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February 10, 2012
CONFIDENTIAL
ASPEX CORPORATION:ANALYTICAL SERVICES GROUP
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
Quality Assurance Program
• Quality Management System
• cGMP‐compliant standard operating procedures
• ISO9002:2008 certification (Expected April 2012)
February 10, 2012
MARKETS SERVED
Introducing
Pharmaceuticals-Particulate MatterPharmaceuticals-Particulate Matter
Hard DrivesHard Drives
MiningMining
Oil Analysis-Wear DebrisOil Analysis-Wear Debris
Metals Inhalers
Medical Devices
February 10, 2012
CONFIDENTIAL
PRODUCTS & SERVICES
CONFIDENTIAL
Laboratory Equipment: SEM-EDX
Experience The Power of ASPEX
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.
Analytical Testing Services
• Microscopic Imaging Services • Failure Analysis (fractures, delamination & corrosion) • Materials Testing (ceramics, composites & metals) • Surface Characterization (porosity & grain structure)
• Elemental Composition by X‐Ray Microanalysis • Contamination Identification • Surface Composition & Coatings • Elemental Analysis• X‐ray mapping, Line Scan, Spot & Area Microanalysis
• Metals Quality Analysis• ASTM E45, ASTM E2142, ISO 4967
• Advanced Quality Control• ISO 4406, ISO 11171• Oil Analysis
• Foreign Particle Identification
• Automated Particle Analysis• Characterization (size, shape and
composition)• Size Distribution
CONFIDENTIAL
ASTM, ISO and USP Standard Services
061 ISO 4406 ‐ Hydraulic and Oil Particle Count Analysis062 ISO 4406 ‐ with Elemental Composition063 ISO 11171 ‐ Fluid Cleanliness Analysis064 ISO 11171 ‐ with Elemental Composition066 ASTM‐E45 ‐ Inclusion Cleanliness Analysis of Rolled Steel067 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
CONFIDENTIAL
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
CONFIDENTIAL
Sample Preparation
• Filtration• Sputter Coating• Metal polishing
February 10, 2012
CONFIDENTIAL
INTRODUCTION TO ASPEX TECHNOLOGYScanning Electron Microscopy and Energy Dispersive Spectrometry
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
CONFIDENTIAL
SEM‐EDX Information
• Secondary electrons are inelasticallyscattered.
• Incident electron loses much of its energy to the sample
• Weakly bound electrons of the sample are “boiled‐off”.
• <50 eV• Topographic information.• SE are drawn to detector with positive
bias.
SECONDARY ELECTRONS
Nucleus
Incident Electron
SE
CONFIDENTIAL
SEM‐EDX Information
• Surface morphology• Shape• Texture• Porosity• Defects
APPLICATIONS: HIGH MAGNIFICATION IMAGING
CONFIDENTIAL
SEM‐EDX Information
• Backscattered electrons are elastically scattered.
• Minimal energy loss.• Large directional change.• >50 eV• Strong correlation with atomic number.
BACKSCATTERED ELECTRONS
Nucleus
Electron BeamBSE
CONFIDENTIAL
• Imaging based on atomic number contrast useful to investigate:> Sample homogeneity> Contamination
SEM‐EDX Information
BACKSCATTERED ELECTRONS
CONFIDENTIAL
SEM‐EDX Information
• 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.
X-RAYS MICROANALYSIS
Nucleus
Incident Electron
SE
Nucleus
Characteristic X‐Rays are generated in a multi‐step process:
Emitted X‐Ray
CONFIDENTIAL
SEM‐EDX Information
• 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.
ENERGY DISPERSIVE SPECTRUM
CONFIDENTIAL
SEM‐EDX Information
keV876543210
Cou
nts
1,000
500
0
Si
MnFe
Fe
SED BSED EDX
• 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
CONFIDENTIAL
Applications
• 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
SELECTED EXAMPLES OF TESTING SERVICES
CONFIDENTIAL
Contaminant Particle Found in a Pharmaceutical Product
keV1514131211109876543210
Cou
nts
800
600
400
200
0
C
OF
P
Cl
Ca
Br Br
Br
200 µm 200 µm
SED BSED
EDX (Chemical Composition)
CONFIDENTIAL
100 µm500 µm
keV1211109876543210
Cou
nts
2,500
2,000
1,500
1,000
500
0
OAl
SiCr
CrFe
Fe
Fe
Ni
Ni
Ni
Contaminant Particle Found in a Pharmaceutical Product
Stainless Steel in raw material sample
CONFIDENTIAL
X‐Ray Mapping used to evaluate elemental distribution in samples
MAGNESIUM STEARATE
Sample: Aleve 220 mg
Scanning conditions: 10 frames at 1ms/pixel
50 µm
CONFIDENTIAL
Surface Characterization:Morphology
1000 µm100 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?
