Pharmaron
The Tipping Point for Scalable Manufacturing Processes to Pivot Gene Therapies
Dr Linda Randall
Advanced Therapies, including cell therapies, gene therapies and gene editing products, are one of the leading current developments in the biopharmaceutical world. Buoyed and driven by the promise of creating a life changing treatment for rare diseases and in some cases, offering the hope of a potential cure for patients, this field is revolutionising the way we approach everything from clinical trial design, to regulatory expectations and re-imbursement policies.
Yet gene therapies themselves are not new. The first gene therapy human dose administration was just over thirty years ago (1990), however, gene therapy faced several setbacks and challenges, but continued investment in technology and regulatory science in this field has supported the advancement. Recent data shows that the number of clinical trials underway in the US with gene therapies rose during the period 2020 to 2021 from 410 to 522 trials, with approaching 7 percent of those trials in Phase 3 and pre-registration stages. In the same report, data showed that 89 percent of gene therapies utilise viral vectors for delivery, with Adeno-Associated Virus (AAV) being the most prevalent gene delivery vehicle.
Two recent approvals of AAV gene therapy drugs are major contributors to the resurgence in investment in gene therapies as medical treatments and potential cures: (1) approval of Luxturna in 2017 by FDA and 2018 by EMA, which is a single injection in each eye of an AAV carrying a functional copy of the RPE65 gene into the retinal cells for the treatment of an inherited form of vision loss and (2) approval of Zolgensma in 2019 by FDA and 2020 by EMA for a one-time intravenous injection of AAV9 which carries a functional copy of SMN1 for treatment of spinal muscular atrophy.
Having originally focused on rare diseases with small patient populations, such as retinal dystrophy (anticipated 1000-2000 patients in US3) and spinal muscular atrophy (10,000 to 25,000 patients in US), drug developers are now turning their attention to treating prevalent diseases. The Alliance for Regenerative Medicine (ARM) presented data that shows that almost 60 percent of the 2,400 Regenerative Medicine clinical trials at the end of 2021 targeted prevalent diseases, such as diabetes and Parkinson’s5.
With rare diseases and the very small number of patients, many of the indications require relatively low doses,for example Luxturna (1.5 x 1011 vector genomes in 0.3ml). This translates into a low drug substance and drug product demand and therefore drug substance manufacturing batch size. In early clinical trials there are tens of patients, and the stability demand can outweigh the demand of drug product for the patients in the trial. As a 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 processesfor 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 bio reactors 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.
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.
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.
