SYRINGE SILICONISATION:
`TRENDS, METHODS, ANALYSIS PROCEDURES
`
`In this paper, Bruno Reuter, Director of Product Development, and Claudia Petersen, Director,
`Business Development, both of Gerresheimer Bünde, provide a detailed description of silicone
`oil and its applications in syringe siliconisation, highlighting the advantages and challenges
`siliconisation brings to the drug formulation and recent developments in the field.
`
`Ready-to-fill, i.e. sterile, prefillable glass syring-
`es, are washed, siliconised, sterilised and pack-
`aged by the primary packaging manufacturer.
`They can then be filled by pharmaceutical com-
`panies without any further processing. These
`days the majority of prefillable syringes are made
`of glass and the trend looks set to continue. The
`siliconisation of the syringe barrel is an extreme-
`ly important aspect of the production of sterile,
`prefillable glass syringes because the functional
`interaction of the glass barrel siliconisation and
`the plunger stopper siliconisation is crucial to the
`efficiency of the entire system. Both inadequate
`and excessive siliconisation can cause problems
`in this connection. The use of modern technology
`can achieve an extremely uniform distribution
`of silicone oil in glass syringes with reduced
`quantities of silicone oil. Another option for
`minimising the amount of free silicone oil in a
`syringe is the thermal fixation of the silicone oil
`on the glass surface in a process called baked-on
`siliconisation. Plastic-based silicone oil-free, and
`low-silicone oil, prefillable syringe systems are
`relatively new developments. Silicone oil-free
`lubricant coatings for syringes are also currently
`in the development phase.
`
`INTRODUCTION
`
`Primary packaging for injectables almost
`exclusively comprises a glass container (car-
`tridge, syringe, vial) and an elastomer closure.
`Ampoules are an exception. Elastomers are by
`nature slightly sticky, so all elastomer closures
`(plunger stoppers for syringes and cartridges,
`serum or lyophilisation stoppers) are siliconised.
`Siliconisation prevents the rubber closures
`from sticking together and simplifies processing
`of the articles on the filling lines. For example,
`it minimises mechanical forces when the stop-
`
`pers are inserted. Siliconisation is therefore
`essential to process capability.
`Although syringes and cartridges are always
`siliconised, this applies to a lesser extent to vials
`and ampoules. On the container the siliconisation
`provides a barrier coating between the glass and
`drug formulation. It also prevents the adsorption
`of formulation components on the glass surface.
`The hydrophobic deactivation of the surface also
`improves the containers’ drainability. In prefill-
`able syringes and cartridges, siliconisation also
`performs another function. It lubricates the syringe
`barrel or cartridge body enabling the plunger to
`glide through it. Siliconisation of the plunger stop-
`per alone would not provide adequate lubrication.
`Silicone oils are ideal as lubricants because
`they are largely inert, hydrophobic and visco-
`elastic. Chemical and physical requirements
`for lubricants are set out in the relevant mono-
`graphs of the US Pharmacopeia (USP) and the
`European Pharmacopoeia (Ph Eur).1,2 Section
`3.1.8 of the Ph Eur also defines a kinematic vis-
`cosity of 1,000-30,000 mm2/s for silicone oils
`used as lubricants.3 In contrast, the monograph
`for polydimethylsiloxane (PDMS) in the USP 2
`permits the use of silicone oils with a viscosity
`of 20-30,000 centistokes (cSt).
`However, increasingly stringent quality
`requirements and new bioengineered drugs are
`now taking siliconisation technology to its lim-
`its. Non-homogenous siliconisation, which can
`occur when simple coating techniques are used
`on longer syringe barrels, can in some cases
`lead to mechanical problems. These include
`the incomplete drainage of the syringe in an
`auto-injector or high gliding forces. Silicone oil
`droplets are always observed in filled syringes.
`The number of silicone oil droplets increases
`in line with the quantity of silicone oil used.
