Delamination PDA Pres

P2: Development Considerations / Glass By: Carol Rea Flynn
Glass Delamination:
Risk Factors and Root Causes
Carol Flynn1
Director of Technical Services
Gerresheimer Glass Inc.
In collaboration with:
Matthew Hall2, Dan McNerney1, Palak Shah1
1. Gerresheimer Glass Inc., Vineland, NJ

2. Kazuo Inamori School of Engineering, Alfred University, Alfred, NY
Glass delamination is a combination of

chemical alteration and mechanical failure
of the interior surface
Forced delamination
utilizing a
high pH of 13
Reference: Gerresheimer pH 13 2012

Glass Delamination: An explanation

Definition
Formation and separation of glass flakes from a glass
surface
Typically glass flakes are nearly invisible to the naked

eye (< 50 micron)
Many different chemical and processing parameters can

lead to glass flaking
Glass delamination, in general, is a

time-dependent process
Altered surface layer fractures

to produce delamination particles
10 m
Reference: D.E. Clark et al., (1976). J. Am.

Reference: Gerresheimer Glass / Alfred University 2012
Ceram. Soc., Vol. 59, pp. 62-65.
Theoretical framework for vial delamination
Intrinsic
Flaw Fracture
Extrinsic
Acting on
Intrinsic
Stress
Extrinsic
Flaws have chemical and mechanical origins

Delamination is a complex picture
Intrinsic Extrinsic
Depyrogenation (Steam)
Glass composition
Glass forming *Chemical composition
technology of drug or API
Glass forming time (Active Pharmaceutical
Ingredients, e.g.buffer,
and temperature
chelating agent,
Surface Alterations ionic strength,
and deposits phosphate, citrate, pH
Phase Separation
*Thermal sterilization
Surface treatment *Time and storage
conditions (Filled)
Annealing temperature * Corrosion creates a porous,
gel like surface or flaws
Stress also has

chemical and mechanical origins
Intrinsic Extrinsic
Glass corrosion*
Thermal Sterilization*
Forming induced
Hydration
stress
Dehydration
Depyrogenation*
Relieved by proper * Can generate both

annealing procedures flaws and stress
Experimental manufacturing and

processing parameters for DOE
Gerresheimer partnered with leading glass experts at Alfred University
Design of Experiment (DOE)
MANUFACTURING PROCESSING (USER)

Glass type (Gx33, Gx51) Depyrogenation
(with residual water)
Vial Size (3ml, 10ml)
Autoclave (1x, 3x)
Forming operation
(Continuous, Indexing) Storage Time / Temperature
(0, 3, 6 months; 1, 2, 3 years)
Forming temperature
(Room, 5C, 40C)
(Low, Standard, High)
Sulfate treatment Formulation (HPW, Citrate, KCL)

pH (5.5, 7, 8, 9.5)
Forming processes alter the glass surface

Standard converting process indexing or continuous
Tube to
Next Cycle
+ Heat ->>> + Heat ->
Cycle ROI
Start -> Vial to
+ Heat -> Annealing
-> Oven
+ Tooling
Glass Tube Finish Forming Flame Cut Bottom Fire

Polishing
Heating and forming steps

transform glass characteristics
Vial bottom forming in more detail
Glass in flux - at annealing, softening, and melting temperatures
Alkali borates evaporate and condense on the glass surface
Deposits change glass chemistry in heat transition zone
Alkali constituents migrate to the surface.
Phase Separation in transition zone
Region of Interest (ROI)

for delamination
5 - 7 mm
(vial heel and shoulder) Transition zone
Heel
Forming processes alter the glass surface

Thermal imaging of converted tubing forming process.
Reference: Gerresheimer Glass 2011 video clip
What are the flaw mechanisms?

Volatilization, Migration, Phase Separation
Volatilization - Remelting volatilizes some of the glass components,
including sodium, calcium, potassium, and boron. The volatiles
condense on the glass surface, thus increasing the alkali concentration.
Migration - Alkali migrates to the surface in the reheated area, driven

by a reduction in surface energy.
Phase Separation - Borosilicate glass excessively phase separates

when held at specific elevated temperatures for an extended time. The
glass can separate into a sodium-rich phase and a silica-rich phase.
If forming parameters are not controlled and the glass composition

at the surface is severely altered, the surface chemical durability is
degraded, and the propensity for delamination increases.
Surface Alterations: Phase separation

Droplet in matrix morphology (DOE heel of vial)
Note: The angle

of the SEM
photos creates
an elliptical
image of the
circular pits.
Reference: Gerresheimer / Alfred University - Autoclave 1 x, 3 months, Citrate
Surface Alterations: Phase separation

Interconnected morphology (not from DOE vial shoulder)
Reference: Gerresheimer / Alfred University - Sample submitted Depyrogenated and Potassium Phosphate Solution
Post-forming treatment: Ammonium Sulfate

HSO4- Heat 2Na+
Bisulfate + ~950F + (glass) Na2SO4 + 2H+
Ion (480 C)
Sodium sulfate deposits

