"Finding a Diamond in the Rough"
How do industry leaders find high-performing clones for their bioprocesses?
Sartorius is a world leader in cell line development technologies. To share some insights, we talked to Ademola Kassim, a Product Specialist for our Cell Line Development Service - North America. Ademola highlights some important points you should consider when performing clone selection and discusses what technology can help you with your quest. He then reveals how we perform clone selection in the Sartorius Cell Culture Technology Center in Ulm, Germany.
This article is posted on our Science Snippets Blog
Cell line development is one of the most costly and time-consuming steps in establishing the manufacturing process for a new biotherapeutic. Increasing the efficiency of these steps can maximize the chances of success and reduce time to market.
Selecting a high-performing clone is critical to the productivity of your host cell line. The higher number of clones analyzed, the more likely you are to find a hidden gem. However, the screening process is very time-consuming and highly labor-intensive. It also raises many questions: what features are important, how many clones do you need to analyze, and how should you rank them?
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First, what makes a high-performing clone?
“An important part of clone selection is defining and prioritizing your selection criteria,” Ademola explains. “Initial parameters could include growth characteristics such as suitable cell viability and density. Downstream, you'll want to consider your target product titer – can you find highly producing clones? Next, you should consider your product's critical quality attributes (CQAs); are your selected clones able to recapitulate all the required features of your biologic?”
It is essential that you define your target parameters, how to evaluate them, and decide which are most important to your bioprocess before diving into clone selection.
Ademola Kassim, Product Specialist for Cell Line Development Service - North America
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How long does clone selection typically take, and what technologies should drug developers harness to streamline the process?
“Clone selection can represent a significant bottleneck in upstream process development, taking up to 20 weeks or more per project. Automation and analysis platforms simplify the workflow for cell line screening and ranking. They also enhance the speed and consistency of clone selection, improving the decision-making process and increasing the likelihood of finding a high-performing clone.”
Clearly, automation is an excellent way to save work hours and ensure consistency throughout the development process. Some may even argue that it is essential for reliable clone selection. Do you agree?
“In some cases, yes. For example, where transfection efficiency is low, and hundreds of clones need to be screened to find an optimal one.”
What solution would you recommend for automating clone selection?
“Sartorius’ Ambr®15 platform is an automated microbioreactor that frees up valuable scientist hours. It enables you to rapidly evaluate multiple bioreactor cultures in parallel and at microscale, increasing your productivity and reducing consumable costs. The platform also has excellent scalability, increasing the likelihood of finding a clone that performs consistently from development to commercial-scale production.”
Is automation alone sufficient to simplify and improve clone selection?
“While automation dramatically reduces the experimental workload, when used in isolation, it simply shifts the bottleneck to the data analysis phase.” Ademola elaborated further, “Screening experiments on automated platforms generate a significant volume of data. This needs to be stored, analyzed, and interpreted so that scientists can maximize their experimental data, extract key insights, make well-informed decisions, and narrow down their clones.”
So, you automated your screening process and made use of data analysis software to help make sense of all the information. Now what?
“Even once the data is evaluated, the decision-making process itself remains complex, and the selection criteria may be inconsistent across projects and users. Scientists require intuitive and integrated analysis software to overcome this hurdle and simplify clone selection.”
What data analysis tools do Sartorius offer to support clone selection?
“Our Umetrics® suite is a selection of user-friendly data analytics software that powers Ambr® clone selection. The platform removes subjectivity and enables consistent and robust screening and ranking. The ranking of candidates is carried out based on application-specific CQAs, targets, and priorities, and the software uses a unique multivariable desirability assessment for clone ranking.”
The technology generates a report recording the selection criteria and details of the selected clone candidates, making it possible to view, understand, and share the selection process with project stakeholders.
Ademola Kassim, Product Specialist for Cell Line Development Service - North America
Can you share how clone selection is carried out at Sartorius?
“Sartorius cell line technology platforms support the early identification of high-performing clones. Unsurprisingly, we use them in our own Cell Line Development Service and CHO Platform Service Packages.”
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At least 1,500 clones are sorted during single-cell cloning using a FACSAria Fusion cell sorter (BD). After further expansion of the cells, the top 24 clones are selected based on growth, productivity, and monoclonality data.
Ademola Kassim, Product Specialist for Cell Line Development Service - North America
“We then evaluate the top 24 clones in a fed-batch process using Ambr® 15. The Ambr® platform allows us to run multiple experiments simultaneously in bioreactor similar mode. The comparability between the performance in the Ambr® 15 and a stirred tank bioreactor has been tested and shown high correlation of performance between the Ambr® and larger scale bioreactors. This correlation means the Ambr® 15 can be easily used to select the top four clones, which we then use to prepare a research cell bank (RCB).”
Streamline Clone Selection
Arming yourself with an abundance of high-quality data and the tools to analyze it is essential in searching for the ultimate cell line development treasure - a high-performing clone. Sartorius cell culture platforms and analysis packages, as well as our service offerings, promote consistency and robustness across the selection process, maximizing your chances of finding an optimal clone for your bioprocess.
