PREFILLED SYRINGES
`
`Baxter
`'
`GERRESHEIMER
`
`VETTER
`
`111/iE'rTPhannaceutica/
`··~ ~Is E R V I C E s
`
`PS0 MED
`
`SE L F' CAR E S O LU TIONS
`
`Regeneron Exhibit 1013.001
`
`

`

`"Prefilled syringes: innovations
`that meet the growing demand"
`
`This is the first in a series of sponsored themed
`publications from ONdrugDelivery Ltd. Each
`issue will focus on a specific topic within the field
`of drug delivery, and contain up to eight articles
`contributed by industry experts.
`
`Full contact information appears alongside each
`article. Contributing companies would be delight(cid:173)
`ed to hear from interested readers directly.
`ONdrugDelivery would also be very pleased to
`pass on to authors, or answer as appropriate,
`any queries you might have in relation to this
`publication or others in the series.
`
`Contact:
`Guy Furness, Managing Director
`T: +44 1273 831 370
`E: guy.furness@ondrugdelivery.com
`
`"Prefilled syringes: innovations that meet the
`growing demand". Published by ONdrugDelivery
`Ltd, Cedar Cottage, Newtimber Place Lane,
`Newtimber, West Sussex, BN6 9BU, United
`Kingdom. Registered in England: No 05314696.
`
`ERY
`
`Copyright <C 2005 ONdrugDelivery Ltd
`
`The views and opnons expressed ii this issue are those of the author.;,
`Oue care has been used in prncl,a,g llis pu,lication, bu: the pubis her
`m~• oo clain flat tt is free of error. Nor does the pubisher oa:epl
`iabityfll"the con.._.,e, of ,ny decismor actm taken
`(..- not 1llkenl .. a resut of any mwmatioo comned ii this piticaticri.
`
`• except the ride: 'O.bcucina: as a stnlel[ic decism"
`© Vettl!" Ph11'111a-f<niKUng
`
`Front wirer phomgroph ~ will pemi"'"°" fnrn
`Buender Glas GmbH
`
`CONTENTS
`
`Introductory comment
`Georg Roessling (Schering AG/ PDA)
`
`Sterile prefilled syringes: market dynamics
`& current issues in manufacturing & control
`Karim Abdelkader, Ryan M Akers,
`and Michael J Akers (Baxter Healthcare)
`
`Prefillable syringes - trends and growth
`strategies
`Glenn A Thorpe (BD Medical)
`
`-
`
`-
`
`-
`
`Why new developments are important
`in injectable delivery today
`Mathias Romacker (Buender Glas)
`
`@jf 1•
`
`The next generation of safety prefill devices:
`NMTs Safety Prefill Needle Unit enters the
`commercial stage.
`Ian Littleton (NMT Group)
`
`Outsourcing as a strategic decision
`Max Horn (Vetter Pharma-Fertigung)
`
`•tJf j
`
`•IIUi
`
`The intricacies of selecting and evaluating
`plungers for prefilled syringe systems
`
`Frances DeGrazio (West Pharmaceutical Services) f lr§fj
`
`New-generation auto-injectors:
`taking self injection beyond prefilled syringes
`Ian Thompson (Ypsomed)
`
`Company profiles
`The Medical House
`Imprint Pharmaceuticals
`
`f1f%8
`
`-
`
`-.ondrugdelivery.com
`
`Copyright © 200 5 ONdrugDelivery Ltd
`
`Regeneron Exhibit 1013.002
`
`

`

`•
`GERRESHEIMER
`pha maSys ems
`
`PREFILLED SYRINGES:
`WHY NEW DEVELOPMENTS ARE IMPORTANT
`IN INJECTABLE DELIVERY TODAY
`
`Within the almost $100 billion injectables market, one snch injection format - the prefilled syringe
`- is becoming increasingly popular. Bnt, as prefilled syringe mannfactnrers and fillers are reqnired
`to deal with an ever-growing nnmber of new types of compounds in new therapeutic classes, they
`enconnter new obstacles, and most devise methods of overcoming them. In this piece, Dr Thomas
`B rachtendorf and Mathias Romacker, Directors of Bnsiness Development at Buender Gb.s
`(a division of Gerresheimer p hannaSystems), outline .some of the advances and innovations that
`have enabled the prefilled syringes sector to keep ahead of rapid changes and growing demand.
`
`Some view the injectables market as the uadi(cid:173)
`tioaal, more conventional side of drug delivery.
