Webinar: Case Studies in Foreign Particulate Analysis

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Case Studies in Foreign Particulate Analysis

© Gateway Analytical, LLC, 2015

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Start Time: 2 pm am EDT (U.S & Canada) Duration: 45 min. including Q&A time

Join Gateway Analytical scientists as they dive into best practice methods for characterizing and identifying foreign particulate

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About Gateway Analytical Located in Gibsonia, Pennsylvania, USA

Particulate Identification Services

Detailed Report Characterizing and

Identifying particulate

Customer Support to help identity the source

of contaminates.

cGMP-compliant | FDA Registered & Inspected | ISO 17025 & ISO 9001


About Gateway Analytical Located in Gibsonia, Pennsylvania, USA

Particulate happens, but that shouldn't stop your progress.

Our focus is to remove the hurdles involved with identifying foreign particulate and guide our

customers to fast remediation.


Meet the Presenters


David Exline Vice President

Gateway Analytical [email protected]

Julia Patterson Scientist


Marina Parra Scientist



Outline

• What is foreign particulate matter? • Commonly found sources of particulate

contamination • How manual analysis compares to automated

technologies • Sample preparation • Specialized foreign particulate testing methods • Foreign particulate analysis methods and case

study examples



Common Characteristics of Foreign Particulate Matter

• Visible and sub-visible particles • Stains and discoloration • Often charred from sterilization processes • Precipitated materials • Typical in all process related manufacturing equipment

– Cleaning system – CIP – Protective Clothing – Stainless steel tanks – Filter systems – Storage containment



Why is Foreign Particulate Matter So Common?

• Product constantly in contact with process • Process of manufacturing has so many stages • Chemical breakdown and aging • Process precipitation • Raw material contamination • Containers and packaging • Washing and storage process • Customer site contamination • Environment • Sterile does not mean “particle free”



Common Types of Foreign Particulate Contaminations in Pharmaceutical

Manufacturing

Stainless Steel Human/Animal Hairs Paint Glass Rubber (stoppers) Polymers Insects Silicone Products


Teflon Synthetic Fibers Natural Fibers Labels Burned Material Paper products Metals Environment

• Often found during 100% inspection process

• Mechanical Failure Investigation

• Customer Return Samples • Contamination studies of

processes • Evaluation of raw

materials • Foreign particulate can be

detected at any stage in the manufacturing process


Pharmaceutical Forensics • Application of forensic testing & problem solving methods • Answer specific questions like:

– How, why and when did it break? – What is this foreign material? – Where did it come from?

• Typical Applications: – Particle contamination / Source Determination – Deviations from in process methods – Product returns – Foreign particulate matter identification – Tablet non-conformance investigation – Parenteral particulate characterization

• Visible and sub-visible

• 100% Particle inspection approach



Overall Sample Flow for Manual or Automated Analysis


Non-Conformance

Issue

Sample Collection/ Evaluation

Manual Analysis

SEM-EDS

FTIR

Raman

Optical/ PLM

Glass Delamination

Automated Analysis

CCSEM

SPE


Manual vs. Automated

Manual Analysis • Typically longer analysis time per

sample • Better suited for a smaller

number of samples • Can determine the size, shape,

and color of each individual particle.

• Can determine both the elemental composition of the sample and spectral data


Automated Analysis • Faster analysis • Better suited for a larger number

of samples • Can provide information on the

size bins of the particles in a population

• Sometimes you will not obtain as much data from each individual particle: Elemental composition OR spectral data


Typical Sample Flow for Manual Analysis


Sample Collection / Evaluation

Physical Properties Color, shape, texture

Optical Evaluation Fiber, glass, paint, metal, organic,

inorganic

Sample Isolation

Non-conformance Issue

Organic Analysis

FT-IR, Raman, Chemistry,

Chromatography

Inorganic Analysis

SEM/EDS, XRD, Inorganic Chemistry

Identification of Foreign Material

Comparison Foreign material with

known

Evaluation

Source Determination


Isolation of Particulate Manual Analysis

• Initial collection – Filtration of parenteral product – Manual isolation

• Washing/ rinsing of samples • Preparation for Analysis

– Microscopy preparations – FTIR preparations – SEM/EDS preparations – Raman preparations


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Preparation of Filter Manual Analysis


