ASPEX Analytical Services

1. ASPEX CORPORATION:
ANALYTICAL SERVICES GROUP
February 10, 2012
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2. Introduction to ASPEX Corporation
• An FEI Company
• An American company located in Pittsburgh, PA.
• Analytical Testing Services provider
> cGMP compliant, FDA Registered
> Electron microscopy services
> X‐Ray microanalysis
• Co‐located with
> ASPEX SEM‐EDX manufacturing facility
> Global Sales and Services
> ASPEX Learning Center

3. Quality Assurance Program
• Quality Management System
• cGMP‐compliant standard operating procedures
• ISO9002:2008 certification (Expected April 2012)

4. MARKETS SERVED
Introducing
Pharmaceuticals- Oil Analysis- Hard Drives
Particulate Matter Wear Debris
February 10, 2012
Metals Inhalers Mining
Medical Devices

5. PRODUCTS & SERVICES
February 10, 2012
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6. Laboratory Equipment: SEM-EDX
ASPEX EXpress™ ASPEX EXplorer™
ASPEX EXpress™ desktop SEM The ASPEX EXplorer™ system
provides a fully integrated SEM and
EDX platform that blends state of the
art hardware with software
sophistication.
Experience The Power of ASPEX
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7. Analytical Testing Services
• Microscopic Imaging Services • Metals Quality Analysis
• Failure Analysis (fractures, delamination & • ASTM E45, ASTM E2142, ISO 4967
corrosion)
• Materials Testing (ceramics, composites & • Advanced Quality Control
metals) • ISO 4406, ISO 11171
• Surface Characterization (porosity & grain • Oil Analysis
structure)
• Foreign Particle Identification
• Elemental Composition by X‐Ray
Microanalysis • Automated Particle Analysis
• Contamination Identification • Characterization (size, shape and
• Surface Composition & Coatings composition)
• Elemental Analysis • Size Distribution
• X‐ray mapping, Line Scan, Spot & Area
Microanalysis

8. ASTM, ISO and USP Standard Services
061 ISO 4406 ‐ Hydraulic and Oil Particle Count Analysis
062 ISO 4406 ‐ with Elemental Composition
063 ISO 11171 ‐ Fluid Cleanliness Analysis
064 ISO 11171 ‐ with Elemental Composition
066 ASTM‐E45 ‐ Inclusion Cleanliness Analysis of Rolled Steel
067 ASTM‐E2142 ‐ Inclusion Cleanliness Analysis of Rolled Steel
068 JIS G 0555 ‐ Inclusion Cleanliness Analysis of Rolled Steel
069 ISO 4967 ‐ Inclusion Cleanliness Analysis of Rolled Steel
070 USP <788> Particulate Matter
071 ASTM Test Method F1877 Life Cycle Testing
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9. General Electron Microscopy Services
• Secondary Electron Imaging
• Backscatter Electron Imaging
• Low‐vacuum Backscatter Electron Imaging
• X‐Ray Microanalysis (elemental composition)
• Features (particles or inclusions) characterization
• X‐Ray Mapping
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10. Sample Preparation
• Filtration
• Sputter Coating
• Metal polishing
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11. INTRODUCTION TO ASPEX TECHNOLOGY
Scanning Electron Microscopy and Energy Dispersive Spectrometry
February 10, 2012
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12. SEM‐EDX Information
• Secondary Electron Imaging
 Topographical/Morphological imaging
• Backscatter Electron Imaging
 Atomic number based contrast
 Low‐vacuum imaging capabilities
• SDD for X‐Ray detection
 Chemical composition using Energy
Dispersive Spectrometry
ASPEX
EXPLORER

13. SEM‐EDX Information
SECONDARY ELECTRONS
• Secondary electrons are inelastically
SE scattered.
• Incident electron loses much of its energy
to the sample
• Weakly bound electrons of the sample are
“boiled‐off”.
Nucleus
• <50 eV
• Topographic information.
• SE are drawn to detector with positive
bias.
Incident Electron
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14. SEM‐EDX Information
APPLICATIONS: HIGH MAGNIFICATION IMAGING
• Surface morphology
• Shape
• Texture
• Porosity
• Defects
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15. SEM‐EDX Information
BACKSCATTERED ELECTRONS
Electron Beam
BSE
• Backscattered electrons are elastically
scattered.
