests and implementing validations to demonstrate clearance at the final product stage.

Rosemarie Hunziker view bio | back to agenda
Program Director, Tissue Engineering/Regenerative Medicine, Biomaterials, and Implantable Medical Devices, National Institutes of Health / National Institute of Biomedical Imaging and Bioengineering

The Federal Investment in Cell Manufacturing for Regenerative Medicine

More than 25 years after the first Tissue Engineering conference (sponsored by the National Science Foundation), the federal government is now spending about a billion dollars a year in developing regenerative medicine strategies to treat illness and injury. Yet, there are very few products in the medical mainstream, and no “blockbusters.” Much of the reason for this slow translation from discovery science to treatment deployment is related to a lack of attention to a robust product development process for cell-based therapies. Current systems are too inefficient for suspension-grown cells, and largely non-existent for adherent cells. Without research on efficient, safe production of cells, cell-based precision therapies will be economically and (in some cases) technically unrealizable.

Sadik Kassim view bio | back to agenda
Associate Director, Cell & Gene Therapies Unit, Novartis

Toward Safer and More Effective CART Therapies

Cancer immunotherapy turns the immune system into a weapon to fight tumors; one way to harness the immune system is to genetically engineer a patient’s own T cells with chimeric antigen receptors (CAR) that target the T cells to tumors. In some cases these experimental CAR therapies have produced remissions in patients who had failed all other therapies. The field is now at a critical juncture where a number of CAR therapies are advancing to pivotal trials. However, little is known about how to characterize these cellular products before administration, and more needs to be understood about how different manufacturing strategies can affect safety and efficacy. This presentation will summarize the state of the field and outline general strategies for potency assay development and implementation in pivotal trials and for market authorization.

Stephen Kennedy view bio | back to agenda
Chief Technology Officer, Histogenics Corporation

Development of Robust Manufacturing Process Technology: Reliable Delivery of Regenerative Medicine Products or Services to Surgeons and their Patients

NeoCart® is an autologous hyaline cartilage tissue repair/cell therapy that is in Phase 3 clinical testing, indicated for use in the knee joint. NeoCart® is representative of a new class of regenerative medicine therapies, and the product has many characteristics of a service. Each NeoCart® is unique to each patient, NeoCart® is provided as part of a surgical repair process, there is no inventory, release is essentially immediate, and provision of NeoCart® to clinics will be localized to an extent. Given these characteristics, manufacturing process development, operation, quality control and compliance methodologies typically associated with robust and reliable production of pharmaceutical products require modification in order to ensure the development of sustainable regenerative medicine therapies. The manufacturing and supply chain challenges associated with new regenerative medicine cell and tissue therapies will be described through this NeoCart® case study.

Bruce Levine view bio | back to agenda
Barbara and Edward Netter Professor in Cancer Gene Therapy, University of Pennsylvania

The Creation of Synthetic Immunity: Chimeric Antigen Receptor T Cells for Relapsed/Refractory Cancers

Chimeric Antigen Receptors (CAR’s) can redirect the specificity of T lymphocytes to see cancers previously invisible to the immune system. Since 2010, following the infusion of autologous CAR T cells, we have observed significant and durable clinical responses in leukemia in patients who are relapsed or refractory to all other available treatments. In Acute Lymphocytic Leukemia, 70% of subjects enrolling in clinical trials have already failed a stem cell transplant and a 90% Complete Response rate has been induced. In 2014, this technology received Breakthrough Designation from the US FDA. An alliance between the University of Pennsylvania and Novartis has allowed significant expansion of the CAR T cell clinical and research programs in hematologic malignancies and other cancers with the initiation of multi-center clinical trials.

Bill Lundberg view bio | back to agenda
Chief Scientific Officer, CRISPR Therapeutics

Translating CRISPR-Cas9 Technology Into Transformative Therapies for Serious Diseases - Manufacturing Considerations

Just a few years ago, a new way to precisely edit the genome using the powerful molecular “scissors” of the CRISPR-Cas9 system was discovered. In 2012, Emmanuelle Charpentier and colleagues reported on the key components of a simple and highly versatile system, involving a single endonuclease that can be guided by a programmable RNA to selectively target any DNA. The system was quickly applied to virtually all cell types that have been tested, from Arabidopsis to zebrafish, making its way into various animal models, including models of human disease. The importance of this discovery - to be able to easily and highly selectively edit DNA - cannot be overstated. The adoption of CRISPR-Cas9 gene editing for use in research, and for developing novel medicines, has been remarkably rapid, in part because it is so easy to apply these fundamental discoveries to higher organisms including humans. Some, but not all, of the key aspects of process development and manufacturing for CRISPR-based gene editing technologies are similar to those of other gene therapy methods. These and other considerations are critical for us at CRISPR Therapeutics, focusing on creating transformative gene-based medicines for patients with serious diseases.

