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TSQ Series™-based Solutions for Drug Discovery and Development
Part of Thermo Fisher Scientific
m a s s s p e c t r o m e t r y
LC-MS/MS Solutions for the Pharmaceutical and
CRO Industries
Drug D
iscovery and Developm
ent
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ACCELERATING THE PACE OF DISCOVERY
The ChallengeQuantitative analyses are usedthroughout the drug discovery anddevelopment process. Whether it is in high throughput lead optimiza-tion or in regulated bioanalyticalassay development, a TSQ Series solution can help meet the rigorousdemands of the various phases ofdrug development.
The drug discovery and developmentprocess involves the bioanalysis ofxenobiotics, metabolites, endogenousanalytes, and biomarkers. Bioana -lytical assay support or quantitationis required throughout the drugdevelopment life-cycle, a processdivided into two diverse paradigms.
First, thousands of structurallydiverse compounds are screened tofind a candidate. Several physico -chemical properties are tested invitro before the lead candidate istested in animal models (preclinicaltesting). If the candidate meets thecriteria of preclinical testing, aninvestigational new drug (IND)application is filed with the U.S.Food and Drug Administra tion (FDA).A TSQ Series mass spectrometer,powered by QuickQuan™ softwareand Galileo LIMS, provides a fullsolution during this phase.
Upon approval, the developmentmoves to the process of evaluatingthe drug in humans (clinical trials).The FDA then evaluates the resultsfrom the clinical trials and if allrequirements are satisfied, approvesthe new drug application (NDA).The drug can then be prescribed. ATSQ Series mass spectrometer withFAIMS, LCQUAN and Watson LIMSprovides a comprehensive solutionto meet the strict compliancerequirements with confidence.
TSQ Series-based integrated solutions provide different levels of
system and data integration to streamline workflows specific to
the drug discovery and development process.
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DRUG DISCOVERY SOLUTIONS: QUICKQUAN
QuickQuan offers a rational approachto workflow automation that sig -nificantly improves the throughputof drug discovery assays such asmetabolic stability, permeability(CACO-2, PAMPA), protein binding,and preliminary pharmacokinetics.It was developed from the scientist’sperspective in order to improve theefficiency of the lead candidateselection process.
Consider this statistic: in 2005, theFDA approved only 20 new molecu-lar entities (NME), the same num-ber it approved in 1974. Clearly,there is a need to screen potentialdrug compounds more accuratelyand to provide flexibility in assay
design, while accelerating earlycompound assessment and offeringa cost-effective, integrated LC-MS/MS solution.
QuickQuan enables automated LC-MS/MS quantitative analysis of chemically diverse compoundsand was developed together withinput from scientists at multi -national pharmaceutical companiessuch as AstraZeneca, Novartis, andBMS. The software manages thedata acquisition and processing forall compounds in the analytical run and generates quantitative results automatically.
Data generated by QuickQuan is stored in a central Microsoft®
Access or Oracle® database. The database provides fast and efficient retrieval of informationabout a specific compound andallows the compound to be used in multiple assays.
QuickQuan software, developed in partnership with the
pharmaceutical industry, supports high-throughput screening
applications with automation and sensitivity.
QuickQuan Benefits
• Increased Throughput~ 70 second tuning time per compound
• High SensitivityAlways selects the most sensitive transition using reverse energy ramp (RER)
• Plug-and-play SoftwareMinimal user intervention is required to generate information
• Database AdvantagesFast and efficient retrieval of analytical information
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BIOANALYSIS SOLUTIONS: LCQUAN AND WATSON LIMS
All of the tools necessary to design, implement, and analyze
pharmacokinetic data on a global basis.
21 CFR Part 11 and LCQUAN
Companies in regulated industries,such as pharmaceutical companies,must comply with numerous regula-tions. On August 20, 1997, 21 CFRPart 11, Electronic Records and Elec-tronic Signatures, was instituted by
the FDA. The purpose isto allow pharmaceu-
tical companies tosubmit their documents
to the FDA in electronicform in place of paper. The
requirements of the regulationsare to ensure the security and
integrity of the electronic recordsand to ensure the electronic signa-ture is treated with the same levelof importance as the handwrittensignature.
Building on the dedicated post-processing standalone application,LCQUAN has been expanded intoa complete, secure data system largely specified and designed bycustomer input. LCQUAN gives theuser the necessary resources forimporting sequence informationfrom external systems, method
development, data review, data processing, data reporting, andexporting results to external sys-tems, all within a 21 CFR Part 11compliant environment. LCQUAN
also provides multi-level securityaccess, giving system administra-tors the freedom to modify userprivileges from full system accessto data review only. In addition, the software enables the user tosafely process data stored on network-based computing systems.
Drug discovery and development is an international effort involving scientists across different continents.
Our integrated solutions facilitate data exchange between different laboratories and locations.
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A SINGLE-VENDOR SOLUTION
When it comes to complying with the exacting standards of 21 CFR Part 11,
LCQUAN and Watson LIMS provide a seamlessly integrated solution that
facilitates confident data submission for regulatory purposes.
Synchronization of the bioanalyticalworkflow with the Watson LIMSsystem provides data managementsecurity. Watson LIMS is widely utilized among the majority of globalpharmaceutical companies, andLCQUAN software is our quantitativedata acquisition tool for GLP studies.