• Minimal energy loss.
• Large directional change.
• >50 eV
• Strong correlation with atomic number.
Nucleus
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16. SEM‐EDX Information
BACKSCATTERED ELECTRONS
• Imaging based on atomic number contrast useful to investigate:
> Sample homogeneity
> Contamination
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17. SEM‐EDX Information
X-RAYS MICROANALYSIS
Characteristic X‐Rays are generated in a multi‐step process:
• An inner shell electron is knocked out by incoming electron.
• An outer shell electron drops down to fill vacancy.
• Energy difference is emitted as a photon.
SE Emitted
X‐Ray
Nucleus Nucleus
Incident
Electron
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18. SEM‐EDX Information
ENERGY DISPERSIVE SPECTRUM
• Energy of emitted X‐Ray is characteristic of chemical element.
• The X‐ray detector collects the X‐rays and results are displayed in a
histogram.
• Used to identify and quantify the elements present in a sample.
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19. SEM‐EDX Information
SED BSED EDX
Si
1,000
Counts
500 Mn
Fe
Fe
0
0 1 2 3 4 5 6 7 8
keV
• Electron images – How the sample looks? What is the size and shape?
• EDX ‐ What the sample is made of?
• Complete physical and chemical characterization of materials
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20. Applications
SELECTED EXAMPLES OF TESTING SERVICES
• Contamination studies in Pharmaceuticals
• Particulate Matter Characterization
• X‐Ray Mapping
• Elemental Distribution in samples
• Surface Characterization of Materials
• Morphology, porosity, size and shape
• Oil Analysis
• Characterize wear debris to understand wear and tear patterns
• Inspection of Medical Devices and Implants
• Wear Debris, fractures and failures
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21. Contaminant Particle Found
in a Pharmaceutical Product
200 µm 200 µm
SED BSED
800 Br Br
C
600 P
Counts
Cl
400
Ca
F
200 O Br
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
keV
EDX (Chemical Composition)
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22. Contaminant Particle Found
in a Pharmaceutical Product
500 µm
100 µm
Stainless
Steel in raw
material
sample
2,500
2,000
Counts
1,500
Fe Fe
Al Cr
1,000 O
500 Ni Si Ni
Cr Fe
Ni
0
0 1 2 3 4 5 6 7 8 9 10 11 12
keV
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23. X‐Ray Mapping used to evaluate
elemental distribution in samples
MAGNESIUM STEARATE
50 µm
Sample: Aleve 220 mg
Scanning conditions: 10
frames at 1ms/pixel
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24. Surface Characterization:
Morphology
100 µm 1000 µm
100 µm
20 µm 20 µm
• How clean is your product?
• Is your product free of defects?
• Are your coatings uniform?
• Does your product meet specifications?
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25. Foreign Particles Identified in
Pharmaceutical Products
Al
20 µm
20,000
C u ts
on
Aluminum 10,000
0
0 1 2 3 4 5 6 7 8 9 10
Teflon keV
100 µm
6,000
C u ts
on
4,000 Fe Fe
Iron 2,000
0
Fe
0 1 2 3 4 5 6 7 8 9 10
keV
200 µm 3,000
C
Synthetic
C u ts
2,000
on
1,000 O
Fibers 0
0 1 2 3 4 5 6 7 8 9 10
keV
Si
20 µm
15,000 O Mg
C u ts
on
Talc
10,000
5,000
0
0 1 2 3 4 5 6 7 8 9 10
keV
Fe Fe
100 µm
4,000
Stainless
C u ts
on
2,000 Cr Cr
Steel 0
0 1 2 3 4 5
C
6
r
Fe
7 8 9 10
keV
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26. Manual Inspection of
Medical Devices
Denuded area
Coated area
Metallic stent with polymer coating
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27. Applications of Automated
SEM‐EDX Technology
WHY USE AUTOMATED SEM-EDX TECHNOLOGY?
• To obtain statistically meaningful metrics.
• To recognize groupings within a population.
• To locate low‐probability features (“needle in haystack”).
• To verify absence of contaminants.
