Webinar Presentation: Proactive vs Reactive Glass Delamination Testing for Pharmaceuticals

Proactive vs. Reactive Glass
Delamination Testing in
Pharmaceuticals
Join Gateway Analytical Scientists as they discuss UPS <1660> recommendations and
Gateway’s approach to different types of glass delamination investigations.
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Duration: 45 min. + Q&A time
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About Gateway Analytical
Located in Gibsonia, Pennsylvania, USA

About Gateway Analytical
Quality laboratory services making our world
healthier and safer . . . one particle at a time!

Meet Today’s Presenters
Emily Landsperger
Scientist
Gateway Analytical
landspergere@gatewayanalytical.com

Outline of Today's Webinar
• Overview of Glass Delamination and common test
methods
• USP <1660> Guidelines
• Proactive vs. Reactive Test Methods
• Conclusions/Recommendations
• Q&A Session

Overview of Glass Delamination
What is it and why does it happen?
.

Glass Delamination
• Phenomenon which occurs when top layers of a glass
surface flake off, due to breakdown of the glass surface.
• Largely caused by the interactions between the glass
surface and the liquid that it contains
• Oxides leach out of the glass surface, which creates a less
resistant layer.
• Formation of flakes, which slough off into solution
• Manufacturing defects already present in the vials can also
be a catalyst of delamination

Factors Contributing to Glass Delamination
• Vial Conditions
– Time exposed to solution
– Temperature fluctuations
– Chemistry of solution contained
• Nature of the Vial
– Vial Manufacture Process
– Chemistry of the glass
– Surface Treatments

Vial Conditions
• Time
– Shelf life
• Chemistry of solution
– pH
– Ionic strength
• Temperature
– Autoclaving/sterilization
– Fluctuations over time/storage
conditions

Nature of the Vial
• Vial Manufacture Process
– Tubing vs. molding
• Chemistry of the Glass
– Type I (COE)
– Glass = silicon dioxide (various additives)
• Surface Treatments
– Sulfur
– Siliconization
– Surface Treatments/coating

Poll Question #1
• Have you ever experienced glass delamination
in any of your products?
YES
NO

USP <1660>
Recommended Approach for Evaluation of the
Inner Surface Durability of Glass Containers
.

Purpose / Scope
• General information about factors that may
contribute to glass delamination (durability)
• Recommendations for predictive
testing/detection of the phenomenon of
delamination
• CMO’s, fill/finish sites, glass manufacturers,
pharmaceutical companies

Details Discussed
• Types of glass
• Formation of containers
• Supply Chain Practices
• Glass surface chemistry

Source: USP <1660>, usp.org

Things to look for during analysis…
• Changes in solution
• SiO2 content
• Number of lamellae in solution
• Changes in pH

USP<1660> Recommended
Analytical Methods
• DIC Microscopy/EM
• SIMS
• pH testing
• ICP-MS/OES
• Particle Size Analyzer
• SEM-EDS of lamellae

DIC/EM Microscopy
• Differential Interference Contrast Microscopy:
– An optical microscopy technique used to enhance
the contrast in an unstained, transparent samples
– Non-destructive
– No need to cut vials
http://journals.cambridge.org/action/display
Abstract?fromPage=online&aid=9031607

DIC/EM Microscopy
• Electron Microscopy
– Utilizing the Secondary Electron Detector
– Allows for detection of minute surface changes
– Requires cutting of vials

SIMS
• Secondary Ion Mass Spec
• Surface analysis (sputter surface with ions,
analyze secondary ions coming off of the
surface)
• Depth profiling
• Very sensitive

pH Testing
• pH meter used to test solution
• Highly alkaline or highly basic solutions can
contribute to delamination
Acidic Neutral Alkaline

ICP-OES/ICP-MS
• Analysis of solution contained by the vial
• Detect/quantify levels of trace elements
commonly found in glass

Particle Sizing and Counting
• Particle size analyzer
– HIAC/Accusizer
– CCSEM
Light
Source
Liquid
Sample
Detector

SEM Analysis
• Lamellae on Filters
– Morphology
– Elemental composition

Screening Methods
Three Parameters to Keep in Mind:
1. Visual and chemical profile of inner surface layer
- DIC/EM and SIMS
2. Amount of elements in solution
- pH testing/ICP-MS/ICP-OES
3. Number of sub-visible and visible particles
present in solution
- Particle Size Analyzer/SEM-EDS

Accelerated Testing
• Examples of models that can be used to
accelerate delamination
– Specific % of KCl (pH 8.0), Citric Acid (pH 8.0), and
Glycine (pH 10.0)
– These are tested at specific temperatures for specific
amount of time
• For a typical drug stored at 25C, every 30 days at
60C is roughly equivalent to a full year of storage
at 25C

Product Specific Model
Source: USP <1660>, usp.org

Poll Question #2
• Do you currently perform glass delamination
testing in-house or do you outsource this
work?
In-house
Subcontract
Neither
Both

Analysis Methods for Glass
Delamination
What analyses do we perform?
.

