This presentation summarizes a framework for considering intrinsic and extrinsic factors that may contribute to the propensity for glass vials to undergo delamination.

1. Risk factors associated with
delamination of glass vials
Matthew M. Hall, Associate Professor of Biomaterials & Glass Science
Kazuo Inamori School of Engineering at Alfred University
E-mail: hallmm@alfred.edu

2. Glass delamination is a coupling of chemical alteration
and mechanical fracture of the vial surface
D. Haines (SCHOTT North America), Image taken
from presentation at the 2011 PDA Glass Quality
Conference/Rx-360 Special Symposium on Glass
Delamination
• Delamination flakes are produced by the localized fracture of the interior vial surface
• Fracture requires two components – a flaw and a stress acting to propagate the flaw
• Time for delamination to occur is variable depending on condition – could range from hours to years

3. Glass delamination is receiving increased attention
due to a series of high profile voluntary recalls
25
21 100,000,000 +
# of Recalled Units
20
# of Recallls
15
10
5 4
3
395,000 1,600,000 +
0
1996-2000 2001-2005 2006-2011 1996-2000 2001-2005 2006-2011
Year Range Year Range
Assuming an average product value of $10/vial, the recalls between 2006 to 2011 represent
more than $1 billion in lost revenues.

4. Altered surface layer fractures to produce glass
delamination particles
• This scanning electron microscopy image
10 μm
represents an extreme case of what can
happen to glass surfaces that are heavily
corroded
• The corroded surface has cracked during
drying of the surface. Under appropriate
conditions, the surface can flake or peel
away from the bulk
• Note that the nominal composition of
this glass is 50Na2O-50SiO2 (mol%), which
places it on a completely opposite end of
Na2O-SiO2 Glass the chemical durability spectrum relative
D.E. Clark et al., (1976). J. Am.
to Type I to III glasses used for parenteral
Ceram. Soc., Vol. 59, pp. 62-65. packaging

5. Altered surface layer fractures to produce glass
delamination particles
• Surface of Type I borosilicate glass
vial after exposure to glutaric acid
solution (2 sterilization cycles and
2 weeks storage at 40°C)
• This image is more characteristic of
typical delamination in that a thin,
corroded surface layer giving rise
to high aspect ratio flakes is observed
• With that said, we have generally
observed that no two cases of
delamination observed in the field
are identical
• Can any sort of universal framework
be applied to the problem?
R.G. Iacocca et al. (2010). Factors affecting the chemical durability of glass
used in the pharmaceutical industry. AAPS PharmSciTech, 11: 1340-1349.

6. Theoretical framework for considering risk factors
associated with glass delamination
Intrinsic
“Flaw”
Extrinsic
Surface
Fracture
Intrinsic
Stress
Extrinsic
• Stress acts on one or more flaws to produce a fracture resulting in glass delamination
• Stresses and flaws can both have intrinsic and extrinsic origins
• Intrinsic Arising from factors primarily linked to decisions made by the vial manufacturer
• Extrinsic Arising from factors primarily linked to decisions made by the vial user

7. Flaws may have chemical and mechanical origins
Intrinsic Extrinsic
Glass type pH
Electrolyte
Phase separation
Active ingredient
Forming
Autoclaving?
Post-forming
treatments Handling?
“Glass type” is an intrinsic source of flaws insomuch as it drives
other factors such as phase separation and forming requirements

8. Type I glasses exhibit phase separation
Droplet in Matrix Interconnected
Morphology Morphology
B. Wheaton and A. Clare (2007). J. Non-Cryst. Solids, Vol. 353, pp. 4767-4778.
• Depending upon composition, glasses may exhibit phase separation – i.e., the glass “unmixes”
into two (and possibly more) chemically distinct phases
• Two basic phase separation morphologies are observed, as shown in the false color images
above that were obtained using atomic force microscopy
• 33 expansion glasses are known to exhibit droplet in matrix morphology; 51 expansion glasses
are also likely phase separated, although the morphology has not been positively characterized
our knowledge; SLS glass (Type III) is not expected to be phase separated

9. Type I glasses exhibit phase separation
• Phase separation potentially matters since the
properties of the chemically distinct phases within
the glass will be different
• For example, a 33 expansion glass nominally
consists of sodium- and boron-rich droplets
dispersed within a continuous silica-rich matrix
• The droplet phase will be more prone to
corrosion, thereby creating a potential flaw
HOWEVER…
• The phase separation issue is also likely linked to
forming-related factors
• The SEM image shown here is taken from the heel
region of a Type IA vial exposed to WFI
• The shape of the pitting is reminiscent of a droplet in matrix phase separation morphology in which a
non-durable droplet phase has been selectively corroded (note: the oblique view of the image is the
cause of the elliptical appearance of the circular pits)
• The size of the pits shown in the SEM image are much, much larger than the size of the droplets
typically expected in a Type IA borosilicate glass (on the order of tens of nanometers)
• Hypothesized sources of the enlarged droplets include:
• Modification of the glass surface chemistry (perhaps through a condensation process), thereby
modifying the scale of phase separation
• Coalescence of phase separated droplets due to holding glass at elevated temperature in
appropriate range
• The full impact of phase separation has yet to be truly addressed and represents an important area
for future research

10. Forming processes can alter the glass surface
Finish forming Flame cutting Bottom fire
Next
cycle
Heat
Heat
Lehr
Heat
Tooling
Illustration provided by Gerresheimer Glass
• Continuous tubing is converted to vials by a multi-step sequence
• Tubing conversion process require the application of heat and tooling to impart
an appropriate geometry
• Specific processing parameters depend upon the manufacturer, glass type,
tubing diameter, machine type, etc.

