Harnessing heterogeneity for the rational design of cell manufacturing.

Recognizing the challenges faced by researchers and clinicians working in the field of cellular therapy, the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, established the Production Assistance for Cellular Therapies (PACT) program in 2003 and expanded it in 2010. The PACT program provides both clinical product manufacturing support that furthers the mission of NHLBI in the areas of cardiac, lung, and blood diseases and broad support of translational development across all disease areas to serve the entire cell therapy community. The program also provides access to expertise in project management, regulatory affairs, and quality assurance and control. Education initiatives include webinars, cell processing facility-hosted workshops, national workshops, and active participation and leadership within the cell therapy community through collaboration with other cell therapy organizations and academia. So far, over 650 PACT-manufactured cell therapy products have been administered in 32 clinical trials for a range of illnesses and diseases such as acute myocardial infarction, sickle cell disease, and graft-versus-host disease.

Uncovering Manufacturing Challenges Behind Cell and Gene Therapy

Redefining the role of blood establishments as raw material suppliers, manufacturers, and distributors for new cell therapies: the Blood Systems experience.

Cell and gene therapy manufacturing capabilities in Australia and New Zealand

Knowing thyself: an audit of cell therapy manufacturing in Australia and New Zealand

Single-use centrifugation solution for volume reduction and cell washing process in cell therapy manufacturing

Cell therapies have the potential to effectively treat and even cure complex, currently untreatable diseases with unprecedented success. The cell therapy industry has been growing rapidly since the Food and Drug Administration approval of the first product in 2017. Despite tremendous promise, there are significant and unique challenges that must be overcome to make cell therapy manufacturing reproducible, scalable, high‐quality, and cost‐effective. Discovery and implementation of critical quality attributes (CQAs) and critical process parameters (CPPs) to the complex cell therapy manufacturing processes is one such grand challenge for the field. The role of process analytical technologies (PATs) in CQA/CPP discovery and eventual in‐process, or at‐process monitoring to maintain consistent process and product quality, is indispensable. Here we discuss the major challenges and the strategic framework for optimizing process development and related PATs for various cell therapies, with a focus on upstream processes. We introduce relevant approaches, such as quality‐by‐design (QbD), and the implementation of PATs to enable QbD in current biomanufacturing processes. We examine state‐of‐the‐art PAT implementation on standard physicochemical parameters in biopharmaceutical operations and consider potential cell therapy‐related parameters that may be instrumental in overcoming the challenges of the current cell therapy manufacturing landscape. Current innovations applied to the field, such as high‐throughput and high‐dimensional analyses, machine learning, and novel sensor technologies, are also discussed. We conclude that advances in PATs are necessary to identify CQAs and CPPs, overcome limitations in current operating processes, reduce overall product cost, and significantly accelerate the translation of laboratory discoveries into commercialized cell therapy products.

Advanced approaches that can mimic the structure and function of natural tissue in tissue engineering applications that use multidisciplinary engineering approaches to repair damaged or dysfunctional tissues are fed forward by current engineering applications. Manipulating cells or cell groups in an integrated manner into the scaffold, similar to the native tissue composition, is the main challenge in these approaches. Synthetic biology approaches, originating from genetic engineering, based on the use of advanced tools in the manipulation of cells at the molecular level, are one of the most current issues in tissue engineering that shed light on the programming of cells. Synthetic biology tools allow the reprogramming of cells whose transcriptional, translational, or post-translational molecular mechanisms have been engineered by stimulating them with intrinsic or extrinsic signals. Combining these advanced and excellent tools from synthetic biology with materials engineering applications of tissue engineering is the latest fashion. This chapter discusses going beyond conventional tissue engineering applications, synthetic biological molecular tools, circuit designs that allow the complex behavior of cells to be manipulated with these tools, and approaches that enable the integration of these tools into the material component of tissue engineering

Manufacture of adoptive cell therapies at academic cancer centers: scientific, safety and regulatory challenges

Cell Fate Plug and Play: Direct Reprogramming and Induced Pluripotency

Development of a robotic cluster for automated and scalable cell therapy manufacturing

Context-aware synthetic biology by controller design: Engineering the mammalian cell.

<!--StartFragment-->As more cell and gene therapies move toward clinical trials, and into commercialization, new trends and challenges are emerging. Technologies and processes are rapidly evolving, and it can be challenging for manufacturers to select the best tools for their unique needs. Focusing on cell therapy manufacture in particular, there is a lack of specific equipment and products, and as such the resulting manufacturing workflows can be highly labor-intensive, often involving open processes and manual manipulations. Closed manufacturing systems, in combination with digital connectivity, can offer a solution to some of these challenges, as these systems enable repeatable, trackable, and GMP-compliant manufacturing processes. This article will discuss the benefits of moving towards modular, closed-system technologies designed for scalable and cost-effective manufacturing, with a focus on the Gibco™ CTS™ Rotea™ Counterflow Centrifugation System – a revolutionary closed benchtop system which offers exceptional flexibility for cell washing, concentration, and separation by size.<!--EndFragment-->

Advancements in high-throughput microscopy imaging have transformed cell analytics, enabling functionally relevant, rapid, and in-depth bioanalytics with Artificial Intelligence (AI) as a powerful driving force in cell therapy (CT) manufacturing. High-content microscopy screening often suffers from systematic noise, such as uneven illumination or vignetting artifacts, which can result in false-negative findings in AI models. Traditionally, AI models have been expected to learn to deal with these artifacts, but success in an inductive framework depends on sufficient training examples. To address this challenge, we propose a two-fold approach: (1) reducing noise through an image decomposition and restoration technique called the Periodic Plus Smooth Wavelet transform (PPSW) and (2) developing an interpretable machine learning (ML) platform using tree-based Shapley Additive exPlanations (SHAP) to enhance end-user understanding. By correcting artifacts during pre-processing, we lower the inductive learning load on the AI and improve end-user acceptance through a more interpretable heuristic approach to problem solving. Using a dataset of human Mesenchymal Stem Cells (MSCs) cultured under diverse density and media environment conditions, we demonstrate supervised clustering with mean SHAP values, derived from the 'DFT Modulus' applied to the decomposition of bright-field images, in the trained tree-based ML model. Our innovative ML framework offers end-to-end interpretability, leading to improved precision in cell characterization during CT manufacturing.

Scale up of allogeneic cell therapy manufacturing in single-use bioreactors: challenges, insights and solutions