Top Industrialization Challenges of Gene Therapy Manufacturing

Manufacturing and scale-up of industrialized processes to manufacture gene therapy products are accompanied by many challenges that must be overcome to succeed in the marketplace. Commercialization of gene therapies for patient use is time consuming and requires substantial financial investment and dedicated resources.

Despite the unique range of challenges associated with gene therapy development, the quest to bring these therapies to market is worthwhile because the therapeutic potential of the treatments is revolutionary and the commercial opportunity is considerable. The process to industrialization is complex, but the benefits of successful development of robust processes are huge. The industry is rapidly expanding and is implementing novel approaches to overcome existing challenges, using innovative methods for medicinal application and developing new drugs to treat rare diseases.

Manufacturing sufficient quantities of high-quality product is an area that requires substantial developmental effort. Challenges surrounding reimbursement for treatment, and the pressures associated with shorter time to approval, both increase burden placed on manufactures to rapidly develop suitable processes that are cost-effective. Cost of goods (COGs) need to be kept below critical threshold levels to drive sufficient profit margins, even though process development timelines are aggressive and short. There are a multitude of critical decisions and considerations to overcome. This article explores some of these fundamental manufacturing challenges in more detail.

Scalable Manufacturing Platform

Technologies used to manufacture gene therapy biologics are advancing at a very rapid pace. Not having a platform that is suitable nor scalable is a significant challenge many manufacturers face. It is a necessity throughout clinical development stages to be able to optimize the manufacturing process. However, any change in the manufacturing process that increases product yield or enhances quality is accompanied by the risk of changing the product. It is therefore essential that close attention is paid to tracking variation throughout the development process at every stage.

A substantial amount of early-stage development is still being performed using outdated, non-commercially viable platforms and transferring processes to new platforms is required. To achieve manufacturing platform advancement, the product needs to be very well characterized during development so that investigators can generate data sets which demonstrate comparability between products used in clinical studies and those generated with the final manufacturing process.

Cost of Goods

COGs associated with manufacturing any drug product impacts the overall price of the therapy and heavily influences the profit margin realized by gene therapy manufactures. High production cost is a challenge that affects profitability. This is reflected in the high costs associated with newly approved gene therapy drugs such as Yescarta♦, Kymriah♦ and Luxturna♦ which are currently priced in the 100,000’s dollar range per dose. The challenge becomes a critical concern when the product in development cannot be sold at a price high enough to achieve a commercially viable profit margin. If acceptable margins cannot be reached, developers may choose to terminate production making the drug unavailable to patients. However, due to the remarkable value and life changing nature of the treatments the entire industry is committed to the pursuit of cost-effective methods for manufacturing. There is a significant effort that has been mounted by all players to reach this end.

Currently, the main cost contributor to the overall COGs for gene therapy products is high quality clinical grade plasmid DNA containing the therapeutic gene of interest. This reagent is required for transient transfection of cells and it is imperative that the reagent is of high quality. It is an essential component of the process to assure an acceptable safety profile. Another example of an expensive gene therapy product is Zolgensma♦. This new drug was recently approved for the treatment of spinal muscular atrophy (SMA), which is a rare disease that causes severe muscle weakness for sufferers. It affects their ability to breathe, speak and move. Most babies born with a common form of SMA die by the time they reach two years of age. Currently there is no cure. Zolgensma represents the only treatment option now available to cure the 10,000 – 25,000 affected individuals in the US. However, the current challenge with this therapy is that it could cost $2.1 million per patient.

Reimbursement

Market size is an important factor that can limit effective commercial return. If the market size is too small, profitability is limited due to the small number of doses required to treat the patient population. This decreases the profit margin realized by the drug developer and can lower motivation to commercialize the therapy. The most encouraging aspect of the gene therapy revolution is that the first round of gene therapy products has been developed for extremely rare diseases, with small patient populations indicating the commitment to treat previously untreatable diseases. Amazingly, these patients can be cured by a single drug application, however, this inherent property of the therapy can further limit commercial profitability. Patients are often not required to pay for these high-cost medicines themselves, and look to government programs and health care insurance providers to reimburse the manufacturer for treatments.

Health insurance reimbursement plans for new products is challenging, particularly so for new category products like gene therapy. It is expected that the process of reimbursement will differ from country to country and it will also be guided by factors like economics, demographic data and politics. If the current cost of manufacturing stands, then drugs such as Zolgensma could place a huge financial strain on health systems. In the US for example, it is surmised that treating common diseases such as hemophilia, which affects around 20,000 people in the US alone, could cause a financial crisis. If we look to the future of modern medicine, commercialization of gene therapies will require not only significant advancement in manufacturing processes to reduce costs but also a practical reimbursement strategy that will allow for drug developers to continue to forge into the new frontiers of medicine.

♦Kymriah is a trademark of Novartis AG., Luxturna is a trademark of Spark Therapeutics, Inc., Yescarta is a trademark of Kite Pharma, Inc., Zolgensma is a trademark of AveXis Inc.

About the author:
Dr Mark Szczypka is Global Director, Process Development Services, Pall Corporation.