February 10, 2012
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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
> XâRay microanalysis
⢠Coâlocated with
> ASPEX SEMâEDX manufacturing facility
> Global Sales and Services
> ASPEX Learning Center
Quality Assurance Program
⢠Quality Management System
⢠cGMPâcompliant 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
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PRODUCTS & SERVICES
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Laboratory Equipment: SEM-EDX
Experience The Power of ASPEX
ASPEX EXpress⢠ASPEX EXplorerâ˘
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 XâRay Microanalysis ⢠Contamination Identification ⢠Surface Composition & Coatings ⢠Elemental Analysis⢠Xâray 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
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ASTM, ISO and USP Standard Services
061 ISO 4406 â Hydraulic and Oil Particle Count Analysis062 ISO 4406 â with Elemental Composition063 ISO 11171 â Fluid Cleanliness Analysis064 ISO 11171 â with Elemental Composition066 ASTMâE45 â Inclusion Cleanliness Analysis of Rolled Steel067 ASTMâE2142 â Inclusion Cleanliness Analysis of Rolled Steel
068 JIS G 0555 â Inclusion Cleanliness Analysis of Rolled Steel
069 ISO 4967 â Inclusion Cleanliness Analysis of Rolled Steel
070 USP <788> Particulate Matter
071 ASTM Test Method F1877 Life Cycle Testing
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General Electron Microscopy Services
⢠Secondary Electron Imaging⢠Backscatter Electron Imaging⢠Lowâvacuum Backscatter Electron Imaging⢠XâRay Microanalysis (elemental composition)⢠Features (particles or inclusions) characterization⢠XâRay Mapping
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Sample Preparation
⢠Filtration⢠Sputter Coating⢠Metal polishing
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INTRODUCTION TO ASPEX TECHNOLOGYScanning Electron Microscopy and Energy Dispersive Spectrometry
SEMâEDX Information
⢠Secondary Electron Imaging Topographical/Morphological imaging
⢠Backscatter Electron Imaging Atomic number based contrast Lowâvacuum imaging capabilities
⢠SDD for XâRay detection Chemical composition using Energy
Dispersive Spectrometry
ASPEX EXPLORER
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SEMâEDX Information
⢠Secondary electrons are inelasticallyscattered.
⢠Incident electron loses much of its energy to the sample
⢠Weakly bound electrons of the sample are âboiledâoffâ.
⢠<50 eV⢠Topographic information.⢠SE are drawn to detector with positive
bias.
SECONDARY ELECTRONS
Nucleus
Incident Electron
SE
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SEMâEDX Information
⢠Surface morphology⢠Shape⢠Texture⢠Porosity⢠Defects
APPLICATIONS: HIGH MAGNIFICATION IMAGING
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SEMâEDX Information
⢠Backscattered electrons are elastically scattered.
⢠Minimal energy loss.⢠Large directional change.⢠>50 eV⢠Strong correlation with atomic number.
BACKSCATTERED ELECTRONS
Nucleus
Electron BeamBSE
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⢠Imaging based on atomic number contrast useful to investigate:> Sample homogeneity> Contamination
SEMâEDX Information
BACKSCATTERED ELECTRONS
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SEMâEDX 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 XâRays are generated in a multiâstep process:
Emitted XâRay
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SEMâEDX Information
⢠Energy of emitted XâRay is characteristic of chemical element.⢠The Xâray detector collects the Xârays and results are displayed in a
histogram.⢠Used to identify and quantify the elements present in a sample.
ENERGY DISPERSIVE SPECTRUM
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SEMâEDX Information
keV876543210
Cou
nts
1,000
500
0
Si
MnFe
Fe
SED BSED EDX
⢠Electron images â How the sample looks? What is the size and shape?⢠EDX âWhat the sample is made of?⢠Complete physical and chemical characterization of materials
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Applications
⢠Contamination studies in Pharmaceuticals⢠Particulate Matter Characterization
⢠XâRay 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
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Contaminant Particle Found in a Pharmaceutical Product
keV1514131211109876543210
Cou
nts
800
600
400
200
0
C
OF
P
Cl
Ca
Br Br
Br
200 Âľm 200 Âľm
SED BSED
EDX (Chemical Composition)
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100 Âľm500 Âľm
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
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XâRay Mapping used to evaluate elemental distribution in samples
MAGNESIUM STEARATE
Sample: Aleve 220 mg
Scanning conditions: 10 frames at 1ms/pixel
50 Âľm
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Surface Characterization:Morphology
1000 Âľm100 Âľm 100 Âľm
20 Âľm 20 Âľm
⢠How clean is your product?⢠Is your product free of defects?⢠Are your coatings uniform?⢠Does your product meet specifications?
