Agenda
Merck KGaA1
2 Central analytical services (CAS)
Special sample analytics in CAS3
Franziska Burkert, Merck KGaA, 13th November 20132
Special sample analytics in CAS3
4 FT-IR microscopy in troubleshooting analytics
FT-IR imaging for Research & Development 5
6 Summary
Milestones in the history of Merck
1668
Friedrich Jacob Merck (1621-1678) buys the Angel Pharmacy (Engel-Apotheke)
1827
Emanuel Merck (1794-1855) startsproduction on an industrial scale
Merck is the oldest pharmaceutical and chemical com pany in the world
Franziska Burkert, Merck KGaA, 13th November 20133
Merck is a leading pharmaceutical, chemical and life sciencecompany that conducts its operations in four divisions:
– Merck Serono: Prescription medicines of both chemical andbiological origin in specialist indications
– Consumer Health: Over-the-counter pharmaceuticals forpreventive health care and self-treatment of minor ailments
Merck at a glance
preventive health care and self-treatment of minor ailments
– Performance Materials: High-tech performance chemicalsfor applications in fields such as consumer electronics, lighting,coatings, printing, plastics, and cosmetics
– Merck Millipore: Products and services for the life science industry, used in research and analytical laboratories as well as in pharmaceutical manufacturing
� Approximately 39,000 employees in 66 countries
� Merck manages its operating activities under the umbrella of Merck KGaA, which was listed on the Frankfurt Stock Exchange in1995 and admitted to the DAX® in 2007
� Around 30% of the total capital is publicly traded, while the Merck family, as general partner, indirectly holds around 70%Franziska Burkert, Merck KGaA, 13th November 20134
Pützer Tower and Pyramidat Darmstadt headquarters
www.merckgroup.com
Central analytical services (CAS)
SO-A(Site Operations-
Analytics)
SO-ASAnalytical Services
SO-ABBioanalytical
ChemistryAssistant
Assistant
AssistantSO-AC
Analytical Chemistry
Physical Methods &Chromatography & Mass Bioprocess Analytics Molecule Characterization
55 Franziska Burkert, Merck KGaA, 13th November 2013
ABB-1Biochemistry,Immunology
ABB-2Microbiology
ABB-3Life Science Analytics
ABB-4Molecular- andCellular Biology
ABB-5Biomolecule Analytics
ABC-6Quant. Bioanalytics
ABC-7Molecule Analytics
ABC-8Phys. Chem. Prop.,
XRD
ABC-9Bio NMR &
NMR Spectroscopy
ASRReporting & Laboratory
Services
ASSSampling & CAS
QM-Support
ASLSAP QM/LIMS
Support & Projects
ASIIT-Support &
Development, PAT
ACC-1Impurity Profiling
ACC-4Mass Spectrometry &Gas Chromatography
ACC-5Chromatography Methods
ACC-6OLED-Analytics
AC9Titration,
Special Analytics
ACP-2Element Analytics
ACP-7Therm. Analysis,
Molec. Spectroscopy
ACP-8Particle Charact., SEM,
Troubleshooting Analytics
Physical Methods &Spectroscopy (SO-ACP)
Chromatography & MassSpectrometry (SO-ACC)
Bioprocess Analytics(SO-ABB)
Molecule Characterization(SO-ABC)
ACC-3Liquid Chromatography
� Troubleshooting analytics� Identification of impurities: fibers, particles, discolorations ...
� Root cause analysis
� Investigations planned, coordinated and documented by SPA team
Special sample analytics in CASTasks
Franziska Burkert, Merck KGaA, 13th November 20136
� Microspectroscopy for Research & Development � Chemical imaging
� Surface-sensitive analyses
� Time-dependent and temperature-dependent analyses
� Clean room (nominally class 10.000)
� Sample preparation in laminar flow box (class 100) inside the clean room
� Four microscope systems located in the clean room
Special sample analytics in CASThe clean room
Franziska Burkert, Merck KGaA, 13th November 20137
Troubleshooting analytics
� Occurrence of unknown substances � during production
� quality control
� customer complaint
� ...� ...
� Impurities in manufacturing processes and products� Unexpected & unwanted occurrence
� Unknown identity & risk
� Analytical method unclear, often various analytical methods necessary for identification
� Short response time important
Franziska Burkert, Merck KGaA, 13th November 201310
Troubleshooting analyticsTypical work flow
Customer
Sample preparation
Documentation1H-NMREI-MS
Special Sample Lab
Franziska Burkert, Merck KGaA, 13th November 201311
IR/Raman microscopy
Sample preparation(e.g. filtration)
Optical microscopy
Electron microscopy/EDS?
Organic
Inorganic
UV/VIS
ToF-SIMS
ICP-MS
XPS
HPLC-MS
XRF…
GC-MS
EI-MS
lab core competence coordination of other methods
Fast, high spatial resolution, non destructive
Troubleshooting analyticsParticle isolation
� Isolation of impurity
� Preparation on sample holder
� Characterization by optical � Characterization by optical microscopy � Documentation of structure, size, color,
number of particles ...