`Droplets which are visible to the naked eye
`
`Claudia Petersen
`Global Director,
`Marketing & Development
`T: +49 5223 164 242
`E: c.petersen@gerresheimer.com
`
`Gerresheimer Bünde GmbH
`Erich-Martens-Strasse 26-32
`32257 Bünde
`Germany
`
`www.gerresheimer.com
`
`16
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`www.ondrugdelivery.com
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`Copyright © 2013 Frederick Furness Publishing Ltd
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`Novartis Exhibit 2021.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Figure 1: Polydimethylsiloxane.
`
`could be viewed as a cosmetic defect. At sub-
`visual level, the issue of whether silicone oil
`particles could induce protein aggregation is
`currently under discussion.4
`In light of this development, there is an
`obvious trend towards optimised or alternative
`coating techniques. Attempts are being made to
`achieve the most uniform possible coating with
`a reduced quantity of silicone oil and to mini-
`mise the amount of free silicone oil by way of
`baked-on siliconisation. In this context, reliable
`analysis technologies that can be used to make
`qualitative and quantitative checks on the coat-
`ing are absolutely essential. Alternative coating
`techniques are also being developed.
`
`SILICONE OILS & THEIR PROPERTIES
`
`Silicone oils have been used for half a cen-
`tury in numerous pharmaceutical applications.
`For example, they are used as lubricants in
`pharmaceutics production and as inert pharma-
`ceutical base materials (e.g. soft capsule walls).5
`Trimethylsiloxy end-blocked polydimethylsilox-
`ane (PDMS, dimethicone) in various viscosities
`is generally used for siliconisation (see Figure 1).
`The most frequently used silicone oil for
`the siliconisation of primary packaging compo-
`nents is DOW CORNING® 360 Medical Fluid.
`PDMS is produced by reducing quartz sand to
`elemental silicon. In the next step, the silicon
`reacts directly with methyl chloride in a pro-
`cess called Müller-Rochow synthesis to create
`methyl chlorosilanes. In this process, a mixture
`of different silanes is produced, the majority of
`which (75%–90%) are dimethyldichlorosilane
`(CH3)2SiCl2. After distillative separation, the di-
`methyldichlorosilane is converted by hydrolysis
`or methanolysis into silanols which condense
`into low-molecular-weight chains and cycles.
`In an acidic (cationic) or alkaline (anionic)
`catalysed polymerisation, polydimethylsilox-
`anes with hydroxyl functions are generated.
`After the addition of trimethylchlorosilane they
`are furnished with trimethylsiloxy end groups.
`The short-chain molecules are removed from
`the resulting polydisperse polymers by way of
`vaporisation, leaving deployable PDMS.
`The characteristic aspect of the PDMS mol-
`ecule is the Si-O bond. With a bond energy of
`
`108 kcal/mol, it is considerably more stable than
`the C-O bond (83 kcal/mol) or the C-C bond (85
`kcal/mol). PDMS is accordingly less sensitive to
`thermal loads, UV radiation or oxidation agents.
`Reactions such as oxidation, polymerisation or
`depolymerisation do not occur until temperatures
`exceeding 130°C. The molecule also typically has
`a flat bond angle (ӨSi-O-Si = 151° ±12°) which
`has low rotation energy and is especially flexible
`(Figure 2). A high bond length (1.63 Å Si-O as
`
`Figure 2: 3D-structure of
`polydimethylsiloxane.
