Comparative Predictive Glass Delamination Study Tubular Borosilicate vs Moulded Borosilicate and Soda Lime 20 ml Vials

Abstract

Glass is by far the predominant material used for pharmaceutical containers especially because of the chemical inertness and the excellent container closure properties. Nevertheless, the interaction with the drug product can alter the interior glass surface and generate adverse effects. In this study, the chemical durability of 20 mL Type I tubular borosilicate glass, Type I moulded borosilicate glass, and Type II moulded soda lime glass vials are assessed based on the methodology recommended in USP <1660> with respect to ultrapure H 2 O and 15 % KCl filling solutions stored up to 48 weeks at 40°C. The study design used can clearly distinguish and rank the extent of a chemical attack based on differences observed on the interior glass surface by stereomicroscope and SEM cross-section analysis, amount of glass elements leached into solution by ICP-OES, and pH shifts. The observed chemical durability differences are directly related to the 2 independent variables, a combination of the glass composition and glass manufacturing/processing conditions. While all 3 vial types behaved similarly when filled with ultrapure H 2 O, significant differences were found when the vials were filled with a more aggressive filling solution of 15 % KCl. In contrast to generally accepted industry views of moulded glass vials having higher chemical durability in general to filling solutions, the moulded glass containers were more severely attacked by the 15 % KCl than the tubular glass containers. This should be considered when selecting containers not alone for drugs with active ingredients but also for water-based diluents with more or fewer salt components. Finally, there is a need for USP <1660> to assess each filling solution/container combination as the results in this study show that generally accepted trends are not always followed.
KEY WORDS • Glass Delamination • Moulded and Tubular Borosili-cate Vials • Moulded Soda Lime • pH-Shift • USP <1660> Testing

Full text

Comparative Predictive Glass
Delamination Study
Tubular Borosilicate vs Moulded Borosilicate and Soda Lime 20 ml Vials
Daniel Haines, Elizabeth Gober-Mangan, Michaela Klause, Uwe Rothhaar
SCHOTT AG, Mainz (Germany)
Correspondence: Dr. Daniel Haines, 400 York Avenue, Duryea PA 18642 (USA)
nABSTRACT
Glass is by far the predominant material used for pharma-
ceutical containers especially because of the chemical
inertness and the excellent container closure properties.
Nevertheless, the interaction with the drug product can alter
the interior glass surface and generate adverse effects. In this
study, the chemical durability of 20 mL Type I tubular
borosilicate glass, Type I moulded borosilicate glass, and
Type II moulded soda lime glass vials are assessed based on
the methodology recommended in USP <1660> with respect
to ultrapure H2O and 15 % KCl filling solutions stored up to
48 weeks at 40 °C. The study design used can clearly
distinguish and rank the extent of a chemical attack based on
differences observed on the interior glass surface by
stereomicroscope and SEM cross-section analysis, amount of
glass elements leached into solution by ICP-OES, and pH
shifts. The observed chemical durability differences are
directly related to the 2 independent variables, a combination
of the glass composition and glass manufacturing/processing
conditions. While all 3 vial types behaved similarly when
filled with ultrapure H2O, significant differences were found
when the vials were filled with a more aggressive filling
solution of 15 % KCl. In contrast to generally accepted
industry views of moulded glass vials having higher chemical
durability in general to filling solutions, the moulded glass
containers were more severely attacked by the 15 % KCl than
the tubular glass containers. This should be considered when
selecting containers not alone for drugs with active
ingredients but also for water-based diluents with more or
fewer salt components. Finally, there is a need for
USP <1660> to assess each filling solution/container combi-
nation as the results in this study show that generally
accepted trends are not always followed.
nZUSAMMENFASSUNG
Vergleichende Studie zur Vorhersage der Delamination
von 20-ml-Fläschchen aus Borosilikat-Röhrenglas, Boro-
silikat-Hüttenglas und Kalknatron-Hüttenglas
Glas ist das bei weitem vorherrschende Material für phar-
mazeutische Behältnisse, vor allem wegen seiner chemischen
Inertheit und der hervorragenden Verschließbarkeit. Den-
noch kann die Wechselwirkung mit dem Arzneimittel die
innere Glasober-
fläche verändern
und nachteilige
Wirkungen hervor-
rufen. In dieser
Studie wird die
chemische Bestän-
digkeit von 20-mL-
Fläschchen aus Bo-
rosilikat-Röhrenglas
des Typs I, aus Bo-
rosilikat-Hüttenglas des Typs I und aus geformtem Kalkna-
tronglas des Typs II auf der Grundlage der in der USP <1660>
empfohlenen Methodik in Bezug auf ultrareines H2O und 15%
ige KCl-Fülllösungen, die bis zu 48 Wochen bei 40°C gelagert
werden, bewertet. Das verwendete Studiendesign ermöglicht
eine klare Unterscheidung und Einstufung des Ausmaßes des
chemischen Angriffs auf der Grundlage der durch Stereo-
mikroskopie und SEM-Querschnittsanalyse beobachteten
Unterschiede auf der inneren Glasoberfläche, der durch ICP-
OES bestimmten Menge der in die Lösung ausgelaugten
Glaselementen und der pH-Verschiebungen. Die beobachte-
ten Unterschiede in der chemischen Beständigkeit stehen in
direktem Zusammenhang mit den beiden unabhängigen
Variablen, einer Kombination aus der Glaszusammensetzung
und den Glasherstellungs- und -verarbeitungsbedingungen.
