JULY 2024LIFE SCIENCES REVIEW9THE TIPPING POINT FOR SCALABLE MANUFACTURING PROCESSES TO PIVOT GENE THERAPIESa result, many drug developers in the field are continuing to use the traditional methods of manufacture, for example adherent cell systems in cell stacks with animal serum and purification through ultracentrifugation. These processes are manual and rely on scaling-out rather than scaling-up. As the demand for drug substance increases, these processes become labour intensive, logistically challenging and open to more opportunities for issues with contamination and batch-to-batch consistency. Whilst the traditional processes have enabled scientists to provide sufficient quantities of drug product for early clinical trials and proof-of-concept, developers are increasingly looking to switch to alternative scalable manufacturing processes for their late phase development and commercial production. At later stages of development, drug product needs escalate as material is required for clinical studies, analytical method validation, product stability, and process characterisation using orthogonal analytical technologies in readiness for registration and commercial supply.Scalable manufacturing processes involve suspension-based cell culture and transfection in bioreactors and chromatography-based purification processes. These processes are in the early stages of adoption for viral vectors, with key challenges to maximise the yield during the production phase and separate the full capsids from the empty capsids during purification, which relies on very small charge differences between the full and empty capsids. However scalable processes have the added benefit of being animal-free, thus offering an improved safety control profile. Innovation in scalable processing is growing and collaborative efforts between vendors and manufacturing scientists are having success and leading to mature and advanced manufacturing approaches.Switching manufacturing processes during the drug development lifecycle requires a robust comparability study to confirm that the new process intended for Phase 3 delivers drug substance that is highly similar in Critical Quality Attributes (CQAs) to the drug substance produced for toxicology and early clinical studies and can require additional bridging studies to confirm safety and efficacy equivalence between the products from the two different manufacturing processes. With other biologics, such as antibodies, the analytical methods are well developed and utilise sophisticated techniques such as mass spectrometry to support comparability studies. By comparison, the analytical techniques available for gene therapies are generally under-developed and availability of representative samples is limited, which adds complexity to the comparability approach.Executing the comparability and bridging strategies is costly and time consuming and a better strategy is to adopt a single-cycle product development approach and employ the scalable process for production of drug substance for the toxicology studies and all clinical studies. In this way, the data set builds as the drug progresses through the drug development lifecycle and at the point of process characterisation and validation the developer has a large body of data to support the process parameter specifications and product specifications for the BLA (Biologics Licence Application) and MAA (Marketing Authorization Application) regulatory submissions.The single-cycle product development approach is expected to be key to support developers evaluating gene therapies for prevalent diseases. The batch sizes are expected to be larger at the outset of clinical development due to the doses required per patient and to escalate quickly as patient numbers for both trials and commercial supply increase. Continued investment in optimising, improving and even revolutionising the scalable processes will become key for gene therapies to make their mark on rare diseases with high dose requirements and prevalent diseases in order to turn the promise of an effective treatment and the hope of a cure into reality for patients. Innovation in scalable processing is growing and collaborative efforts between vendors and manufacturing scientists are successfully leading to mature and advanced manufacturing approaches and supporting single-cycle development strategies
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