PREFILLED SYRINGES
`
`Baxter
`•
`GERRESHEIMER
`
`VETTER
`
`~BO
`
`PS0 MED
`
`SElF'C RE SOLUTIONS
`
`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, Newtirnber Place Lane,
`Newtirnber, 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.;,
`Due care hos 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
`iabityfil"the con.._.,e, of ,ny decismor actm taken
`(<I" not 1llkenl .. a resut of any mwmatioo cornned ii this pit,icaticri.
`
`• excep1: the ride: "O.DIUci1111 •• a strategic decism"
`l!:I Veit!!" Pharrna-f<nil(Ung
`
`Front cover 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)
`
`The next generation of safety prefill devices:
`NMTs Safety Prefill Needle Unit enters the
`commercial st.age.
`Ian Littleton (NMT Group)
`
`Outsourcing as a strategic decision
`Max Horn (Vetter Pharma-Fertigung)
`
`-
`
`-
`
`-
`
`@§• 1j
`
`•tJlj
`•lit+
`
`The intricacies of selecting and evaluating
`plungers for prefilled syringe systems
`
`Frances DeGrazio (West Pharmaceutical Services) f if§Fr
`
`New-generation auto-injectors:
`taking self injection beyond prefilled syringes
`Ian Thompson (Ypsomed)
`
`Company profiles
`The Medical House
`Imprint Pharmaceuticals
`
`f1148
`
`-
`
`,._,ondrugdelivery.com
`
`Copyright © 200 5 ONdrugDelivery Ltd
`
`Regeneron Exhibit 1013.002
`
`

`

`•
`GERRESHEIMER
`pha maSystems
`
`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 must devise methods of overcoming them. In this piece, Dr Thomas
`B rachtendorf and Mathias Romacker, Directurs of Bnsiness Development at Buender Gb.s
`(a division of Gernsheimer pharmaSystems), 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 marlret as the tradi(cid:173)
`tion.al, more cOJ1ventional side of drug delivery.
`As snch., they do not tend to associate it with the
`level of mtting-edge science and tecbnnlogy
`that is readily linked with olher delivery meth(cid:173)
`ods. such as advanced inhalers.
`In reality though. the experienre of illlyone
`close to the injectables sector would lead them
`to take a quite different view. The rmmber of
`injectable products is rocketing - not least
`because injection is cwrentl:y the only viable
`way of delivering many of them. As a conse(cid:173)
`qlleDCe, demand for technologies that improve
`the production. 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 Pouleoc-Rorer in the early
`1980s At that time, the prefilled-syringes mar(cid:173)
`lret was viewed as a relatively insigoificant
`niche area within the huge injectahles marlret..
`Therapeutically, prefilled syringes were limited
`to a narrow nmge of applications in a fuw vac(cid:173)
`cines and anticoagulant products. Their use was
`also limited geographically to Enrnpe.
`Initial interest, during the 1980s and 1990s,
`was sparked primarily by the clear advantages
`prefilled syringes have over traditional vials and
`amponle"- The procedure fur using a prefilled(cid:173)
`syringe product ofteo involves nothing more
`than removing the syringe from the packaging
`and injecting the formulation. In cOJ1trast, any(cid:173)
`ooe administering a traditiOJlai injection from a
`
`vial might typically have to: read the required
`dose 6:om the physician's dosing directions,
`withdraw from the vial slightly more formnla(cid:173)
`tion than is required. invert the syringe to allow
`any air bubbles to reach the top. depress the
`plunger slightly to expel any air and. finally,
`dq,,xss the plunger slightly fmther still to leave
`precisely the required dose, which they measure
`using the scale along the syringe barrel
`Prefilled syringes, with their single-use, dis(cid:173)
`posable format, together with the fact that they
`eliminate several of the procedures required
`prim: to administering a formulation presented
`in a. vial are significantly quicker and mm:e con(cid:173)
`venient. Ease of use, in addition to simply mak(cid:173)
`ing them more convenient, means that prefilled
`syringes are safer.
`The maj m: safety benefit is the redoced 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 prefilled syringe is filled
`mechanically and is checked electronically dur(cid:173)
`ing quality control.