11. Forming processes can alter the glass surface
Image taken from Stevanato Group web site
Condensation
Volatilization
Diffusion
Intense, localized heating during the conversion process can lead to modifications of the glass vial
surface through a combination of possible mechanisms, including mass transport driven by thermal
gradients, evaporation of volatile species, and condensation of vapors on the interior surface.
Glass vials produced from converted tubing experience the greatest heating in the heel and shoulder.
The altered surface chemistry of these regions can potentially impact properties, including chemical
stability.

12. Forming processes can alter the glass surface
Blistering of interior surface in the
heel region of a Type I glass vial (a
defect that is rarely observed in
our experience)

13. Forming processes can alter the glass surface
Methylene
blue stain
• Methlyene blue is a cationic dye molecule that is known to bind to negatively
charged surfaces such as silicate glasses at near-neutral pH values
• The intensely stained region is likely due to sub-visible porosity in the surface
of the heel region that concentrates the dye
• Methylene blue staining can serve as a qualitative indicator of regions that are
potentially more susceptible to corrosion

14. Post-forming treatments alter the glass surface
Alkali-depleted Sodium sulfate deposits produced by surface treatment
surface
“Bulk Glass”
• Sulfate treatments were originally developed for improving the chemical durability of SLS glass
(Type III), not borosilicate glass (Type I)
• Evidence has been found that sulfate treatments of Type I glass can produce irreversible surface
damage to the interior of glass vials
• A conclusive link between sulfate treatments and delamination has yet to be established, but
we would generally recommend avoiding sulfate treatment in the interest of being conservative
• No one to our knowledge has reported on the possibility of using alternative treatments for
removing surface alkali – e.g., why not rinse with a dilute mineral acid such as HNO3?

15. Parenteral formulations can effect glass dissolution
behavior
~100 C ~60 C
-7 8
pH 12.7
1. Pyrex (Type I glass) 2. SLS (Type III glass)
mg SiO2/g Glass Powder
pH 4
7
log Dissolution Rate (cm/s)
pH 11.9
pH 7
-8 6 pH 10.4
pH 9
5 pH 9.5
pH 8.7
-9 4
3
-10 2
1
-11 0
2 2.2 2.4 2.6 2.8 3 3.2 0 50 100 150
1000/T (1/K) Time (min)
Increasing Temperature
1. G.W. Perera and R.H. Doremus (1991). J. Am. Ceram. Soc., Vol. 74, pp. 1554-8.
2. R.W. Douglas and T.M.M. El-Shamy (1967). J. Am. Ceram. Soc. Vol. 50, pp. 1-8.
• The above examples are taken from fundamental literature on glass corrosion that were not specifically focused
on chemical stability within the context of parenteral packaging – results are nonetheless applicable
• The left-hand figure demonstrates that the dissolution of a Type I glass (as measured by surface removal) can be significantly
influenced by temperature and pH. As expected, dissolution increases with increasing temperature and increasing pH
• The right-hand figure demonstrates that the dissolution rate of a Type III glass (as measured by extraction of SiO 2) is also
significantly influenced by pH. In general, we expect Type III glass to be less durable than Type I glass with increasing pH.

16. Parenteral formulations can effect glass dissolution
behavior
3.0
0.1M NaCl
2.5
Dissolution Rate (g/m2-d)
2.5M NaCl
2.0 SLS glass (Type III glass)
1.5
1.0
0.5
0.0
0 5 10 15
Number of semi-weekly interval
C.L.Wickert et al. (1999). Phys. Chem. Glasses. Vol. 40, pp. 157-170.
• This is another example taken from the fundamental literature on glass corrosion
• The results show the effect of changing electrolyte concentration (in this case NaCl)
on the dissolution rate of a Type III glass as measured by weight loss over time

17. Parenteral formulations can effect glass dissolution
behavior
• Phosphate solutions appear to
be a special case in which the
silicate network is attacked
• The SEM image shows the heel
region of a Type I glass vial
exposed to a concentrated
phosphate solution (the dendritic
structure in the upper right-hand
region is likely a salt deposit)

18. Parenteral formulations can effect glass dissolution
behavior
14
Glass Attack Rate (a.u.) 0.2% EDTA SLS glass (Type III)
12
0.2% EDTA + 0.4% Catechol
10 0.5M Sodium Acetate
8
6
4
2
0
8 10 12 14
pH
F.M. Ernsberger (1959). J. Am. Ceram. Soc., Vol.42, pp. 373-5.
• Chelating compounds can accelerate the dissolution of silicate glasses
• Effect of chelating agents is linked to a reduction in the solution-phase thermodynamic activity of the
complexed ion, thereby driving continued extraction from the glass
• Common species used in parenteral formulations that chelate cations relevant to glass include acetate
anions, citrate anions, and EDTA; larger biomolecules may also contain chelating groups