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28. Applications of Automated
SEM‐EDX Technology
• For each feature (a particle or material inclusion):
• Total number of features per area analyzed
• Exact location on specimen to relocate for advanced analysis
• Size (average diameter, area)
• Shape information (aspect ratio)
• BSE contrast level (~average atomic number)
• Elemental composition
• Electron Images
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29. How does an automated
SEM‐EDX works?
Spectrum Analyzed
Composition Determined
Particle Identified
Iron Rich Class
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30. How does an automated
SEM‐EDX works?
WHAT IS USED FOR CHARACTERIZATION?
Size and Shape Parameters Elemental Chemistry
• Elemental Composition
• Average diameter
• Maximum Diameter
• Minimum Diameter
• Aspect Ratio
• Area
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31. Applications of automated
SEM‐EDX Technology
Understanding
Distributions
Particle-by-Particle
Elemental Composition
Rare Feature
Location
Contamination
Studies
Specialized QC
Investigations
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32. Case 1
PARTICLE COUNT IN PARENTERAL SOLUTIONS
• USP Test Chapter <788>
– Enumeration standard for foreign particles
– Recommended for particles ≥10 µm and ≥25 µm
– Two step inspection:
• light obscuration for inspection with a given set of limits
Small Volume Large Volume
Parenterals Parenterals
<6000 @ 10um <25/ml @ 10um
U.S. Pharmacopoeia
<600 @ 25um <3/ml @ 25um
• microscopy if sample does not pass the limits
Small Volume Large Volume
Parenterals Parenterals
<300 @25 mm
<6000 @ 10um <2/mL @ 25 mm
<25/ml @ 10um
U.S. Pharmacopoeia
<3000 @10 mm
<600 @ 25um <12/mL @10 m
<3/ml @ 25um
– SEM‐EDX analysis provides elemental composition in addition to enumeration
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33. Case 1
PARTICLE COUNT IN PARENTERAL SOLUTIONS
E-Beam Analysis is used to understand distributions
195 Particles >10 um
85 Particles >25 um
Filter particulate onto
40
a membrane 35
Scan filter 30
25
Parenteral
Count
20
Solution 15
10
5
0
0-5 10-15 25-30 40-45 55-60 70-75 85-90 100-105 120-125 140-145
DMAX
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34. Case 2
OIL ANALYSIS: UNDERSTANDING KNOWN CONTAMINANTS
Filtered solution
with know
contaminants ready
High pressure wash for automated
E-beam analysis
Manufactured parts
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35. Case 2
OIL ANALYSIS: UNDERSTANDING KNOWN CONTAMINANTS
Contour plot of the average elemental composition for each particle type
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36. Case 2
OIL ANALYSIS: UNDERSTANDING KNOWN CONTAMINANTS
Particle Size Distributions What do they look like?
90
80
70
Number of Particles
60 Aluminum
Al/Cu/Zn
Al/Fe
50 Al/Cu/Zn/Fe
Aluminum Aggs
Misc
40 Misc Metals
Titanium and Lead
30 Titanium (Paint)
e
yp
Misc Salts
eT
20 Brass
icl
Bushing
rt
10 Fe/Zn/Cu
Pa
Iron
0 Stainless
20-60
Silicates
60-100
100-150
150-300
300-450
450-600
600-1000
1000-1600
>1600
Particle Size Ranges
(micrometers)
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37. Case 2
UNDERSTANDING KNOWN CONTAMINANTS
• Assess if your cleaning process is performing as it should.
• You may be producing products that may fail later on
down the line.
• Are you expending too much effort – and money — on
cleaning?
• Cleanliness analyzers are resulting in over 30%
reductions in warranty cost
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38. Case 3
FOREIGN PARTICLE DETECTION
• Foreign particle: contaminated particle derived from
active, recipients, containers, formulation,
environment, process of manufacture/actuating drug
device
• A number of different regulatory authorities demand
the evaluation of foreign particles in all types of
respiratory drugs.
• Number, size, elemental composition
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39. Case 3
FOREIGN PARTICLE DETECTION
Investigation into manufacturing contamination of an
inhalable drug powder
Dissolve drug powder and pass through a polycarbonate filter membrane
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40. Case 3
FOREIGN PARTICLE DETECTION
Distribution of inhalable drug product
on a filter membrane
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41. Case 3
FOREIGN PARTICLE DETECTION
Elemental composition table for inhalable drug powder.