Sample Collection / Isolation Manual Analysis


• Isolation / cleaning of sample critical step • Understand substrate conditions


Particle Isolation – Analysis Substrates Manual Analysis


Microscopy – Temporary mount with glass slides

FTIR – Low-e slide Raman – Al Slide

SEM – Stub with carbon tape


Preparation of Filter – Automated Raman Automated Analysis

Gold Coated Polycarbonate Filter Filtration Preparation

• Low blanks • Cleanroom manufactured • System integrated • High sensitivity • No background signal for ID



Microscopy – Key Techniques Manual Analysis


• Size • Morphology • Consistency • Color • Documentation • Unique features • Organic vs. inorganic • Comparison • Optical properties • Fluorescence properties


Optical Microscopy Manual Analysis

• Efficient method of particle characterization • Cost effective • Critical evaluation for particle comparison and differentiation


Optical and Polarized Light Microscopy Fluorescence Microscopy

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Fourier Transform Infrared Spectrometry (FTIR)

Manual Analysis


• A microscope attachment is usually required for precise analysis

• Light can be passed through the

sample (transmission) or reflected through the sample (reflectance)

• The interaction of the light with

the sample is interpreted as an FTIR spectrum

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Raman Spectroscopy Manual Analysis

• Generally a surface analysis method

• Useful for: – Embedded materials – Pigments – Oxides – Amorphous Carbon

• Is a complementary technique to FTIR analysis



Manual SEM-EDS Manual Analysis

• The analyst manually drives the instrument to perform the analysis.

• Useful for determining: – Surface features of a

sample – Elemental composition

of the sample • Can visualize and

analyze different areas of a heterogeneous sample


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Automated CCSEM Automated Analysis

• The analyst inputs an area and analysis criteria for the instrument to scan and analyze.

• Useful for determining: – Elemental

composition – Size for a population of

particles



Glass Delamination Specialized Analysis

What is Glass Delamination? • Small, thin, glass fragments,

termed “glass lamellae”, which are shed from the interior portion of glass containers and vials

• Glass lamellae are shed into, and suspended in the liquid drug contained in the glass vial

• Detection of glass lamellae can be very difficult during visual product inspections © Gateway Analytical, LLC, 2015

High resolution SEM imaging analysis identifying regions on the interior vial surface which show indications of pitting and delamination


Why Does Glass Delamination Occur? Specialized Analysis

• Glass delamination is an effect of glass corrosion

• Glass corrosion can occur in silicate glasses through three types of chemical reactions: – Acidic (H3O+) – Basic (OH-) – Neutral (H2O)


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Automated SEM-EDS analysis identifying Si-rich particles which are elementally and morphologically consistent with delamination


Screening Studies per USP General Chapter <1660>

PARAMETER TEST PARAMETER ANALYTICAL METHODS

Glass surface • Degree of surface pitting • Chemical composition as a function of depth

• DIC Microscopy or EM • SIMS

Extracted elements in solution

• Conductivity/pH • Individual and total extractables

• SiO2 concentration • SiO2/B2O3 or Si/Al ratio

• Conductivity/ pH meter • ICP-MS or ICP-OES

Visible/ Subvisible glass particles

• Particle number and size • Particle morphology and composition

• Particle size analyzer • SEM-EDS



Specialized Analysis - Automated Raman Spectroscopy Overview



How Does Combined Raman/LIBS Compare to Other Technologies?

Method Sizing and counting

Elemental Chemical Automation Specific Level of

expertise Cost Speed

Optical Microscopy

Yes No No Possible No High Low Slow

HIAC Yes No No Yes No Low Low Fast

Manual Raman

No No Yes Possible Yes High Middle Fast

Automated Raman

Yes No Yes Yes Yes High Middle Fast

FTIR No No Yes Possible Yes High Middle Fast

SEM-EDS Yes Yes No Possible Yes Middle High Fast

Automated LIBS

YEs Yes Yes Yes Moderate High High Fast



Overall Filter Montage Automated Raman Spectroscopy



Database Search of Selected Particles Automated Raman Spectroscopy


Raman Database Search Consistent with Plunger Material


Particle Size and Identification Using SPE™ Automated Raman System


Spectra # Material Size Distribution [µm]

