Genetic Engineering & Biotechnology News

JUL 2017

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28 | JULY 2017 | GENengnews.com | Genetic Engineering & Biotechnology News Tony Hitchcock The successes seen in a number of clinical studies on viral vector-based gene therapies (AAV, retroviral, and lentiviral vectors) are well documented, with an ever-broadening pipeline of products entering late-phase clini- cal trials and hopefully, through to becoming licensed medicines. Almost all of the AAV- based therapies under development target devastating and potentially fatal diseases, which severely impact the quality of life of the patient and their families (Table). While for some diseases there may be exist- ing treatments available, these are often very expensive and far from ideal from a patient perspective. For this reason, clinical develop- ment programs for innovative gene therapies have been actively accelerated by regulatory bodies such as the MHRA and the FDA by the application of a "Fast Track" or "Break- through" designation, enabling expedited ac- cess to these new medicines. The flip side of accelerated pathways is that timelines for the manufacture of viral vectors becomes compressed, making it more difficult to develop commercial manufactur- ing processes that can produce vectors at the right quality, in the required amounts, and at costs that are reasonable enough to secure re- imbursement from healthcare providers while still making financial sense to the developer. Although there are a number of potential ap- proaches for the production of viral vectors, including baculovirus expression systems and the development of producer cell lines, the most commonly applied approach used to date is transient transfection in adherent cell culture systems. This approach is ideal for early-stage development in terms of speed, simplicity, and limited process development or infrastructure investment, and has been used for the majority of ongoing clinical stud- ies (Figure 1). However, this method is recog- nized to have serious constraints with regards to productivity levels, process scale up, and large-scale production. From a production and regulatory perspec- tive, manufacturers are now faced with the di- lemma of how we should approach the transi- tion from clinical to commercial manufactur- ing for these highly complex products. Ideally, one would like to start from a clean sheet and rebuild the process around scalable platforms. However, time, cost, and most importantly, regulatory constraints prevent this approach. For many products, process development opportunities are limited, with manufacturing groups having to maintain the supply of prod- ucts for ongoing clinical studies, while simulta- neously working to develop and improve pro- cesses. If successfully licensed and launched, it is likely that these products will be made us- ing processes that are far from optimal. The challenge, from a manufacturing perspective is, therefore, to ensure that this approach does not restrict patient access or safety. Inherent Complexity The inherent complexity of viral vector-based products, due to their physical size, formula- tion, and the fact that they often utilize a com- bined drug targeting/delivery vehicle function, makes their physical and biological charac- terization highly challenging from a regula- tory perspective. Consequently, a fallback ap- proach is adopted where the product is defined by the manufacturing process. This approach then makes the introduction of potentially product-impacting process changes difficult to implement and by default, the process be- comes "locked down" within the early stages of development, severely restricting the scope for process improvement and scale up. Classical process scale up tends to be via a vertical approach, with a focus on increasing the size of single operations (such as fermen- tation vessels) while keeping similar labor levels, subsequently achieving reduction in cost. This approach is valid if the process is well understood and amenable to linear scale up. The reality is that a large number of the key operations in the production of viral vec- tors are neither well characterized nor easily scaled. Lack of time and analytical tools will eventually direct developers to take a more horizontal approach to process scale up. It seems likely that scale up will be based on limited vertical scale up, with multiple and overlapping production streams, poten- tially exploiting options around the adop- tion of closed single-use production systems to maximize outputs from production facili- ties. While this may not be the most efficient approach with regard to labor and facility costs and end-product testing, it is likely to be the only realistic option for many prod- uct development groups. It is inevitable that some process changes will need to be introduced, for example, the requirement to replace purification of vectors by ultracentrifugation, as these processes are perceived as not only being unscalable, but also as highly operator-dependent with regard to yield and purity. The challenge becomes how engineers replace this type of operation. From a regulatory perspective, the key is an understanding of the critical quality attributes (CQAs) that impact product safety, purity, and potency; the critical process parameters (CPPs) required to control them; and the availability of the tools to measure CPPs. This approach then, in theory, will allow process development groups to develop strate- gies for introducing and verifying the impact of desired process changes. However, the suc- cessful process development of these "legacy" processes will be dependent on the availabil- ity of suitable in-process and final-product assays. There is a clear regulatory, as well as operational, need for drug developers to in- vest in the analytical tools required to achieve greater understanding of AAV vectors and the processes used to make them for the products to receive commercial licensing. The production of vectors through tran- sient production routes entails a complex materials supply chain. At the front end is the supply of plasmid DNA constructs used to generate the vectors; clearly the quantities Figure 1. A sample manufacturing process using AAV vectors. DS = drug substance. Figure 2. Challenges for scale up. Building Processes for the Future Manufacturing of AAV Vectors for Gene Therapy Bioprocessing Tutorial Table. Development Pipelines for Products Using AAV Vectors (Phase II/ III) Therapeutic Area Disease Key Companies Clinical Phase Blood Beta Thalassemia bluebird bio III Hemophilia B Spark Therapeutics II Hemophilia A BioMarin II CNS Canavan Disease Asklepioas BioPharmaceutical II Genetic Mucopolysaccharidosis Type III (MPSIII) Lyosgene SAS II/III Musculoskeletal Spinal Muscular Atrophy (SMA) AveXis III Ocular Choroideremia NightstaRx III Leber Hereditary Optic Neuropathy (LHON) Gensight III RPE65 Spark Therapeutics III Stargardt Disease Oxford BioMedica II

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