With LCQUAN and Watson LIMSworking seamlessly together, you can:
• Meet the most stringent 21 CFR Part 11 and othercompliance mandates
• Track study progress
• Simplify the auditing process
• Review and print chromatogramswithin Watson LIMS
And this is just the beginning. With complete control over futuredevelopments of the world’s mostadvanced quantitative LC-MS/MSsystem, Thermo Fisher Scientific is committed to providing you witheverything you need to be confidentin the quality, security, and efficiencyof your GLP studies.
A robust bioanalytical assay consis-tently delivers precise quantitativeresults regardless of the challengesposed by the matrix or othersources of chemical noise.
A TSQ Series mass spectrometerwith high-Field AsymmetricWaveform Ion MobilitySpectrometry (FAIMS) and H-SRMprovides significant immu nity
against chemical interferences andfacilitates development of robustbioanalytical assays that withstandthe test of time. Faster method devel -opment at the highest possible sen-sitivity is routinely achievable withthese two highly desirable features.
The increases in selectivity offered byFAIMS and H-SRM result in cleanerchromatograms that are more easily
and more reproducibly integrated.Therefore, a bioanalytical methoddeveloped using FAIMS and H-SRMwill be robust enough to withstand-ing the challenges posed by differ-ent matrices and their samplepreparation procedures, withoutsignificant method redevelopment.This translates to consistent, highlysensitive quantitative results, injec-tion after injection.
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FAIMS reduces chemical noise and matrix interferences, resulting in improvedassay robustness and increased assay sensitivity.
Representative LC - FAIMS - H-SRM chromatogram forclenbuterol in human urine. High (0.1 FWHM) mass resolution, combined with FAIMS selectivity.
Representative LC - SRM chromatogram for clenbuterolin human urine. Unit mass resolution without FAIMS.
Robustness of FAIMS interface on TSQ Quantum Ultra
RSD = 6.4%, 250 fg on-column
NOISE REDUCTION TECHNOLOGY FOR LC-MS/MS QUANTITATION
Significantly enhance assay robustness and sensitivity by
eliminating drug-related, endogenous, and non-endogenous
chemical interferences using FAIMS.
Drug D
iscovery and Developm
ent
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LC - FAIMS - H-SRM
LC - SRM
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Using TurboFlow methods on the TLX System allows you to remove most of the time-consuming steps in the sample preparation process,which speeds sample throughput while minimizing errors and variability.
SIGNIFICANTLY REDUCE MATRIX EFFECTS
“In the case of LC-MS-MS-based procedures, appropriate steps
should be taken to ensure the lack of matrix effects throughout
the application of the method, especially if the nature of the
matrix changes from the matrix used during method validation.”
–Page 8, Guidance for Industry, Bioanalytical Method Validation, FDA, CDER, May 2001.http://www.fda.gov/cder/guidance/index.htm
High linear velocities and large particlescreate turbulence within the column
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Why TurboFlow Technology is Superior
Flow
Particle PoreProtein(large molecule)
Salt,lipids,sugars
Small molecules bind to the column chemistry while large molecules flow to waste
Small drug molecules
Particle chemistry binds small molecules whilelarge molecules flow to waste
The ability to directly inject samplesfrom urine, plasma or serum into atriple stage quadrupole and performhighly sensitive bioanalysis is thedirect result of TurboFlow™ technology.
When samples are analyzed usingTurboFlow technology, ion suppres-sion-causing sample componentssuch as proteins and hydrophilicmacromolecules are removed.TurboFlow technology uses the
combined effects of column chem-istry and size exclusion technologyto clean every injected samplebefore it is ionized, resulting inhighly sensitive LC-MS/MS analysis.
The Thermo Scientific Transcend™
system combines the power of on-line sample clean-up using our patented TurboFlow technology,with the speed of ultra high pres-
sure liquid chromatography (uHPLC).A Transcend-enabled TSQ Seriesmass spectrometer harnessing thepower of FAIMS and H-SRM tech-nology is the most sensitive inte-grated single-vendor solution forPhase I-III bioanalysis.
Liquid-Liquid Extraction (LLE)
1. Aliquot of sample2. Spike with IS3. Add buffer4. Add MTBE5. Shake 10 min6. Centrifuge7. Remove organic8. Evaporate to dryness9. Reconstitute
10. Transfer to plate11. Inject onto column
Solid Phase Extraction (SPE)
1. Aliquot of sample2. Spike with IS3. Add 0.1N HCL4. Condition sorbent5. Add sample to sorbent6. Wash7. Evaporate8. Reconstitute9. Transfer
10. Inject onto column
Protein Precipitation (PPT)
1. Aliquot of sample2. Spike with IS3. Add acetonitrile4. Centrifuge5. Remove supernatant6. Reconstitute7. Transfer to plate8. Inject onto column
The number of sample preparation steps is significantly reduced with TurboFlow technology.
TurboFlow technology leverages the difference in diffusion rates ofsmall and large molecules
FasterResults!
TurboFlow – 4 Steps
1. Aliquot of sample2. Spike with IS3. Centrifuge4. Inject onto column
BR62225_E 12/09S
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