Während sich alle 3 Fläschchentypen bei der Befüllung mit
hochreinem H2O ähnlich verhielten, wurden signifikante
Unterschiede festgestellt, wenn die Fläschchen mit einer
aggressiveren Fülllösung von 15 % KCl befüllt wurden. Im
Gegensatz zu der in der Industrie allgemein akzeptierten
Ansicht, dass Fläschchen aus Borosilikat-Hüttenglas im
Allgemeinen eine höhere chemische Beständigkeit gegenüber
Fülllösungen aufweisen, wurden diese von der 15%igen KCl
stärker angegriffen als die Röhrenglasbehälter. Dies sollte bei
der Auswahl von Behältern nicht nur für Arzneimittel mit
Wirkstoffen, sondern auch für wässrige Verdünnungsmittel
mit mehr oder weniger Salzbestandteilen berücksichtigt
werden. Schließlich ist eine USP-<1660>-Bewertung der
einzelnen Kombinationen von Fülllösungen und Behältern
erforderlich, da die Ergebnisse dieser Studie zeigen, dass die
allgemein anerkannten Trends nicht immer eingehalten
werden.
nKEY WORDS
•Glass Delamination
•Moulded and Tubular Borosili-
cate Vials
•Moulded Soda Lime
•pH-Shift
•USP <1660> Testing
Pharm. Ind. 84, Nr. 8, 1001–1012 (2022)
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1. Introduction
Glass delamination in pharmaceutical packaging, de-
scribed by the FDA [1] as “the potential for glass under
certain conditions to shed thin, flexible fragments called
glass lamellae”, became a topic of intense industry and
regulatory attention in 2011 due to a large and costly re-
call event [2]. While the majority of personnel in the
pharmaceutical companies and regulatory agencies
were unfamiliar with the root causes of this phenome-
non [3] due to its sporadic occurrence in approved drug
products, the issue was known and published in the
glass manufacturing literature and/or pharmaceutical
focused journals in each of the last 9 decades. During
this time, significant numbers of studies have been con-
ducted concerning the various factors contributing to
the root causes of glass delamination.
In 1940 Bacon and Burch [4] were one of the first to
discuss the formation of flakes in various glass bottles
and alcoholic solutions. Dimbleby [5] published 1953 a
review of glasses for pharmaceutical purposes describing
“the production of insoluble matter ( flakes) in solutions
stored in glass” from 3 sources with a discussion of the
various root causes. A key observation was made at this
early date as to certain filling solutions having a higher
rate of glass attack, “alkali solutions relatively quickly
produce flakes from some glasses”. Rehm [6] 1965 pub-
lished a detailed paper on the production conditions of
borosilicate ampoules that contributed to an increase or
decrease of glass chemical resistance to various solutions
with some production conditions increasing the risk for
flakes to appear in filling solutions upon storage.
In 1973 Adams [7] conducted a study with borosilicate
and soda lime ampoules to provide evidence and a mecha-
nism for spicule formation that supported commonly held
knowledge: “Glass container manufacturers know that
glasses containing magnesium have a greater tendency to
form spicules, even though their chemical durability may
be better”. This is one of the first papers to discuss a differ-
ent glass delamination mechanism whereby the “lamellae”
were deposited as a thin layer onto the surface over stor-
age time due to a first glass dissolution attack causing
glass elements to leach into the solution. Roseman et al
[8] published 1976 one of the first SEM (EDS) focused
studies of glass delamination on borosilicate ampoules
and treated borosilicate ampoules, confirming delamina-
tion originating from the heel location. Over the next dec-
ades, additional publications [9–15] provided helpful
pieces to understand the delamination mechanisms.
In 2010 Iacocca et al [16] published a detailed study
using glutaric acid with various vials and processing
conditions, assessed by a variety of techniques including
dynamic secondary ion mass spectroscopy (D-SIMS). Of
note from this study are the observations of a pH de-
crease over storage time, the use of a coated vial to slow
down the attack of the native glass surface, and that the
observed significant differences in the chemical durabil-
ity of the vials were proposed to be due to “the differ-
ences in the manufacturing processes between vendor A
and vendor B vials”. Sloey et al [17] published 2013 an
accelerated attack procedure for incoming testing of
glass vials to check for glass delamination. Jiang et al
[18] published in 2013 on mechanical stress thermally
induced mechanism from protein solutions frozen to
–70 °C and thawed leading to glass delamination. Ogawa
et al [19,20] published in both 2013 and 2015 on a novel
glass delamination mechanism that occurred only in
phosphate buffer-containing solutions, a 2-step process
that resulted in aluminium-phosphorus-rich containing
flakes being observed in solution after storage.
In response to the increased number of glass delami-
nation recalls, the pharmaceutical packaging industry
developed different glass container solutions that were
claimed to reduce or eliminate the risk of glass delami-
nation. SCHOTT was the first supplier to provide a tubu-
lar borosilicate vial with increased control of the con-
verting process leading to a reduced risk for glass dela-
mination in 2013 (branded as SCHOTT EVERIC pure®),
supplemented by a production release test for the inner
surface chemical durability called the ‘Quicktest’ [21].
