Today, large-scale gene therapy manufacturing faces challenges such as mounting regulatory requirements and the need to improve processes and reduce manual labor and costs. What role will automation play in tackling these issues and aiding affordable patient access in the future?
The global gene therapy market has seen immense progress over the last decade and is set to grow from a valuation of €2.8B ($3.22B) in 2019 to €18B ($20.9B) by 2027. The growing number of approved gene therapy products and clinical trials is continuously refining our knowledge base on the therapies and production platforms involved.
With increasing information, gene therapy manufacturing processes are also moving towards achieving consistency, similar to what the biopharma industry experienced with the antibody platform technology in the past.
In fact, the manufacturing standards required from gene therapies are similar to those expected of other regulated biological drugs.
“Gene therapy production needs to have controls that can keep process parameters in check, from process development and scale-up, through to Commercial large-scale manufacturing.”
“The entire process is subject to regulatory oversight, and we need to abide by regulations to ensure that therapies are efficacious and safe,” explained Kevin Lynch, Manufacturing Head for Gene Therapy Operations at the Life Sciences business sector for Merck*.
However, due to the inherent complexities of novel treatments like gene therapies, meeting the required manufacturing standards can be challenging.
Improving compliance in gene therapy manufacturing with automation
Gene and cell therapies fall under the category of precision medicine and face a significant risk of batch-to-batch variability due to the biological raw materials involved in their production. Such variability can make compliance with strict regulatory frameworks and manufacturing budgets a complex task.
Limited reproducibility and high costs are exactly the sorts of problems that automation, accompanied by predictive analysis, could solve. The goal of automated technologies in the biomanufacturing sector is to mitigate risks and optimize production during the gene therapy development and production process.
With automation, live readings can be collected over time and the resulting datasets can be leveraged to derive insights on what drives changes during or between production runs. This, in turn, can guide operators in adjusting parameters, optimizing the process, and minimizing variability between batches.
“By using automated technologies, you can see if set targets are being achieved early on in the process. This allows for prompt termination of non-ideal processes,” Lynch added.
Thus, by preventing unsuccessful production runs, real-time monitoring can enable cost- and time savings in biomanufacturing.
In the process of assuring reproducibility, automation also indirectly helps in adhering to regulatory processes because it involves consistent data collection and archiving.
“Essentially, with automation, you get quicker access to the data. Once you have enough data, that data can drive decisions, which enables built-in compliance,” explained Lynch.
Leveraging automation to optimize gene therapy production
Manufacturing for gene therapies has heavily relied on manual processes thus far. This makes gene therapy production not only labor-intensive but also vulnerable to human error, risking contamination, high expenditure, and compromised end-products.
A good example of manual platforms used in upstream gene therapy manufacturing are cell stacks, which are plastic containers that enable cell growth. These cell incubators need to be operated manually, within the confines of a biosafety hood.
Due to the set-up of the cell stack, its operators have limited information on the environmental conditions surrounding the cultured cells as well as on the consistency of such conditions across different production runs. This results in restricted control over the actual cell culture process, limiting the level up to which the process can be optimized.
Automation can prove handy in this instance, as it enhances control over the entire production process, resulting in improved efficiency. And we only need to look at bioreactors – the automated technology meant to replace cell stacks in the gene therapy production process – to understand this better.
Using bioreactors for cell culturing allows live monitoring with minimum human involvement while providing an active read-out on the environment surrounding the cells.
“Along with monitoring metabolites, most bioreactors today take sample measurements at regular intervals, allowing control over process parameters like dissolved oxygen, CO2, pressure, temperature, and pH,” elaborated Lynch.
By automating both the gene therapy manufacturing process and systematic data evaluation, the yields, as well as the production capacity, can be optimized. Ultimately, this facilitates long-term production planning.
Investing in automation for gene therapy manufacturing
While the advantages that automation presents in managing costs and reducing manual labor in gene therapy production are evident, scientists and manufacturers know that incorporating automation into gene therapy manufacturing will be challenging.
As speed-to-market is crucial to meet the unmet medical need gene therapies target, these therapies are frequently sped through pre-clinical and clinical phases via fast-track programs. This means that often datasets from only three to five production runs may be available before large-scale gene therapy manufacturing needs to begin.
“Automating gene therapy production is a difficult task because of the limited data points we have at hand today to optimize the production pathways for these therapies.”
“But such constraints make it all the more critical to have identified the best-suited process controls, data collection, and evaluation strategies, as well as the automated system itself,” cautioned Lynch.
What bodes well however is that ever since the first use of automation systems, these platforms have been rapidly evolving and are getting better at addressing challenges such as the one presented by limited data.
Platforms today incorporate the latest technologies and can auto-capture a comprehensive list of parameters. In the past, significant monetary investment in data analytics was needed in addition to the investment on these platforms. Today, however, analytics forms a core feature within these systems.
“As wireless technologies and process control systems continue to evolve, so does the ability to combine the data and notifications from these tools into a common alarm notification system and database.”
“This allows different tasks, such as resource planning, process-parameter monitoring, and system performance adjustments to be integrated and automated, with the option of remotely controlling the entire set-up. Such a consolidation of databases and servers decreases the amount of IT and compliance resources required for support as well,” said Lynch.
The increasing relevance of automated technologies in gene therapy manufacturing is reflected in the large investments seen in this sector made by biopharma leaders like in the Life Sciences business sector of Merck.
With the goal to more than double its gene therapy manufacturing capacity, Merck has invested over €95M ($110M) to set up a second state-of-the-art viral vector facility in Carlsbad, California.
“The new site is fitted with the latest fully-automated technologies, such as the new Mobius® single-use bioreactors as well as separation and purification systems like single-use chromatography and tangential flow filtration.”
“All of these systems are controlled and monitored via a common platform. The production systems are synced with our material planning and supply chain systems, enabling real-time access and control through a secure network,” explained Lynch.
By tying in all the steps from material inputs to production and leveraging data analytics, the Carlsbad facility aims to create a robust manufacturing environment, with speed-to-market in mind.
“We put patient health first. Towards this, we are constantly improving our technologies and processes to bring life-changing products to market,” Lynch added.
Looking to an automated future
As automation and enabling technologies become more integrated into gene therapy and viral vector manufacturing processes, increased control and risk reduction will ensue, asserted Lynch. As we move towards bioprocessing 4.0, the incorporation of artificial intelligence and machine learning tools into biomanufacturing processes is also not too far off.
By delivering on the promise of increased optimization, enhanced compliance, reduced redundancies, and lowered costs, automation could ultimately aid in improving fast patient access to gene therapies.
“Today, we have the ability to monitor events in real-time and to control them within operating parameters. It is not a question of how, but a question of when we will let automation and analytics steer the decision-making to improve gene therapy products, process robustness, and speed-to-market,” concluded Lynch.
To learn how you can partner with the Life Sciences business sector of Merck to ensure cGMP compliant Viral Product Development and Manufacturing, please visit the company’s website.
*The Life Science business of Merck operates as MilliporeSigma in the United States and Canada.
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