CGTP Summit 2023 / Cell and Gene Therapy Products Symposium 2023

Comparability assessments are necessary for life cycle management of all biological products, including cell and gene therapies (CGT), and are conducted to ensure that manufacturing changes do not adversely impact product quality, safety, or efficacy.  The complexity and diversity of CGT product modalities can pose considerable challenges to the usual approaches, which are guided by the principles in ICH Q5E.  In this summit, we will discuss a range of CGT modalities and some new concepts in comparability required for certain CGT products.

Viral vector-based gene therapy products are the fastest growing segment of the gene therapy field, with adeno-associated virus (AAV)-based vectors dominating the landscape. The possibility of a one-time injection, and a relatively low-risk safety profile, increased demand for application of AAV-based vectors for the treatment of rare, serious, and life-threatening diseases. As sponsors scale-up and scale-out to meet the increasing demands and implement changes to optimize manufacturing process productivity and performance, it is imperative to effectively design and carry out comparability studies. 




A well thought out comparability study is critical for demonstrating that the product attributes indicative of quality, safety and efficacy are similar pre and post change. Data derived from a robust comparability study also ensures that the preclinical and clinical data derived pre-change can be leveraged for future clinical studies and/or for supporting licensure without the need for repeat studies with post change product to demonstrate comparability. Implementing manufacturing changes to meet the demands of clinical supply and commercialization has presented challenges when evaluating comparability of the pre- and post-change product.  For example, transition from an adherent to a suspension process may increase output while simultaneously impacting process- and product-related impurities. Limitations in the current understanding of how structure impacts function thus limits our ability to know which product quality attributes are important when making manufacturing changes. Inadequate comparability studies can lead to delays and misalignment of the clinical and CMC development and sometimes to the stalling of promising clinical programs. 




This session will include case studies that illustrate the challenges and the strategies used for assessing comparability at different stages of development of viral vector-based gene therapies, and a discussion of the key considerations in the design of comparability studies.




Session Speakers: 




Case Study: Comparability between AAV manufactured by Triple-plasmid transfection/HEK293 and Double-baculovirus/Sf9 Processes 

Garrett Daniels, Prevail Therapeutics




Analytical Comparability – Evolution of Analytical Methods & Case Study for Late-Stage Change

Phillip Ramsey, Sangamo Therapeutics




De-Risking Analytical Comparability for an AAV Manufacturing Process Change in Late Development

Taro Fujimori, Ultragenyx




Assessing Comparability: It’s More Than Just Numbers 

Julia O'Neill, Direxa Consulting

Comparability assessments for cell-based therapies are challenging due to complex manufacturing processes, inherent variability of cell starting materials, and evolving understanding of product quality attributes and analytical technologies. Many of these products are made-to-order for a specific patient, and materials are limited for any type of analytical evaluation.  Early generation of the first autologous cell therapy products applied fast-to-market CMC approaches to expedite the delivery of life-saving treatments to patients.




As the focus of the field shifts towards optimized manufacturing, better understanding of CQAs, and superior product performance, well designed comparability strategies can streamline cell therapy product development, reduce the costs of manufacturing, and provide faster access to these important medicines. Limited characterization and understanding of the relationship between the product and its function further complicate the ability to rigorously compare pre- and post-change product. 




In this session, comparability strategies used with commercial and investigational cellular therapy products will be presented as case studies. In addition, industry stakeholders and regulators will engage in discussions to address uncertainties in comparability including planning comparability studies during early and late stages of drug development, and challenges involved in showing clinical relevance. The relevance of the lessons learned to newer generations of autologous and allogeneic CAR-T cell products will be discussed. Discussions will also include gene editing and healthy donor considerations to maximize product and process consistency while ensuring product quality, safety, and efficacy.