Other glass manufacturing companies followed suit ad-
dressing other solution approaches of improved control
of converting processes or introducing glass with a bor-
on-free composition. Leave boron out should reduce
evaporation and diffusion processes during the vial con-
version process that lead to micro-areas with altered
composition as shown in [21]. But to fulfil the regulatory
requirements for Type I borosilicate glass vials in USP
and Ph. Eur., an ion exchange pre-treatment process is
needed for boron-free glass compositions [22].
As the preceding brief review of investigations into the
glass delamination has shown both a breadth/depth of
knowledge and some uncertainty over the interpretation
of the generated data that contribute to a glass delamina-
tion event. As a result some key industry and regulatory
assumptions remain that require additional data, particu-
larly with the tubular vs moulded manufacturing pro-
cesses and associated glass compositions. This work con-
ducts an accelerated glass delamination screening assess-
ment utilising 2 filling solutions to compare head-to-head
the extent of glass attack as a function of glass vial com-
position and vial manufacturing processes of a borosili-
cate tubular Type I glass vial vs. borosilicate moulded
Type I glass vial vs. soda lime moulded Type II glass vial.
2. Materials, Methods and Equipment
Materials
Commercially available vials with 3 different glass compositions hav-
ing a nominal filling volume of 20 ml were used in this study. 2 vial
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types were made directly from the glass melting tank via moulding
(one borosilicate and one soda lime glass composition), while the third
vial type was manufactured on state-of-the-art converting lines from
borosilicate glass tubing. The 2 borosilicate vials meet USP <660>
Type I specifications while the soda lime vial meets USP <660> Type II
specifications. This means that the inner surface of the soda lime vials
was treated with ammonium sulfate to create a de-alkalised surface
layer. The inner diameter of all the glass vials was about 20 mm.
Table 1 summarises the main oxide components of the 3 glass compo-
sitions; the moulded borosilicate glass contains all of the main oxide
components, the soda lime glass does not contain boron oxide, and
the tubular borosilicate glass is free of magnesium oxide.
The tubular borosilicate vials (EVERIC pure) were formed using
Type I B borosilicate glass tubing (FIOLAX®) and applying parameters
based on a delamination-controlled converting process. This opti-
mised converting procedure ensures that the durability of the entire
inner vial wall is more homogeneous including the critical wall near
the bottom area. The production control of these vials is additionally
performed with the so-called “Quicktest” [21, 23] with validated limit
values.
Before the filling, storage and analyses, the vials were labelled with
a waterproof pen and cleaned in 2 steps: First fill and empty 3 times
with tap water, second fill and empty 3 times with ultrapure water fol-
lowed by drying in a laminar airflow cabinet. The vials were then filled
by using a pipette with 2 solutions. The solutions consist of:
a) Ultrapure water with a conductivity less than 5 µS/cm at 25 °C
b) Potassium chloride solution 15 wt%
(15 g KCl dissolved in 100 ml ultrapure
water)
All 3 vial types were filled with both filling
solutions resulting in 6 different sample
types. The vials were filled with a 20 ml filling
solution. After capping the filled vials with
sterilised Westar RS B2-40 Fluro-Tec stop-
pers, the vials were autoclaved for 30 min at
121° C and stored upright in an oven at 40 °C
for 24 weeks and 48 weeks. The relative hu-
midity was not controlled . The 48 weeks
storage exceeds the period instructions giv-
en in the ICH Q1A (R2) guideline for acceler-
ated studies (40 °C and 6 months minimum)
[24]. Using the Arrhenius rate law and a con-
servative value of 54 kJ/mol for the activa-
tion energy, 0, 24, and 48 weeks of acceler-
ated storage at 40 °C corresponds to 0, 68,
and 136 weeks of real-time storage at 25 °C
[25].
The concentrations of the typical “glass”
elements within the solutions as prepared
and without storage (blank values) were ana-
lysed using ICP-OES for ultrapure water and
15 % KCl solutions. None of the glass ele-
ments analysed in the blank solutions fea-
tured a concentration above the limit of
quantification (LoQ) as listed in table 2.
Methods
An ICP-OES method was applied to deter-
mine the concentration of the typical glass
elements in the ultrapure water and
15 % KCl solutions. After autoclavation of
the filled containers and after 24 weeks and
48 weeks of storage, the 100 ml total filling
volume was pooled to 2 × 50 ml of each sam-
ple type and diluted in 2 % HNO3prior to the
analyses, single determination of each 50 ml
pool. The dilution factors varied between
1:5 (water) and 1:40 (KCl solution) concerning the concentration range
of the samples. Consequently, the LOQ values for the KCl solution are
about 10 times higher compared to water. For quantitative evaluation,
single element standards from Alfa Aesar were chosen.
Equipment
Visual Inspection (Eye & Video camera)
For the optical inspection of the filled containers for particulate mat-
ter, an inspection box was used following USP <790> and
Ph. Eur. 2.9.20. For the optical inspection of the filled containers for
reflective flake-like particulate matter, a fibre optic light source
(SCHOTT AG KL1500) and a video camera (Imaginesource DFK) were
used.
Stereomicroscopy
For the optical inspection of the vulnerable area in the heel region and
mid-body reference area of the emptied containers a stereo-micro-
scope (Zeiss Discovery V20) equipped with a camera system was used.
Scanning Electron Microscopy (SEM)
The characterisation of the morphology of surfaces and cross-sections
was performed with scanning electron microscopy (SEM, Hitachi
S4700).
nTable 1
Oxide components of the glasses used for the vials.
