De-Risking Gene Therapy Biomanufacturing Early to Unlock Late-Stage Success and Cost Savings

Gene therapy biomanufacturing is undergoing a true paradigm shift as the industry is quickly moving toward data-driven AI-enabled and streamlined production with manufacturability designed into the process right from the start. 

The cell and gene therapy industry represents a $58 billion market opportunity over the next 5 years and the potential to treat millions of people with life threatening diseases¹. But getting these breakthroughs to patients is being held back by critical design problems causing millions in wasted manufacturing costs, elevated risk of adverse events and prohibitively high cost per dose. To keep up with the many competitors, companies big and small need to shift their focus from gene therapy candidate ID and pre-clinical efficacy to include manufacturability, predicting potential construct failures and taking proactive steps to eliminate issues during pre-clinical phase.

Doing so in the early stages of development presents a serious challenge: With the emergence of a plethora of available data to base pre-clinical and clinical downstream decisions on, many working in the filed have limited or no experience in computational training to navigate what has become a complex digital expanse. 

Overcoming these challenges requires those embarking on the novel treatment discovery journey to embrace a new phase in gene therapy production: Next-generation biomanufacturing.

What is Next-Generation Biomanufacturing?

The CDC defines biomanufacturing as “the use of biological systems that have been engineered, or that are used outside their natural context, to produce a product.” ²

These “biological systems” are generally microorganisms and cell cultures, including plant or animal cells, traditionally Chinese hamster ovary (CHO) cells. ^3,4. Typically, these cells have been genetically engineered to produce the molecule of interest in large quantities, as biomanufacturing aims not to produce small amounts sufficient for experimental purposes but to make commercially important products at scale.

In essence, biomanufacturing uses living cells as mini-factories.

With the introduction of gene therapies that modify genes in patients cells, next-gen biomanufacturing has emerged applying bioinformatics and AI as an integral part of the biomanufacturing process, uncovering data insights and making predictions and preventing failures saving gene therapy developers time and money on their path from lab bench to patient.

De-risking Construct Design: Next-Generation Biomanufacturing of Gene Therapies

One early pitfall many virus-based gene therapy developers overlook is the importance of vector design for biomanufacturability early on, during pre-clinical development.  As has been appreciated for decades with recombinant DNA technology, even silent mutations can have unforeseen consequences on gene expression, immune response, and a number of other factors.  

For example, AAV-based vectors have been linked to quality issues due to inefficient manufacturing processes.  More specifically, impurities of AAV viral capsid production have been shown to be contaminated with non-therapeutic genomes¹³ which lead to higher relative dosing, inducing an inflammatory immune response in patients causing significant adverse events¹³ and in some cases death.¹⁴ Empty capsids or capsids with partial genomes are caused by secondary and tertiary DNA structures in the genome that lead to replication errors and increased mutation rates.  Removing these structures through sequence optimization is reliant on trial and error and not often addressed until the manufacturing phase in the later stage of clinical development.  Therefore, as cell and gene therapy development progresses, attention shifts from efficacy alone to manufacturability, cost efficiency and preventing FDA regulatory hurtles early on.

With next-generation biomanufacturing, these risks can be mitigated during pre-clinical development before going to clinical trials. For instance, large language models can be trained to achieve multiple goals, such as predicting production impurities in viral manufacturing preparations, gene expression levels, and/or viral packaging efficiency based solely on the DNA sequence of candidate gene therapies in pre-clinical development.⁵ In doing so, gene therapy developers can predict bioreactor output before spending millions and months, chose and optimize constructs for ideal dose, safety and cost.

Recent Investments in Biomanufacturing Emphasize Need for Novel Approaches to Overcome Challenges

Given the potential of biomanufacturing to transform how we design gene therapies and solve broader problems, like creating more sustainable production routes for laundry detergent and plastics, it is no surprise that biomanufacturing has recently received significant interest and investments. In the US, President Biden signed an Executive Order on September 12, 2022, that launched the National Biotechnology and Biomanufacturing Initiative to grow domestic biomanufacturing capacity, expanding market opportunities for bio-based products, driving R&D, and training a skilled workforce.⁶

This $2 billion initiative also funds the international cooperation necessary to address urgent worldwide challenges such as global warming and health inequities.⁷ 

Initiatives supporting the development of biomanufacturing capabilities can be found around the world. Canada has developed a Biomanufacturing and Life Sciences Strategy to grow a strong biomanufacturing industry. In addition, the Horizon Europe Programme includes funding for biomanufacturing, and the UK’s Engineering and Physical Sciences Research Council is investing in manufacturing hubs that support a range of sectors, including biomanufacturing.^{8, 9}

Given these initiatives, along with private funding that flows into the sector, it’s no surprise that forecasters estimate robust annual growth rates and a total market size of over $43 billion by 2030 for the biomanufacturing sector.¹⁰

Accelerating Biomanufacturing Development With AI and Data Literacy Skills & Labor

Advancing next-generation biomanufacturing not only provide access to life saving treatments to those who need it most, it also requires a skilled workforce with multidisciplinary training, the ability to solve complex problems, and a willingness to continue to learn. Importantly, in addition to a solid education in STEM disciplines, knowledge of automation, digitalization, artificial intelligence and an understanding of information technology (IT) are crucial for the biomanufacturing workforce of tomorrow. The March 2023 published report from the Office of Science and Technology references developing the current and future STEM workforce to be skilled in the areas of data literacy as critical for solving global challenges, through biotechnology and biomanufacturing.¹¹ 

While highly educated individuals are needed to drive ongoing innovations, it isn’t only PhDs that will drive biomanufacturing, but also a large number of undergraduate and graduate level professionals who have the training and expertise to build advanced biomanufacturing capabilities and keep production running.¹² Opportunities will mainly be in disciplines like automation and software engineering, chemical and materials engineering, and skills that we may not even have a name for just yet.  

Training and education are critical for the development of a skilled biomanufacturing workforce. Specialized undergraduate and graduate programs and vocational training programs with a biomanufacturing focus are needed. 

Closer collaboration between educational institutions and industry is required to ensure students learn the skills they need to succeed in biomanufacturing. Companies focusing on biomanufacturing must provide relevant ongoing education and upskilling opportunities to their workforce.

The Crucial Role of Biomanufacturing in Creating an Equitable Treatment Access for Gene Therapy Patients

Biomanufacturing has the potential to play a crucial role in creating a more equitable future by providing access to life-saving drugs, vaccines, and medical devices to underserved communities worldwide. By leveraging the capabilities of biomanufacturing, we can create more affordable and accessible healthcare options for all, regardless of their socio-economic status or geographic location. Furthermore, biomanufacturing can be used to address global challenges such as climate change and food security, providing sustainable solutions for the world's most pressing problems. Through innovative and sustainable biomanufacturing practices, we can create a more equitable and just world, where everyone has access to the resources and technologies necessary to thrive.

Are you going to ASCGT Annual Meeting this year?  If so, please visit us at Booth 506 and Poster 986. We'd love to learn about your work and tell you more about the impact of AI on spearheading change from scientist to patients with optimized biomanufacturing.

AI Disclosure: Feature image was generated by an AI image tool, MidJourney.