`As well as reducing errors in the dose quanti(cid:173)
`ty, pre:lilled syringes reduce the risk of adminis(cid:173)
`tering the wroog prodnct because the syringe and
`packaging are cleady 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 syringe can be left full of
`drug but completely nmnarked, on a tray ready to
`use. This is a danger period since the identity of
`the drug in the syringe is typically known only to
`
`Copyright Cl 2005 ONdrugDellvery Ltd
`
`www.ondrugdellvery.com
`
`Regeneron Exhibit 1013.003
`
`

`

`Figure 1a
`
`Figwe 1b
`
`Oily Siliconised Syringes
`
`Baked-on-Silicone Syringes
`
`l§1=~1 " '="
`
`Dlr«t contact rubbtr to glass surface
`leads OV<!r time to higher b~ak-out forces.
`
`Baked liUXll11.1 provides consistent
`Coaling of the ~ bamil wall&.
`.,. Break-<JUt ton::es 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 peISOIL If they are
`dislra.cted during the dimgerpaiod, or""' pcrlmps
`calkd away to an emagency and have to hand
`over to another p= the job of giving the injcc(cid:173)
`ticm, there is a real risk of a mistake ocruo:iog.
`Ano1het- safety benefit is the reduced risk of
`needle-sliclc in_ju,:y. Accidents are more likely with
`ttaditional formats because the user is required to
`expose the m,e&c tip fur longcr-, while pedimning
`a series of actions requiring dexterity and concen(cid:173)
`tJ:ation. The fact that prefilled syringes are s.ingle(cid:173)
`use devices also eliminates the possibility of
`cross-infeciion arising from noedu, re-use.
`Prefilled syringes contain the precise am01mt
`of drug that is to be injected. but vials and
`ampoules have to con1ain more liquid than the
`actual dose in order fur the correct amount to be
`withdrawn. The excess formulation is wasted
`and, especially with expensive biotech products,
`elimination of wastage allows the manufacturer
`to mah, signifu:ant 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
`marlret. with its shorter history of pre.filled
`syringes, was piHl: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 Europ,,. new drugs that have
`been presented in prefilled syringes include: ery(cid:173)
`thropoietins such as Recormon and Eprex; inter(cid:173)
`furons lih, Betaferon, AVOJIBX, Copaxone and
`Rebif; and dieumatoid arthritis drugs lih, Enbrel
`and Hnmira. to name just a few.
`Cnicially, biotech provided. a late but very
`
`profound entry into the previously UDtapped US
`market, where many of the aforementioned
`products, and many other biotech products,
`were developed and launched fust - often in
`prefillcd syringes.
`
`RECENT INNOVATIONS
`
`The continually inaeasiog demand for pre(cid:173)
`filled syringes has maintained pressure on man(cid:173)
`ufacturers to devise methods for increasing pro(cid:173)
`duction capacity and driving down costs.
`Alongside these ongoing advances, which focus
`on improving the overall efficiency of the pro(cid:173)
`duction process, recent trends in the industry,
`and in the healthcare environment generally,
`have given rise to several specific innovations
`that improve the quality of prefilled syringes:.
`Like many manufacturers, Buender Glas has
`experienced a rapid expansion in the number of
`therapeutic classes its prefilled syringe products
`must serve, end foresees a continuation of this
`trend. Its novel technologies broaden the range
`of products that cao be presented in prefilled
`syringes and, crucially, increase the acceptabili(cid:173)
`ty of prefilled syringes amcmg the patients and
`medical professionals that use them.
`
`BAKED-ON SILICONE
`
`Among the most important innovations are
`those that have overcome the compatibility and
`stability issues that arise when dealing with
`biotechnology fu.rnrulatinns. One particularly
`common problem has been that such products
`cao 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 propensity for silicone to 1eact with the
`fommlation is dependent on the concentration
`
`of silioone in the syringe and its chemical IICtiv(cid:173)
`ity. The latter is determined by the number of
`terminal hydroxyl groups, which is greater the
`shorter the sihccme polymer chain length..