`As such, they do not tend to associate it with the
`level of cutting-edge science and technology
`that is readily linked with othei- deliveIY meth(cid:173)
`ods,, such as advanced inhalers.
`In n,ality though, the experience of anyone
`dose to the injectables sector would lead them
`to take a quite differnnt view. The number of
`injectable products is rocketing - not least
`because injection is cmrently the ooly viable
`way of delivering many of them. As a conse(cid:173)
`quence, demand for technologies that improve
`the pmduction, administration, and the experi(cid:173)
`ence of receiving injectable products., is strong.
`The first products presented in prefilled(cid:173)
`syringes were heparins, launched in Europe by
`Saoofi and Rhone Poulenc-Rorer io the early
`1980s At that time, the pre:filled-syringes mar(cid:173)
`lret was viewed as a relatively insignificant
`niche area withio the huge injectables marlret.
`Therapeutically, prefilled syringes were limited
`to a llllITOW range of applications in a fuw vac(cid:173)
`cines and aoticoagulaot products. Their use was
`also limited geographically to Enrnpe.
`Initial internst, during the 1980s and 1990s,
`was sparked primarily by the clear advantages
`prefilled sycinges have over traditional vials and
`ampoale"- The procedw:-e :for using a prefilled(cid:173)
`syringe product often involves nothing morn
`than rnmoviog the syringe from the packaging
`and injecting the formulation. In contrast, any(cid:173)
`one administering a traditional injection from a
`
`vial might typically have to: read the required
`dose from the physician· s dosing directions,
`withdraw from the vial slightly more fononla(cid:173)
`tioo than is required, invert the syringe to allow
`any air bubbles to ~each the top. depress the
`plunger slightly to expel aoy air and. finally.
`dq,ress the plmigec slightly fmthe.- still to leave
`precisely the reqoi.-ed dose, which they measure
`using the scale along the syringe barrel
`Prnfilled syringes, with their single-use, dis(cid:173)
`posable format, together with the fact that they
`eliminate several of the prncedures required
`prior to administering a fomwlation presented
`in a. vial, are significantly quicker and more con(cid:173)
`venient. Ease of use, io addition to simply mak(cid:173)
`ing them more oomrenient, means that pre:filled
`sycinges are safe,-_
`The major safety benefit is the rndnced like(cid:173)
`lihood of dosing errors - which can occur at
`each of the steps in the vial/ampoule procedure.
`The fixed dose in a prnfilled syringe is :filled
`mechanically and is checked electronically do.-(cid:173)
`ing quality conb:ol.
`As well as reducing enor.; in the dose quanti(cid:173)
`ty, pre:filled syringes mduce the risk of adminis(cid:173)
`tering the wrong product because the syringe and
`packaging are clea.-ly labelled with the dmg
`name. F O£ syringes filled at the point of adminis(cid:173)
`tration, there is a period - between filliog and giv(cid:173)
`ing the dose - when the S}'linge can be left full of
`drug but completely nomarl<ed, on a tray ready to
`use. This is a danger period since the identity of
`the drug in the syringe is typically known mtly to
`
`Copyright Cl 2005 ONdrugOellvery Ltd
`
`www.ondrugdellvery.com
`
`Regeneron Exhibit 1013.003
`
`

`

`Figure 1a
`
`Figwe 1b
`
`Oily Siliconised Syringes
`
`l§I = ~I
`
`Dlr«t contact rubbtr to glass surface
`leads <M!r time to higher b~ak-out forces.
`
`Baked-on-Silicone Syringes
`
`~1'= P1
`
`Baked liUXll11.1 provides consistent
`Coating of the ~ barrEII walls.
`• Break-<JUt forces stay low di.ring
`storage.
`
`Figwes 1a and 1b: the break loose effect
`
`the person who filkd it md the infmmation only
`exists in the memory of that person_ If they are
`dislra.cted during the dimgerpaiod, or""' pcrlmps
`calkd away to an emagency and have to hand
`over to illlOlher P""""'- the job of giving the injec(cid:173)
`tion, there is a real risk ofa mistake occmriog_
`Anolhe< safety benefit is the reduced risk of
`aeedle-stick in_jucy_ Accidents are more likely with
`traditional formats because the user is required to
`expose the needle tip fur longa-. while pemmniog
`a series of actions n,quiriog dexterity and concen(cid:173)
`uation. The fact that prefilk,d syringes are s.ingle(cid:173)
`use devices also eliminates the possibility of
`cross-infection arisiog from needle re-use.
