Ehavnesh D Shah
`M.Phann
`S.K.Patel College of Pharmaceutical
`Education and Research,
`Ganpat University, Gujarat
`
`Bhupendra. G. Prajapati
`Assistant Professor
`S.K.Patel College of Pharmaceutical
`Education and Research,
`Ganpat University, Gujarat
`
`Pre- Filled Syri11ges:
`A New Co11cept
`
`The administration of therapeutic drugs via injection is an
`indispensable delivery method for numerous drugs critical to
`patient health and well-being. Now this segment is evolving
`in response to changing patient populations, new classes of
`powerful therapeutic drugs and healthcare administration
`initiatives. Population demographics and efforts by managed
`care providers to control healthcare costs are driving the growth
`in drug self-administration, particularly for chronic conditions,
`introducing a new class of nai·ve users to parenteral drug
`delivery. User-friendly syringe and injection device designs and
`the availability of an increasing number of drugs in pre-filled
`insertable and disposable cartridges are propelling the growth
`of prefilled syringes for self-administration.
`
`5 I I AUGUST 2009 I PHARMA EIO WIJRI.D
`
`www.pharmabioworld.com
`
`Regeneron Exhibit 1011.001
`
`

`

`1
`I l
`~ :If
`•
`~ --· ~~ ;....__:...
`
`14i
`
`s
`-$-
`~
`
`~
`
`I
`1 1
`I
` •
`
`.....
`
`._a..,
`
`.....
`-
`
`-i
`
`I
`
`--
`
`Figure l : Different pre-filled syringes
`
`annular wall;
`• A flexible plastic film tube within the
`barrel hermetically bonded to the
`needle-connecting member and the
`plunger at each end;
`• Needle-connecting member having at
`its rear end a skirt portion of an outer
`diameter equal to an inner diameter
`of barrel, skirt portion being fitted in
`the distal end of the barrel, film tube
`being bonded to the outer wall of the
`rear side of the skirt portion .
`
`from non elastomeric material, such as
`polypropylene, polycarbonate or other
`medical grade plastic, within at least a
`class 100 environment.
`2. Optionally, providing a tip seal and/or
`a piston which is also molded under
`conditions which are substantially free
`of pyrogens and viable and non-viable
`particulates.
`3. The plunger cover and tip seal are
`moulded from an elastomeric material,
`such as rubber, by any suitable molding
`
`ASSEMBLY INSTRUCTIONS FOR
`SYrnge Cornpon@nts
`
`PREFILLED SYRINGE
`
`.
`
`: gJ:.u;;,:
`
`.
`
`up :
`
`tampar..
`
`nooa1a
`
`3~FI-·;:~~-; ~crk
`
`ts
`
`PLUNC.ER FIOD
`
`SYRINGE BARF!EL
`
`'
`
`STERILE NEEDLE
`
`Figure 2 : Components of pre-filled syringe
`
`PREPAR~TION OF PRE-Fl LLED
`SYRINGES
`
`The method for the preparation of a
`pre-filled plastic syringe, comprising the
`steps of:
`(a) Preparation of components
`
`1. Providing a barrel and plunger
`molded under conditions which are
`substantially free of pyrogens and
`viable and non -viable particulates,
`
`method such as compression molding.
`After moulding and contaminant
`removal, the plunger cover and tip
`seal are lubricated with silicone oil,
`hereinafter referred to as 'silicone', to
`facilitate the assembly of the plunger
`cover onto the plunger substrate to
`form the plunger, and the assembly
`of the tip sealed to the distal end of
`the barrel to form the barrel/tip seal
`combination. The plunger cover and
`
`PHARMA l!ID WORLD I AUGUST 2009 I 52
`
`Regeneron Exhibit 1011.002
`
`Many of the innovative products
`
`like monoclonal antibodies,
`proteins and peptides need to
`be deliverd via parenteral route, require
`accurate dosing and safe handling. Pre(cid:173)
`ti lied syringes are now the primary
`container of choice for most parenteral
`drug delivery systems. Prefilled syringes
`have traditionally been made of a glass
`body formed from USP type 1 borosilicate
`glass, elastomeric plunger and plastic rod.
`The drug is packed in the glass body and
`is covered on both sides by elastomers. A
`plunger rod is fitted behind for the drug to
`be administered.
`
`The definite advantages of using the
`system are:
`• Prefills of syringe require less
`overfill. e.g. for a 0.5 ml vial, the
`USP recommends 20-25% overfill.
`In contrast, for a 0.5 ml BD Hypak
`dose, required overfill is less than 2%.
`Low risk of contamination e.g. Use
`of pre-filled syringes eliminates the
`possibility of cross infection arising
`from needle reuse.
`• Accurate measurement of dosage
`• Easier product identification
`• Speed in emergencies
`• Shorter preparation time
`• Pharmaceutical product
`differentiation
`Improved product and company
`image
`• Convenient to medical staff
`• Boost to sales and marketing efforts
`
`•
`
`PRE-FILLED SYRINGE COMPONENTS
`Pre-filled syringes includes following
`parts:
`• A barrel having an opening at
`opposite ends and an inwardly
`projecting annular wall at a distal end
`• A plunger fluid-tightly inserted in the
`proximal end of the barrel so as to be
`slidable along the inner wall of the
`barrel;
`• A needle-connecting member,
`attached to the annular wall to
`fluid-tightly close the opening of the
`
`www.pharmabioworld.com
`
`