Oxides included Type I Borosilicate
Moulded
Type II Soda Lime
Moulded
Type I Borosilicate
Tubular
SiO2Yes Yes Yes
Al2O3Yes Yes Yes
B2O3Yes No Yes
Na2O Yes Yes Yes
MgO Yes Yes No
CaO Yes Yes Yes
nTable 2
ICP-OES results for blank solutions.
Element Ultrapure Water
ICP-OES (µg/mL)
15 % KCl Solution
ICP-OES (µg/mL)
Conc LoQ Conc LoQ
Si <0.05 0.05 <0.5 0.5
B <0.05 0.05 <0.5 0.5
Na <0.10 0.10 <0.5 0.5
Al <0.05 0.05 <0.5 0.5
Ca <0.05 0.05 <0.5 0.5
Ba <0.05 0.05 <0.5 0.5
K <0.10 0.10 – (*) –(*)
(*) K is not measured as a part of the formulation in high concentration.
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Inductively Coupled Plasma – Optical Emission
Spectrometry (ICP-OES)
The measurement of the concentration of typical glass elements was
conducted with an Agilent ICP-OES 5100 VDV series.
pH
For the measurement of pH of the pooled solutions taken from filled
and stored containers, an Acumet Research AR50 was used.
3. Results and Discussion
Following USP <1660> guidance [26], the recognised
gold standard for the assessment methods of chemi-
cal durability and delamination risk of glass contain-
ers requires analysis of 3 important attributes: Pre-
sence/absence of glass flakes/lamellae in solution (vi-
sual inspection methodology), the extent of glass
attack on the interior drug formulation contacting
surface (stereomicroscope, SEM cross-section), and ex-
tent of glass leaching into the drug formulation (ICP-
OES/MS). Assessment for each attribute is conducted
in 2 parts, identification of the various features and
classification based on limit criteria. A risk assess-
ment or suitability for use statement, respectively, is
then made by combining the test results throughout
the study. While some approaches have been pro-
posed using alternative methods to address perceived
shortcomings, the current USP <1660> testing is ‘THE’
accepted testing methodology by worldwide regula-
tory bodies such as the FDA and EMEA and interna-
tional working groups such as the Technical Commit-
tee 12 of the International Com-
mission on Glass [27, 28].
Accordingly, a study protocol
was applied that follows the recom-
mendations for a so-called predic-
tive screening concerning delami-
nation. By using different analytical
techniques, a predictive study
should focus on the occurrence of
early indicators (precursors) of de-
lamination embedded in an evalua-
tion scale that allows a predictive
statement regarding the delamina-
tion propensity. In detail, we com-
bined SEM cross-section investiga-
tions to visualise the corrosion-in-
duced changes in the morphology
of the interior vial surface with ICP
analyses of the glass element con-
centration leached into the filling
solution and with stereo-micro-
scopic inspection of the emptied
vials under special illumination
conditions to observe indications
for glass attack on a larger scale.
Some more background information regarding the
principles of such a study design is given elsewhere
[25]. In addition, a visual inspection with respect to
particles and flakes of filled and stored vials was per-
formed.
Visual Inspection of stored Solutions for
presence/absence of Glass Lamellae
Results for the visual inspection by eye and video cam-
era for particulates and flake-like particles are shown in
table 3 for the 24-week storage time point for both ultra-
pure H2O and 15 % KCl solutions. No flake-like particles
nor visible particulates were found in any container by
eye. Sub-visible dimension particulates were found in all
vial types and all formulations by video camera evalua-
tion. Analysis of solutions held for 48 weeks also found
no flake-like particles by eye and a small percentage of
vials with visible particulate matter.
Visual inspection by itself cannot confirm yes/no if
an observed particle is a glass flake. This requires sub-
sequent filtration, isolation, and analysis by spectro-
scopic methods (primary SEM-EDS, secondary Raman
or FTIR) for a definitive determination. However, a
useful selection criterion when using a multifaceted
study design approach such as this study is the pre-
sence/absence of flake-like particles that sparkle or
twinkle intermittently during visual inspection due to
solution swirling and the particles moving in and out
of the light path. If particles are found that sparkle or
twinkle, then the vial that contains most of these par-
ticles, has its solution filtered through a porous mem-
nTable 3
Visual inspection results for 24 weeks of storage at 40 °C.
Filling Solution In-house method(*) USP <790> /
Ph. Eur. 2.9.20
Flakes camera Flakes eye Particles
Moulded Type I Vials
Ultrapure Water I (100 %) 0 (100 %) No
15 % KCl I (100 %) 0 (100 %) No
Moulded Type II Vials
Ultrapure Water I (100 %) 0 (100 %) No
15 % KCl I (100 %) 0 (100 %) No
Tubular Type I Vials
Ultrapure Water I (40 %)
0 (60 %) 0 (100%) No
15 % KCl I (60 %)
0 (40 %) 0 (100%) No
(*) Quantity of flakes: 0 = none, I = a few, II = a lot (#’s in parenthesis indicates the percentage
of containers with classification compared to a total number of vials evaluated). The camera
system can detect smaller flakes compared to the inspection by eye, approximately ≥30 mi-
crons.