`Prefilled syringes contain the precise amount
`of drug that is to be injected, but vials and
`ampoules have to contain more liquid than the
`actual dose in onler fur the correct ammmt to be
`withdrawn. The excess formulation is wasted
`and, especially with expensive biotoch products,
`elimination of wastage allows the maonfacturer
`to mah, significant cost savings
`As demand increased, and the range of
`viable applications of prefilled syringes broad(cid:173)
`ened, the market began to grow_ Notably. the US
`market. with its shorter history of pre.filled
`syringes, was piHt:icularly keen on the advan(cid:173)
`tages this format gave, to the extent that it is
`now exclusively an RTF syringe marlret_
`The emergence ofbiotechnology drugs in the
`eady 1990s gave demand for pre.filled syringes a
`colossal boost worldwide and this product class
`today still represents the highest potential fur
`future growth_ In Eurt!p<l. new drugs that have
`been presented in prefilled syringes include: ery(cid:173)
`thropoietins such as Reconnon and Eprex; inter(cid:173)
`furons lih, Betafemn, Avoru,x, Copaxone and
`Rebif; and dieumatoid arthritis drugs lih, Enbrel
`and Hmnira. to name just a few.
`Cnicially, biotech p:rovided a late but very
`
`µrofound entry into the previously UDtapped US
`marlret, where many of the aforementioned
`µroducts, and many other biotech p:roducts,
`were developed and launched fust - often in
`p:refilled syringes_
`
`RECENT INNOVATIONS
`
`The continually increasing demand for pre(cid:173)
`filled syringes has maintained pressure on man(cid:173)
`ufacturers to devise methods fur increasing µre(cid:173)
`duction capacity and driving down costs.
`Alongside these ongoing advances, which focos
`on improving the overall efficiency of the µre(cid:173)
`duction process, recent trends in the industry,
`and in the healthcare environment generally,
`have given rise to several specific innovations
`that imp:rove the quality of prefilled syringes_
`Like many manufacturers. Buender Glas has
`experienced a rapid expansion in the number of
`therapeutic classes its µrefilled syringe µroducts
`mnst serve, and foresees a continoation of this
`trend_ Its novel technologies broaden the range
`of prodncts that can be presented in p:refilled
`syringes and, crucially, increase the acceptabili(cid:173)
`ty of prefilled syringes among the patients and
`medical µrofessionals that use them_
`
`BAKED-ON SILICONE
`
`Among the most important innovations are
`those that have overr.ome the compatibility and
`stability issnes that arise when dealing with
`biotechnology :fumrulations. One particularly
`common problem has been that such µroducts
`can react with the oily fonn of silicone, which is
`used as a lubricant to coat the sliding compo(cid:173)
`nents of the syringe.
`The p:ropensity for silicone to react with the
`formulation is dependent on the concentration
`
`of silicone in the syringe and its chemical activ(cid:173)
`ity_ The latter is detennined by the number of
`terminal hydroxyl groups, which is grnate:r the
`shorter the silicm1e polymer chain length__
`Baking-on the silicone - which involves heat(cid:173)
`ing the silirone--coaled syringe to a specific tem(cid:173)
`perature for an appropriate time-results in longer
`chains that are more closely adhered to the sur(cid:173)
`faces they coat_ Thns the conceouation of silicone
`in the syringe and its chemical reactivity are both
`reduced md the pmduct's stability is increased.