`
`compared with 1.43 Å for C-O) makes the mol-
`ecule comparatively gas-permeable.6
`The spiral shaped (and therefore easily com-
`pressible) molecule is surrounded by CH3 groups
`which are responsible for the chemical and
`mechanical properties of PDMS. The molecule’s
`methyl groups only interact to a very limited
`extent. This ensures low viscosity, even with
`high molecular weights, which simplifies the
`distribution of PDMS on surfaces and makes it
`a very effective lubricant. PDMS is also largely
`inert and reactions with glass, metals, plastics
`or human tissues are minimal. The CH3 groups
`make PDMS extremely hydrophobic. It is insolu-
`ble in water, but soluble in non-polar solvents.6
`
`SILICONISED SYRINGES
`
`As already explained the syringe system
`only works if the glass barrel and plunger
`stopper siliconisation are homogenous and opti-
`mally harmonised. For needle syringes, siliconi-
`sation of the needle is also essential to prevent
`it sticking to the skin, thereby minimising injec-
`tion pain. For the so-called oily siliconisation
`of the syringe glass barrel DOW CORNING®
`360 with a viscosity of 1,000 cSt is used. The
`DOW CORNING® 365 siliconisation emulsion
`
`is often used in the baked-on siliconisation pro-
`cess (describe later). The needle is siliconised
`using a wipe technique during ready-to-fill
`processing. DOW CORNING® 360 with a vis-
`cosity of 12,500 cSt is used. Another option is
`the thermal fixation of silicon oil on the needle
`during the needle mounting process.
`The goal of syringe barrel siliconisation is to
`obtain the most even anti-friction coating possi-
`ble along the entire length of the syringe in order
`to minimise break loose and gliding forces when
`the plunger stopper is deployed (Figure 3).
`Inadequate siliconisation of the syringe
`barrel, particularly the existence of unsilicon-
`ised areas, can cause slip-stick effects that
`impair the syringe’s function. The forces in
`the injection process can then be too high or
`the entire system can fail. Since inadequate
`siliconisation and gaps in the coating are often
`found on the lower end of the syringe (luer
`tip/needle end), it is possible that the syringe
`will not be completely emptied. Such defects
`can remain undiscovered, particularly in auto-
`injectors since these are closed systems. The
`result could be that an inadequate dosage of the
`medication is administered.
`The obvious solution is to increase the
`amount of silicone oil used to achieve a homog-
`enous coating. However, as already mentioned,
`increasing the amount of silicone oil used is
`also associated with higher quantities of silicone
`particles in the solution.
`With protein-based drugs in particular, unde-
`sirable interactions with silicone oil particles
`cannot be ruled out. Sub-visual silicone oil par-
`ticles are thought to promote protein aggrega-
`tion which can increase the severity of immune
`responses and reduce the drug’s tolerability.
`However, the underlying mechanism is not yet
`fully understood. There is a discussion as to
`whether protein aggregation is influenced by
`additional motion, e.g. shaking the syringe.7
`Experiments have also shown that when
`silicone oil in excess of 1 mg/syringe is used the
`additional silicone oil does not further reduce
`gliding forces.
`The interior siliconisation of glass syringe
`barrels has another advantage. It prevents the
`drug solution from interacting with the glass
`surface and minimises related problems such as
`the loss of active ingredients through adsorption
`or pH value changes due to alkali leaching.
`Prefillable glass syringes are only manu-
`factured from high-quality type 1 borosilicate
`glass. However, sodium ions can still leach out
`of the glass surface if the 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:
`
`Copyright © 2013 Frederick Furness Publishing Ltd
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`www.ondrugdelivery.com
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`Novartis Exhibit 2021.002
`Regeneron v. Novartis, IPR2021-00816
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`

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`OPTIMISED SILICONISATION
`
`For the abovementioned reasons, the main
`objective in siliconisation is to achieve the most
`homogenous possible coating with the mini-
`mum possible quantity of silicone oil. Initially it
`is necessary to establish the minimum quantity
`of silicone oil which will reliably satisfy the
`quality requirements of the application. In the
`production of ready-to-fill syringes, siliconisa-
`tion generally takes place after washing and
`drying. Fixed nozzles positioned at finger flange
`level under the syringe barrel spray the silicone
`oil onto the inside surface. In long syringes, the
`silicone oil is sometimes unevenly distributed
`and the concentration of the silicone oil is lower
`at one end of the syringe (luer tip/needle end).