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brane and subsequently, the captured particles are
analysed to determine their elemental composition/
functional group composition. Spectroscopic analysis
is key to determining yes/no glass lamellae and if not
glass lamellae, then assignment to another particle fa-
mily type. Not all vials in a sample set at a given time
point will exhibit glass flakes [28, 29]. An example of a
reference vial with numerous flake-like particles is
shown in fig. 1. None of the particles observed in this
study at any time point appeared to sparkle or twinkle
or had a flake-like appearance, thus no filtration and
particle analysis were conducted.
Stereomicroscopic inspection of emptied vials
for qualitative assessment
Results for the illuminated stereomicroscopic inspection
for the appearance of light scattering and/or interfer-
ence bands (i.e. colouration) for the heel region of con-
tainers stored for 24 weeks at 40 °C with ultrapure H2O
and 15 % KCL solutions are shown in fig. 2 and fig. 3.
The general trend for light scattering was Type I
moulded < Type II moulded < Type I tubular as can be
seen exemplary for 24 weeks storage in table 4. For inter-
ference bands, Type I moulded, and Type I tubular vials
did not exhibit any colouration while the Type II
moulded exhibited strong colouration.
Stereomicroscopic inspection (and its related method
differential interference contrast imaging) [26] in the
heel region of the vial interior surface by itself cannot
confirm glass delamination as its low magnification
(typically 1–150x) and 2-dimensional view (i.e. x and
y vectors) lack the resolving capability necessary to dis-
tinguish between a thin layer detaching from the surface
and generation of reaction zones with a depth down into
the near-surface region (i.e. z vector). This requires sub-
sequent sample preparation for cross-section analysis at
higher magnification (5,000–100,000x) using SEM. How-
ever, a useful selection criterion is the presence/absence
and severity of light scattering and especially coloura-
tion/interference bands. In this manner, containers from
different sample sets can be evaluated quantitatively for
ranking the containers from most to least colouration as
explained in the following section (primarily) or light
scattering and the “worst” containers selected for
nTable 4
Summary of the results of optical inspection after 24 weeks at 40 °C by stereomicroscope.
Results Stereo-
microscopy
Moulded Type I Moulded Type II Tubular Type I
KCl Solution Ultrapure Water KCl Solution Ultrapure Water KCl Solution Ultrapure Water
Scattering YES
up to weak
YES
up to weak
YES
up to strong
YES
weak
YES
strong
YES
strong
Colouration NO NO YES
up to strong NO NO NO
nTable 5
Summary of the characteristic features after 24 weeks at 40 °C storage found by SEM analyses.
SEM Features Moulded Type I Moulded Type II Tubular Type I
KCl Solution Water KCl Solution Water KCl Solution Water
Delaminated Areas NO NO NO NO NO NO
Reaction Zones
YES
up to
~60 nm
NO
YES
up to
~390 nm
NO NO NO
Micro-Roughness YES NO YES NO YES NO
Figure 1: Reference vial with flake-like particles
exhibiting sparkling/twinkling.
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further assessment of the interior surface by SEM cross-
section analysis.
While there is no direct correlation between results
from the stereomicroscopic inspection and yes/no glass
delamination, the extent/severity of colouration and
light scattering indicates the degree of changed surface
morphology. Light scattering can be observed for sev-
eral reasons including particulates present on the sur-
face, drying stains, glass manufacturing artefacts (i.e.
shallow bumps, shallow pits), and micro-roughness.
The observation of strong interference bands/coloura-
tion normally appears with a surface near the region
that has been significantly corroded exhibiting reaction
zones (i.e. a thin surface layer with an altered, often
more porous morphology) or delaminated areas. These
interference bands appear under grazing illumination
with intensive light due to a difference in the index of
refraction between these reaction zones and the bulk
glass. The presence of colouration is a good indicator
for reaction zones, the depth and (in)homogeneity of
which has to be confirmed via SEM cross-section anal-
ysis The classification is performed by using reference
samples with increasing intensity to the eye for the
training of the operators and comparison to the sam-
ples being investigated.
SEM cross-section quantitative analysis of vial
interior surface
Results for the SEM cross-section inspection for the con-
firmation of the extent of glass surface attack for con-
tainers stored for 24 weeks at 40 °C with ultrapure water
and 15 % KCl solutions are shown in table 5. For vials
stored with ultrapure water, no surface feature that indi-
cated even glass attack was observed for all 3 vial types,
confirming no glass delamination is occurring and no
early indicators were found at this storage interval.
Figure 2: Representative stereomicroscope pictures of the heel area of empty vials previously filled with ultrapure H2O after 0, 24, and 48 weeks of
storage. (Note: the 2 white dots come from the fibre optic light guides used to illuminate the samples).
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Further storage out to 48 weeks at 40 °C gave similar re-
sults.
Some shallow pits were observed on the tubular
Type I interior surface (see fig. 4) as a by-product result
of the vial converting and washing process. These shal-
low pits with lateral dimensions up to 1–2 µm were gen-
erated by the interaction of mainly sodium borate-rich
condensates with the glass surface. The shallow pits
confirm the observed light scattering found by stereomi-
croscope in the tubular vials.
The general trend for increasing level of glass corro-
sion found for vials stored with 15 % KCl solution at
40 °C for 24 weeks was Type I tubular < Type I
moulded < Type II moulded. The surface features rele-
vant for indicating the extent of glass corrosion found as
shown in fig. 4 ranged from micro-roughness (Type I
tubular) to micro-roughness and reaction zones up to
60 nm (Type I moulded) to micro-roughness and reac-
tion zones up to 390 nm (moulded Type II). The ob-
served reaction zones were homogenous in appearance
(no distinct layers/interfaces within the reaction zones,
no cracking or peeling observed), varying only in-depth.