`The second benefit of baked-on silicone is
`that it reduces the frequency of the D'.feak
`loose" effect_ The effect can occor during stor(cid:173)
`age when the rubber closure, inside the syringe
`barrel, expands outwards so that eventwilly it
`displaces the low-friction silicone coating and
`comes into direct contact with the inner glass
`surfi.ce {see figure la)_
`The oser carmot detect the p:roblem until the
`poinl of administration when they try to depress
`the plunger_ Becaose the rubber closure is essen(cid:173)
`tially stock to the inside surface of the syringe, a
`high initial force is needed to shift it_ The needle
`has already penetrated the patient's skin and the
`tip is positioned in their tissue at this point, so
`the lack of control as the extra force is applied,
`and the potential :fur a sudden movement as the
`rubber closure is freed up, is cleady nndesirable_
`As shown in :figmc I b. baked-on silicone
`p:rovides a more consistent coating of the
`syringe walls. which p:revents the expanding
`rubber closure from touching the glass wall
`Lubrication is maintained so that the initial
`furce requued to inject using p:refilled 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 siliconisa(cid:173)
`tion process. Until oow, baked-on silioone was
`not available with stalred-in needle syringes
`since a needle could not be glued into the chan(cid:173)
`nel of a syringe after baking process m the bak(cid:173)
`ing p:rocess itself would soften the glue in the
`channel, resulting in a bad fixation of the needle_
`The key to prnducing staked-in needle
`syringes with baked-on silicone lies in the inac(cid:173)
`tivation of silicone located in the channel where
`the needle will be glued in_ For this purpose
`Buender Glas had developed a patented process_
`
`AVOIDING PH CHANGES
`
`Another challenge has been to prevent the
`nndesirable pH change that sometimes occurs in
`liquids stored in prefilled syringes_ It has been
`observed in solvent syringes conlllioing watec for
`injection {WFI) m saline solution, in diluent pm-(cid:173)
`filled syringes. which contain WF1 for reconsti(cid:173)
`tuting lyophi1ised products, and in syringes con-
`
`•••
`
`IIIJWW.ondrugdellvery.com
`
`Copyrlgnt © 2005 ON!lrugDellveiy Ltd
`
`Regeneron Exhibit 1013.004
`
`

`

`needle tip and smooth smfaces.
`
`Sodium Oxide Releases Sodium Ions
`
`These are achieved through a
`validated, reliable production
`pmcess. Secondly, there are less
`critical, subtle.- factors soch as
`the nnmbe.- of bevels at the nee(cid:173)
`dle tip, the angle of the bevels
`and the bevel length_ Thndly,
`the coating substance and
`method of application., fm
`example silicooisation, have
`been recognised as key in deter-
`mining the pain of injection_
`The increase in the number
`of prefilled syringes being used to self-inject,
`often at home, is in pa:rt a reflection of the trend
`towa:rds more patient-centred treatments, hut
`equally doe to the application of
`µrefilled syringes in new indica(cid:173)
`tions, such as Ihemn.atoid arthri(cid:173)
`tis and multiple sclerosis_
`Prefilled syringe manufactul"(cid:173)
`ers a:re developing design fea(cid:173)
`tmes 1hat talre into account that in
`diseases such as these, the self(cid:173)
`inJectiog patieot is likely to be
`physically impaired in terms of
`the :furce they can apply and thei.-
`degree of maoual
`control.
`
`This INds to an lncm.1se of the pH.Yalu. In non•buff,u·&d solutions
`
`Fig...., 2, pH shift in all-glass syringes
`
`delivery" systems such as µrefilled syringes a:re
`perhaps mindful that, one day, the predictions
`a:re likely to be fulfilled. Like its peen;, Boender
`
`• S~nges a-e made by haalng and forming glass llbes
`
`• USP T)1)8 I gl8Sll is a ~licale g!ISIS
`
`• Alcaline release from the gass is C8Utling pH-<1tih
`
`R"1at:i:vely simple, though impo.-- Figure 3: Sodiwn oxide releases sodiwn ions
`tant, new fuatnres include a bug-
`er finger flange DO the syringe barrcl aod a larger
`thnmb plate on the phmger, to make the device
`easia- to handle.
`
`Glas is :fu,-ging links and building expertise out-
`side prefilled syringes_ Indeed. specific applica(cid:173)
`tions of its core teclmologies in the areas of nee(cid:173)
`dle-free injection and nasal delivery are aheady
`being explored internally and wi1h partners_
`
`taming non-buffered drug solutions_ Fa< WFL the
`"PP"'" pH limit specified in the USP is 7.
`The shift in pH occurs because the USP
`
`Type l glass used in prefilled syringe manufac(cid:173)
`tme is a borosilicate glass, which must he sub(cid:173)
`j ected to varioll5 temperature changes during
`the glass hlhe pmdoction process (see Figure
`2)_ Around the beginning of the cooling phase,
`at 580 C, sodium oxide fonns and remains in
`the glass_ Doring storage, sodimn ions a:re
`released into the WFI and, as shown in figure 3,
`increase the concentration of hydroxide ions,
`thus increasing alkalinity
`Sodium oxide is transported during the tem(cid:173)
`pering process to the surface of the syringe glass
`barrel. Ove.- time, the ions DO the inside of the
`syringe a:re released into the Wfl_ This results
`finally in ao increase of the cDOcentration of
`hydroxide ioos, yielding a change in the pH.
