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PACKAGING

Syringe Siliconisation
Trends, Methods, Analysis Procedures

Summary mechanical forces when the stoppers of silicone oil droplets increases in line
Ready-to-fill, i.e. sterile, prefillable glass are inserted. Siliconisation is therefore with the quantity of silicone oil used.
syringes, are washed, siliconised, essential to process capability. Droplets which are visible to the naked
sterilised and packaged by the primary Although syringes and cartridges are eye could be viewed as a cosmetic
packaging manufacturer. They can always siliconised, this applies to a defect. At sub-visual level, the issue
then be filled by the pharmaceutical lesser extent to vials and ampoules. of whether silicone oil particles could
companies without any further On the container the siliconisation induce protein aggregation is currently
processing. These days the majority of provides a barrier coating between under discussion4.
prefillable syringes are made of glass the glass and drug formulation. It also In light of this development, there
and the trend looks set to continue. prevents the adsorption of formulation is an obvious trend towards optimised
The siliconisation of the syringe barrel components on the glass surface. or alternative coating techniques.
is an extremely important aspect of The hydrophobic deactivation of the Attempts are being made to achieve
the production of sterile, prefillable surface also improves the containers’ the most uniform possible coating with
glass syringes because the functional drainability. In prefillable syringes a reduced quantity of silicone oil and
interaction of the glass barrel and cartridges, siliconisation also to minimise the amount of free silicone
siliconisation and the plunger stopper performs another function. It lubricates oil by way of baked-on siliconisation.
siliconisation is crucial to the efficiency the syringe barrel or cartridge body, In this context, reliable analysis
of the entire system. Both inadequate enabling the plunger to glide through technologies that can be used to make
and excessive siliconisation can cause it. Siliconisation of the plunger stopper qualitative and quantitative checks on
problems in this connection. The use alone would not provide adequate the coating are absolutely essential.
of modern technology can achieve lubrication. Alternative coating techniques are also
an extremely uniform distribution Silicone oils are ideal as a being developed.
of silicone oil in glass syringes with lubricant because they are largely
reduced quantities of silicone oil. inert, hydrophobic and viscoelastic. Silicone Oils and their Properties
Another option for minimising the Chemical and physical requirements Silicone oils have been used for half a
amount of free silicone oil in a syringe for lubricants are set out in the relevant century in numerous pharmaceutical
is the thermal fixation of the silicone monographs of the American (United applications. For example, they are
oil on the glass surface in a process States Pharmacopoeia, USP) and used as lubricants in pharmaceutics
called baked-on siliconisation. Plastic- European (Pharmacopoeia Europaea, production and as inert pharmaceutical
based silicone oil-free or low-silicone Phar. Eur) pharmacopoeia1,2. Section base materials (e.g. soft capsule
oil prefillable syringe systems are a 3.1.8 of Phar. Eur. also defines a walls)5. Trimethylsiloxy end-blocked
relatively new development. Silicone kinematic viscosity of between 1000 polydimethylsiloxane (PDMS, dimeth-
oil-free lubricant coatings for syringes and 30,000 mm2/s for silicone oils icone) in various viscosities is generally
are also currently in the development used as lubricants3. By contrast, the used for siliconisation (Fig. 1).
phase. monograph for polydimethylsiloxane Figure 1. Polydimethylsiloxane
(PDMS) in the USP2 permits the use
Introduction of silicone oils with a viscosity of
Primary packaging for injectables 20 to 30,000 centistokes. However,
almost exclusively comprises a glass increasingly stringent quality
container (cartridge, syringe, vial) and requirements and new bioengineered
an elastomer closure. Ampoules are drugs are now taking siliconisation The most frequently used silicone
an exception. technology to its limits. Non- oil for the siliconisation of primary
Elastomers are by nature slightly homogenous siliconisation, which packaging components is DOW
sticky, so all elastomer closures can occur when simple coating CORNING® 360 Medical Fluid, which
(plunger stoppers for syringes and techniques are used on longer syringe has a viscosity of 1000 cSt. PDMS
cartridges, serum or lyophilisation barrels can, in some cases, lead to is produced by reducing quartz
stoppers) are siliconised. Siliconisation mechanical problems. These include sand to silicone metal. In the next
prevents the rubber closures from the incomplete drainage of the syringe step, the silicone reacts directly with
sticking together and simplifies in an auto-injector or high gliding methyl chloride in a process called
processing of the articles on the forces. Silicone oil droplets are always Müller-Rochow synthesis to create
filling lines. For example, it minimises observed in filled syringes. The number methyl chlorosilanes. In this process,