The observed features confirm significant glass corro-
sion is occurring for the moulded glass vial types, with
reaction zones being classified as an early indicator. The
major significant result of further storage out to
48 weeks at 40 °C was the significant increase in reaction
zone thicknesses of up to approximately 1 000 nm for
the moulded Type II vials ( fig. 5). The observed reaction
zones covered more or less the entire interior surface,
but in some smaller areas no reaction zone was present
indicating non-homogeneities in the corrosion behav-
iour. Such layers with altered composition and morphol-
ogy can detach under thermal or mechanical load and
generate flakes with glass-like composition.
Assessing the extent of glass attack on the interior
vial surface by SEM cross-section, while confirming indi-
cations/precursors for delamination, requires investiga-
Figure 3: Representative stereomicroscope pictures of the heel area of empty vials previously filled with 15 % KCl after 0, 24, and 48 weeks of storage.
(Note: the 2 white dots come from the fibre optic light guides used to illuminate the samples).
Pharm. Ind. 84, Nr. 8, 1001–1012 (2022)
© ECV •Editio Cantor Verlag, Aulendorf (Germany) Haines et al. •Glass Delamination 1007

tions minimally at the heel region
and mid-body locations. During the
converting process, the heel region
of a tubular vial is exposed to strong
heating while the mid-body region
is the region least affected by the
vial manufacturing processes. Thus,
observation of glass attack (i.e. mi-
cro-roughness), early indicators (i.e.
reaction zones), or delamination
(i.e. delaminated areas, flakes sitting
on the surface, reaction zones peel-
ing off) usually starts in the wall
near the bottom region of a tubular
glass container. For moulded glass
containers features found in one lo-
cation only implicate a hot spot (i.e.
thinning or wear out of the mould
used to produce the vial) while fea-
tures found in multiple locations
implicate the glass composition in
general.
Reaction zones consist of materi-
al of slightly different chemical com-
positions caused by the interaction
of the filling formulation solution
with the near-surface region. These
are different in appearance, thick-
ness, and mechanical and chemical
durability than compound layers
formed in phosphate buffer-based
formulation solutions previously re-
ported [19, 20, 23].
Drug formulation container in-
teractions [30] can either be differ-
ently pronounced per “glass” ele-
Figure 4: Representative heel and mid-body region SEM cross-section micrographs of empty vials
previously filled with 15 % KCl after 24 weeks of storage at 40 °C.
Figure 5: Heel region SEM cross-section micrographs of empty moulded Type II vial previously filled with 15 % KCl after 48 weeks of storage at 40 °C.
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1008 Haines et al. •Glass Delamination
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© ECV •Editio Cantor Verlag, Aulendorf (Germany)

ment (i.e. ion leaching as an inhomogeneous mechanism
of chemical interaction) or homogenous dissolution. For
ion leaching attack, the glass near the surface region is
attacked by the filling solution exchanging positively
charged species (i.e. H+/H3O+) with the alkali (Na+, K+)
and alkaline earth (Mg++, Ca++) glass ions. Replacement
of the larger alkali and alkaline earth metals with the
smaller diameter hydronium ion through the diffusion
of the filling solution into the glass matrix leads to a
more porous layer, which then further invites additional
diffusion-controlled attack. Whether or not the formed
reaction layers generate glass lamellae/flakes depends
on the chemical nature of the filling solution (i.e. buf-
fered or unbuffered solution, pH, presence/absence of
excipients, salt concentration, chelation ability, etc.) for
the attack of the glass backbone (i.e. Si-O-Si bonds) and/
or processing/storage conditions/delivery conditions
(terminal sterilisation yes/no, freeze/thaw processes)
that generate chemical attack or/and mechanical load-
ing forces on the reaction zones.
ICP-OES quantitative analysis of glass leaching
into filling solution
The ICP-OES results of the concentrations of glass ele-
ments in the filling solution for the confirmation of the
chemical attack mechanism for containers stored for
24 weeks at 40 °C with ultrapure water are shown in
table 6 (Note: Limits of quantification are shown in
table 2). Glass element concentrations were on a low
amount of ≤1.7 µg/ml for Si and <0.5 µg/ml for B, Na, Ca,
Al, Ba, and K. Further storage out to 48 weeks at 40 °C
resulted in glass element amounts of ≤2.0 µg/ml for Si
and <0.6 µg/ml for B, Na, Ca, Al, Ba, and K. The concen-
trations were quite low and similar for all 3 vial types,
with very minor differences. This level of glass element
concentrations indicates only a small interaction (i.e. at-
tack) of the filling solution with the glass surface, in
agreement with the SEM cross-section analyses.
The ICP-OES results of the concentrations found in
containers stored for 24 weeks at 40 °C with 15 % KCl are
shown in table 7. Glass element concentrations were in a
much higher range for Type II of around ≤67 µg/ml for
Si, around ≤22 µg/ml for Na, around ≤19 µg/ml for Ca
and ≤0.5 µg/ml for B, Al, Ba, and K. The amounts found
for moulded Type II exceeded significantly the values for
the moulded Type I and tubular Type I borosilicate.