Session Speakers:




Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products

Elizabeth Lessey-Morillon, CBER, FDA




Statistical Perspectives on Analytical Comparability Studies for Autologous Cell-based Therapies

Kedar Dave, Bristol-Myers Squibb Company




Challenges and Considerations for Allogeneic CAR T Therapy Comparability Studies 

Mark DiMartino, Allogene Therapeutics

Keynote Speaker: 




Gene Therapy Drug Development for Ultra-Rare Disease: Challenges & Opportunities

Becky Schweighardt, Grace Science LLC

With the significant progress in the development of individualized medicines, several issues with respect to their routine quality testing have emerged. As a new batch has to be tested for each patient, an extensive set of quality attributes to be analyzed and elaborate testing methods can be a challenge on both number of samples that are needed and the time that is required for testing. The latter is especially true for verifying the sterility of the drug product. As batches for individualized medicines cannot be stocked and the medical needs often require fast treatment of the patients, standard sterility testing can become the limiting factor for the success of an individualized therapy. In addition, it has to be ensured that the assays will function independent of the patient-specific aspects of the final product. 




In this session, we will discuss key challenges and opportunities with respect to product quality testing for Individualized medicines to enable the successful development of such therapies.




Session Speakers:




USP Evolving Position on Use of Rapid Microbial Methods

Huiping Tu, United States Pharmacopeia 




Defining Microbial Control Strategies for Cell-free and Cell-based Individualized ATMP's

Friedrich von Witzingerode, Genentech, a Member of the Roche Group




Delivering Next Generation Cell Therapy Manufacturing Faster without Compromising Quality

Scott Nichols, Kite, A Gilead Company




Additional Panelists:




Elvira Argus, CBER, FDA

Bryan Silvey, A2 Biotherapeutics, Inc. 

Bringing treatment to those afflicted with an ultra-rare disease is complex. These products are encumbered with challenges ranging from high development costs with a limited ROI, to issues with executing and interpreting clinical trials with unusually small patient populations. Furthermore, the cost to generate the quantities of product required to support an approvable CMC package can be prohibitive for many organizations. 




This session will address ways in which companies have tackled the CMC and regulatory challenges when bringing these life changing therapies to patients in need.




Session Speakers:




Manufacturing Challenges Limiting the Access to ATMPs 

Ralf Altenburger, F. Hoffmann-La Roche Ltd.




Development of a Single Patient CRISPR Therapeutic 

Richard Horgan, Cure Rare Disease




Additional Panelists:




Emmanuel Adu-Gyamfi, CBER, FDA

Becky Schweighardt, Grace Science LLC

Ensuring the Virus Safety Profile of Your Product - Expectations and Recommendations From the Latest Update to ICH Q5A

Rebecca Bova, MilliporeSigma

Kathryn Martin Remington, MilliporeSigma

Potency testing is a critical part of the assessment and release of cell therapy products. These functional assays provide quantitative assessments of the biological activity of a cell or gene therapy product that are associated with that product’s in vivo mechanism(s) of action (MOA). Current state-of-the-art analytical methods still rely mainly on in vitro assays including immune-assays, cell-based proliferation, cytokine release as well as cytotoxicity assays and involve complex technology such as flow cytometry. In some cases, these assays may lack the required robustness, simplicity, sensitivity and/or throughput required to function well in the QC GMP environment.   In other cases these assays reflect an average measurement that represents the entirety of a sample and do not provide information regarding the function associated with individual cell phenotypes. Next generation potency assays are needed which are easy to use, robust and provide a more comprehensive evaluation of the quality attributes of the Drug Substance (i.e. Viral Vector, plasmid) and Drug Product.   




This session will involve case studies highlighting innovative approaches being used to develop potency assays in support of programs from early phase to late phase and commercialization. Assay design strategies focused on reflecting a cell therapy product’s complex MOA, while balancing this with attributes that are important for a method to function effectively to perform QC release and stability testing will also be included. Points to consider for critical reagents used to support potency assays for cell/gene products as well as viral vector will also be discussed.