`Baking-on the silicone - which involves heat(cid:173)
`ing the silicone-coated. 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 concentration of silicone
`in the syringe and its chemical reactivity am both
`reduced and the product's stability is increased.
`The second benefit of baked-on silicone is
`that it reduces the frequency of the ornak
`loose" effect. The effect can occur during stor(cid:173)
`age when the rubber closure, inside the syringe
`barrel, expands outwards so that eventually it
`displaces the low-fiiction silicone coating and
`comes into direct contact with the inner glass
`surfiice {see figure la).
`The user cannot detect the problem until the
`poinl of administration when they try to depress
`the plunger. Because the rubber closure is essen(cid:173)
`tially stuck to the inside surface of the syringe, a
`high initial force is needed to shift it. The needle
`has already penctndcd the patient's skin end the
`lip is posilioned 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 clo,ure is freed up, is clearly nndesirable.
`As sh<JWJ1 in fig111e 1 b. baked-on silicone
`provides a more consistent coating of the
`syringe walls, which prevents the expanding
`rubber closuce from touching the glass wall
`Lubrication is maintained so that the initial
`furce required to inject using prefilled syringes
`with baked-on silicone remains consistently law
`before and after storage.
`Syringes with staked-in needles have yet
`another advantage from the baked-on sihconisa(cid:173)
`tion process. Until now, baked-on silicone was
`not available with stabd-in needle syringes
`since a needle could not be glued into the chan(cid:173)
`nel of a syringe after baking process or the bak(cid:173)
`ing process itself would soften the glue in the
`chaJ:mel, 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
`undesirable pH change that sometimes OCCUIS in
`liquids stored in prefilkd syringes. It has been
`observed in solvent syringes conlllioing watec for
`injection {WFI) or saline solution, in diluent pm(cid:173)
`filled syringes, which contain WF1 for reconsti(cid:173)
`tuting lyophi1ised products, and in syringes con--
`
`www.o11c:1rug11e11very.com
`
`Copyright <i, 2005 ONdrugDellvery Ltd
`
`Regeneron Exhibit 1013.004
`
`

`

`Sodium Oxide Releases Sodium Ions
`
`needle tip and smooth surfaces.
`These are achieved through a
`validated, reliable production
`process. Secondly, there are less
`critical, subtler facmrs such as
`the nnmber of bevels at the nee(cid:173)
`dle tip, the aogle of the bevels
`and the bevel length_ Thndly,
`the coating substance and
`method of application,
`for
`example silicooisation, have
`been recognised as key in deter-
`mining the pain of injection.
`The increase in the number
`of prefilled syringes being used ID self-injoct,
`often at home, is in pa:rt a reflection of the trend
`IDwa:rds more patient--centroo treatments, hut
`equally due to the application of
`prefilled syringes in new indica(cid:173)
`tions, such as memn.a1oid arthri(cid:173)
`tis and multiple sclerosis_
`Prefilled syringe manufactur(cid:173)
`ers a:re developing design fea-(cid:173)
`tmes that talre into account that in
`diseases su:h as these, dlfO self(cid:173)
`injecting patient is likely to be
`physically impaired in tams of
`1he force they can apply aod !heir
`degree of manual
`control.
`
`This loads to an lncmas.o of th• pH-valua In non-buff9r&d oolutlons.
`
`Fig...., 2, pH shift in all-glass syringes
`
`deliveiy systems such as pre£lled syringes a:re
`perhaps mindful that, one day, the predictions
`a:re likely 1o be fulfilled. Like its peers, Boender
`
`• S)ti!VIS 1n1 made by h8afng ind forming gla$8 1.Jbes
`• USP T)Pe I gl- is e boroeilicete gas,,
`• Alceline release from the gl1111$ is caa,ing pH~ti11$
`
`Relatively simple, though impor- Figure 3: Sodiwn oxide releases sodiwn ions
`tant. new reatnres inclnde a llllg-
`er finger flange on the syringe bancl and a larger
`thumb plate on the phmger, 1o make the device
`easie:i: to handle.
