Process evolution in cell and gene therapy from discovery to commercialization

Abstract

The field of cell and gene therapy (CGT) is maturing at a rapid rate. Manufacturing remains a major challenge and manufacturing failures and limitations are a notable source of CGT products not meeting specification or being held back from regulatory approvals. To ensure that products remain compliant and competitive throughout their lifecycle, CGT process development requires both ongoing advancement of fit‐for‐purpose technologies to allow for and support well‐designed development studies, and a methodology that enables these studies to occur effectively during focused product development campaigns. We describe a framework for ongoing innovation in CGT process development, manufacturing, and clinical testing, based on the quality by design (QbD) approach. We propose use of the concepts of process discovery, process characterization, and process development in an iterative way to refine the design space as a product matures. This strategy is enabled by the early implementation of broad and robust analytics, and a modular approach to accelerate optimization. With these strategies, CGT developers can prospectively plan for comparability studies and develop in a stage‐appropriate manner, to allow for ongoing innovation and improvements from discovery through to commercialization.

A Quality by Design Approach in Pharmaceutical Development of Non-Viral Vectors with a Focus on miRNA

“…They are categorized as high-impact CPPs, low-impact CPPs, or non-CPPs [ 103 ]. The CPPs are the parameters whose sensitivities significantly impact the QTPPs [ 104 ]. Table 6 summarizes the main preparation methods of nanoparticles for nucleic acid delivery and the process parameters considered critical for each method.…”

Bioprocess Economic Modeling: Decision Support Tools for the Development of Stem Cell Therapy Products

“…Bioprocesses which aim to manufacture CTPs involve highly variable cell-based raw materials and often fragile final products with short shelf lives [ 15 ]. At the same time, they must adhere to rigorous guidelines in order to obtain regulatory approval, which is frequently the source of costly setbacks.…”

“…Evidently, the TPP of a CTP cannot be fully defined during the early stages of its development, given that there is limited knowledge available regarding how the product will really act in a clinical setting [ 15 ]. This is unavoidable, and thus the concept of iterative refinement is at the core of QbD.…”

“…Iterative refinement can best be guided by taking advantage of two complementary strategies, namely design of experiments (DOE) and computational modeling [ 14 , 15 ]. DOE comprises a set of methodologies that attempt to evaluate multiple factors simultaneously so as to understand the impact of their interactions on the output of a given bioprocess [ 22 ].…”

“…The lack of viable CTPs derived from stem cells clearly reveals the difficulty intrinsic to their development. The same biological complexity which makes stem cells so promising for therapeutic applications simultaneously presents an immense barrier to the translation of laboratory-scale experiments into reliable and cost-effective bioprocesses [ 14 , 15 ]. These bioprocesses are invariably intricate affairs composed of a multitude of steps, namely acquisition or generation of the initial cell type, cultivation, modification, harvest, concentration, purification, formulation, fill and finish [ 14 ].…”