`The use of diving nozzles can considerably
`improve the evenness of the coating across the
`entire length of the syringe body. In this pro-
`cess, the nozzles are inserted into the syringe
`to apply the silicone oil (finely atomised) in
`motion. The result is practically linear as is
`shown by the closely bundled gliding forces in
`the force path diagram (Figure 4).
`Studies on 1 ml long syringes have revealed
`considerable potential for reducing the amount
`of silicone oil required. In one experiment, the
`quantity of silicone oil per syringe could be
`reduced by 40% without any impairment of the
`system’s functional properties (see Figure 5). In
`practice the calculation of the optimum quan-
`tity of silicone oil has to take syringe volume,
`plunger stopper type (coated/ uncoated), plung-
`er stopper placement method (seating tube/vac-
`uum) and application requirements (injection
`systems) into account. Plunger stoppers from
`different suppliers not only differ in terms of
`the type of rubber used and their design, they are
`also coated with silicone oils of different vis-
`cosities. The siliconisation methods also differ
`considerably. These variables can have a bigger
`impact on the syringe system’s functional prop-
`erties than the syringe siliconisation of different
`suppliers, as shown by Eu et al.8
`
`BAKED-ON SILICONISATION
`
`Another key advancement in siliconisation
`technology is the baked-on siliconisation tech-
`nology. It involves the application of silicone
`oil as an emulsion which is then baked on to
`the glass surface in a special kiln at a specific
`temperature and for a specific length of time.
`In the baked-on process, both hydrogen
`and covalent bonds form between the glass
`surface and the poly-dimethylsiloxane chains.
`The bonds are so strong that part of the silicone
`oil cannot be removed with solvent and a per-
`manent hydrophobic layer is created (Figure 6).
`
`Figure 3: Extrusion force profile of a prefillable syringe.
`
`Fixed Nozzle
`– Fav break loose force = 2.1 N
`– Faw gliding force = 2.4 N
`
`Diving Nozzle
`– Fav break loose force = 1.7 N
`– Faw gliding force = 0.5 N
`
`Distance (mm)
`
`Distance (mm)
`
`Force (N)
`
`Force (N)
`
`m = 0.8 mg, v = 300 mm/min, empty 1 ml long LC Syringes
`
`Figure 4: Comparison of extrusion force profiles – fixed nozzle (top) versus diving
`nozzle (bottom).
`
`Standard 1ml long syringe*
`Fixed Nozzle
`m = 0.8 mg
`V = 100 mm/min
`BFmean = 2.5 N
`EFmean = 1.7 N
`
`Optimised siliconisation
`
`Standard 1ml long syringe*
`Diving Nozzle
`m = 0.5 mg
`V = 100 mm/min
`BFmean = 1.7 N
`EFmean = 0.5 N
`* Empty syringes
`
`Distance (mm)
`
`Distance (mm)
`
`Force (N)
`
`Force (N)
`
`Figure 5: Baked-on siliconisation.
`
`Si-O-Na + H20
`
` SiOH + NaOH
`
`In alkaline environments, on the other hand, an
`etching process is observed:
`
` Na2SiO3 + H2O
`2NaOH + (SiO2)X
`Aqueous solutions with a high pH value
`
`cannot therefore be stored for long periods in
`unsiliconised borosilicate glass containers. They
`have to be lyophilised and reconstituted before
`use. In extreme cases, the etching of the glass
`surface can cause delamination. Hydrophobic
`deactivation of the container by siliconisation
`effectively protects the glass surface.
`
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`Copyright © 2013 Frederick Furness Publishing Ltd
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`In addition the average molecule weight
`increases as a result of polymerisation and the
`vaporisation of short chain polymers. The result-
`ing extremely thin layer of silicone, in conjunc-
`tion with the low quantity of silicone oil used
`in the emulsion, minimises free silicone in the
`syringe and ensures that the required quality of
`finish is achieved. The layer thickness measures
`15-50 nm. By comparison, the average layer
`thickness with oily siliconisation is 500-1,000 nm.