`

`tip seal may also require sterilization
`by any suitable method, such as use of
`ethylene oxide or autoclaving.
`4. Maintaining said barrel and, optionally,
`tip seal and/or piston, under clean
`conditions for use in step (b).
`
`(b) Filling and assembling the syringe.
`The pre-filling and terminally sterilizing
`a syringe, consists of the following
`sequential steps:
`1. Providing an empty syringe barrel
`havingfirstand second opposite ends,
`where first end having a port through
`with a connector member formed
`about an exterior of port and second
`end being open;
`2. Removing particulate matter from the
`interior of syringe barrel;
`3. Sterilizing the cap and stopper, stopper
`being at the first and second opposite
`longitudinal ends;
`4. Prior to filling empty syringe barrel,
`insert first end of stopper into the
`second open end of empty syringe
`barrel and move stopper toward first
`end of empty syringe barrel until first
`end of stopper reaches a position
`against first end of empty syringe
`barrel;
`5. Prior to connecting the cap to the
`connector member to seal the port,
`fill syringe barrel with a desired fluid
`medicament through the port of
`first end of syringe barrel wherein
`substantially no air enters syringe
`barrel, then stopper moves from first
`end to second end of syringe barrel by
`fluid pressure of fluid medicament as
`the syringe barrel is filled;
`6. After filling the syringe barrel through
`the port, connect the cap to connector
`member of first end of filled syringe
`barrel to seal port; and
`7. Terminally sterilize pre-filled and
`assembled syringe barrel, stopper and
`cap in an autoclave having a spray
`over-pressure cycle which maintains
`pressure about the exterior of syTinge
`barrel at least equal to the pressure
`within the interior of syringe barrel.
`
`53 I AUGUST 2009 I PHARMA EIO WIJRI.D
`
`Figure 3: Different pre-filled devices for lyophilized drug products
`Prefilled Diluent Syringe
`PRE-FILLED DEVICES IN THE MARKIT
`While dual-chambered syringe or dual(cid:173)
`syringe delivery systems are elegant, they
`are not compatible with many lyophilized
`drugs. Most of the freeze dried product
`must be put into a vial due to the volume
`of liquid filled and the corresponding
`lyophilized plug size but also to get the
`best freeze-drying characteristics, which in
`turn yields longer stability. West currently
`offers Clip'n'Ject, a reconstitution system
`consisting of a prefilled diluent syringe
`packaged with the drugvi al, containing the
`lyophilized or dry powder drug.
`
`Dual-Chambered Syringe
`To extend the advantages of a prefilled
`syringe to manufacturers of lyophilized
`drugs, Vetter Pharma Fertigung offers the
`Vetter Lyo-Ject dual chambered syringe.
`This system is a glass-barreled syringe
`with a stopper in the middle to serve as a
`barrier between the two chambers. Vetter
`lyophilizes the drug in the syringe itself and
`seals that chamber while the syringe is still
`in the lyophilizer. Filling equipment then
`dispenses the diluent into the remaining
`volume of the syringe and adds another
`stopper. On the distal portion is a screw(cid:173)
`taper plunger rod that goes through the
`finger rest. As the user advances the
`plunger, it puts pressure on the diluent.
`The diluent then moves the center stopper
`into a bypass in the side of the glass.
`Eligard delivered by atrigel drug delivery
`technology is an example of the same.
`
`Uniject Pre-filled Syringe (non-reusable
`injection device)
`UniJect is a plastic disposable injection
`device, pre-filled with a single dose of
`medication. It is activated by pushing the
`needle cap toward the body of the device,
`opening the fluid path between the needle
`and the blister. The cap is then removed,
`
`www.pharmabioworld.com
`
`Regeneron Exhibit 1011.003
`
`

