How icIEF-MS Can Help Biopharma Scientists Close the Developability Gap

Pressure to obtain analytical information faster and earlier on in the drug development process is a major challenge for biopharma scientists. New and improved technologies are needed that can help measure molecular attributes rapidly and accurately, accelerating the biotherapeutic development process.

Technology Networks spoke to Mani Krishnan, vice president and general manager, Biopharma and CE, at SCIEX, to learn how a new category of analytical instrumentation – imaged capillary isoelectric mass spectrometry (icIEF-MS) – is helping to address this issue and close the developability gap.

Anna MacDonald (AM): From your partnerships with biopharma scientists, what are the main issues that they report facing?

Mani Krishnan (MK): One of the biggest challenges facing our biopharma partners today at the highest level is the need to address the developability gap and accelerate the drug development process. During early-stage development, one of the primary activities is identification of the optimum clone or cell line for production of the target biologic that will provide high yields and ideally a product with the right physicochemical characteristics. With existing analytical tools, it is difficult to rapidly and cost-effectively obtain detailed characterization information at this early stage. That information is often not obtained until much later in the development process after significant investment has already been made. What our biopharma partners need is new technologies that provide comprehensive information quicker and earlier to reduce costly late-stage failures.

AM: icIEF-MS was developed to help address these challenges and close the developability gap. Can you give us an overview of the technology, some examples of its key capabilities and explain how it can help to accelerate the biotherapeutic development process?

MK: Imaged capillary isoelectric focusing is a separation mode based on capillary electrophoresis that gives a fingerprint of a particular biotherapeutic by separating proteoforms based on charge, such as monoclonal antibodies (mAbs) with different post-translational modifications, glycoforms, sites of degradation, etc. Because it is a rapid, sensitive and high-resolution method, icIEF is used throughout the development process to track changes in the drug substance as process conditions are modified and to demonstrate comparability when processes are scaled. It has, in fact, become an essential tool for understanding the critical quality attributes of mAbs, and its use is required by regulatory agencies for lot release. 

Coupling icIEF charge variant analysis directly with high-resolution mass spectrometry allows for direct in-line peak identification of each icIEF peak, providing significant information about the quality of the drug substance within an hour. As such, icIEF-MS is an attractive alternative to much more complex and time-consuming liquid chromatography-MS workflows. The ability of icIEF-MS to quickly monitor multiple product quality attributes in a single integrated assay can streamline and accelerate the biotherapeutic development process, allowing for meaningful decisions earlier and reduced risk of costly downstream failures.

The microfluidic chip in the IntaBio system is the key to the new icIEF-MS technology. It separates charge variants by capillary isoelectric focusing, enables UV quantification and performs electrospray ionization (ESI) directly into a mass spectrometer for further mass analysis.

AM: New icIEF-MS findings and developments were recently presented at ASMS. Can you tell us more?

MK: At ASMS, a key collaborator presented results on the rapid characterization of charge variants by online cIEF-MS during cell-line selection and for the identification of lead molecules. This collaboration was to help understand changes in icIEF profiles of clinical candidates during process scaleup, particularly when using new cell lines and new fermentation process conditions. Using icIEF-MS allowed them to very quickly make decisions about their process and in which direction they wanted to move ahead.

In this collaboration, we also worked to evaluate several candidates during the clone selection process. Based on the icIEF-MS data, they were able to eliminate one unsuitable candidate at a very early stage. Doing so saved the company a significant amount of money because the development of selected candidates was outsourced to a contract development and manufacturing organization; investment in a candidate that was doomed to fail was avoided from the outset.

In addition to this presentation at ASMS, several of our biopharma partners have discussed their successes using icIEF-MS at other recent conferences like CASSS Mass Spec. The projects discussed covered a variety of interesting sample types, including fusion proteins, bispecifics and antibodies produced using novel engineered CHO cell lines, among others.

AM: Why are customer partnerships so important in product development? How is customer feedback helping to steer the development of icIEF-MS technology?

MK: One of our core values is “Customers Talk, We Listen”. Working closely with our customers has always been a priority to ensure that we truly understand their challenges and develop technologies and workflows that enable them to accomplish their key objectives.  

In close partnerships, we are able to work with complex new modalities rather than just using off-the-shelf standards, and thus make sure our technology and characterization capabilities are relevant for existing and next-generation biologics. In addition, we are able to understand better the key gaps and bottlenecks that our biopharma partners are facing and focus our development efforts where it matters the most. We truly listen to our customers so we can develop products that meet their needs.

Many of our recent collaborations were funded by a grant from the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), which fosters close partnerships between technology companies and biopharma manufacturers to help accelerate the development of solutions that address key manufacturing issues.

AM: Do you have plans for further developments in icIEF-MS that you are able to share?

MK: We have an exciting roadmap for further technology development using our unique portfolio of CE, CE-MS and LC-MS technologies. We look forward to engaging these capabilities to help our customers bring life-changing therapies faster to patients. 

Mani Krishnan was speaking to Anna MacDonald, Science Writer for Technology Networks.