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a mixture of different silanes is reactions with glass, metals, plastics The obvious solution is to increase
produced, the majority of which (75% - or human tissues are minimal. The the amount of silicone oil used to
90%) are dimethyldichlorosilane (CH3)2 CH3 groups make PDMS extremely achieve a homogenous coating.
SiCl2. After distillative separation, the hydrophobic. It is insoluble in water, However, as already mentioned,
dimethyldichlorosilane is converted but soluble in non-polar solvents6. increasing the amount of silicone oil
by hydrolysis or methanolysis into used is also associated with higher
silanols which condense into low- Siliconised Syringes quantities of silicone particles in the
molecular-weight chains and cycles. As already explained, the syringe system solution. With protein-based drugs, in
In an acidic (cationic) or alkaline only works if the glass barrel and plunger particular, undesirable interactions with
(anionic) catalysed polymerisation, stopper siliconisation are homogenous silicone oil particles cannot be ruled
polydimethylsiloxanes with hydroxy and optimally harmonised. For needle out. Sub-visual silicone oil particles
functions are generated. After the syringes, siliconisation of the needle is are thought to promote protein
addition of trimethylchlorosilane they also essential to prevent it sticking to the aggregation which can increase the
are furnished with trimethylsiloxy end skin, thereby minimising injection pain. severity of immune responses and
groups. The short chain molecules For the so-called oily siliconisation of the reduce the drug’s tolerability. However,
are removed from the resulting syringe glass barrel DOW CORNING® the underlying mechanism is not yet
polydisperse polymers by way of 360 with a viscosity of 1000 cSt is used. fully understood. There is a discussion
vaporisation, leaving deployable The DOW CORNING® 365 siliconisation as to whether protein aggregation is
PDMS. emulsion is often used in the baked- influenced by additional motion, e.g.
The characteristic aspect of the on siliconisation process. The needle shaking the syringe7. Experiments
PDMS molecule is the Si-O bond. With is siliconised using a wipe technique have also shown that when silicone oil
a bond energy of 108 kcal/ during ready-to-fill processing. DOW in excess of 1mg/syringe is used the
mol, it is considerably more stable CORNING® 360 with a viscosity of additional silicone oil does not further
than the C-O bond (83 kcal/mol) or 12,500 cSt is used. Another option is reduce gliding forces.
the C-C bond (85 kcal/mol). PDMS is the thermal fixation of silicone oil on The interior siliconisation of glass
accordingly less sensitive to thermal the needle during the needle mounting syringe barrels has another advantage.
loads, UV radiation or oxidation process. It prevents the drug solution from
agents. Reactions such as oxidation, The goal of syringe barrel interacting with the glass surface and
polymerisation or depolymerisation do siliconisation is to obtain the most even rules out related problems such as
not occur until temperatures exceed anti-friction coating possible along the the loss of active ingredients through
130°C. The molecule also typically entire length of the syringe in order to adsorption or pH value changes due
has a flat bond angle (Si-O-Si 130 °C) minimise break loose and gliding forces to alkali leaching. Prefillable glass
which has low rotation energy and is when the plunger stopper is deployed syringes are only manufactured from
especially flexible (Fig. 2). A high bond (Fig. 3). high-quality type 1 borosilicate glass.
However, sodium ions can still leach
Figure 2. Visual image of polydimethylsiloxane Figure 3. Sample force profile of out of the glass surface if the syringe
a prefillable syringe.
contains an aqueous solution and
is stored for a long period of time.
This leads to higher pH values which
could be problematic in unbuffered
systems. Acidic environments foster
this process.