Alkali-depleted produced by surface treatment
surface
Bulk Glass
Sulfate treatments were originally developed for soda lime glass.
Flaws have chemical and mechanical origins

Delamination is a complex picture
Intrinsic Extrinsic
Depyrogenation (Steam)
Glass composition
Glass forming *Chemical composition
technology of drug or API
Glass forming time (Active Pharmaceutical
Ingredients, e.g.buffer,
and temperature
chelating agent,
Surface Alterations ionic strength,
and deposits phosphate, citrate, pH
Phase Separation
*Thermal sterilization
Surface treatment *Time and storage
conditions (Filled)
Annealing temperature
* Corrosion creates a porous,
gel like surface or flaws
Depyrogenation
Rapid steam generation may
cause surface micro-fractures.
Previous studies have indicated

that depyrogenation may
increase the propensity for
delamination.
As a part of the Gerresheimer

DOE, we introduced residual
water prior to depyrogenation.
Reference: Elllab.com
Formulations can influence glass corrosion

Increased pH increases the glass corrosion rate
-7
Pyrex Type 1
log Dissolution Rate (cm/s)
-8 pH 4 pH 7 pH 9
-9
-10
-11
2 2.2 2.4 2.6 2.8 3 3.2
1000/T (1/K)
Reference1. G.W. Perera and R.H. Doremus (1991). J. Am. Ceram. Soc., Vol. 74, pp. 1554-8.
.
Formulations can influence glass corrosion

Chemical
Potassiumdurability issues mechanism of attack
phosphate
Di-pole moment. [the polarity of the ion in solution directly influences the
degree of attack of the network]. Neucleosilicate attack.
Charge on the silicon ion (+) attracts (-) charges in solution. This is the
reason [OH]- attacks the network so well
ll
Oxygen very negatively charged O are bad.
This negative charge attacks and breaks down the
silica network.
Mechanism consistent with alkaline attack resulting in dissolution of silica

network:
Corrosion may produce stress

in altered surface layer
Glass fractures only in tension
30
20
Surface Stress (MPa)
Tensile
10
0
Compressive
-10
-20
0.5M HCl
-30
5M HCl
-40
0 2 4 6 8
Time (hr)
Reference: T.A. Michalske et al., (1990). J. Non-Cryst. Solids, Vol. 120, pp. 126-137.
Glass delamination has been simulated

for analytical purposes
Intentional generation of glass flakes
Vials were filled with HPW of pH 13 followed by two autoclave cycles
Formation of glass flakes through chemical attack from strong base
For demonstration only (pH 13 should not be stored in glass
containers)
Reference: Gerresheimer / Pisa University 13 pH Solution
Glass surface has been etched

with a strong base for simulation
Topography of delaminated inner glass surface
Pitting and striations of the interior glass surface are visible
Surface erosion is a precursor of delamination
Filling limit of aqueous solution with pH 13 is evident
Reference: Gerresheimer / Pisa University 13 pH Solution

Vials have been inspected

with variety of analytical techniques
Time zero (t0) vial characterization
Particle detection with pH measurement

dynamic light with -electrode
Liquid path
scattering (DLS)
method
Inductively
coupled plasma
Screening of glass
(ICP) extractables
surface morphology
analysis by
with scanning
-nebulizer,
electron microscope
EPHR 3.2.1A
(SEM) and
tests
methylene blue
Vial path staining test.
Imaging of stress EDAX, XPS and
zone by Polariscope. AFM methods
Glass type affects alkalinity levels

and pH shifts
Alkalinity / EP HR 3.2.1 A
Vials from Gx33 glass show lower alkalinity levels

Correlation to delamination not established to date
EP 3 ml pH Rise Comparison 10 ml pH Rise Comparison
250.0% 250.0%
Gx-51 EPHR GX-51 EPHR
EP Gx-33 EPHR
Gx-33 EPHR
200.0% 200.0%
150.0% 150.0%
100.0%
100.0%
50.0%
50.0%
0.0%
0.0%
0.00 1.00 2.00 3.00 4.00
0.50 0.50 1.50 2.50 pH pH
Glass extractables depend on

vial manufacturing parameters
Inductively coupled plasma (ICP) extractables after autoclaving with HPW
Concentration of extracted silicon correlates with EP HR 3.2.1 A

Alkali ICP (Na+, K+, Ca2+) is proportional to EP HR
ppm ppm
EP EP
DLS (Dynamic Light Scattering)

Measuring the size Mv and number Mn of the particles
Established reference point with known visible delamination / glass flakes
Due to the thin flat shape of delamination flakes, the average volume of the
delaminated flakes is less than what the DLS estimates for round particles.
Data still in process; found hits, but of much lower size values relative to
visual size of delamination particles due to shape.
Suspended
Scattered Light Particles
from Particles
Laser
No Reflected
Detector
Light
Controlled Reference is developed at the interface of the probe tip and fluid
Reference: Microtrac.com
Particle Size Analysis:

DLS (Dynamic Light Scattering)
General trends of 3 month data
Higher incidents of detectable particles in vials stored for 3 months,
compared to time zero vials (immediate analyzed after filling)
With 3 month vials, increased particle frequency with increased processing:

1XAutoclave, 3XAutoclave, and Depyrogenation (pH = 9.5)
120
% Particle Count Increase from
100
Reference (Baseline)
80
60
40
20
0
1XAutoclave 3XAutoclave Depyrogenation
Process
Forming processes may alter the glass surface

Methylene Blue staining patterns as indicators of surface alterations
Methylene
blue stain
DOE to determine if
methylene blue
staining can be used
as a leading indicator
for delamination.
Reference: Gerresheimer / Alfred University

Methylene Blue staining identifies ROI

Methylene Blue staining patterns: Comparison of 49 manufacturing parameters
Confirms ROI
Reference: Gerresheimer / Alfred University
SEM (Scanning Electron Microscope) patterns

Topography of the inner surface in ROI Pits, deposits, loose layers
1000 x 5000 x
Note: The angle of the SEM photos create an elliptical image of the circular pits.
Reference: Gerresheimer / Alfred University 2011

Anticipating and reducing risk of delamination

in pharmaceutical glass packaging
Manufacturing trials are evaluating a broad variety of converting parameters
The vast majority of injectable drugs on the market are
safely packaged in Type I glass containers.
Container solutions are as many and varied as customer

applications.
Single parameters (e.g., EP HR) do not provide reliable

indications in every case.
For delamination screening, a variety of parameters should be

considered. Early indicators will be a combination of leached
glass constituents, pH shift, staining, topography of the glass
surface, and other screening techniques.
Suppliers may need a broad base of glass technologies to

meet the needs of the customers drug formulations.
Understanding the
Root Causes and Risk Factors
What have we learned?
Flaw Stress analysis provides framework for

determining propensity for glass delamination.
Understanding the root causes of delamination should lead

your glass manufacturer to control glass volatiles.
Understanding the root causes of chemical durability should

lead your glass manufacturer to control alkali migration.
Understanding the root causes of delamination should lead

your glass manufacturer to control phase separation.
More supporting data to come

The continuing DOE will be yeilding information for the next 3 years
Six month results August 2012
One year results June 2013
Two year results June 2014
Three year results June 2015
Final paper September 2015
To further discuss these technical results or if you

would like to be updated on the future DOE results.
Please feel free to contact Mike Fischer at
M.Fischer@Gerresheimer .com

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P2: Development Considerations / Glass By: Carol Rea Flynn

1. Gerresheimer Glass Inc., Vineland, NJ

Glass delamination is a combination of

Reference: Gerresheimer pH 13 2012

Glass Delamination: An explanation

Typically glass flakes are nearly invisible to the naked

Many different chemical and processing parameters can

Glass delamination, in general, is a

Altered surface layer fractures

Reference: D.E. Clark et al., (1976). J. Am.

Theoretical framework for vial delamination

Flaws have chemical and mechanical origins

Stress also has

Relieved by proper * Can generate both

Experimental manufacturing and

MANUFACTURING PROCESSING (USER)

Sulfate treatment Formulation (HPW, Citrate, KCL)

Forming processes alter the glass surface

Glass Tube Finish Forming Flame Cut Bottom Fire

Heating and forming steps

Alkali borates evaporate and condense on the glass surface

Deposits change glass chemistry in heat transition zone

Alkali constituents migrate to the surface.

Phase Separation in transition zone

Region of Interest (ROI)

(vial heel and shoulder) Transition zone

Forming processes alter the glass surface

Reference: Gerresheimer Glass 2011 video clip

What are the flaw mechanisms?

Migration - Alkali migrates to the surface in the reheated area, driven

Phase Separation - Borosilicate glass excessively phase separates

If forming parameters are not controlled and the glass composition

Surface Alterations: Phase separation

Note: The angle

Reference: Gerresheimer / Alfred University - Autoclave 1 x, 3 months, Citrate

Surface Alterations: Phase separation

Post-forming treatment: Ammonium Sulfate

Sodium sulfate deposits

Sulfate treatments were originally developed for soda lime glass.

Flaws have chemical and mechanical origins

Previous studies have indicated

As a part of the Gerresheimer

Formulations can influence glass corrosion

Formulations can influence glass corrosion

Mechanism consistent with alkaline attack resulting in dissolution of silica

Corrosion may produce stress

Glass delamination has been simulated

Reference: Gerresheimer / Pisa University 13 pH Solution

Glass surface has been etched

Reference: Gerresheimer / Pisa University 13 pH Solution

Vials have been inspected

Particle detection with pH measurement

Glass type affects alkalinity levels

Vials from Gx33 glass show lower alkalinity levels

EP 3 ml pH Rise Comparison 10 ml pH Rise Comparison

Glass extractables depend on

Concentration of extracted silicon correlates with EP HR 3.2.1 A

DLS (Dynamic Light Scattering)

Particle Size Analysis:

With 3 month vials, increased particle frequency with increased processing:

Forming processes may alter the glass surface

Reference: Gerresheimer / Alfred University

Methylene Blue staining identifies ROI

Reference: Gerresheimer / Alfred University