IPT 24 2007 3/1/08 13:49 Page 73
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`Ingredients, Formulations & Excipients
`
`Advances in Prefilled Syringe Technology
`Developments in areas such as component materials, surface
`treatments and filling processes are continuing to boost the appeal
`of prefilled syringes and expand their use with many of today’s
`parenteral products
`
`By Andrea Wagner at Hyaluron Contract Manufacturing
`
`Dr Andrea Wagner, PhD, is the Vice President of Business Development at Hyaluron Contract Manufacturing (HCM), a
`position she has held for six years. Prior to joining HCM, she was employed by the New Jersey Institute of Technology
`and Niton Corporation, in the capacities of Senior Scientist and Business Development Manager, respectively. Andrea
`holds a PhD in Toxicology and a Masters in Analytical Chemistry.
`
`Prefilled syringes are a fast-growing alternative to vials
`for many of today’s parenteral products. According to
`one recent estimate, the market for prefilled systems
`has grown by over 20 per cent in the last three years and
`is likely to see a sustained growth rate of between 10
`and 15 per cent in the foreseeable future (1).
`
`The increased interest in prefilled syringes is largely
`driven by the many advantages they offer relative to
`vials. These include greater ease of use, reduced waste,
`improved dosing accuracy and enhanced product
`differentiation. Recent advances in syringe technology
`promise to further enhance the benefits of a prefilled
`syringe. For example,
`there have been new
`developments in component materials, as well as
`surface treatments and filling/stoppering processes,
`which offer
`important advantages to both the
`manufacturer and the end-user.
`
`sterilise and offers better visibility as well as enhanced
`barrier properties; it also has low reactivity and its
`nature and content are better defined and understood.
`For companies moving their product from a vial to a
`prefilled syringe, this factor is important since they
`know what to expect and how to compensate for any
`challenges that might arise.
`
`Glass, however, contains small amounts of alkali ions
`which can cause a pH shift in some sensitive products
`(2). It can also harbour residual traces of tungsten, a
`byproduct of the glass-forming process, which can
`cause protein aggregation (3). Furthermore, proteins
`and peptides adsorb to glass which can, potentially, lead
`to a decrease in potency of the drug (4). Additionally,
`glass is breakable and requires
`added care when filling and
`handling.
`
`Several studies conducted by a leading provider of
`aseptic manufacturing services to companies in the
`pharmaceutical and biotechnology sectors have found
`that the advantages of a prefilled syringe can be
`significantly improved by decreasing the size of the gas
`bubble inside the syringe. The gas bubble is not intrinsic
`to the syringe but is a by-product of sub-optimal filling
`processes. Reducing the gas bubble, these studies
`showed, offers greater assurance with regard to dosing
`accuracy and precision as well as product sterility.
`Additionally, removing the gas bubble entirely from a
`prefilled syringe can improve the stability of many
`oxygen-sensitive compounds, as well as proteins that
`rearrange due to the gas-liquid interface.
`
`COMPONENT MATERIALS
`
`Borosilicate glass has long been the industry standard
`for parenteral products in prefilled syringes. It is easy to
`
`Plastic has been an alternative to
`glass in prefilled syringes since
`the early 1990s. The earliest
`plastics, however, were made of
`polypropylene which did not
`offer the clarity of glass, or many
`of its barrier properties and ease
`of sterilization. Polypropylene
`plastics also presented more
`challenges with
`regard
`to
`extractables and leachables than
`glass due to a lack of historic
`data.
`
`Manufacturers have begun to
`develop new plastics – such as
`cyclic olefin copolymers – that are
`able to hold their own against
`glass. These plastics offer high
`
`Innovations in Pharmaceutical Technology
`
`Barrel
`
`Figure 1: A prefillable
`syringe consists of a
`barrel, a plunger rod,
`stopper and tip cap.