• “Twinkling”
– Light reflected off lamellae
• Signs of extensive
glass breakdown
• Can be difficult to detect
Initial Stereomicroscopic Examination

Filtration of Vial Contents
• The liquid vial contents are filtered onto
polycarbonate filter membranes for further
analysis
• Polycarbonate filters allow for the visualization
of lamellae in subsequent steps
– Thin, smooth surface to the filter membrane

Stereoscopic Evaluation
• Analysis of filter for the presence of
lamellae
– Co-axial lighting recommended
– Distinctive, thin, colorful or reflective flakes
indicate glass lamellae
– Thin, smooth, flat; can have
straight/angular edges

Stereoscopic Evaluation
• Analysis of filter for
the presence of
lamellae
– Variability in
appearance of
lamellae between
samples
– Due to thickness of
the lamellae

SEM-EDS of Lamellae
500 µm 200 µm
keV
1086420
Counts
2,000
1,500
1,000
500
0
C
O
Al
Si
filename=100515_Lamellae3.TIF
Manual SEM-EDS of glass lamellae
• SEM-EDS: Scanning Electron
Microscopy – Energy Dispersive
Spectroscopy
– Determine elemental composition of a
sample
• Filter surface evaluated using SEM-
EDS to detect elements consistent
with glass in the lamellae
• Lamellae are so thin, large
contributions from substrate

Stereomicroscopy and SEM-EDS
• Stereomicroscopy with a coaxial light source
and SEM-EDS are used in conjunction to
confirm that the particles identified are both
morphologically and elementally consistent
with glass lamellae
• Addresses the USP<1660> test parameter
“visible and sub-visible glass particles”

Particle Number and Size
• Quantity/Size of lamellae in solution
• Particle Size Analyzer
– Difficulty in detecting lamellae
– Not chemical specific
• CCSEM
– limitations in detecting glass
lamellae due to thin nature of lamellae
• Manual counting/sizing using stereomicroscope and
software is best current option
– Image shown above
Manual counting and sizing of glass
lamellae using LAS software.

Limitations of CCSEM of Lamellae
500 µm 200 µm
keV
1086420
Counts
2,000
1,500
1,000
500
0
C
O
Al
Si
filename=100515_Lamellae3.TIF
Manual SEM-EDS of glass lamellae Attempt to set automated thresholds for the
detection of glass lamellae on polycarbonate filter.
• Even thick/overlapping lamellae could not be
flagged by the automated system’s thresholds
• Overwhelming background signal

EM of Vial Interiors
• Secondary Electron
Detector of EM
• Minute changes in
surface topology
detected
• Pitting, delamination,
corrosion, manufacture
defects
• Magnifications of
2500x – 10,000x or more

EM of Vial Interiors
• Pitting, delamination, manufacture defects
• Addresses the USP<1660> test parameter “glass surface”

Analyses Sent for Subcontract
• pH testing
– Changes in the pH of the solution
• ICP-OES
– Extracted elements in solution from the glass
• These two analyses address the USP<1660>
parameter of “extracted elements in solution”

Analyses We Don’t Perform
• DIC
– SED allows us higher resolution and magnification
– More detail obtained using SED
• SIMS
– Little-used method
– Few laboratories with this capability operate
under the FDA Good Manufacturing Practices

Proactive vs. Reactive
Analytical Approaches
What’s the difference?
.

They are addressing different questions:
• Proactive: Will THIS drug cause THIS
vial/container to delaminate?
– This is performed as part of drug formulation
testing, and prior to manufacturing or distribution
– Finding the best vial/container for a particular
drug of interest
• Least likely to delaminate

Proactive Testing
• Durability testing
• Aggressive investigation to determine suitability
of a specific drug in a specific container
• Most extreme circumstances it will face
• Over life of the vial
• Accelerated testing methods are often employed

So many factors…
• A good idea is to take a proactive approach
– Stability Studies
– So many variables, it is hard to state that one
particular vial has better overall durability than
another
– Each situation is unique

Proactive Testing
• USP<1660> specifically addresses proactive
testing methods
• We utilize all available test methods for proactive
testing
– Twinkling
– Stereomicroscopy of Filters
– SEM-EDS of Filters
– SED of Vial Interiors
– pH/ICP-OES of Solution

Proactive Testing
• Recommendations:
– At least three lots of drug product
– At least two different vial types
– Several time points
• From time of fill to expected expiration date
– All temperature ranges it may be subjected to
– Changes in pH may also be evaluated

They are addressing different questions:
• Reactive: Is delamination already present in
this vial?
– This is performed typically as a spot check or part
of a recall or customer complaint
– Vials that have been in circulation for a given
amount of time are sent for analysis to determine
the presence/absence of glass lamellae

Reactive Testing
• Testing for presence of lamellae or surface breakdown
after it has been manufactured and put into circulation
• A less-extensive analysis is needed when delamination
is already suspected
– Twinkling
– Stereomicroscopy of Filters
– SEM-EDS of Filters
– SED of Vial Interiors
• Three samples are typically sufficient to confirm or
reject the presence of active delamination

Reactive Testing
• Drug product has already been manufactured
– The “study” phase is over
• Therefore, no need for:
– Extracted elements in solution
– Temperature Changes
– pH Changes

Poll Question #3
• Has your lab ever performed a stability study
for glass delamination?
YES
NO

FDA Requirements
.

FDA Requirements
• Unfortunately the FDA has not issued
requirements for glass delamination testing
• UPS<1660> is a guidance document
– Does not address a “reactive” approach
• No cut and dry guidelines or protocols

Q&A Session
Please submit any questions using the chat box in the lower left of your screen

Contact Us & Follow-up
For more information about our analytical services, please visit:
www.gatewayanalytical.com
Connect with us on social media:
Contact Information
Emily Landsperger
Scientist
landsperger@gatewayanalytical.com
Tel: 724-443-1900 x107
Patrick Lehr
Global Marketing Manager
lehrp@gatewayanalytical.com
Tel: 724-443-1900 x132

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