Inadequate siliconisation of the Si-O-Na + H20 – SiOH + NaOH


syringe barrel, particularly the existence
length (1.63Å Si-O as compared to of unsiliconised areas, can cause slip- In alkaline environments, on the other
1.43Å for C-O) makes the molecule stick effects that impair the syringe’s hand, an etching process is observed.
comparatively gas-permeable6. function. The forces in the injection
The spiral-shaped (and therefore process can then be too high or the 2NaOH + (SiO2)X – Na2SiO3 + H2O
easily compressible) molecule is entire system can fail. Since inadequate
surrounded by CH3 groups which siliconisation and gaps in the coating Aqueous solutions with a high pH value
are responsible for the chemical and are often found on the lower end of cannot therefore be stored for long
mechanical properties of PDMS. the syringe (luer tip/needle end), it is periods of time in borosilicate glass
The molecule’s methyl groups only possible that the syringe will not be containers. They have to be lyophilised
interact to a very limited extent. This completely emptied. Such defects can and reconstituted before use.
ensures low viscosity, even with high remain undiscovered, particularly in In extreme cases, the etching of the
molecular weights, which simplifies auto-injectors since these are closed glass surface can cause delamination.
the distribution of PDMS on surfaces systems. The result could be that an Hydrophobic deactivation of the
and makes it a very effective lubricant. inadequate dosage of the medication is container by siliconisation effectively
PDMS is also largely inert, and administered. protects the glass surface.

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Optimized Siliconisation closely bundled gliding forces in the Baked-on Siliconisation
For the above-mentioned reasons, force path diagram (Fig. 4). Another key advancement in
the main objective in siliconisation Studies on 1ml long syringes have siliconisation technology is the
is to achieve the most homogenous revealed considerable potential for baked-on siliconisation technology. It
possible coating with the minimum reducing the amount of silicone oil involves the application of silicone oil
possible quantity of silicone oil. Initially required. In the experiment, the quantity as an emulsion which is then baked
it is necessary to establish the minimum of silicone oil per syringe could be on to the glass surface in a special
quantity of silicone oil which will reliably reduced by 40% without any impairment kiln at a specific temperature and for
satisfy the quality requirements of the of the system’s functional properties a specific length of time.
application. In the production of ready- (Fig. 5). In practice, the calculation of In the baked-on process, both
to-fill syringes, siliconisation generally the optimum quantity of silicone oil hydrogen and covalent bonds form
takes place after washing and drying. has to take syringe volume, plunger between the glass surface and the
Fixed nozzles positioned at finger stopper type (coated/uncoated), polydimethylsiloxane chains. The
flange level under the syringe barrel plunger stopper placement method bonds are so strong that part of the
spray the silicone oil onto the inside (seating tube/vacuum) and application silicone oil cannot be removed with
surface. In long syringes, the silicone requirements (injection systems) solvent and a permanent hydrophobic
oil is sometimes unevenly distributed into account. Plunger stoppers from layer is created (Fig. 6). In addition the
and the concentration of the silicone different suppliers not only differ in average molecule weight increases
oil is lower at one end of the syringe terms of the type of rubber used and as a result of polymerisation and the
(luer tip/needle end). The use of diving their design, they are also coated with vaporisation of short chain polymers.
nozzles can considerably improve the silicone oils of different viscosities. The resulting, extremely thin, layer
evenness of the coating across the The siliconisation methods also differ of silicone in conjunction with the
entire length of the syringe body. In considerably. These variables can have low quantity of silicone oil used in
this process, the nozzles are inserted a bigger impact on the syringe system’s the emulsion minimises free silicone
into the syringe to apply the silicone oil functional properties than the syringe in the syringe and ensures that the
(finely atomised) in motion. The result siliconisation of different suppliers, as required quality of finish is achieved.
is practically linear as is shown by the shown by Eu et al.1. The layer thickness measures 1 5
Figure 4. Comparison of force profiles diving nozzle vs. fixed nozzle -50 nm. By comparison, the average
layer thickness with oily siliconisation
is 500-1000 nm.
Baked-on siliconisation reduces
the measurable quantity of free
silicone oil to approx. 10 % of the
normal value. As a result, there are
fewer sub-visual and visual silicone
oil particles in the solution. This
siliconisation process is therefore
recommended for use with sensitive
protein formulations. It is also
advantageous for ophthalmological
preparations which are associated
with very stringent requirements as
regards particle contamination.
Another benefit is the stability of
Figure 5. Force profile after optimised siliconisation the mechanical properties of the
filled syringe throughout its shelf-life.
The ribs of a plunger stopper press
into the silicone layer when a syringe
with oily siliconisation is stored for
long periods of time and the glass
comes into direct contact with the
rubber. Since elastomers are always
slightly sticky, the break loose forces
increase over the storage period. With
baked-on siliconisation, however, this
phenomenon is not observed to the
same extent (Fig. 7). The break loose
force remains practically constant
over the entire storage period.