`Advances in surface
`treatments used to
`facilitate the movement
`of the individual parts
`have decreased the
`amount of free silicone
`that could potentially
`interact with a drug
`product
`
`Piston
`
`Stopper
`
`73
`
`Tip cap
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`Novartis Exhibit 2025.001
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`
`

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`IPT 24 2007 3/1/08 13:49 Page 74
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`Figure 2: The
`expansion and
`contraction of a
`bubble inside a
`syringe can cause
`the stopper to rise
`into non-sterile
`areas of the barrel,
`potentially pulling
`silicone and other
`contaminants into
`the product
`
`Hsb
`
`FILLING/STOPPERING PROCESSES
`
`Until recently, there were three principal methods for
`filling and stoppering syringes, each with its own
`advantages and challenges.
`
`The most common filling and stoppering process uses
`high-speed equipment to expel the product into the
`syringe and force the stopper – which is first compressed
`in a narrow insertion tube – into place. The advantages
`of this method include minimal operator intervention
`and high-throughput, making it less costly and faster. A
`significant disadvantage is the large air bubble – 2.5mm
`minimum – which is left in the syringe. This bubble can
`increase the risk of stopper movement during shipping,
`and cause loss of product during expulsion activities
`prior to administration. It can also cause stability issues
`for some proteins and oxygen-sensitive compounds.
`Additionally, online stopper placement does not work
`well with coated stoppers since the compression of the
`stopper in the insertion tube and the force of the
`insertion rod can cause the coating to wrinkle and tear.
`
`The second most common method for filling and
`stoppering syringes is online high-speed filling followed
`by offline vacuum stoppering. With this method,
`syringes that have been filled online are manually moved
`from the filling machine and placed into a vacuum
`chamber. The advantage of this method is that it is
`effective in removing over 99 per cent of the air bubble,
`resulting in a bubble that is significantly smaller
`than that
`left by traditional online stoppering
`methods. One disadvantage, however, is that this
`method requires additional operator handling and
`significantly reduces throughput.
`
`Online vacuum filling followed by online vacuum
`stoppering was recently introduced by fill equipment
`manufacturers and is becoming increasingly popular.
`With this method, a vacuum is applied both before and
`after filling, and vacuum stoppering is done online. The
`primary advantage of this method is reduced operator
`handling and the ability to obtain bubble-free filling of
`viscous liquids. Online vacuum stoppering also works
`well with coated stoppers, as there is no compression of
`the stopper via the insertion rod.
`
`The latest innovation in filling and stoppering syringes
`uses online vacuum
`filling and stoppering
`in
`conjunction with other proprietary technology to
`produce a syringe that is bubble-free. This method,
`known as bubble-free filling, is most advantageous for
`non-viscous products, since viscous products can be
`
`Starting position
`of stopper
`
`Reduced atmospheric
`pressure #1
`
`Back to original
`ambient pressure
`
`Reduced atmospheric
`pressure #2
`
`Back to original
`ambient pressure
`
`Reduced atmospheric
`pressure #3
`
`Back to original
`ambient pressure
`
`heat resistance and a low level of extractables and
`leachables, and are less permeable to water (5). They are
`also more transparent, lightweight and shatter-resistant,
`enhancing visibility and facilitating filling operations as
`well as ease of use.
`
`SURFACE TREATMENTS
`
`In addition to making enhancements to the component
`materials of a container/closure system, syringe
`manufacturers are finding ways to mitigate the effects of
`silicone on sensitive biopharmaceuticals. Unlike a vial,
`the various parts of a syringe must be free to move in
`order to facilitate administration of the product. In the
`past, syringe manufacturers have used silicone to
`lubricate the stopper and plunger, enabling these parts
`to move freely. However, silicone, which is used in
`both glass and plastic syringes, can cause issues with
`product stability.
`
`More recently, some syringe manufacturers have
`started baking the silicone onto the syringe to limit
`the amount of free silicone that is available, thus
`decreasing the potential for interaction with the
`product (3). Others have developed barrier films to
`aid in lubricating the components, while protecting
`the drug product from contaminants that could
`potentially be leached from the elastomeric stopper
`which, in a syringe, is in constant contact with the
`product. West Pharmaceuticals, for example, has
`introduced FluroTec, a fluropolymer barrier film used
`on syringe components to facilitate administration of
`the product and to guard against extractables and
`leachables. This syringe system provides a silicone-
`free container which is advantageous to silicone-
`sensitive products.
