What are some “must-have” features that pharma companies are looking for when evaluating Liquid Chromatography and Mass Spectrometry equipment?
Dr. Patrick Bulau, Roche Diagnostics GmbH: For application in a quality control/GMP environment: Long-term robustness and technical support > 10 years. Instrument and data evaluation software: Developed and qualified according to data integrity guidelines of health authority’s (FDA, EMEA, WHO).
Jeff Reid, Global Market Manager, Wheaton: I believe proteomics is one of the more critical studies when it comes to drug discovery due to the variety of its applications and LC/MS is the analytical method of choice for the analysis. There have been significant technical advances in the technique on both the separation and mass spectrometry levels that supports proteomic studies, but the “must-have” feature I am finding is the utilization of a mass spectrometer with a triple quadrupole. A triple quadrupole ensures high sensitivity and accuracy along with better reproducibility at low concentrations.
Gurmil Gendeh, Ph.D., Marketing Manager, Pharmaceuticals: One general trend in the MS industry over the past decade has been the drive to higher and higher sensitivity. Depending on the structure and functional groups of a molecule, vastly different ionization efficiencies exist for various target analytes. Therefore, the ability to detect one compound with adequate sensitivity in no way guarantees that another target compound – even within the same chemical class – can also be detected adequately. Because pharma companies are often required to accurately detect trace levels of drugs, metabolites, or biomarkers, the LCMS must be optimized to deliver that sensitivity potential. The frontend system dwell volume needs to be minimized. This spells increased MS sensitivity. Robustness, dependability, reproducibility and uptime are also some of the “must-have” attributes.
The LCMS platform also needs to be GMP/GLP (GXP) capable. While nearly every lab must submit to a variety of regulations, the world of pharma is such that the pharma lab is arguably the most heavily regulated lab in the world. Laboratory compliance should really be thought of not as a set of hardware that functions according to a particular paradigm, but rather as a set of tools that satisfies an audit. Complete analytical instrument connectivity – from LC to MS, to balances and spectrophotometers is required.
Are HPLC’s and Mass Spec instruments moving toward a “universal” detector model? Are there pros and/or cons to this approach?
Bulau: Liquid Chromatography coupled to Mass Spectrometry is essential to increase sensitivity and resolution for the assessment of critical quality attributes for complex protein formats .
David Elder, Consultant: HPLC-UV detection is and will continue to be the “work horse” of the Industry. Firms will only adopt “universal” detection if it is simple to use and reasonably non-expensive.
Gendeh: Pharma labs include method development, discovery, and QA/QC for manufacturing. In all, there is a convergence to MS. There is a distinct trend for the LC UV detector to be replaced by the MS. The cost is justified by consolidation of multiple platforms, such as LC, CE, gel based platforms, into one. Training and use is unified and streamlined, and multiple data points per analysis are yielded. Conventional LC methods are often specific to a single attribute. But mass spectrometric analysis is more comprehensive. Multiple attributes of the sample, such as modifications to a protein drug like deamidation, truncation, or oxidation, can all be determined simultaneously in the same analysis.
Is it important to pharma companies for vendors to offer data collection and analysis software with their equipment?
Bulau: Yes, instrument and data evaluation software must be developed and qualified according to data integrity guidelines of health authority’s (FDA, EMEA, WHO).
Elder: This is a very germane question. Interfaces between instrument software and LIMS (Laboratory Information Management Systems) or specific control systems, e.g. chromatography data software systems, can often be problematical.
In the future, instrument software could be ‘on demand’, i.e. a customer may be able to purchase a simpler software version in the knowledge that their own control systems can fully process the data.
Gendeh: High complexity tests and a trend for users to be less expert in the disciplines of chromatography and mass spectrometry points to a need for automation. There is a trend towards full walkup systems: automated data acquisition, analysis and reporting, a trend that has been widely accepted in the applied markets. With new drugs continually coming to market, and a trend from small molecule production to large biomolecule production, pharma have started to adopt walkup LCMS platforms to satisfy a growing number of biologists with low LCMS instrumentation and operation knowledge who are increasingly adopting LCMS platform to get their answers. Sample prep and sample information data flow are also critical. Thus, a trend to a complete solutions approach, an “analyzer” model, exists.
Are pharma companies interested in ongoing service and support and possibly upgrades to their systems? Is making a “future-proof “ system possible and practical?
Bulau: Yes, see question 1.
Reid: I have found that service is a more important feature than the actual product in terms of analytical instrumentation. This is due to the fact that with scientific instrumentation there will always be moving parts meaning repair is inevitable. Knowing a vendor can offer superior service allows researchers to know their projects will not be put on hold if a system goes down. I always recommend going with a vendor who can be a true solution partner from the time of purchase to post sales service and application support.
A “future-proof” system is already a reality as many vendors are manufacturing LC/MS systems that can easily be upgraded whether it is a switch out of detector for better sensitivity or upgrade in software for more intuitive use.
Elder: Yes, this sounds like a great idea. However, vendors should avoid change for change’s sake and support the axiom that, “if it ain’t broke, don’t fix it”.
Gendeh: Software updates can be pushed automatically (cloud based or a la iPhone.) This includes artificial intelligence to auto update and parts replacement scheduling.
Future proofing is essential to make the unit last for the life cycle of the product to satisfy SOPs. Capital lab equipment vendors need to consider themselves trusted partners to their customers. Pharma customers expect vendors to provide products and solutions that ensure data consistency over the life cycle of their molecule. Sacrificing this trust to product recalls, inability to provide service and support, or unfortunate changes to product firmware could result in costly delays and that will have a long-term impact on the pharma/instrument vendor relationship.
What do you foresee as some future features/ technologies that will be added to LC and Mass Spec systems in the next five years?
Bulau: Since Liquid Chromatography coupled to Mass Spectrometry is not regularly applied in the quality control/GMP environment for product release yet I don’t see the need for additional features/ technologies within the next five years.
Reid: The biggest area for improvement is not so much on the analytical side, but more the sample preparation side. I see the improvement of autosamplers being a big push. Autosamplers will start to be manufactured larger and to be ran faster, eliminating potential bottle necks of sample introduction to the LC.
Elder: SIFT (single ion flow tube) mass spectrometry offers real time rapid analysis of volatile organic compounds (VOCs), without prior concentration or separation offers real opportunities in the areas of VOCs, volatile leachables and extractables, flavor analysis; possibly even cleaning qualification, when allied to swab desorption techniques.
ASAP (Atmospheric Solids Analysis Probe)/DESI (Desorption ElectroSpray Ionization)DART (Direct Analysis in Real Time) MS has the potential for use on counterfeited and adulterated pharmaceuticals and has the advantage that samples can be non-destructively assayed so that they can still be used as samples in ongoing court cases.
Ion Funnels (IF) can increase sensitivity through an increase in ion transmission efficiency. Although not new they have recently been interfaced with proton transfer reaction (PTR) MS and shown enhanced sensitivity.
Gendeh: Data integrity and compliance with CGMP would be essential as LCMS instruments continue their steady march from early discovery and R&D to the more regulated QC environment. With the increasing numbers of large molecule drugs in the pharma pipelines, LCMS systems will see deeper integration with complex sample preparation typical of biologic samples. LCMS opens the possibilities for multi-attribute analysis. The data complexity for these types of analyses will mandate intuitive and easy-to-use software that is more application specific, and will drive the “analyzer” concept that will integrate sample prep, data acquisition, analysis and reporting in walkup manner.