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Figure 6. Baked-on siliconisation an indirect method of determining
the evenness of the siliconisation
(Fig. 9). This process is also destructive
and associated with problems. For
example, the results are influenced by
the positioning of the plunger stopper
and there is no standard for extrusion
speed. A value of 100 mm/min is often
taken for empty syringe systems; and
Figure 9. Glide force measurement

Figure 7.Comparison of syringes with oily and baked-on siliconisation

Figure 8. Glass dust test: left - syringe


siliconised with a diving nozzle; right -
Analysis Methods syringe siliconised with a fixed nozzle
The optimisation of the siliconisation
process necessitates reliable
qualitative and quantitative analysis
methods. Online methods for the
one hundred per cent control of
siliconisation during production are not
currently available. In process control,
random samples are taken and several
destructive and non-destructive
methods are used.
In the glass dust test, the up to 380 mm/min. for filled systems.
siliconisation is made visible by Relatively fast quantitative and non-
dusting it with finest glass particles destructive results can be obtained
(Fig. 8). This destructive method with reflexometry. For example, the
is simple but time-consuming. It is Layer Explorer UT (Fig. 10) which
also associated with the problems is manufactured by rapID scans
that the quality of the siliconisation is the syringe body line-by-line. It can
subjectively evaluated and the results measure layer thicknesses of 15 nm to
are affected by temperature and air several thousand nm with a precision
humidity. of 5 nm (Fig. 10.1). Scanning a 40 mm
Measuring the gliding force is syringe with the Layer Explorer takes

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Figure 10.Silicone layer thickness measurement with the Layer Explorer RapID (own data) approximately one minute.
Another non-destructive technique
such as the one developed by Zebra
Science (Fig. 11) is based on digital
image processing. The entire inside
surface of the syringe barrel is imaged
to visualise typical siliconisation
surface structures. The technology
captures these visual cues as a direct
indication of silicone oil presence and
poorly siliconised areas (Fig. 11.1).
It delivers fast qualitative results
and is suitable for empty and filled
syringes. However, empty syringes
should be measured immediately after
siliconisation because even just half an
hour after siliconisation the distribution
of the silicone provides a completely
different picture, and it takes a very
experienced person to interpret the
results properly.
Unfortunately, this method is also
not fast enough to facilitate 100 %
online control during the washing and
siliconisation process.
Figure 10.1. Silicone layer thickness measurement with the Layer Explorer
Outlook
There is a trend towards reduced-
silicone systems or baked-on
siliconisation in glass syringe finishing.
Improved analysis techniques
and a better understanding of
the phenomena involved support
optimised use of silicone oil.
New issues are arising as a result
of the use of innovative materials or
coatings. In light of the increasing
complexity of devices and the
more widespread incidence of
biopharmaceuticals with specific
requirements, new alternative materials
for primary packaging products are
becoming increasingly interesting. For
example, the inside surfaces of vials
and syringes can be coated with pure
SiO2 in a plasma process to minimise
Figure 11. ZebraScience visualisation of siliconisation (own data) their interaction with drugs. Plastic