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Teflon
20 Âľm
keV109876543210
Cou
nts
20,000
10,000
0
Al
100 Âľm
keV109876543210
Cou
nts
6,000
4,000
2,000
0
Fe
Fe
Fe
200 Âľm
keV109876543210
Cou
nts
3,000
2,000
1,000
0
C
O
20 Âľm
keV109876543210
Cou
nts
15,000
10,000
5,000
0
O Mg
Si
Aluminum
Iron
SyntheticFibers
Talc
Stainless Steel
100 Âľm
keV109876543210
Cou
nts
4,000
2,000
0
Cr
Cr
Cr
Fe
Fe
Fe
Foreign Particles Identified in Pharmaceutical Products
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Manual Inspection of Medical Devices
Metallic stent with polymer coating
Denuded area
Coated area
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Applications of Automated SEMâEDX Technology
⢠To obtain statistically meaningful metrics.⢠To recognize groupings within a population.⢠To locate lowâprobability features (âneedle in haystackâ).⢠To verify absence of contaminants.
WHY USE AUTOMATED SEM-EDX TECHNOLOGY?
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⢠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 SEMâEDX Technology
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How does an automated SEMâEDX works?
Spectrum Analyzed
Iron Rich Class
Composition Determined
Particle Identified
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⢠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 SEMâEDX works?
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Applications of automated SEMâEDX Technology
Understanding Distributions
Particle-by-Particle Elemental Composition
Rare Feature Location
Contamination Studies
Specialized QC Investigations
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Case 1
PARTICLE COUNT IN PARENTERAL SOLUTIONS
⢠USP Test Chapter <788>â Enumeration standard for foreign particles â Recommended for particles âĽ10 Âľm and âĽ25 Âľmâ Two step inspection:
⢠light obscuration for inspection with a given set of limits
⢠microscopy if sample does not pass the limits
â SEMâEDX 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
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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
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Case 2
OIL ANALYSIS: UNDERSTANDING KNOWN CONTAMINANTS
High pressure wash
Filtered solution with know
contaminants ready for automated
E-beam analysis
Manufactured parts
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Case 2
OIL ANALYSIS: UNDERSTANDING KNOWN CONTAMINANTS
Contour plot of the average elemental composition for each particle type
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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
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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 â and money â on
cleaning?⢠Cleanliness analyzers are resulting in over 30%
reductions in warranty cost
UNDERSTANDING KNOWN CONTAMINANTS
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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
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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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Case 3
FOREIGN PARTICLE DETECTION
Distribution of inhalable drug product on a filter membrane
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Case 3
FOREIGN PARTICLE DETECTION
Elemental composition table for inhalable drug powder.
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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
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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
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Case 4
COATING DURABILITY OF METALS
Light-on-Dark Dark-on-Light
Organic Mica
Aluminum Silica Bead
Gold coat
Reverse Contrast
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Case 5
⢠Active drug processed into a respirable dry powder. The product is administered with a handâheld 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> 20â10 mm, 25â50 mm, 50â150 mm, 150â500 mm > 0â1 mm, 1â2 mm, 2â3 mm, 4â5 mm, 5â6 mm, 6â7 mm, 7â8 mm, 8â
9 mm, 9â10 mm> >10 mm> >25 mm
⢠Elemental composition data and total particle count
PARTICLE ENUMERATION IN INHALABLE ASTHMA KIT
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Case 5
PARTICLE ENUMERATION IN INHALABLE ASTHMA KIT
DMAX (m) [0.00 â1.00)
[1.00 â2.00)
[2.00 â5.00)
[5.00 â10.00)
[10.00 â25.00)
[25.00 â50.00)
[50.00 â100.00)
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 â1.10)
[1.10 â3.25)
[3.25 â5.50)
[5.50 â7.75)
[7.75 â10.00)
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
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Case 5
PARTICLE ENUMERATION IN INHALABLE ASTHMA KIT
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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
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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
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Contact Information
Marie C. VicĂŠns, PhDManager, Analytical ServicesEâmail: [email protected]; [email protected]: (724) 468â1618Web: http://www.aspexcorp.com/Solutions/ContractServices/Analytical.aspx