Ekaterina V. Melnikova, Marina A. Vodyakova, Nikita S. Pokrovsky, Vadim A. Merkulov

Orthogonal approach and critical quality attributes for gene and cell therapy products

Introduction

Orthogonal approach and critical quality attributes for gene and cell therapy products. Explore orthogonal approaches to assess critical quality attributes (identity, potency, purity) for complex gene and cell therapy (GCT) products. Ensures efficacy, safety & batch consistency, addressing regulatory needs.

Abstract

Introduction: Gene and cell therapy (GCT) products are revolutionizing medicine because they are made up of unique biological components like genetic material, viral vectors, and viable cells. However, their complexity necessitates rigorous quality control strategies to ensure efficacy, safety, and batch consistency. This manuscript explores the application of an orthogonal approach – employing multiple independent methods – to assess critical quality attributes, such as identity, potency, and purity of GCT products. Materials and Methods: To achieve the aim of our work, we analyzed 15 GCT products for 11 different types of diseases and reports of multiple regulatory agencies. Results: For cell-based therapies, identity is confirmed through genotypic, phenotypic, and morphological analyses, while potency is evaluated using functional assays tailored to the product’s mechanism of action, such as cell viability, differentiation status, or cytokine secretion. Viral vector-based therapies require characterization of structural integrity, transgene expression, and the ratio of full to empty capsids, employing techniques like dynamic light scattering (DLS), PCR, and ELISA. Conclusion: The paper highlights regulatory recommendations from the FDA, EMA, and WHO, emphasizing the need for validated assays during product release and stability testing. Case studies, including CAR-T cells and AAV-based therapies, illustrate the practical implementation of orthogonal methods. Challenges such as assay variability and the need for clinical correlation are discussed, underscoring the importance of assay development early in the product lifecycle. By integrating diverse analytical techniques, the orthogonal approach ensures comprehensive product characterization facilitating the translation of GCTs from research to clinical application.

Review

This manuscript addresses a critically important and timely topic: the quality control of gene and cell therapy (GCT) products. Given the inherent complexity of these novel biological therapeutics, comprising diverse components like genetic material and viable cells, robust and multi-faceted analytical strategies are indispensable to ensure their safety, efficacy, and consistency. The authors propose and explore the application of an "orthogonal approach," which involves employing multiple independent methods to assess critical quality attributes (CQAs) such as identity, potency, and purity. The scope of the work, as described, involved an analysis of 15 GCT products across 11 disease types, supplemented by an examination of reports from multiple regulatory agencies, suggesting a comprehensive review of current practices and guidelines. The paper effectively illustrates the practical implementation of orthogonal methods by providing specific examples tailored to different types of GCT products. For cell-based therapies, the abstract highlights the use of genotypic, phenotypic, and morphological analyses for identity confirmation, alongside functional assays (e.g., cell viability, differentiation status, cytokine secretion) for potency evaluation. In the context of viral vector-based therapies, the authors detail the characterization of structural integrity, transgene expression, and the crucial ratio of full to empty capsids, utilizing techniques such as dynamic light scattering (DLS), PCR, and ELISA. The inclusion of case studies, specifically CAR-T cells and AAV-based therapies, further strengthens the paper by demonstrating real-world applications of these diverse analytical techniques. In conclusion, the manuscript underscores the vital role of orthogonal approaches in achieving comprehensive product characterization, thereby facilitating the successful translation of GCTs from research into clinical application. The paper thoughtfully integrates regulatory recommendations from key bodies like the FDA, EMA, and WHO, emphasizing the necessity of validated assays throughout the product lifecycle, including release and stability testing. Furthermore, the discussion of challenges such as assay variability and the crucial need for clinical correlation, alongside the importance of early assay development, demonstrates a nuanced understanding of the complexities inherent in this field. Overall, this work serves as a valuable resource for researchers, developers, and regulators navigating the intricate landscape of GCT product development and quality assurance.

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