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42. Case 3
FOREIGN PARTICLE DETECTION
• Relocated Particles
 Mica
 Quartz
 Calcium Rich (precipitates)
• Relocated Organic/Carbonaceous
 no sample preparation
 use Variable Pressure mode
 Invert contrast mechanism
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43. Case 4
COATING DURABILITY OF METALS
• Characterization of coating durability of implantable
metals
• Need to know: How many particles are generated by the
device under typical use?
• Problem: Coating is organic, all other particles are
inorganic, or organics with inorganic components.
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44. Case 4
COATING DURABILITY OF METALS
Organic Mica
Light-on-Dark Dark-on-Light
Gold coat
Reverse
Contrast
Aluminum Silica Bead
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45. Case 5
PARTICLE ENUMERATION IN INHALABLE ASTHMA KIT
• Active drug processed into a respirable dry powder. The product is
administered with a hand‐held device
• Determine origin, profile and number of foreign particle material
in drug powder, packaging and device.
• Data was tabulated in the following detection size ranges
> 20‐10 mm, 25‐50 mm, 50‐150 mm, 150‐500 mm
> 0‐1 mm, 1‐2 mm, 2‐3 mm, 4‐5 mm, 5‐6 mm, 6‐7 mm, 7‐8 mm, 8‐
9 mm, 9‐10 mm
> >10 mm
> >25 mm
• Elemental composition data and total particle count
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46. Case 5
PARTICLE ENUMERATION IN INHALABLE ASTHMA KIT
DMAX ( m) [0.00 ‐ [1.00 ‐ [2.00 ‐ [5.00 ‐ [10.00 ‐ [25.00 ‐ [50.00 ‐
Classification Total
1.00) 2.00) 5.00) 10.00) 25.00) 50.00) 100.00)
Talc 32
Talc 0 5 13 11 3 0 0
Calcium Rich 16
Calcium Rich 0 0 5 7 3 1 0
Aluminum Rich 1
Aluminum Rich 0 0 0 0 1 0 0
Si Rich 106
Si Rich 6 30 38 19 7 0 5
Chromium Rich 0
Chromium Rich 0 0 0 0 0 0 0
Stainless 17
Stainless 2 10 5 0 0 0 0
Iron Rich 49
Iron Rich 10 22 13 4 0 0 0
Misc 23
Misc 1 9 4 4 3 2 0
All particles 244
DAve DMin DMax ASPECT [1.00 ‐ [1.10 ‐ [3.25 ‐ [5.50 ‐ [7.75 ‐
Classification Total m m m RATIO 1.10) 3.25) 5.50) 7.75) 10.00)
Aluminum Rich 1 15.2 13.4 17.3 ( m)
Talc 0 30 1 1 0
Calcium Rich 16 6.0 4.3 8.0
Calcium Rich 0 13 2 0 1
Chromium Rich 0
Aluminum Rich 0 1 0 0 0
Iron Rich 49 1.4 0.8 2.2
Si Rich 6 75 13 3 2
Misc 23 5.6 3.9 7.8 Chromium Rich 0 0 0 0 0
Si Rich 106 3.4 1.7 8.8 Stainless 0 15 1 0 1
Stainless 17 1.1 0.6 1.7 Iron Rich 1 38 8 1 0
Talc 32 3.4 2.2 5.3 Misc 2 18 3 0 0
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47. Case 5
PARTICLE ENUMERATION IN INHALABLE ASTHMA KIT
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48. Case 6
ACTIVE PHARMACEUTICAL INGREDIENT
• API has significant exposure to FP during dissolution,
filtering, spray drying , milling and blending with
excipients.
• If the API is obtained from outside sources, the supplier
should be included in the control process.
API containing Br
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49. Case 6
ACTIVE PHARMACEUTICAL INGREDIENT
Particle map showing distribution of
API on filter membrane
Particle image (thumbnail), percentage composition and
EDS spectra of API using
ASPEX AFA Data ViewerTM
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50. Contact Information
Marie C. Vicéns, PhD
Manager, Analytical Services
E‐mail: mvicens@aspexcorp.com; Marie.Vicens@fei.com
Phone: (724) 468‐1618
Web: http://www.aspexcorp.com/Solutions/ContractServices/Analytical.aspx
CONFIDENTIAL