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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Meet Today’s Presenters

Emily LandspergerScientist

Gateway [email protected]


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?

YESNO


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


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

Na11

Sodium

22.990

B5

Boron10.811Ca20

Calcium40.078

Si14

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

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


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

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


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?

YESNO


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 SessionPlease submit any questions using the chat box in the lower left of your screen


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Contact InformationEmily [email protected]: 724-443-1900 x107

Patrick LehrGlobal Marketing [email protected]: 724-443-1900 x132


http://www.gatewayanalytical.com/

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proactive vs reactive glass delamination testing in pharmaceuticals

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