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.
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.
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
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.
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
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.
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
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
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.
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
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.
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
Andrew Byrnes, CBER, FDA