`

`Reservoir
`
`Port
`
`§
`
`I
`
`Needle Shield
`
`Figure 4 : UniJect pre-filled syringe
`
`the needle inserted into the subject, an dthe
`dose is delivered by squeezing the blister
`until it=llapses.
`
`BD Hypak PhysiolisTM Class Pre-fillable
`Syringe
`The B D Hypak Physiolis syringefeatures
`patented needle-point geometry and a new
`latex-free needle shield material. The needle
`has five bevels and, at29 gauge, is thinner
`than previous offerings. Its unique design
`results in a needle point that, while being
`thinner, is actually stronger. In combination
`with a new needle shield material, the BD
`Hypak Physiolis syringe needle is sharper
`and penetrates the skin more easily, which
`enhances patient comfort.
`
`and innovation, differentiating it from those
`that need vials or ampoules.
`Compared to alternative prefilled
`devices, the unique combination of
`integrated features of the BD Readyfill'"
`syringe offers increased product
`differentiation, including:
`Quality staked needle: Using only the
`highest quality preattached needle helps
`ensure the smoothest, most =mfortable
`injection possible. The need le never
`punctures oris embedded in rubber.
`
`Fagid Needle Shield: A hard plastic shield
`promotes end-user safety and enables easy
`cap removal
`
`BD Readyfill'"
`The BD Readyfill"' syringe adds value
`
`Needle Isolation: Separating the liquid from
`the needle ensures that drugs sensitive
`to needle contact are not affected during
`
`-(cid:173)
`
`Enlarged
`Flngergrlp
`
`H·gure 5 : BD Readyfill- pre-filled syringe
`
`I
`
`Baked
`Silicone
`
`\,
`Needle
`Isolation
`
`\
`
`Quality
`Staked
`Needle
`
`' Rigid
`
`Needle
`Shield
`
`storage
`
`Baked Sifirone: Binding the silicone to
`the glass barrel through a proprietary
`technology reduces the level of free
`silicone. This is a clear benefit for silicone(cid:173)
`sensitive drugs.
`
`Integrated Backstop: Integrating the
`backstop and the syringe barrel prevents
`accidental removal of the plunger during
`aspiration.
`
`Ergonomic Design: Oversized fi ngergrip
`means maximum ease of use for the
`end user and promotes overall injection
`safety.
`
`BD Preventis™ Prefilled Syringe
`Automatic Needle Shielding System
`The main features of the BD Preventis
`are:
`• Compatible with 0.5 ml and 1 ml long
`BD Hypak "' syringes with attached
`needle
`• Single hand activation
`• Designed for either low or high speed
`assembly lines
`• No change in sterile filling operation
`• Secondary packaging for filled syringe
`• Enables easy visualization of the syringe
`contents
`
`ChaSyr Pre-filled Syringes
`The ChaSyr DDS is a prefilled, multi(cid:173)
`chamber, sequential delivery syringe.
`In a nutshell, it means that the syringe
`has more than one medication chamber
`separated by a rubber stopper with a valve
`that keeps the medications disparate and
`prevents air/gas from passing through
`the valve. The syringe comes prefilled
`with saline or heparinized saline in the
`posterior chamber. The clinician aspirates
`medication into the front chamber using
`conventional practices. After infusion of
`the medication from the front chamber,
`the clinician simply continues to push the
`syringe plunger. When the rubber stopper
`(ChaSyr valve) comes in contact with the
`tip of the syringe a valve opens allowing
`
`www.pharmabioworld.com
`
`PHARMA l!ID WORLD I AUGUST 2009 I 54
`
`Regeneron Exhibit 1011.004
`
`