`Buender Glas has developed ao ammonium
`sulfate pre-treatment process that solves this prob(cid:173)
`lem_ Ammonium sulphate is sprayed into the glass
`barrcl before the lelllpmng process of the fmmed
`syringe is started During the fullowiog heating
`pmcess, the funned sodium oxide rnacts widi the
`ammooium sulphate by :funning highly soluble
`sodium sulphate plus wateo: and ammonia.
`A study compared the pH increase in bi-dis(cid:173)
`tillr,d water in an uom,ated glass syringe with that
`of water in an ammonimn sulfate treated syringe_
`After being heaterl to 121 C for ooe how-, the pH
`of the water in the untreated syringe incrnased
`from 5_5 to 6_6 while the pH of the liquid inside
`tl,e trnated syringe incrcued funn 5_5 to 5 9. This
`effect was checked in srahility studies aod long(cid:173)
`term data is expected. soon
`
`INCREASING FOCUS ON THE
`PATIENT
`
`The general trend in the wider heallhrare sec(cid:173)
`tor, iocreasingly to place the patient more at the
`centre of treatment slrategies, rathe.-1han focusing
`purely on then- disease, is having a considerable
`impact on the prefilled syringes sectm and
`prompting new thinking
`The mqoin,ment from coosumern :fur more
`convenient treatments is ooe of the factors driv(cid:173)
`ing the pre filled S)'ringe ma:cket en masse.
`Howeva;. this demand fo.- convenience also
`gives companies within the sector an opportuni(cid:173)
`ty to differentiate themselves_
`Uppermost in the thoughts of many patients
`receiving injectioos are pain and discom:furt_ The
`needle is cleady the main component that dete.-(cid:173)
`mines how pleasant m nnpleasant a patient finds
`the injection. Buender Glas has identified three
`paramelel" sets that exert the greatest influence.
`The fut a:re the basic needle-quality charac(cid:173)
`teristics, soch as the requirement fin- a hook-free
`
`LONG-TERM VIEW
`
`Looking ahead, the continual prngress
`towa:rds ever cheaper and qoicke.- prndoctioo
`µrocesses, which has been underway from the
`fut days of prefilled syringe manufacture, will
`no dmibt continue in the background.
`One specific development µredicted in the
`coming yea:rs is an increased interest in the nse
`of plastics, instead of glass, fm the syringe body.
`Plastic is already widely used in syringes, but its
`application has hitherto been limited to hu-ge(cid:173)
`volume {20-50 ml) syringes fm delivering con(cid:173)
`trast media, fm example_
`For smalle,- volume syringes (0_5-2_0 ml)
`glass is the material of choice. Howeva;. pre-(cid:173)
`filled syringe l1lllillllllClorel"s are investigating
`the potential of plastic in therr products perhaps
`:fur use in certain niche areas yet to be identified.
`Buender Glas, for example, has a plastic µrodw:t
`ready fm- initial testing
`Finally, the predicti1111S made in the 1990s
`that invasive drug delivery was nea:ring its end
`were clearly somewhat prematnre. However,
`those involved in the prndnction of invasive
`
`CONCLUSION
`
`1be examples of innovations given above are
`just a :li,w among many new technologies and pro(cid:173)
`cesses that have been adopted in prefilled syringe
`production. Others involve, for example, increas(cid:173)
`ing further the sterility of the finished pmduct aod
`decreasing the number of particulates fuuod in the
`fommlation; optimising the design, cmnposition
`aod coatings fm elastormeric components such as
`plung=; aod noodle shields; and even iogeoioos
`advanced lahelliog technologies, including peel(cid:173)
`off tabs and radio fu:queucy traosmitters, to
`increase product sorely and security_
`The need :lb,- prefilled syringe p.-oducen to
`innovate and make real breakthrnughs has
`never been ga-eater than in ,ecent years. With
`the madet for µrefilled syringes estimated to
`have grnwn by more than 20% annually in the
`US since 1999. to reach its current size of $200
`million. and by around 8% annually in Emope
`to reach $1 billion, we appea:r to be rising to
`the challenge.
`
`•••
`
`Regeneron Exhibit 1013.005
`
`Copyright Cl 2005 ONdrugOeitvery Ltd
`
`www.ontlrugdellvery.com
`
`