`Baked-on siliconisation reduces the measur-
`able quantity of free silicone oil to approximate-
`ly 10 % of the normal value. As a result, there
`are fewer sub-visual and visual silicone oil par-
`ticles 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 the mechan-
`ical 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
`(Figure 7). The break-loose force remains prac-
`tically constant over the entire storage period.
`
`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 biopharmaceuti-
`cals 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 their interaction with drugs. Plastic
`systems based on cyclic olefins (COP/COC)
`are also gaining in significance for prefilled
`syringes and vials. COP syringes such as the
`ClearJect™ TasPack™ by from Kako Co Ltd
`(Osaka, Japan) have glass-like transparency.
`Additionally, they have a higher break resist-
`ance, their pH stability range is larger and there
`is no metal ion leaching.
`Excellent dosage precision is also very
`
`Figure 6: Extrusion force profile after optimised siliconisation.
`
`Oily siliconised syringe
`
`Baked-on siliconised syringe
`
`Storage
`
`Storage
`
`Direct rubber/glass contact leads to higher
`break-loose forces over the storage period
`
`The baked-on siliconisation provides
`a permanent coating
` Smaller increase in break-loose
`
`forces over the storage period
`
`Figure 7: Comparison of syringes with oily and baked-on siliconisation.
`
`important in packaging for bio-pharmaceuticals.
`In most cases siliconisation is also essential in
`COP syringes. Silicone oil-free systems are a
`brand new approach. The gliding properties of
`the fluoropolymer coating on specially devel-
`oped plunger stoppers eliminate the need to
`siliconise plastic syringes. There are as many
`innovative ideas for the development of pri-
`mary packaging products as there are innovative
`drugs and syringe systems.
`
`REFERENCES
`
`1. US Pharmacopeia 35 NF 30. Dimethicone,
`The United States Pharmacopeial
`Convention Inc (Rockville, MD, US), 2011
`2. Pharmacopoea Europaea. 7. Ausgabe.
`Dimeticon, Deutscher Apotheker Verlag,
`Stuttgart, Deutschland, 2011, s. 2788.
`3. Pharmacopoea Europaea. 7. Ausgabe. 3.1.8
`Siliconöl zur Verwendung als Gleitmittel,
`Deutscher Apotheker Verlag, Stuttgart,
`
`Deutschland, 2011, s. 486.
`4. Jones L, Kaufmann A, Middaugh C,
`“Silicone oil-induced aggregation of pro-
`teins”. J Pharm Sci 2005, Vol 94(4), pp
`918-927.
`5. Colas A, Siang J, Ulman K, “Silicone
`in Pharmaceutical Applications Part
`2: Silicone Excipients”. Dow Corning
`Corporation (Midland, MI, US), 2001.
`6. Colas A, “Silicone in Pharmaceutical
`Applications”. Dow Corning Corporation
`(Midland, MI, US), 2001.
`7. Thirumangalathu R, Krishnan S, Speed
`Ricci M, Brems D, Randolph T, Carpenter J,
`“Silione oil- and agitation-induced aggrega-
`tion of a monoclonal antibody in aqueous
`suspension”. J Pharm Sci, 2009, Vol 98(9),
`pp 3167-3181.
`8. N, Pranay P, Eu B, “Variability in syringe
`components and its impact on functionality
`of delivery systems”. PDA J Pharm Sci &
`Tech, 2011, Vol 65, pp 468-480.
`
`Copyright © 2013 Frederick Furness Publishing Ltd
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`www.ondrugdelivery.com
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`Novartis Exhibit 2021.004
`Regeneron v. Novartis, IPR2021-00816
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`

`

`Our comprehensive offering:
`RTF® syringe systems
`| High-quality ready-to-fill syringes
`| Innovative accessories
`| Proprietary baked-on siliconization
`
`www.gerresheimer.com
`
`
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`02/07/2013 08:0202/07/2013 08:02
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`Novartis Exhibit 2021.005
`Regeneron v. Novartis, IPR2021-00816
`
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