CONFIDENTIAL
Teflon
20 µm
keV109876543210
Cou
nts
20,000
10,000
0
Al
100 µm
keV109876543210
Cou
nts
6,000
4,000
2,000
0
Fe
Fe
Fe
200 µm
keV109876543210
Cou
nts
3,000
2,000
1,000
0
C
O
20 µm
keV109876543210
Cou
nts
15,000
10,000
5,000
0
O Mg
Si
Aluminum
Iron
SyntheticFibers
Talc
Stainless Steel
100 µm
keV109876543210
Cou
nts
4,000
2,000
0
Cr
Cr
Cr
Fe
Fe
Fe
Foreign Particles Identified in Pharmaceutical Products
CONFIDENTIAL
Manual Inspection of Medical Devices
Metallic stent with polymer coating
Denuded area
Coated area
CONFIDENTIAL
Applications of 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.
WHY USE AUTOMATED SEM-EDX TECHNOLOGY?
CONFIDENTIAL
• 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
Applications of Automated SEM‐EDX Technology
CONFIDENTIAL
How does an automated SEM‐EDX works?
Spectrum Analyzed
Iron Rich Class
Composition Determined
Particle Identified
CONFIDENTIAL
• Elemental Composition
• Average diameter
• Maximum Diameter
• Minimum Diameter
• Aspect Ratio
• Area
WHAT IS USED FOR CHARACTERIZATION?
Size and Shape Parameters Elemental Chemistry
How does an automated SEM‐EDX works?
CONFIDENTIAL
Applications of automated SEM‐EDX Technology
Understanding Distributions
Particle-by-Particle Elemental Composition
Rare Feature Location
Contamination Studies
Specialized QC Investigations
CONFIDENTIAL
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
• microscopy if sample does not pass the limits
– SEM‐EDX analysis provides elemental composition in addition to enumeration
Small Volume Parenterals
Large Volume Parenterals
<6000 @ 10um <25/ml @ 10um
<600 @ 25um <3/ml @ 25umU.S. Pharmacopoeia
Small Volume Parenterals
Large Volume Parenterals
<6000 @ 10um <25/ml @ 10um
<600 @ 25um <3/ml @ 25umU.S. Pharmacopoeia
<2/mL @ 25 mm
<12/mL @10 m
<300 @25 mm
<3000 @10 mm
CONFIDENTIAL
Case 1
PARTICLE COUNT IN PARENTERAL SOLUTIONS
E-Beam Analysis is used to understand distributions
Filter particulate onto a membrane
Parenteral Solution
Scan filter
DMAX0-5 10-15 25-30 40-45 55-60 70-75 85-90 100-105 120-125 140-145
Cou
nt
40
35
30
25
20
15
10
5
0
195 Particles >10 um85 Particles >25 um
CONFIDENTIAL
Case 2
OIL ANALYSIS: UNDERSTANDING KNOWN CONTAMINANTS
High pressure wash
Filtered solution with know
contaminants ready for automated
E-beam analysis
Manufactured parts
CONFIDENTIAL
Case 2
OIL ANALYSIS: UNDERSTANDING KNOWN CONTAMINANTS
Contour plot of the average elemental composition for each particle type
CONFIDENTIAL
Case 2
20-6
0
60-1
00
100-
150
150-
300
300-
450
450-
600
600-
1000
1000
-160
0
>160
0
SilicatesStainless
IronFe/Zn/Cu
BushingBrass
Misc SaltsTitanium (Paint)
Titanium and LeadMisc Metals
MiscAluminum Aggs
Al/Cu/Zn/FeAl/Fe
Al/Cu/ZnAluminum
0
10
20
30
40
50
60
70
80
90
Num
ber o
f Par
ticle
s
Particle Size Ranges (micrometers)
Parti
cle
Type
Particle Size Distributions What do they look like?