`
`74
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`Innovations in Pharmaceutical Technology
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`Novartis Exhibit 2025.002
`Regeneron v. Novartis, IPR2020-01318
`
`

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`IPT 24 2007 3/1/08 13:49 Page 75
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`filled without bubbles using online vacuum filling and
`stoppering alone.
`
`The advantages of bubble-free filling include:
`
`Enhanced Dosing Accuracy
`Studies show that reducing or eliminating the bubble
`inside a prefilled syringe assures the same dose will be
`delivered regardless of syringe orientation, ensuring the
`end-user receives the entire deliverable dose.
`
`Improved Product Sterility
`A gas bubble inside a syringe can cause the stopper to
`move into non-sterile areas of the syringe when the
`syringe is exposed to changes in atmospheric pressure,
`potentially pulling contaminants and/or silicone oil into
`the product. Reducing the size of the gas bubble limits
`stopper movement, offering greater assurance with
`regard to package integrity and product sterility. Further,
`decreasing the size of the bubble inside a prefilled syringe
`prevents the growth of aerobic microorganisms and
`inhibits the growth of facultative microorganisms.
`
`Decreased Waste/Greater Safety
`The expansion of a gas bubble inside a syringe can result
`in a drip from the needle when the tip cap is removed.
`Decreasing the size of the bubble – or eliminating it
`altogether – ensures that less product will be wasted as a
`result of the drip and reduces the likelihood of
`administrator exposure to cytotoxic compounds.
`
`Increased Product Stability
`The liquid-gas interface inside a prefilled syringe can
`cause molecular rearrangement in some proteins, while
`air bubbles, in conjunction with silicone, may lead to
`protein aggregation. Eliminating the liquid-gas interface
`increases the stability of these products. In addition,
`removing the air from a prefilled syringe enhances the
`stability of oxygen-sensitive compounds.
`
`CONCLUSION
`
`Figure 3: A bubble
`inside a syringe can
`cause the product to
`drip from the needle
`when the tip cap is
`removed. A bubble-free
`syringe does not leak
`when the tip cap is
`removed, enhancing
`dosing accuracy
`and safety
`
`enhanced ease-of-use and reduced waste, as well as the
`potential to one day lyophilise products in standard,
`commercially available syringes – will continue to boost
`the appeal of prefilled syringes and expand their use
`with many of today’s parenteral products.
`
`The author can be contacted at
`ctracanna@hyaluron.com
`
`Acknowledgement
`The author would like to thank Kelly Jenkins Lin at
`Hyaluron Contract Manufacturing for her assistance
`in the preparation of this article.
`
`References
`
`1. Furness G, Prefilled Syringes: Where have we got to?
`ONdrugDelivery, p4, September 2007
`
`2. Polin JB, Injecting Excitement into Parenteral Drug
`Packaging, Pharmaceutical Manufacturing and
`Packaging News, p72, April 2005
`
`As prefilled syringes continue to find favour as an
`alternative to vials for many drug products, advances in
`prefilled syringe technology will continue to provide
`added benefits. These advances include developments
`in component materials, surface treatments and
`filling processes.
`
`One new filling process, bubble-free filling, offers
`improved dosing accuracy and greater assurance with
`regard to product sterility and stability in a prefilled
`syringe. These benefits, together with others – including
`
`3. Lahendro B, The next generation of prefillable
`syringes: specialised plastics lead the way,
`ONdrugDelivery, p7, September 2007
`
`4. DeGrazio FL, Parenteral Packaging Concerns for
`Biotech Drug Products, Drug Delivery Technology,
`p44, May 2006
`
`5. Harrison B and Rios M, Big Shot: Developments
`in Prefilled Syringes, Pharmaceutical Technology,
`March 2007
`
`Innovations in Pharmaceutical Technology
`
`75
`
`Novartis Exhibit 2025.003
`Regeneron v. Novartis, IPR2020-01318
`
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