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Analyzing and Interpreting Mass Spectral Data

Douglas Kiehl is a principal research scientist at Eli Lilly & Company, and is currently leader for the Spectroscopy & Raw Materials team. His group performs characterization and structural elucidation of impurities, related substances, and contaminants as well as testing and qualification of process raw materials through development and commercialization. Additionally, his team leads Lilly’s technical strategy for evaluating extractables and leachables associated with pharmaceutically relevant materials. 

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Doug has over 30 years’ experience with the application of mass spectrometry in the structural characterization of small molecules, 20 years of which are in the pharmaceutical industry. His research interests include applying mass mapping and visualization techniques in the characterization of complex molecular mixtures.

Q: Can you expand a bit about what your team does?

A: The Spectroscopy & Raw Materials (SRM) team comprises a group of individuals with deep expertise across several advanced spectroscopic techniques, including LC-MS, NMR, NIR, FTIR, XRF, Raman, and ICP-OES/ICPMS. The SRM team applies this suite of techniques and expertise toward solving difficult and complex problems involving the characterization of unknown impurities, related substances, degradation products, and contaminants, and to support development of control strategies. The SRM team is also responsible for development and establishment of the company’s global technical strategy for evaluation of extractable and leachable compounds associated with packaging materials, drug delivery devices, container closure systems, process contact materials, and single-use system components. Additionally, the SRM team is the “gateway” for the acquisition and qualification of all raw materials and excipients that are used in development and commercialization process streams for large and small molecules. This includes evaluation of technologies for raw materials supply chain surveillance and contamination detection.

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Q: What do you use mass spectrometry for?

A: We typically employ high resolution mass spectrometry as one of our primary front-line problem-solving capabilities for characterizing unknown compounds detected during development and commercialization of drug products. LC-MS is a technique which is particularly well-suited to characterizing complex mixtures of diverse organic molecules of pharmaceutical relevance, such as we commonly encounter when profiling process impurities or extractables associated with polymer and elastomer materials. My team is fortunate to have at its disposal several sophisticated high resolution mass spectrometry platforms, including FT-ICR and orbital trap LC-MS systems routinely capable of resolution of >100K (FWHM) and sub-ppm mass accuracy. This enables the assignment of elemental composition to unknown compounds with a high degree of confidence, and the MSn capability inherent with these MS systems can reveal important diagnostic structural features permitting characterization of unknown compounds.

Q: What are your greatest challenges in analyzing and interpreting mass spec data?

A: I’ve been fortunate over the last few decades to have had the opportunity to work with a variety of mass spectrometry systems. There have been great leaps in hardware advancements which have contributed to vastly improved resolution, sensitivity, mass accuracy, diversity of means for achieving ionization of diverse molecules, and innovative ion activation techniques for structurally diagnostic fragmentation. However, it is my observation that advances in hardware have historically outpaced software and data processing capabilities. Incremental hardware advances may often result in a disproportionately large expansion in the diversity and amount of data that can be acquired and consequently must be analyzed and interpreted. One of our greatest challenges lies in developing or acquiring an effective solution for processing and interpreting data from multiple instrument platforms, and then reporting results in a meaningful way. Our options have included developing a solution in-house or evaluating and employing a commercially available solution for processing data from our various mass spectrometry systems.

Q: What other ways are you tackling this huge amount of data?

A: In addition to exploring either custom or commercial options to address the vast amount of raw data that we acquire, we seek ways to automate our workflow as much as possible, particularly in the areas of sample preparation and selection of multiple chromatographic separation conditions to make the acquisition of data as rapid and efficient as possible. Focusing on automation and innovative data processing, analysis, and interpretation solutions permits our lab to more rapidly and effectively solve difficult problems.

Q: You’ve already touched on this, but what are the key changes you’ve seen in analyzing and interpreting mass spec data over the past few years?