Session Speakers:




Rethink the Potency Paradigm for Gene Therapy Products 

Xiaohui Lu, Ultragenyx




Success Story: Luxturna Potency Assay Development to Validation 

Ravindra Kumar, Spark Therapeutics




Unleashing the Power: Assessing CAR T Cell Therapy Potency and Maximizing Life Cycle Management 

Seema Bansal, Bristol-Myers Squibb




Additional Panelists:




Andrew Byrnes, CBER, FDA

Many cell and gene therapy products use special delivery devices. Generally, there are two approaches for development and commercialization. 1: specify a device brand in the label to be used with the cell or gene therapy products. Under this approach, the sponsor is developing a drug/device combination product, need to navigate complex, often rather different, regulatory pathways in different countries, regions. 2: not to specify a brand but only describe device characteristics so that end users can source the device on their own to the defined characteristics. Under this approach, the sponsor needs to consider data required to support drug compatibility with potentially a class of device products. The US FDA has issued a guidance in 2019 on CGTP delivery devices. In the EU, regulatory requirements differ between integral, non-integral co-packaged, or not co-packaged (e.g. referenced) medical devices. In addition, distinct legislative frameworks for medicinal products and medical devices require joint input of respective experts. 




This session will use case studies to explore and discuss each approach, share lessons learned during early and late stage CGTP development on managing regulatory procedures, overcoming regulatory hurdles.




Session Speakers:




The Regulatory Interface of ATMPs and Medical Devices in Europe 

Ilona Reischl, Austrian Medicines and Medical Devices Agency




U.S. FDA’s Perspective on Delivery Devices Used to Administer Cell and Gene Therapy Products 

Laura Ricles, CBER, FDA




What Device Engineers Can Teach You About CGTP Delivery Devices 

Saran Baskaran, AstraZeneca
Samir Shah, AstraZeneca

Raw material selection decisions early in the development of ATMPs are crucial and can impact the final product quality and ultimately patient safety. Therefore, it is imperative that developers employ a risk-based approach when selecting and qualifying materials to establish the necessary controls to ensure process robustness and safety of the product.  




Material classification is key to a successful implementation of a risk-based approach. The same material (e.g. plasmids) may be classified differently according to its use in different products and thus warrant a different control strategy. Classification of materials should be considered early in development with input from regulators as appropriate. Current guidance from many regulatory and standards bodies including FDA, EU, ICH, PIC/S, USP, and Ph. Eur., provide a foundation though some inconsistencies and use of alternate terminology do exist.  




Control strategies for materials should be commensurate to their classification and, therefore, their potential to affect critical quality attributes of the product. Suppliers are an extension of an ATMP developer’s manufacturing process and the rigor of suppliers’ qualification activities and controls can impact the manufacturing process and the product.  As suppliers are often unfamiliar with therapeutic manufacturing requirements (e.g. the need to minimize or eliminate the use of animal-derived materials),a partnership mindset by both parties to ensure transparency and joint mitigation of risks is crucial.   




Session Speakers:




Material Considerations for The Manufacture of Pluripotent Stem Cell Derived Products

Saran Karumbayaram, CBER, FDA




Challenges and Perspectives in the Manufacture of Synthetic sgRNA used in Cell and Gene Therapy

Joe Guiles, Agilent Technologies Inc.




Material Qualification from a CDMO Perspective: A Phase Appropriate Approach to Material and Component Risk Control

Athenesia Faggins, WuXi Advanced Therapies

Cell and Gene Therapy programs are progressing from early academic settings to commercial manufacturing at increasingly faster pace and in greater numbers. These therapies are complex, difficult to manufacture in large quantities, and involve many bespoke technologies to make, test and release. Stability of these products is important to determine, and demonstrate the quality, safety and efficacy throughout the product shelf life which can vary widely between cell therapy products (e.g., autologous T cell products which are dosed immediately) and some gene therapies (e.g., AAV or LVV products that can be manufactured for inventory and require longer shelf storage stability). 




In this session, we will explore challenges in the design, execution and interpretation of stability studies for Cell and Gene therapy products. Additional topics include addressing short shelf life, in-use stability, product heterogeneity, lack of standardized protocols and harmonized health authority requirements and expectations and challenges with sample collection and storage.




