Mass Spec Lab Blog

Keep up on the latest blogs from Mass Spec Lab.

Custom vs Contract Research Organization – Which C in CRO are YOU looking for?

Contract Research Organizations (CROs) around the country and around the world serve the pre-clinical and clinical phase development of pharmaceuticals and biomedical devices. Most CROs continuously add capabilities to support large and multisite studies, and, in the current outsourcing climate, have attracted substantial venture capital and grown rapidly. Among other services, CROs provide long term, and large scale bio-analytical support, however, their rapid growth in this area seems to come with caveats. For example, the centralization of the bio-analytical services to a limited number of sites has promoted “factory” style, productivity driven, bio-analytical testing. The resulting emphasis on productivity and routine quantitative and qualitative studies predisposes the large contract analytical divisions to prefer large scale projects, especially those that come with less inherent analytical difficulty.

Mass Spec Lab is a new bioanalytical startup in Irvine, CA, launched by InVision Biomedical Group, which provides CRO preclinical and clinical build services to the ophthalmic biomedical device sector. Mass Spec Lab itself is a bio-analytical CRO, but as it grows it has carefully tried to distinguish itself as a Custom rather than Contract Research Organization. Let us explain. Mass Spec Lab formed in 2014 and launched its online presence in late 2015. The requests for analytical services have since been coming in from startups as well as large established companies, but they all have common themes. Most potential project requests to Mass Spec Lab are accompanied by the desire for:

1) fast turn-around time on sample analysis
2) timely and transparent online or in person communication about findings throughout study period
3) ability to summarize, on short notice, analytical method and topline study results tailored to customer need
4) flexibility to depart from typical quantitative or qualitative protocol on short notice to pursue identification of potentially important molecules in a data driven manner
5) ability to provide in depth sample characterization including MS based structural identification of major signals of interest.

We posit that whereas Contract Research Laboratories typically deliver on 1, 2 of the above requests, in routine projects, in addition to 1 and 2, it is the customer tailored components of 3, 4 and 5, which embody the capabilities of a Custom Research Organization like Mass Spec Lab.

Contract analytical laboratories undoubtedly do great work, and are well suited for large scale, long term, and routine quantitative and qualitative studies. On the other hand, smaller, more fleet-footed Custom research laboratories should be the first option considered in cases where the custom component of an analytical study outweighs the routine, such as untargeted analysis, unknown chemical identification (impurities, degradants and side products), studies with very tight timelines, go/no go data critical to discovery project decisions, in other words, projects requiring high levels of versatility, flexibility, and technical expertise.

Contact us for information about Mass Spec Lab’s portfolio of analytical instrumentation for your custom research need, including high resolution, accurate mass UPLC and APGC/QTof Mass Spectrometer, GC/MS, GPC and HPLC, microscopic FTIR spectroscopy, and DSC, NIST and in-house compound UV and MS libraries.

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Alignment of Emerging Biomedical R&D Challenges with Tof-HRMS Capability and Versatility

The Biomedical device sector is undergoing rapid expansion and its qualitative and quantitative analytical needs are expanding in unison with this growth. The causes behind this increase are many. One major factor is the availability of venture capital for biomedical devices which has been driven by the “rapid development” timeline of devices which deliver both novel and generic active pharmaceutical ingredients (APIs) using innovative and targeted technological platforms.

Biomedical devices and pharmaceutical drug delivery devices encompass a broad range of products. As examples, intraocular lenses (IOLs), insulin pumps, orthopedic implants, coated stents, blood oxygenators and pacemakers are all biomedical devices. Production of such a diverse range of devices involves a multitude of different materials, procured from an army of different suppliers, constructed using a long sequence of assembly steps, utilizing processes which more often than not require a long list of processing aids, e.g., surfactants, stabilizers, mold release agents, and plasticizers and exposure to extreme process conditions such as temperature, UV exposure (in photo curing) and laser exposure.

The extreme challenges inherent in ISO 10993 extractables and leachables testing of biomedical devices are clearly evident. E&L is a regulatory driven activity and difficulties encountered in biomedical device E&L can pose real hurdles in the regulatory approval process and ultimately to commercialization of the therapeutic product. A universe of analytes is out there and E&L testing regulatory expectations are that the chemical analyst will detect, structurally identify and quantify analytes present even down to the ppm level. In contrast, the analytes of a conventional small molecule drug product are far more well-defined. Lower cost triple quad mass spectrometers with low resolution (unit mass resolution) and high sensitivity have been the workhorses of the traditional (small molecule) pharmaceutical industry because this tool has met the need for sensitive quantification of “known” analytes in targeted analyses such as DMPK studies. Non-targeted analysis is the norm and the first level of attack in the biomedical device world. Once identified and characterized, targeted quantification becomes pivotal.

High resolution mass spectrometry is the only developed, readily available instrumentation capable of meeting the analytical challenges (qualitative and quantitative) presented by E&L testing of biomedical devices. Q-Tof MS and the Orbitrap are currently the two most popular HRMS platforms on the market. The mass resolution and sensitivity of the Orbitrap in the “low mass” (i.e. 0-200 amu) range is excellent for specialty impurity ID testing, while the affordability, mass range, sufficient sensitivity, and mass resolution of the Q-Tof platform, makes it the most versatile instrument for comprehensive, nontargeted screens of device leachates and extracts and thus influenced our choice of HRMS platform. Mass Spec Lab selected the Q-Tof mass spectrometer because of the inherent flexibility to do qualitative and quantitative (i.e. non-targeted and targeted) analysis on a single platform.