2 - 10 10 - 25 25 - 50 50 - 100 100-1000 Totals

1 Amorphous Carbon 7 0 0 0 0 7 2 beta-Carotene 1 0 0 0 0 1 3 Blue Pigment 28 3 2 4 2 39 4 Boot cover 0 0 0 1 0 1 5 Boron Carbide 1 1 1 6 3 12 6 Calcium Chloride 1 0 0 0 0 1 7 Cellulose 1 0 0 1 0 2

10 storage bag 0 0 1 1 0 2 11 Filling suite, Ext 12 2 0 3 0 17 12 Filter from air line 0 0 0 0 1 1 13 Fluorescence 175 24 26 74 28 327 17 Gowning material 1 0 0 3 0 4 18 Plunger 0 1 6 26 10 43 20 Laurylsulfate Sodium, SDS 0 0 0 1 0 1 21 Nitrate Sodium 0 0 0 2 0 2 25 Plastic bags 0 0 0 1 0 1 26 Poly(acrylonitrile) 4 2 0 1 1 8 28 Polycarbonate 2 0 0 0 0 2 30 Polysulfone 1 0 0 0 0 1 31 Porous Particle Production Air 7 0 0 0 0 7 32 Sample 1 1 0 0 0 0 1 33 Sample 5 0 0 0 1 0 1 37 Smalt 1 0 0 0 0 1 38 Starch 1 0 0 1 0 2 40 Talcum 8 3 0 1 0 12 41 Titanium(IV)oxide, Anatase 2 0 0 1 0 3 42 gasket 0 0 1 0 0 1

All Particles 10,260 1548 460 128 45 12,441



Looking at Unknown Clear Particles Internal Case Study



A Common Problem

• Clear particles are a common form of particulate contamination

• They can be anything from glass to polymers, to cellulose, or crystalized drug product

• Optical analysis can give you some idea of what the particle is however, further analysis is often required

• Additional analysis can include: – SEM – PLM – FTIR – Raman



Unknown Particle - Optical Image

Unknown particle recovered from membrane filter


Optical Image


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SEM/EDS & FTIR of Clear Particulate


SEM / EDS Spectra

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You can tell its not glass because it is carbon rich instead of silicon rich

FTIR Infrared Spectra



Imbedded Foreign Particulate in Vial Case Study



Case Study: The Problem

• A drug developer had an issue with vials that were flagged during a visual inspection.

• They identified several vials with a black and brown material visible on the side of the glass wall.

• The unknown contaminate could not be reach for extraction due to its location in the vial.



Case Study: The Solution

• Vials were sent to Gateway Analytical for extraction and analysis

• Vial was broken to expose the unknown material

• Material was found to be embedded in the vial wall

• Preformed SEM and Raman on the material as it could not be isolated from the glass vial wall.



Case Study: Iron Oxide Embedded in Glass Vial



Case Study: Iron Oxides (i.e. Rust)


Iron oxide particulates may be present in glass vial mold materials

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Hair Discovered in Manufacturing Process Case Study




Hair Examination – Value

High resistance to degradation

Each species has characteristic color, length, shape, root appearance, and internal characteristics

Human Hair Racial Origin Body area Disease Natural Vs. Forcibly Removed Cosmetic Treatment Environmental Factors Comparison mtDNA or nuclear DNA

Animal Hair Species of Origin Dyeing Methods Possible Sources

Forensic Hair Comparisons required to associate source


Case Study: The Problem

• Customer found a hair in their manufacturing process

• They were able to isolate it with forceps and package it between two glass slides in order to send it out for analysis.



Case Study: The Solution

• Gateway Analytical utilized PLM analysis to – Confirm that the

sample was a hair – Determine the species

of the hair (human or animal)



Case Study: PLM Analysis – Canine Hair


1. Spade shaped root 2. Wide, amorphous medulla

3. Physical damage – splitting 4. Narrow, tapered distal end


It’s Time for the Q&A Session. Please Submit Your Questions!



Contact Us & Follow-up

Get Insights from our Blog: www.gatewayanalytical.com/blog

Contact Information

David Exline Vice President Gateway Analytical [email protected]

Julia Patterson Scientist Gateway Analytical [email protected]

Marina Parra Scientist Gateway Analytical [email protected]

Brittney Norris Marketing & Creative Director Gateway Analytical [email protected]

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Webinar: Case Studies in Foreign Particulate Analysis

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