A: I would emphasize that since hardware advancements have set the pace for the development and commercialization of highly sophisticated mass spectrometry instrument systems, software and data processing applications have been challenged with having to effectively manage the large sets of data which are produced. There are some very good commercial solutions now available to address head-on the challenges of taking large amounts of data that are produced in today’s analytical laboratory and helping this become useful information from which decisions can be made and problems solved.

Q: What are some of the newest tools/software out there for interpreting mass spec data and what are your thoughts on those tools?

A: There are some attractive tools and software commercially available for processing and interpreting mass spectrometry data. One of the attractive attributes of some software packages is that they’re able to take data from various mass spectrometry vendor platforms and transform these into a vendor-neutral format. They’re able to provide a unified solution for looking at multiple mass spectrometry data streams in a single format. Then there is opportunity to apply additional tools in the interpretation of this data, such as spectral libraries and common processing parameters. There is also the ability to organize and report results in an efficient and effective manner.

An interesting concept in lab informatics is the idea of a so-called “unified laboratory intelligence” approach which enables analytical labs to make data rapidly accessible, live, and re-useable. In my lab, for example, we have instrumentation from different vendors and each comes with its own piece of software and proprietary data format. If I desire to use legacy information to help me identify an unknown, I would typically have to employ manual searches across several databases and document repositories to see if I’ve observed anything similar in the past. With this approach, analytical data from different instrument platforms and vendors, and even different spectroscopic techniques could be unified in a vendor-neutral format in a single software platform. I could search mass spectra for an unknown against the database to quickly determine if it’s been previously identified, or identify structural fragments based on comparing fragmentation patterns. This not only saves time but also means the data being generated every day is adding to our overall corporate knowledge space. Additionally, having raw data and results readily retrievable from a common repository is essential in a regulated environment such as ours.

Q: What other resources for interpreting mass spec data have you found to be the most useful?

A: There are some useful online resources available and in development for both for small and large molecule mass spectrometry data interpretation. Some are free and others require a subscription. There are efforts underway to develop comprehensive open-access cloud-based solutions, which in my opinion will provide a wealth of helpful spectral information across various industries and fields. The usefulness and value of this information will of course depend on the quality of the data that is used to populate the database, and this represents its own set of challenges for stewards of this information. There are also a number of books and journals available with great reference information, but the web-based or electronic solutions that have proliferated in recent years have become increasingly attractive, as some offer the capability to directly upload and process electronic datasets or provide significant information that permits the local interpretation of mass spectral data. The large molecule arena in particular has seen the advancement of some very useful, high quality openly accessible online libraries and tools as a result of academic and industry collaborative efforts.

Q: Where do you see the analysis and interpretation of mass spec data moving in the future?

A: Recent advancements in both hardware and software have resulted in the capability to generate great amounts of very high quality mass spectrometry data, particularly accurate mass and MSn data. Accurate mass capability in years past was more of a luxury than a commodity, but with the recent advancements in instrumentation and the proliferation of accurate mass capability across vendor instrument platforms, accurate mass data has now become a commodity instead of a luxury. That has opened up exciting opportunities for the development of advanced software tools to generate meaningful information from complex multi-vendor mass spectrometry datasets, including employment of innovative decision-making and visualization capabilities. I am very interested in exploring solutions that have been uniquely developed to interpret complex datasets for diverse applications outside of pharmaceuticals. For example, we’re working with collaborators who are developing software solutions for the petroleomics, fuels, and defense industries to see how we can potentially use diverse concepts and approaches to provide unique perspective to interpreting and understanding our data. There is profound beauty and elegance in taking a highly complex, multidimensional dataset and transforming it into something that is immediately intuitive and meaningful.

Q: Did you have anything else you wanted to add?

A: As a front-line capability for solving difficult problems, mass spectrometry continues to be for my team one of the most powerful tools in our analytical toolbox, enabling us to rapidly solve difficult problems and deliver meaningful answers to our customers—and in our world, ultimately our patients.