OIL ANALYSIS: UNDERSTANDING KNOWN CONTAMINANTS
CONFIDENTIAL
Case 2
• 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
UNDERSTANDING KNOWN CONTAMINANTS
CONFIDENTIAL
Case 3
• 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
FOREIGN PARTICLE DETECTION
CONFIDENTIAL
Case 3
FOREIGN PARTICLE DETECTION
Investigation into manufacturing contamination of an inhalable drug powder
Dissolve drug powder and pass through a polycarbonate filter membrane
CONFIDENTIAL
Case 3
FOREIGN PARTICLE DETECTION
Distribution of inhalable drug product on a filter membrane
CONFIDENTIAL
Case 3
FOREIGN PARTICLE DETECTION
Elemental composition table for inhalable drug powder.
CONFIDENTIAL
Case 3
• Relocated Particles Mica Quartz Calcium Rich (precipitates)
• Relocated Organic/Carbonaceous no sample preparation use Variable Pressure mode Invert contrast mechanism
FOREIGN PARTICLE DETECTION
CONFIDENTIAL
Case 4
• 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.
COATING DURABILITY OF METALS
CONFIDENTIAL
Case 4
COATING DURABILITY OF METALS
Light-on-Dark Dark-on-Light
Organic Mica
Aluminum Silica Bead
Gold coat
Reverse Contrast
CONFIDENTIAL
Case 5
• 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
PARTICLE ENUMERATION IN INHALABLE ASTHMA KIT
CONFIDENTIAL
Case 5
PARTICLE ENUMERATION IN INHALABLE ASTHMA KIT
DMAX (m) [0.00 ‐1.00)
[1.00 ‐2.00)
[2.00 ‐5.00)
[5.00 ‐10.00)
[10.00 ‐25.00)
[25.00 ‐50.00)
[50.00 ‐100.00)
Talc 0 5 13 11 3 0 0Calcium Rich 0 0 5 7 3 1 0Aluminum Rich 0 0 0 0 1 0 0
Si Rich 6 30 38 19 7 0 5Chromium Rich 0 0 0 0 0 0 0
Stainless 2 10 5 0 0 0 0Iron Rich 10 22 13 4 0 0 0Misc 1 9 4 4 3 2 0
ASPECTRATIO(m)
[1.00 ‐1.10)
[1.10 ‐3.25)
[3.25 ‐5.50)
[5.50 ‐7.75)
[7.75 ‐10.00)
Talc 0 30 1 1 0Calcium Rich 0 13 2 0 1Aluminum Rich 0 1 0 0 0
Si Rich 6 75 13 3 2Chromium Rich 0 0 0 0 0
Stainless 0 15 1 0 1Iron Rich 1 38 8 1 0Misc 2 18 3 0 0
DAve DMin DMaxClassification Total m m mAluminum Rich 1 15.2 13.4 17.3Calcium Rich 16 6.0 4.3 8.0Chromium Rich 0
Iron Rich 49 1.4 0.8 2.2Misc 23 5.6 3.9 7.8Si Rich 106 3.4 1.7 8.8Stainless 17 1.1 0.6 1.7Talc 32 3.4 2.2 5.3
Classification TotalTalc 32
Calcium Rich 16Aluminum Rich 1
Si Rich 106Chromium Rich 0
Stainless 17Iron Rich 49Misc 23
All particles 244
CONFIDENTIAL
Case 5
PARTICLE ENUMERATION IN INHALABLE ASTHMA KIT
CONFIDENTIAL
Case 6
• 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.
ACTIVE PHARMACEUTICAL INGREDIENT
API containing Br
CONFIDENTIAL
Case 6
ACTIVE PHARMACEUTICAL INGREDIENTParticle map showing distribution of
API on filter membrane
Particle image (thumbnail), percentage composition and EDS spectra of API using
ASPEX AFA Data ViewerTM
CONFIDENTIAL
Contact Information
Marie C. Vicéns, PhDManager, Analytical ServicesE‐mail: mvicens@aspexcorp.com; Marie.Vicens@fei.comPhone: (724) 468‐1618Web: http://www.aspexcorp.com/Solutions/ContractServices/Analytical.aspx
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