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systems based on cyclic olefins (COP/ Pharmacopeial Convention Inc,


COC) are also gaining in significance Rockville, USA, 2011
Ms. Petersen
for prefilled syringes and vials. COP 2. Pharmacopoea Europaea. 7th edition.
studied from
syringes such as the ClearJect Dimeticon, Deutscher Apotheker
1990 to 1996
TasPack™ by Taisei Kako Co. Ltd have Verlag, Stuttgart, Germany, 2011,
bioprocess
glass-like transparency. Additionally, p.2788 engineering at
they have a higher break resistance, 3. Pharmacopoea Europaea. 7th edition. the Technical
their pH stability range is larger and 3.1.8 Silicon oil for use as a lubricant, University of
there is no metal ion leaching. Excellent Deutscher Apotheker Verlag, Stuttgart, Berlin. After two years post-graduate
dosage precision is also very important Germany, 2011, p.486 work in the field of oncology research
in packaging for bio-pharmaceuticals. 4. Jones LS, Kaufmann A, Middaugh CR. she joined in 1998 company Life
In most cases siliconisation is also Silicone oil induced aggregation of Sciences Meissner & Wurst working
essential in COP syringes. proteins. J Pharm Sci 2005; 94(4):918- finally as a lead validation engineer
Silicone oil-free systems are a brand 927 mainly on projects for biopharma
new approach. The gliding properties 5. Colas A, Siang J, Ulman K. Silicone customers. From 2000 – 2007 she
of the fluoropolymer coating on in Pharmaceutical Applications Part held different positions at West
specially developed plunger stoppers 2: Silicone Excipients. Dow Corning Pharmaceutical Services (a leading
eliminate the need to siliconise plastic Corporation, Midland, USA, 2001 supplier of elastomer components
syringes. There are as many innovative 6. Colas A. Silicone in Pharmaceutical for the pharmaceutical industry)
ideas for the development of primary Applications. Dow Corning European Technical Support and
Marketing department finally as
packaging products as there are Corporation, Midland, USA, 2001
Senior Manager Biotechnology. Since
innovative drugs and syringe systems. 7. Thirumangalathu R, Krishnan S, Speed
Dec 2007 she is working as Director
Ricci M, Brems DN, Randolph TW,
Business Development for the Tubular
Reprinted with the permission by ECV· Carpenter JF. Silicone Oil and agitation-
Glass Devision at Gerresheimer
Editio Cantor Verlag für Medizin und induced aggregation of a monoclonal Bünde. Ms. Petersen is a member of
Naturwissenschaften GmbH. Originally antibody in aqueous suspension. J pharmaceutical organisations like PDA
published as: Petersen, C. Containers Pharm Sci 2009; 98(9):3167-3181 and APV. She is a frequent speaker on
Made of Cyclic Olefins as a New Option 8. Rathore N, Pranay P, Eu B. Variability in international congresses and seminars
for the Primary Packaging of Parenterals. syringe components and its impact on related to primary packaging and drug
Pharm. Ind. 2012;74(1):156-162. functionality of delivery systems. PDA delivery devices for injectable drug
J Pharm Sci and Tech 2011; 65:468- products.
References 480 Email: c.petersen@
1. United States Pharmacopoeia 35 NF gerresheimer.com
30. Dimethicone, The United States

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