Further storage out to 48 weeks at 40 °C resulted in
roughly doubled concentrations for Si, Na, and Ca found
for the Type II moulded glass. This level of glass leaching
for the Type II moulded glass indicates a significant in-
nTable 6
Concentration of leached glass elements in µg/ml after 24 weeks of storage at 40 °C with ultrapure
water.
Vial Na
[µg/mL]
Si
[µg/mL]
B
[µg/mL]
Al
[µg/mL]
K
[µg/mL]
Ca
[µg/mL]
Ba
[µg/mL]
Type I Borosilicate Moulded 0.18
±30 %
1.2
±15 %
0.09
±20 % <0.05 <0.10 0.05
±15 % <0.05
Type II Soda Lime Moulded 0.21
±30 %
0.53
±20 % <0.05 <0.05 <0.10 <0.05 <0.05
Type I Borosilicate Tubular 0.44
±30 %
1.7
±15 %
0.2
±20 % <0.05 <0.10 0.08
±15 % <0.05
nTable 7
Concentration of leached glass elements in µg/mL after 24 weeks of storage at 40 °C with 15 wt% KCl
solution.
Vial Na
[µg/ml]
Si
[µg/ml]
B
[µg/ml]
Al
[µg/ml]
K
[µg/ml]
Ca
[µg/ml]
Ba
[µg/ml]
Type I Borosilicate Moulded 2.1
±30 %
1.5
±20% <0.5 <0.5 NM (*) <0.5 <0.5
Type II Soda Lime Moulded 22
±30 %
67
±15 % <0.5 <0.5 NM (*) 19
±15% <0.5
Type I Borosilicate Tubular 2.1
±30 %
1.0
±20 % <0.5 <0.5 NM (*) <0.5 <0.5
(*) NM = Not measured. The relative measurement uncertainties were calculated using k = 2.
Pharm. Ind. 84, Nr. 8, 1001–1012 (2022)
© ECV •Editio Cantor Verlag, Aulendorf (Germany) Haines et al. •Glass Delamination 1009

teraction of the filling solution with the glass surface
and is consistent with the deep reaction zones observed
in the SEM cross-sections. The low level of glass leaching
for the tubular borosilicate vial is similar to that found
in a similar study under the same conditions with a
2R vial size format [30].
pH quantitative analysis
Results for the pH change of the filling solutions after
autoclaving (0 weeks) to 24 and 48 weeks storage at
40 °C are shown in table 8. For ultrapure water, the pH
shift behaviour of the moulded Type I and tubular Type I
borosilicate were in a similar range, increasing by around
0.6–0.7 pH over the 48-week storage period, while the
moulded Type II soda lime exhibited a larger shift of
around 1.1 pH units. For 15 % KCl solution the pH shifts
were different for each vial type, with the tubular Type I
borosilicate having the lowest pH shift (around 0.2), the
moulded Type I borosilicate having a moderate pH shift
(around 0.8), and the moulded Type II soda lime having a
massive pH shift (around 5.0). These pH shifts are consis-
tent with the SEM cross-section and ICP-OES results
showing the varying extent of the attack on the glass sur-
face and near-surface regions. Dissolution (i.e. Si-O-
Si backbone) or leaching (e.g. of alkaline ions) takes place
simultaneously or preferentially over the storage period,
depending on the pH and ionic strength of the solution
and local pH at the surface. Assessment of the pH, the to-
tal amount of soluble glass elements, and the ratios of the
glass elements involved are crucial to determining which
chemical attack mechanism is predominant at a given
time point (i.e. preferential or homogeneous dissolution).
Combined results
Putting together the results from the various analyses
conducted within this study (visual inspection, glass sur-
face inspection, concentration of glass elements, solu-
tion pH change) gives a clear picture of the extent and
root causes of glass attack behaviour exhibited by the
3 different vial types interacting with 2 different formu-
lation types. This study demonstrated for the filling solu-
tion ultrapure water that all 3 vial types do not feature
glass delamination nor early indicators or glass attack
throughout the study. Visual inspection of the filled vials
did not find any flake-like particles. Stereomicroscopy
and SEM cross-section analyses revealed only glass
manufacturing by-product shallow pits, and some de-
posits of sub-visible particles. A very modest amount of
glass elements was found in the solution by ICP-OES
measurements. This observation corresponds to the low
increase of the pH value even after 48 weeks at 40 °C.
The pH increase observed is consistent with an ion-
exchange mechanism of H3O+from the solution repla-
cing alkali and alkaline earth ions on the glass surface
and in the near-surface region. Unwanted pH increases
may be combatted in several ways: Using glass contain-
ers with a higher starting hydrolytic resistance (i.e. lower
value in comparison to the given limits according to
USP <660>/Ph. Eur. 3.2.1 glass surface tests), treatment
after vial production before vial annealing with ammo-
nium sulfate, good vial cleaning procedures to ensure
surface available alkali and alkaline earth metals are re-
moved, and use of a barrier coating container made of
silicon dioxide (e.g.‘SCHOTT Type I plus®’).
On the other hand, the results have proven for the fill-
ing solution 15 % KCl that all 3 vial types behave differ-
ently in terms of the extent of glass corrosion. Visual in-
spection of the 15 % KCl-filled vials did not find any flake-
like particles. Stereomicroscopy found weak light scatter-
ing for the moulded Type I borosilicate vials, but strong
light scattering for the moulded Type II and tubular Type I
borosilicate vial types. For the tubular vials, the strong
scattering can be correlated to the shallow pits found at
the interior surface by SEM analyses, therefore it is not an
nTable 8
Summary of the results of the pH-measurements change from 0 to 48 weeks storage at 40 °C.
