Electron Microscopy Services

50
February 10, 2012 CONFIDENTIAL ASPEX CORPORATION: ANALYTICAL SERVICES GROUP

Transcript of Electron Microscopy Services

Page 1: Electron Microscopy Services

February 10, 2012

CONFIDENTIAL

ASPEX CORPORATION:ANALYTICAL SERVICES GROUP

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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

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Quality Assurance Program

• Quality Management System

• cGMP‐compliant standard operating  procedures

• ISO9002:2008 certification (Expected April 2012)

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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 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.

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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

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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

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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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Sample Preparation

• Filtration• Sputter Coating• Metal polishing

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INTRODUCTION TO ASPEX TECHNOLOGYScanning Electron Microscopy and Energy Dispersive Spectrometry

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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

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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

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SEM‐EDX Information

• Surface morphology• Shape• Texture• Porosity• Defects

APPLICATIONS: HIGH MAGNIFICATION IMAGING

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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

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• Imaging based on atomic number contrast useful to investigate:> Sample homogeneity> Contamination

SEM‐EDX Information

BACKSCATTERED ELECTRONS

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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

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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

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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

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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

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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 µm 200 µm

SED BSED

EDX (Chemical Composition)

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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

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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

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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?

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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

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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 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?

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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 SEM‐EDX Technology 

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How does an automated SEM‐EDX 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 SEM‐EDX works?

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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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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

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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 – and money — 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 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

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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

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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. Vicéns, PhDManager, Analytical ServicesE‐mail: [email protected];  [email protected]: (724) 468‐1618Web: http://www.aspexcorp.com/Solutions/ContractServices/Analytical.aspx