� Decision which methods will be usedfor further characterization
12 Franziska Burkert, Merck KGaA, 13th November 2013
Troubleshooting analyticsFT-IR microscopy
� FT-IR spectroscopy is viable for identification of most organic and many inorganic materials
� Direct structural information from characteristic group frequencies
Franziska Burkert, Merck KGaA, 13th November 201313
characteristic group frequencies
� Fast computer-aided identification: search in spectral databases
� High sensitivity compared to other methods:
Particle size 100 x 10 x 10 µm3
Particle mass ~ 10 ng
After dissolution in 100 µL solvent � concentration ~ 100 ppb
Troubleshooting analyticsLUMOS – IR-Microscope
� Measurement with micro-ATR
� Ge-crystal, tip 100 µm diameter
� Fast measurement (< 1 min)
� High quality FT-IR spectra of� High quality FT-IR spectra ofindividual particles
Franziska Burkert, Merck KGaA, 13th November 201314
Troubleshooting analyticsIdentification of unexpected impurities with LUMOS microscope
Franziska Burkert, Merck KGaA, 13th November 201315
Combination with element composition/distribution from SEM/EDS mapping enables a reliable identification of single particles.
The subsequent allocation of impurity source within hours safes cost, enables expert handling of complaints and avoids compensation claims.
IR microscopy for R&DHyperion 3000 & accessories
Franziska Burkert, Merck KGaA, 13th November 201317Linkam Stage
IRRAS
Macro-ATR
� Tissue sections of histological samples embedded in paraffin
� FT-IR microscopy in transmission mode� Fast, non-destructive
� Qualitative and quantitative results
FT-IR imaging for R&DParaffin-embedded tissue sections
� Qualitative and quantitative results
� Focal Plane Array (FPA) detector: in each rectangle 64 x 64 pixel � 64 x 64 spectra� 4096 spectra per single measurement (170 µm x 170 µm)
� 5 x 6 FPA mapping � 122800 spectra (850 µm x 1020 µm)
� Visualization of proteins, fats, bones, pharmaceutical drugs, …
Franziska Burkert, Merck KGaA, 13th November 201318
FT-IR imaging for R&DChemical imaging using ATR
� Problem: Sample preparation for transmission IR is sometimes not possible
� Solution: FT-IR imaging using ATR techniques
19
Micro-ATRImaging area 32 µm x 32 µm
Macro-ATRImaging area 600 µm x 600 µm
Franziska Burkert, Merck KGaA, 13th November 2013
1732
1653
1546
1162
1 . 5
2 . 0
FT-IR imaging for R&DChemical imaging of tissue sections
� FT-IR imaging of cryo tissue sections
� Increased spatial resolution compared totransmission IR measurements
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W a v e n u m b e r c m - 1
Abs
orba
nce
Uni
ts
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0
6.51e+03
3.2e+03
2.8e+03
2.4e+03
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1.6e+03
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800
400
3.6e+03
4e+03
4.4e+03
4.8e+03
5.2e+03
5.6e+03
6e+03
36400 36500
1115.34-1059.79 X-Achse [µm]
21900
22000
22100Y-A
ch
se [
µm
]
0
1.23e+04
6.2e+03
5.4e+03
4.6e+03
3.8e+03
3e+03
2.2e+03
1.4e+03
7e+03
7.8e+03
8.6e+03
9.4e+03
1.02e+04
1.1e+04
36400 36500
1070.90-963.50 X-Achse [µm]
21900
22000
22100Y-A
ch
se [
µm
]
0
2.33e+04
1.15e+04
9.5e+03
7.5e+03
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1.35e+04
1.55e+04
1.75e+04
1.95e+04
2.15e+04
36400 36500
1715.28-1485.67 X-Achse [µm]
21900
22000
22100Y-A
ch
se [
µm
]
Micro beads Bone Proteins320 µm x 320 µm 102400 spectra
Franziska Burkert, Merck KGaA, 13th November 2013
wavenumber
FT-IR imaging for R&DOther examples for ATR-IR imaging
� Chemical imaging of tablets
0
703
360
260
160
460
560
21800
22000
22200
22400
Y-A
ch
se [
µm
]
� Chemical imaging of multilayered materials
Franziska Burkert, Merck KGaA, 13th November 201321
36200 36400 36600 36800
Baseform X-Achse [µm]
21600
Summary
� IR analysis is a powerful technique to identifydifferent organic and inorganic substances
� The LUMOS microscope is the perfect tool foridentification of single small particles
� The Hyperion 3000 is a flexible instrument for� The Hyperion 3000 is a flexible instrument fordifferent R&D setups� IR imaging of tissue sections, tablets, packaging materials,
melt extrudates …
� Surface-sensitive analyses (IRRAS)
� Time-dependent and temperature-dependent analyses
Franziska Burkert, Merck KGaA, 13th November 201322