Session Speakers:




Stability Challenges for Gene Therapy (GTx) Programs

Bingli Yan, Pfizer Inc.




Minimizing Volume Requirements for Stability Studies of Viral Vector-Based Gene Therapy Products

Ying Xu, Sanofi




Critical Quality Attributes, Stability-Indicating Test Methods and Cell-based Products: Untangling the Gordian Knot 

Don Fink, Dark Horse Consulting Group, Inc.




Additional Panelists:




Julia O'Neill, Direxa Consulting

Allogeneic cell therapies have a potential to revolutionize life-saving Cell and Gene therapy (CGT) field by removing the bottlenecks created by long scheduling delays, lengthy manufacturing times and potential product failures of autologous cell therapies. Despite some early data showing promising clinical results, allogeneic cell therapies have not yet achieved the clinical benchmark set by their predecessors. Some of the challenges unique to allogeneic cell therapies include limited understanding of donor characterization and variability, diminished persistence of allogeneic cells in patients, rapidly evolving need for novel techniques such as gene-editing approaches, and lack of suitable analytical techniques. As already seen in the first generation of autologous cell therapies, the Achilles heel of the commercialization of allogeneic cell therapies remains the CMC challenges. While the industry and regulators have collaborated immensely to advance the CGT field by bringing a number of autologous cell therapy products to the market, similar efforts are warranted for allogeneic cell therapies as the industry is experiencing a shift towards an allogeneic approach. 




In this session, we will hear from the industry stakeholders and regulators on the challenges and opportunities in allogeneic cell therapies. Speaker presentations will be followed by a panel discussion and live Q&A with panel members representing both industry and regulators.




Session Speakers:




Donor Qualification and Procurement of Allogeneic Cellular Starting Material: A Global Regulatory Perspective 

Jared Schuster, National Marrow Donor Program




Allogenic Cell and Gene Therapy Production, Opportunities and Challenges in the Use of iPSCs

Francois Gianelli, TreeFrog Therapeutics




CMC Considerations for Manufacturing Allogeneic CAR T Products

Athena Wong, Sana Biotechnology




Additional Panelists:




Pankaj Mandal, CBER, FDA

Analytics for Process-related Impurities in Viral Vector Manufacturing 

Alla Zilberman, Cygnus Technologies, Inc.

The further advance of techniques for genetic modification also necessitates development of novel and more comprehensive genetic characterization tools to identify intended and unintended genetic changes in (subpopulations of) genetically modified cells. But the proliferation of these tools poses both opportunities and challenges for those developing cell and gene therapy products. The selection of global and/or targeted genomic analysis methods requires developers to consider the questions they wish to answer and the intended purposes behind the testing. 




Is the analysis intended as a one-time highly-detailed survey of a gene-modified product, or will it be used for lot release testing? For viral vector products, what methods are best to confirm transgene identity and integrity? For gene-edited cells, how does one approach assessment of on-target versus off-target edits? For induced pluripotent stem cells (iPSCs), how does one detect genetic variants? What is the role for sequencing methods in testing of critical components and starting materials? How can bioinformatics tools be qualified in order to reliably use the large datasets generated by methods such as Next Generation Sequencing (NGS)? What are the strengths and limitations of the tools available to us, and how do more traditional methods such as karyotyping fit into the control strategy for cellular therapies? 




In this session, we will explore the varied technologies available for genetic characterization and how they can be applied to ensure product quality and patient safety.




Session Speakers:




Characterization of VivoVec: A Surface-Engineered Lentiviral Vector Platform That Generates CAR T Cells in Vivo

Richard Rogers, Umoja Biopharma




Control of Chromosome Integrity in the Routine Manufacturing of Allogeneic CAR T Cell Therapies

Kimberly Davis, Sana Biotechnology




INDUCE-seq: Ensuring the Safe Development of Cell and Gene Therapies by Gene Editing

Simon Reed, Cardiff University




Additional Panelists:




Anna Kwilas, CBER, FDA