`

`Figure 6(0)
`
`the saline solution in the back chamber to
`flow through the valve thus flushing the
`Y-site and IV line of the odginal medkant
`and leaving a saline lock in the system. The
`ChaSyr DDS with its prefilled inline post(cid:173)
`flush simplifies nursing procedure, reduces
`line manipulations and line breaks by up to
`50':'bthereby reducing contaminations rates
`and nosocomial infections.
`From figure 6 (a) 1t can be seen that
`rear chamber of the ChaSyr DDS has a
`prefilled saline flush. The front chamber of
`theChaSyrDDS is filled by the pharmacist
`with the drug of choice and a sahne lock is
`placed in an extension set with a clamp.
`
`From figure 6 (b) it can be seen that
`the clinician removes the cap from the
`extension set {only clinician exposure is to
`saline) and attaches the extension set to
`
`-
`
`Figure 6(bl
`
`the catheter. After opening the clamp, the
`sydnge plunger is pushed thus infusing
`the saline pre-flush then the drug through
`the IV.
`
`Figure 6(c)
`
`5 5 I AUGUST 2009 I PHARMA EIO WIJRI.D
`
`From figure 6(c) it can be seen that
`the plunger is continually pushed until the
`vafve 1n the first plunger is activated. Saline
`then flushes the hazardous medication
`from the Y-site and the IV catheter thus
`rendering the catheter free of medicant and
`filling ,t with the flush solution.
`
`They include:
`1. Traditional filllng and stoppering
`2. Online vaccum filling and stoppedng
`and
`3. Online vaccum filllng followed by
`offline vaccum stoppering in a vaccum
`chamber.
`
`ACCESSORIES USED WITH PRE-FILLED
`SYRINGES
`
`LEVA® Autoject
`
`LEVA® is disposable and designed for
`subcutaneous injections of fixed doses. A
`skin sensor and automatk need le retraction
`
`Figure 7 : LEVA® Autojeci
`
`assure a maxi mum safety. With an intuitive
`design, small size and few user steps;
`LEVA® provides a fast, easy and safe
`pathway to injection.
`Flex Pen® Device
`Product benefits
`• Enhanced safety features
`• Enhanced simplicity
`
`In traditional processes, syringes are
`filled and stoppered using conventional
`filling equipment In these processes,
`a needle is inserted into a presterilized
`syringe and product is expelled. Next, the
`syringe stopper is forced into a tube- the
`insertion tube, whkh is narrower than the
`syringe. The insertion tube 1sthenplacedin
`the syringe above the liquid level line and
`a rod pushes the stopper out the 1nsert1on
`tube into the syringe. The drawback,
`however, is that conventional methods
`leave a gas bubble inside the syringe
`which can pose s1gn1fkant challenges.
`Additionally, conventional methods which
`use insertion tubes are not suitable for
`coated stoppers since the force of the
`compression of the stopper and the action
`of the insertion rod can cause the coating
`to wrinkle or tear.
`In onllne vacuum filling and vacuum
`stoppering, syringes are first evacuated
`and filled under vacuum. Next, they are
`advanced to the stopperang position
`where a vacuum 1s again applied to the
`filled syringes, and a stopper is pushed
`into position by differential pressure. In
`this process, there 1s no compression of
`
`Dos•~·
`
`h1e11cator
`w.-.c1ow
`
`PYSh
`button
`
`Aubbiar
`stoJ]peir
`
`Figure 8 : Flexpen® device
`
`• Discreetness
`• Sample, single-step dose setting and
`delivery
`FILLING PROCESS
`There are three processes forfillingand
`stoppering prefilled syringes.
`
`the stoppers and insertion rods are not
`required . This process leads to bubble free
`filllng of sydnges.
`Some of the notable advantages are:
`• Reduction/elimination of stopper
`movement in reduced atmospheric
`
`www.pharmabioworld.com
`
`Regeneron Exhibit 1011.005
`
`