Filling Solution pH-value change from 0W (24W pH value) pH-value change from 0W (48W pH value)
Moulded Type I Borosilicate
01: Ultrapure water 0.1 (6.0 ± 0.3) 0.7 (6.6 ± 0.3)
05: KCl 15 % 0.3 (5.2 ± 0.3) 0.8 (5.7 ± 0.3)
Moulded Type II Soda lime glass
01: Ultrapure water 0.4 (6.1 ± 0.3) 1.1 (6.8 ± 0.3)
05: KCl 15 % 4.8 (9.7 ± 0.3) 5.0 (9.8 ± 0.3)
Tubular Type I Borosilicate
01: Ultrapure water 0.4 (6.8 ± 0.3) 0.6 (7.0 ± 0.3)
05: KCl 15 % 0.2 (5.4 ± 0.3) 0.2 (5.4 ± 0.3)
The relative measurement uncertainties were calculated using k = 2.
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1010 Haines et al. •Glass Delamination
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© ECV •Editio Cantor Verlag, Aulendorf (Germany)

indication of glass corrosion in contrast to the moulded
Type II vials. Strong colouration was only observed for the
moulded Type II vials over the entire filled surface area.
SEM cross-section analyses found none (tubular Type I
borosilicate), small up to 60 nm (moulded Type I borosili-
cate), and large reaction zones ranging from about 300 to
1300 nm (moulded Type II). All vial types exhibited micro-
roughness and particulate deposits throughout the study.
The tubular Type I borosilicate vials further exhibited
shallow pits, a by-product result of the glass manufactur-
ing process. Much higher concentrations of glass elements
were found in solution by ICP-OES for the moulded
Type II vials compared to the tubular and moulded Type I
borosilicate vials. As depicted in fig. 6 pronounced differ-
ences in the pH increases after storage for 48 weeks of 0.2
(tubular Type I borosilicate), 0.8 (moulded Type I borosili-
cate), and 5.0 (moulded Type II) are found. This very illus-
trative demonstrates the high chemical resistance of the
tubular borosilicate glass versus salty solutions especially
compared to the Type II soda lime glass.
While none of the 3 vial types exhibited glass delami-
nation with the 15 % KCl filling solution, both of the
moulded borosilicate vials exhibited the second critical
stage of glass corrosion having early indicators features
as reaction zones (both) and high concentrations of
“glass” elements (only Type II). Of the 2 moulded vials
the Type II vial was the most attacked, having signifi-
cantly thicker reaction zones, higher levels of leachable
glass elements, and strong colouration. This is reason-
able based on the reduced chemical durability of soda
lime glass compositions and their known increased dis-
solution and surface cracking while in contact with KCl
containing aqueous solutions [31] most probably pro-
moted by easier access to water and in particular with
increasing pH of OH-groups to the silica network. The
tubular Type I borosilicate vial was the least corroded of
the 3, featuring only micro-roughness as an indication of
glass attack. The pronounced thickness of the reaction
zone together with the porous morphology ( fig. 5) ob-
served for the Type II vials confirm the preferred dissolu-
tion/leaching of the weaklier bound alkaline and earth
alkaline ions, which caused the strong pH-value increase
of the KCl solution and as a consequence, a further ac-
celerated dissolution of the SiO2network from nucleo-
philic attack by OH-groups. For the moulded and tubu-
lar borosilicate vials, the very low amount of glass ele-
ments in the solution indicates an early stage of glass
corrosion ( far away from glass delamination).
While the results of this study are specific to the vials
and filling solutions and storage conditions used, the
study protocol and testing methodology are appropriate
to assess any drug formulation and glass container for de-
termining the extent of glass corrosion and delamination
propensity. In addition and not surprisingly, the results
demonstrated impressively that the chemical durability
of the container is not a material constant but strongly
dependent on the properties of the drug filling even for
such simple systems like water and KCl solution and sup-
ports the results gathered for other drug-container com-
binations [23, 30, 32, 33]. We strongly caution that testing
Figure 6: Difference in pH measurements for between 0 weeks and 48 weeks storage at 40 °C for vials filled with water (blue) and 15 % KCl (orange).
Pharm. Ind. 84, Nr. 8, 1001–1012 (2022)
© ECV •Editio Cantor Verlag, Aulendorf (Germany) Haines et al. •Glass Delamination 1011

using “aggressive” solutions with no reasonable link to the
intended application is not appropriate as a substitute for
testing the real drug formulations (with or without API in
case of API expensiveness or instability). Aggressive solu-
tion testing is useful primarily as a control to ensure that
the testing methods being used can distinguish between
different levels of glass corrosion. Thus, for the ‘purpose
of the glass screening to determine the suitability of a giv-
en glass container for a specific product’ [26], a different
screening strategy is required also including ‘a higher
number of vials’ following recommendations of USP
<1660> and as described in this article and our previous
publication, respectively [25].
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1012 Haines et al. •Glass Delamination
Pharm. Ind. 84, Nr. 8, 1001–1012 (2022)
© ECV •Editio Cantor Verlag, Aulendorf (Germany)