proactive vs reactive glass delamination testing in pharmaceuticals

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.

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Duration: 45 min. + Q&A time

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About Gateway AnalyticalLocated in Gibsonia, Pennsylvania, USA

About Gateway Analytical

Particulate Identification Services

Detailed Report Characterizing and

Identifying particulate

Customer Support to help identity the

source of contaminates.

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Meet Today’s Presenters

Emily LandspergerScientist

Gateway Analyticallandspergere@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?

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/displayAbstract?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

• 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

Sodium

22.990

Boron10.811Ca20

Calcium40.078

Silicon28.086

Particle Sizing and Counting

• Particle size analyzer– HIAC/Accusizer– CCSEM

LightSource

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

Poll Question #2

• Do you currently perform glass delamination testing in-house or do you outsource this work?In-houseSubcontractNeitherBoth

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

keV1086420

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

keV1086420

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

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?

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

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

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

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?

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 SessionPlease 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 InformationEmily LandspergerScientistlandsperger@gatewayanalytical.comTel: 724-443-1900 x107

Patrick LehrGlobal Marketing Managerlehrp@gatewayanalytical.comTel: 724-443-1900 x132

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