19. Parenteral formulations can effect glass dissolution
behavior…an interesting counter-example
70
• In this study, the dissolution behavior of
Borosilicate
borosilicate glass fibers (not equivalent
60 glass fibers to Type I glass) was evaluated in the
Dissolved Silica (mg/L)
50 presence of pre-dissolved silica
• The extent of glass fiber dissolution
40 generally decreased with increasing
concentration of pre-dissolved silica
30 0 ppm • These observations raise an interesting
conjecture – could formulations be
50 ppm
20 “spiked” with dissolved inorganic
75 ppm species such as silicon to suppress
10 corrosion?
100 ppm
• While this an academically interesting
0 question, it clearly raises a number of
0 5 10 15 20 25 30 regulatory issues
Time (days)
P. Baillif et al. (2000). J. Mater. Sci., Vol. 35, pp. 967-973

20. Stresses can also be produced by intrinsic and
extrinsic mechanisms
Endogenous Exogenous
Glass corrosion
Hydration/Dehydration
Forming induced
stress
Depyrogenation?
Handling?
Nominally erased by proper annealing procedures, although thin surface
layers of modified glass within heel region are likely under tensile stress

21. Reactions associated with glass corrosion can
generate stress in the glass surface
H3O+ H2O
≡Si-OH + HO-Si ≡
≡Si-O-Si ≡ Surface
Na+
≡Si-O-Si ≡ + H2O
≡Si-OH + HO-Si ≡
Bulk
Ion Exchange Network Hydrolysis Repolymerization
Various reactions associated with glass corrosion can lead to mass
transport and structural arrangement within the surface layer. This
can in turn cause volumetric changes that lead to stress generation.

22. Reactions associated with glass corrosion can
generate stress in the glass surface
30
20
Surface Stress (MPa)
Compressive Tensile
10
0
-10
-20 SLS Glass
0.5M HCl
-30
(Type III Glass)
5M HCl
-40
0 2 4 6 8
Time (hr)
T.A. Michalske et al., (1990). J. Non-Cryst. Solids, Vol. 120, pp. 126-137.

23. Hydration/dehydration cycles can generate stress
in corroded glass surfaces
This is extreme example of how a glass with poor chemical
durability can undergo failure when subjected to fluctuations
in humidity. This phenomenon, also called “glass disease” or
“crizzling”, occurs as the corroded glass surface swells and
shrinks in response to humidity changes.
It should be noted that no one has openly identified storage
conditions as a contributing factor towards the propensity
for glass delamination. Furthermore, there is no reason to
necessarily predict that Type I glass vials would be particularly
sensitive to this issue.
Nevertheless, it begs the question – how are your vials being stored?
Crizzling and the Preservation of Glass, Corning Museum of Glass, http://www.cmog.org/dynamic.aspx?id=5678#.Tx7Wu28V1Cg

24. Does the depyrogenation process matter?
• The potential influence of depyrogenation is still an open issue
• There is anecdotal evidence that depyrogenation of “wet” vials
can increase the propensity for delamination
• Assuming that the glass surface (particularly within the heel region)
has a porous, silica-rich gel layer that retains liquid, one could
hypothesize that a rapid depyrogenation process might further weaken
the surface due to rapid expansion of steam
• Could be regarded as an extreme example of crizzling
• Similar behavior is seen bulk porous glass that contains liquid
and is rapidly heated; the glass fractures by decrepitation
• This issue could clearly benefit from further study; parameters of
interest include:
• What is the impact of retained water versus dry vials?
• What is the impact of time/temperature profiles associated
with the depyrogenation process?

25. Does handling matter?
• For example, would mechanical impact of vials increase the
propensity for delamination?
• It is unlikely that handling-induced stress is a significant factor
• It is however possible to consider a situation in which vibration,
shock, etc. may help to dislodge a surface layer that is already
prone to delamination
• In this case, avoiding mechanical trauma is not a cure
• The surface is already compromised, and delamination is
almost certain at some point in the future
• These comments are based on educated guesses – further
study of handling-induced effects are justified but perhaps not
as urgent as the depyrogenation issue

26. Summary
• Delamination in pharmaceutical glass vials is a combination of chemical ateration
and mechanical fracture of the vial surface
• Intrinsic and extrinsic factors can give rise to both factors leading to delamination
• Forming processes are known to alter the glass surface, particularly in the heel
region of the vial that is subject to the most intense heating
• Heel region is more susceptible to corrosion and most likely to undergo
detectable delamination
• Delamination is not a new problem and may never fully go away since any vial
can be made to fail if subjected to inappropriate usage conditions
• Vial compatibility must be evaluated on a case by case basis and by close
collaboration between the suppliers and users of packaging products
Matthew M. Hall, Associate Professor of Biomaterials & Glass Science
Kazuo Inamori School of Engineering at Alfred University
E-mail: hallmm@alfred.edu