Selection of the “front end” or LC of the platform was equally critical. Our system includes a UPLC system which has operated trouble free and with impressive separation capability because of its low dispersion properties. We have found that we can often accomplish the separations we need with 5 minute screening runs which rapidly span the reverse phase polarity range (95% aqueous to 100% acetonitrile), while collecting the non-targeted and, when necessary, targeted information that the assay might require. The Tof-HRMS platform allows us to take full advantage of this speed and efficiency in separation with no drop in qualitative or quantitative performance including chromatographic resolution, sensitivity, linearity, mass spectral resolution and other analytical merits.

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Extractables&Leachables Small Molecule Impurity ID - Current Approaches and Opportunities

Analytical scientists across industries are often tasked with identification of small molecule impurities in extractables and leachables (E&L) studies of materials used in biomedical devices, contacts and closures (C&C), labels and packaging. Impurity ID is also a key activity throughout the drug development process. Successful identification of an impurity facilitates its thorough toxicological risk assessment, and helps R&D teams make important chemicals and materials sourcing and processing decisions.

Liquid and gas chromatography coupled to various detection platforms are both heavily utilized for low concentration impurity analysis. Mass spectrometry detectors have over the last decade improved in resolution, mass accuracy, as well as dynamic range. Consistent instrumentation and software improvements now also allow very high sensitivity detection and quantitation of impurities.

High resolution mass spectrometry systems can be used to identify the accurate mass, and often the elemental composition of an impurity. Elemental composition alone, however, does not guarantee structural identification, in fact, most often a combination of analytical techniques is required. Orthogonal chromatography retention and UV data, coupled with high resolution MS fragmentation of a known impurity mass, helps to narrow down the number of possible structures that can explain a given intact accurate mass and its fragments.

This series of the Mass Spec Lab blogs is dedicated to those analytical scientists, R&D managers, and teams who have a high vested interest in successful impurity ID. In this series, we will showcase, in a case study format, E&L impurity identification of rubber additives. We will share data from aforementioned techniques, but also move beyond the typical high resolution MS hardware and data acquisition software capabilities into the territory of chemical computation. We plan to show how we use MassFrontier1,2 (Thermo, HighChem) theoretical fragment prediction software, and discuss the need for computational structure generators, such as MOLGEN3.

We invite you to take a look at the recently presented case study poster 'Determination of an Unknown E&L Impurity Based on Accurate Mass Detection, Elemental Composition Matching, Chemicals Database Searching, and MassFrontier Theoretical Fragmentation'

We want to hear from you . Please tell us about your experience and approaches in successful small molecule impurity ID. What instrumentation do you currently use, is it LC-UV, low or high resolution GC-MS or LC-MS? Have you considered or are you currently using computational structure and fragment prediction to help with structural elucidation of impurities? Please do share the successes, but also the caveats, the difficulties that often arise due to chromatography, ionization efficiency, and ambiguity of elemental composition and MS fragmentation. When we share both the successes and difficulties, as we intend to do in this blog, we collectively learn the most. Look forward to your feedback! Mass Spec Lab team.

1 V. Petrusevski, S.T. Jolevska, J.T. Ribarska, M. Chachorovska, A. Petkovska, S. Ugarkovic (2016) Development of complementary HPLC-DAD/APCI MS methods for chemical characterization of pharmaceutical packaging materials, Journal of Pharmaceutical and Biomedical Analysis, Vol 124, p.228

2 Hua Yang, Kate Comstock, Linda Lopez (2014) Comparison of Soxhlet and Accelerated Solvent Extraction for Leachable and Extractable Analysis of Packaging Material, ThermoScientific Application Note 1108

3 Ralf Gugisch, Adalbert Kerber, Axel Kohnert, Reinhard Laue, Markus Meringer, Christoph Rücker, Alfred Wassermann (2014)  MOLGEN 5.0, a Molecular Structure Generator In: Advances in Mathematical Chemistry and Applications, Vol. 1  Edited by:Subhash C. Basak, Guillermo Restrepo, José L. Villaveces.   113-138 Bentham Science Publishers Ltd.

 

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Marie Dvorak Speaking At the AAPS Southern California In February

We are presenting a talk entitled "Exploiting High Resolution Accurate Mass QTof MSMS for the Identification of Unknown Analytes in Biomedical Device Leachates and Extracts"at the AAPS Southern California discussion group monthly meeting on February 11th.   To make this forum more valuable let us know what you are interested in learning about ISO 10993 leachables and extractables testing.  We  plan on posting the presentation on our website after the presentation but also invite you to the meeting.  Read more for details.

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Fingerprinting for Equivalence in Biomedical Device Testing

Mass Spec Lab is launching a new service for our biomedical and chemical industry customers - mass spectrometry based fingerprinting of materials for equivalence assessment.

Our state-of-the-art UPLC-UV-QTof Mass Spectrometer XevoR G2-S (Waters) and ProgenesisR QI software package (Nonlinear Dynamics) have been rigorously evaluated by our scientists and found to be well-suited to provide detailed and timely chemical fingerprint and equivalence information.

What is the output of a fingerprint analysis?

 

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