`

`involves heating the silicone-coated syiinge
`to a spedfic temperature for an appropriate
`time which results in longer chains that are
`more closely adhered to the surfaces they
`coat. Thus the concentration of silicone 1n
`the syringe and its chemical reactivity are
`both reduced and the product's stability is
`increased.
`The other benefit of baked-on silicone
`is that it reduces the frequency of the
`"break loose" effect. The effect can occur
`during storage when the rubber closure,
`inside the syringe barrel, expands outwards
`so that eventually it displaces the low(cid:173)
`fraction silicone coating and comes into
`dfrect contact with the inner glass surface
`(figure 1 O(a)).
`As shown ,n figure 10(b), baked-on
`sllkone provides a more consistent coating
`of the syringe walls, which prevents the
`expanding rubber closure from touching
`the glass wall.
`Lubrication is maintained so that the
`initial force required to inject using prefi((ed
`syringes with baked-on silicone remains
`consistently low before and after storage.
`Syringes with staked-in needles have yet
`another advantage from the baked-on
`siliconisation process.
`
`AVOIDING pH CHANCES
`Sometimes pH changes are observed
`in solvent syringes containing water for
`
`Baked-on-Siliconised Syringes
`
`r1~r1
`
`llalcod omoa,io P.ro.rli:!Hconois1ont
`C~11,ig o11he glaM bllrlel wolls.
`• ::,~J.ul fctcos •lay low during
`
`compatibility and stability issues that
`arise when dealing with biotechnology
`formulations. One particularly common
`problem has been that such products can
`react with the oily form of silicone, which
`is used as a lubrkant to coat the sliding
`components of the syringe.
`The propensity for silicone to react
`with the formulation is dependent on the
`concentration of sillcone in the syringe and
`its chemical activity. The latter is determined
`by the number of terminal hydroxyl groups,
`which 1s greater the shorter the silkone
`polymer chain length.. Baking-on the silicone
`
`Oily SlllconlSE!d Syringes
`
`storage -- t~
`
`Dil'eet contact rllbbc>r lo !1"'-- "urfall9
`lea<b ,ner lime to lllgiti.r-i.Nollk-outforoe,o.
`
`Figure l O(a)
`
`Figure lO(b}
`
`Figure 9: Bubble free filling
`
`•
`
`pressures during shipment
`• Enhanced stability profile of oxygen
`sensitive compounds.
`• Enhanced stability profile of certain
`protein products that rearrange
`themselves at gas-liquid interfaces
`Improved accuracy and precision of
`delivered dose
`• Creation ofan unfavorable environment
`for the growth of aerobic micro(cid:173)
`organisms.
`The major benefit of this method over
`the conventional method is the reduction
`of the bubble which exists between the
`product and the stopper in traditionally
`filled syringes. It also works well with
`coated stoppers since the stopper is
`placed using differential pressure rather
`than force.
`In onllne vaccum filling followed by
`offline vaccum stoppering, the syringes
`are filled under vaccum. Then filled
`syringes could alternatively place into an
`offline vaccum chamber for stoppering.
`However, offline vacuum stoppering
`requires increased operator intervention
`whkh raises the potential for contamination
`and can slow the process down.
`
`BAKED-ON SILICONE
`Among the most important innovations
`are those that have overcome the
`
`www.pharmabioworld.com
`
`PHARMA l!ID WORLD I AUGUST 2009 I 56
`
`Regeneron Exhibit 1011.006
`
`