Mark McCall view bio | back to agenda
Lecturer, Loughborough University

Understanding Manufacturing Costs in T-Cell Production and Distribution

This work quantifies the highest cost activities and interdependencies in cell therapy manufacture with a specific focus on autologous modification and expansion of T-cells.

A simulation model based upon activity based costing methods in combination with discrete (event simulation) evaluated the inter-dependencies between critical manufacturing and delivery tasks. Input data was collected from case studies of publish process performance and financial reports of biotechnology manufacturing companies. Successfully planning and managing manufacturing processes is problematic in an emerging industry lacking precedents and standardized technology platforms. Methods of understanding and reducing developmental uncertainty and risk are needed to focus resourcing decisions. A particular requirement is to understand the impact of manufacturing, in this highly regulated sector. Relative costs for process validation and cost of goods supplied (COGS), are significantly higher than for established pharmaceutical industries.

Results from the model quantify the cost impact of distributions in process performance and manufacturing failures. High impact areas are the interdependence of shelf-life, number of manufacturing locations and regulatory burden on demonstrating comparability. The model also allows for the calculation of the cost impact of improved process performance and standardization.

Knut Niss view bio | back to agenda
CMC Team Director, Pharmaceutical Operations & Technology, Biogen

Successful Cell Therapy Manufacturing: Think Big!

The manufacturing of cell therapies differs from traditional drug manufacturing in various ways. In this respect autologous therapies are a special case since the manufacturing is tied to a single patient. In addition, product cannot be made in advance and therefore close logistical coordination is required from obtaining the starting material to delivering the product (“bedside to bedside” or “arm-to-arm”). While these challenges can be managed in early clinical trials through close interaction between the manufacturing organization and the clinical site, commercial needs require a focus on cost effective operations. Thus, to reach a commercially successful cell therapy, logistical challenges in combination with processing technologies need to be evaluated early on in the clinical development path.

Michael Paglia view bio | back to agenda | back to panel
Senior Director of Technical Operations, bluebird bio

Autologous Gene Therapy Manufacturing Comparability: Meeting the Challenge Through Process Understanding and Product Characterization

The demonstration of biochemical, biophysical and cellular comparability of ex vivo autologous gene therapy products across multiple facilities may be required to meet capacity requirements for clinical manufacturing. Additionally, the comparability plan may be required to be suitable to support both GMP manufacturing in the US and EU. A comprehensive comparability plan should therefore incorporate elements required to support a Biological License Applications and Marketing Authorization Application as early in the process as possible. This planning requires cross-functional collaboration and process understanding gained throughout the development life cycle of the product.

A summary of comparability approaches to support US and EU GMP manufacturing will be presented. The elements of the comparability planning and technology transfer activities to ultimately support GMP manufacturing include facility readiness, training runs, aseptic process validation, process engineering runs, assay qualification/validation and traceability. The data generated from the robust technology transfer process are compared to development and historical GMP manufacturing data in order to evaluate the comparability and suitability of the transfer across multiple facilities. Having a strong development infrastructure allows for the ability to gather data to increase process understanding, define acceptance criteria and, most importantly, aid in solving challenges as they arise.

Anne Plant view bio | back to agenda | back to panel
Chief of the Biosystems and Biomaterials Division, and Director of Biological Programs, National Institute of Standards and Technology

Measurement Challenges for Cell Therapies

Cell therapies pose unique challenges associated with determination of the biological character and function of a complex living product. These challenges are at least partly measurement challenges. Robust and meaningful assays that provide metrics of safety and effectiveness are needed for characterization of product, and for release assays. As manufacturing processes mature, it becomes increasingly important to establish comparability between product produced at different times and places and after changes in the manufacturing process. A key is to apply the principles of measurement assurance, supporting data, and documentation to provide confidence in the comparability of measurements. NIST is working with the community to help establish better measurement technologies and quantitative methods for comparability of measurements at the cellular level. Examples in cell counting, flow cytometry, and quantitative imaging will be presented.

Jerome Ritz view bio | back to agenda
Executive Director, Connell O’Reilly Cell Manipulation Core Facility, Dana-Farber Cancer Institute, Brigham and Women’s Hospital

cGMP Cell Manufacturing at Academic Medical Centers

Many academic medical centers have experienced cell-manufacturing facilities that can support clinical trials evaluating a variety of extensively manipulated cellular products. These cGMP facilities are located primarily in comprehensive cancer centers and have experience manufacturing hematopoietic stem cells, genetically modified stem cells and lymphocytes, cellular cancer vaccines, antigen specific T cells, natural killer cells, mesenchymal stromal cells and other cell types. These are often autologous cell products that are individually manufactured for specific patients. Academic cGMP facilities offer an alternative manufacturing resource for early phase clinical trials needed to establish the safety and potential efficacy of novel cellular products.

