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Proactive vs. Reactive Glass Delamination Testing in
PharmaceuticalsJoin Gateway Analytical Scientists as they discuss UPS <1660> recommendations and
Gateway’s approach to different types of glass delamination investigations.
How to Listen & Participate in Today’s Webinar:Streaming audio is available through your computer speakers
Questions can be asked at any time though the chat function interface
Duration: 45 min. + Q&A time
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Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
About Gateway AnalyticalLocated in Gibsonia, Pennsylvania, USA
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
About Gateway Analytical
Particulate Identification Services
Detailed Report Characterizing and
Identifying particulate
Customer Support to help identity the
source of contaminates.
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Quality laboratory services making our world healthier and safer . . . one particle at a time!
Meet Today’s Presenters
Emily LandspergerScientist
Gateway [email protected]
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
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
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Overview of Glass Delamination What is it and why does it happen?
.
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
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
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
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
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Vial Conditions
• Time– Shelf life
• Chemistry of solution– pH– Ionic strength
• Temperature– Autoclaving/sterilization– Fluctuations over time/storage
conditions
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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
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Poll Question #1
• Have you ever experienced glass delamination in any of your products?
YESNO
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
USP <1660> Recommended Approach for Evaluation of the
Inner Surface Durability of Glass Containers
.
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
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
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Details Discussed
• Types of glass
• Formation of containers
• Supply Chain Practices
• Glass surface chemistry
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Source: USP <1660>, usp.org
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Things to look for during analysis…
• Changes in solution
• SiO2 content
• Number of lamellae in solution
• Changes in pH
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Source: USP <1660>, usp.org
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
USP<1660> Recommended Analytical Methods
• DIC Microscopy/EM
• SIMS
• pH testing
• ICP-MS/OES
• Particle Size Analyzer
• SEM-EDS of lamellae
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
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/displayAbstract?fromPage=online&aid=9031607
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DIC/EM Microscopy
• Electron Microscopy– Utilizing the Secondary Electron Detector – Allows for detection of minute surface changes – Requires cutting of vials
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SIMS
• Secondary Ion Mass Spec
• Surface analysis (sputter surface with ions, analyze secondary ions coming off of the surface)
• Depth profiling
• Very sensitive
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
pH Testing
• pH meter used to test solution
• Highly alkaline or highly basic solutions can contribute to delamination
Acidic Neutral
Alkaline
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
ICP-OES/ICP-MS
• Analysis of solution contained by the vial
• Detect/quantify levels of trace elements commonly found in glass
Na11
Sodium
22.990
B5
Boron10.811Ca20
Calcium40.078
Si14
Silicon28.086
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Particle Sizing and Counting
• Particle size analyzer– HIAC/Accusizer– CCSEM
LightSource
Liquid Sample
Detector
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
SEM Analysis
• Lamellae on Filters– Morphology– Elemental composition
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
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
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
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
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Product Specific Model
Source: USP <1660>, usp.org
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Poll Question #2
• Do you currently perform glass delamination testing in-house or do you outsource this work?In-houseSubcontractNeitherBoth
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Analysis Methods for Glass Delamination
What analyses do we perform?
.
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
• “Twinkling”– Light reflected off lamellae
• Signs of extensive glass breakdown
• Can be difficult to detect
Initial Stereomicroscopic Examination
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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
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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
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Stereoscopic Evaluation
• Analysis of filter for the presence of lamellae– Variability in
appearance of lamellae between samples
– Due to thickness of the lamellae
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SEM-EDS of Lamellae
500 µm 200 µm
keV1086420
Cou
nts
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
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
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”
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
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.
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Limitations of CCSEM of Lamellae
500 µm 200 µm
keV1086420
Cou
nts
2,000
1,500
1,000
500
0
C
O
Al
Si
filename = 100515_Lamellae3.TIFManual 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
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
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
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EM of Vial Interiors
• Pitting, delamination, manufacture defects
• Addresses the USP<1660> test parameter “glass surface”
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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”
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
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
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Proactive vs. Reactive Analytical Approaches
What’s the difference?
.
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Proactive vs. Reactive
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
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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
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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
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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
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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
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Proactive vs. Reactive
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
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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
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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
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.
Poll Question #3
• Has your lab ever performed a stability study for glass delamination?
YESNO
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FDA Requirements
.
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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
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Q&A SessionPlease submit any questions using the chat box in the lower left of your screen
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Contact Us & Follow-up
For more information about our analytical services, please visit:
www.gatewayanalytical.com
Connect with us on social media:
Contact InformationEmily [email protected]: 724-443-1900 x107
Patrick LehrGlobal Marketing [email protected]: 724-443-1900 x132
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For Attending Today’s Presentation!
Please remember to complete the short survey following this slide
Gateway Proprietary Information©Gateway Analytical, LLC 2016. All Rights Reserved. Gateway Products and Services are protected by U.S. and International issued patents and pending patent applications.