`
`Glas is forging links and building expertise out-
`side prefilled syringes. Indeed. specific applica(cid:173)
`tions of its core: tr:clmologies in the areas of nee(cid:173)
`dle-free injection and nasal deli:very are aheady
`being explored internally and wi1h partners_
`
`taming non-buffered drug solutions_ Fa< WFL the
`"PP"'" pH limit specifi...t 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 oo the inside of the
`syringe a:re released into the WA_ This results
`finally in an increase of the coocentration 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
`
`process., the formed sodium oxide reacts with the
`ammonium sulphate by fuo:ning highly soluble
`sodium sulphate plus water and ammonia.
`A study compared the pH increase in bi--dis(cid:173)
`tilled water in an uotreated glass syringe with that
`of water in an ammonium sulfate treated syringe.
`After being heated to 121 C for ooe hour, the pH
`of the water in the untreated syringe increased
`from 5.5 to 6.6 while the pH of the liquid inside
`Ibo, 1reaJed ~")'Iinge increased funn 5.5 to 5 9. This
`effect was checked in stability studies aod long(cid:173)
`term da.ta is expected soon.
`
`INCREASING FOCUS ON THE
`PATIENT
`
`The general trend in the widel" healthcare sec(cid:173)
`lDr, iocreasingly to place the patieot more at the
`centre of treatment strategies, rathe.-1han focusing
`purely on their disease, is having a considerable
`impact on the prefilled syringes sec1or aod
`prompting new thinking
`The mqoiremen.t from coosume:rs :fur more
`convenient treatments is ooe of the facmrs driv(cid:173)
`ing the pre filled syringe market en masse.
`Howeva;. this deroaod fur convenieoce also
`gives companies within the sector an opportuni(cid:173)
`ty to ddrerentiate themselves.
`Uppermost in the thoughts of many patients
`receiving injections are pain and discom:furt_ The
`needle is clearly the main component that deter(cid:173)
`mines how pleasant or nnpleasant a patieot finds
`the injection. Bueoder Glas has identified three
`parameter sets that exert the greatest influence.
`The £:rst a:re the basic needle-quality charac(cid:173)
`teristics, such as the requirement for a hook-free
`
`LONG-TERM VIEW
`
`Looking ahead, the continual progress
`towards ever cheaper and quicker prodoction
`processes, which has been underway from the
`first days of prefilled syringe manufacture, will
`no doubt continue in the background.
`One specific development predicted in the
`coming yea:rs is ao increased interest in the use
`of plastics, instead of glass, for the syringe body.
`Plastic is already widely us...t io syringes, but its
`application has hitherto been limited to hu-ge(cid:173)
`volume {20-50 ml) syringes for delivering con(cid:173)
`trast media, for example_
`For smaller volume syringes (0_5-2_0 ml)
`glass is dlfO material of choice. Howeva;. pre-(cid:173)
`filled syringe manufacturers are investigating
`the potential of plastic in their products perhaps
`fur use in certain niche areas yet to be identified.
`Buender Glas, for example, has a plastic prodw:t
`ready fm- initial testing
`Finally. the predictiOIIS made in the 1990s
`that invasive chug delivery was nea:ring its end
`were clearly somewhat prematnre. However,
`those involv...t in the production of invasive
`
`CONCLUSION
`
`The examples of innovatioos given above are
`just a few among many new teclmologies 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 and
`decreasing the number of particulates fuuod in the
`fommlation; optimising the design, composition
`and coa:tiogs for elastmmeric components such as
`plung=; and noodle shields; and even ingenious
`advaoced labelling teclmolog:ies, including peel(cid:173)
`off tabs and radio frequeucy transmitters, to
`increase pmduct safety and security_
`The need fur prefilli,d syringe producer-s ID
`innovate and make real breakthroughs has
`never been greater than in recent yea:rs. With
`the llllllket for prefilled syringes estimatoo ID
`have grown by more than 20% annually in the
`US since 1999. to reach its current size of $200
`million. and by a:round 8% annually in Europe
`to reach $1 billion, we appea:r to be rising ID
`the challenge.
`
`•••
`
`Regeneron Exhibit 1013.005
`
`Copyright Cl 2005 ONdrugDellvery Ltd
`
`-
`
`.ondrugdellvery.com
`
`