`

`injection {WFI) or saline solution, in diluent
`pre-filled syringes, which contain WFI for
`reconstituting lyophillsed products. The
`shift in pH occurs because the USP Type 1
`glass used in prefilled syTinge manufacture
`is a borosilicate glass, which must be
`subjected to various temperature changes
`during the glass tube production process.
`Around the beginning of the cooling phase,
`at580"C, sodium oxideformsand remains
`in the glass. During storage, sodium ions
`are released into the WR and increase
`the concentration of hydroxide ions, thus
`increasing alkalinity.
`Buender Clas has developed an
`ammonium sulfate pre-treatment process that
`solves this problem. Ammonium sulphate
`is sprayed into the glass barrel before the
`tempering process of the formed syringe
`is started. During the heating process,
`the formed sodium oxide reacts wath the
`ammonium sulphate by forming highly
`soluble sodium sulphate plus water and
`ammonia.
`
`TRIBOCLIDE-SILICON FREE
`LUBRICATION SYSTEMS
`Among lubricants, Silicone oil has one
`of the lowest Cohesive Energy Densities (a
`measure ofintermolecularforces that keep
`the molecules together) . Hence, silicone
`oil tends to migrate and can be a source
`
`of contamination. Perfluoropolyether, the
`precursor for TriboClide '" has a higher
`Cohesive Energy Density, thus reducing
`the tendency to migrate.
`Benefits over Silicone Oil
`TriboClide '" overcomes inconsistent
`device performance due to lubricant
`migration.
`• Reduces particulates in the drug
`medium
`Increased stability of biological drugs.
`•
`• Lower adsorption and degradation of
`proteins .
`• Low break-free forces.
`• Prevents silicone contamination
`issues wathin manufacturing facilities.
`
`REFERENCES
`1. Romacker M ., Dr Schoenknecht T.,
`Dr Forster R., The rise of prefilled
`syringes from niche product to
`primary container of choice: a short
`history on drug delivery.
`2. U.S.patent number EP0847770.
`3. Shandilya H., Sewa Medicals Limited,
`Understanding the complexities
`involved in manufacturing and
`meeting customer's expectations in
`delivering prefillable syringes.
`4. Kubo, Tomohiko (1-30-1108,Sibukawa
`1-chome, Kusatsu-shi, Shiga-ken, JP),
`patent no. EP0847770
`5. C Heffernan, A Welsher - US Patent
`App. 10/921,678, 2004.
`6. Process for the manufacture of prefiUed
`syringes, W0/1997/008054, WIPO
`7. C N Smith, J C Tanner, C John - US
`Patent 5,597,530, 1997
`8. Polin J B., The ins and outs of pre(cid:173)
`filled syringes, Pharmaceutical and
`medical packaging news, Vol. 11, No.
`5, May 2003.
`9. Bradley F. Otto, I. Made Suarnawa,
`At-birth immunisation against
`hepatitis B using a novel pre-filled
`immunisation device stored outside
`the cold chain.
`10. Thorpe C.A, Prefillable syringes
`- Trends and grov.1:h strategies.
`11. Romacker M . (Buender Glas), Why
`new developments are important in
`injectable delivery today.
`..
`
`5 7 I AUGUST 2009 I PHARMA EIO WIJRI.D
`
`www.pharmabioworld.com
`
`Regeneron Exhibit 1011.007
`
`