Martha Rook view bio | back to agenda
Director, Stem Cell Bioprocessing Group, EMD Millipore

Scalable Manufacturing Solutions for T Cell and MSC Cell Therapy Products

The long-term view of cell therapies predicts an increased need for expansion solutions that are scalable, utilize animal origin-free materials and are compatible with limited downstream processing steps. Current in vitro culture methods in 2D vessels do not generate sufficient cell yields at the desired cost of goods to meet these commercial goals. Transition to stirred tank bioreactor cultures can address issues of scale and novel media and supplements can increase cell yield while decreasing dependence on fetal bovine serum. However, these changes will require additional harvest solutions if microcarriers are used and must have minimal impact on the cell characteristics and clinical efficacy. We have developed a manufacturing paradigm that uses a scalable, single-use, stirred tank bioreactor for both T cell and human mesenchymal stromal/stem cell (hMSC) expansion and filtration based downstream purification. Such a manufacturing scheme enables direct monitoring for the specific cell characteristics at any point during the culture, thus assuring product quality and consistency. In addition, bioreactor expansion provides ease of use in handling and lower medium volume requirements reducing cost of goods.

Jamie Thurman-Newell view bio | back to agenda
Principal Investigator – Healthcare Technologies Group, Loughborough University

Analysis of Biological Variation in Blood-based Therapy as a Precursor to Biomanufacturing

Currently cellular therapies, such as haematopoietic stem cell transplantation, are produced at a small scale on case-by-case basis, usually in a clinical or near-clinical setting. To meet demand for future successful cellular therapies will require a robust and scalable manufacturing process that is either designed around, or controls the greater degree of variation that is associated with biological starting materials. However, very little systematic evidence has been developed explaining the extent and distribution characteristics of input, or, process variation within these therapies.

Using haematopoietic stem cell therapy (HSCT) as an exemplar, this work begins to quantify the magnitude of the variation encountered when working with a biological starting material, and explores potential sources and causes thereof.

Michael Washabaugh view bio | back to agenda
Senior Director of Research and Development, MedImmune

Manufacturing Challenges for Viral-Vectored Vaccine & Gene-Therapy Products

Viral biopharmaceuticals present a major challenge to bioprocess development because of the complex nature of virus structures and our limited understanding of the critical structure-function relationships. CMC and Quality challenges for manufacturing viral biopharmaceuticals include: aseptic processing vs. sterile filtration; measuring the particle-to-infectivity ratio; controlling process residuals; establishing a correlation of genome copies with infectivity; controlling virus aggregation; selecting an appropriate host-cell substrate; and controlling the viral particle-size distribution and morphology. This talk reviews the scientific challenges in the production and characterization of viral-vectored vaccines and gene-therapy products, strategies to accelerate their development, and emerging ‘disruptive’ approaches to ensure a robust manufacturing process.

David Williams view bio | back to agenda
Professor of Healthcare Engineering, Loughborough University

Manufacturing Challenges for Cell and Gene Therapies

This presentation will take a translational perspective and overview the manufacturing challenges for cell and gene therapies taking account of their commercial and regulatory context. After introducing some of the work in the field to date, it will identify key areas for pre-competitive work that will assist the growth of the industry and permit the patient benefits that these therapies have the potential to bring. The presentation will also briefly introduce the UK innovation eco-system for these products.

Alison Wilson view bio | back to agenda
Principal Consultant, CellData Services

Risk-Based Approach to Comparability: The Regulatory Expectations

Comparability is a critical element of development of cell and gene therapy products, and getting it right can mean the difference between a smooth application process and a minefield of justifications and retrospective studies. Understanding the regulators’ expectations can help to ensure a rational and systematic approach as your product moves from first clinical study to MAA/BLA and beyond.

J. Fraser Wright view bio | back to agenda
Co-Founder and Chief Technology Officer, Spark Therapeutics

Development of AAV Vector Product Chemistry, Manufacturing and Controls to Support Clinical Program Advancement

Recombinant adeno-associated vectors have shown the potential to establish a new therapeutic paradigm to meet unmet medical needs for many serious diseases by therapeutic gene transfer. This presentation will review aspects of investigational product chemistry, manufacturing and controls for AAV to support clinical program advancement.