Qrug ;Jel/118 ry tedmol, •J V
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`
`May 2009 Vol 9 No s
`
`Technology
`
`www.drugdeliverytech.com
`IN THIS
`ISSUE
`
`PROPERTY OF THE
`NATIONAL
`LIBRARY OF
`MEDICINE
`The ;cience & business of drug development in specialty pharma, biotechnology, and drug delivery
`
`Characterization
`Services
`Derek G. Hennecke, MBA
`
`20
`
`Inhaled
`Fonnulations
`M.W. Samaha, PhD
`
`32
`
`, Biophannaceutical
`Development
`40
`Dave Mead, PhD
`
`Particle Size
`Distribution
`Philo Morse, MS
`
`44
`
`FEATURING
`SPECIALTY~
`-~...':PHARMA
`
`Protein/Peptide
`Manufacturing
`Cindy H. Dubin
`
`Winning
`Partnerships
`Matt Siefert, MBA
`
`66
`
`69
`
`Regeneron Exhibit 1012.001
`
`

`

`AZt[Jf2bi![lJJi[
`
`The Total Product Development Company 1
`
`"
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`Get the most out of your resources
`with a single outsourcing partner!
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`
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`
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`Human clinical pharmacology and monitoring
`services for Phase 1-111 clinical trials.
`
`~ 2;LQ/,~ ,U,[J'
`
`Preclinical services in support of early
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`
`'
`
`):!5:.~:i;;;:
`-~;.:ilt,~
`
`Drug D!~~V.~fY FR E E
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`' - - · ... -.,,,.._-. .,i:!..!tl.L. L
`May 2009 Vol 9 No 5
`
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`
`Th is materia I was co,pied
`3tthe NLMa11d.mayoe
`
`Regeneron Exhibit 1012.002
`
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`~·-· -·---<·-·~·-·"·::,~··; .. . .:.,, _________________ ~
`
`antibodies, and other
`
`Drug Delivery of Sensitive Biopharmaceuticals With
`Prefilled Syringes
`By: Arno Fries, PhD
`' i · .... ··,_,.:_ .. _ ....... > ......... · ............. · ..
`:!
`'
`1
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`
`R cco.mbi~ant proteins, monoclona l
`
`'
`..
`
`_
`
`.. _biopharmaceuticals offer medication
`
`Silicone Oil
`
`Tungsten Needle Shield
`
`for life-threatening diseases. llowcver, these
`
`products consist of sensitive molecules. Among
`
`the causes for chemical and physical instability
`
`,.l
`
`are leachables in container closure systems.'·'
`
`Plunger
`
`Glass
`
`Adhesive Needle
`
`Interactions of leached contaminants with
`
`Product Contact Materials in Syringe Systems
`
`therapeutic proteins can result in aggregation,
`
`particulate formation, and loss of native protein
`
`tertiary structures.'·' Even small fractions of
`
`aggregated proteins might reduce biological
`
`activity and enhance immunogenicity.' for these
`
`reasons, strategies to prevent aggregation
`
`pathways and monitor aggregate levels in
`
`biopharmaceutical formulations arc important
`
`elements of product development.''
`
`BIOMOLECULES RAISE
`THE BAR
`
`of proteins). I3iopharmaccutic;1ls are primari ly
`
`commercialized in vials as lyophilizcd
`
`administered as injcctables, and liquid
`
`formulations. This means the advantages of
`
`formulations increase the risk posed by
`
`ready-to-use injection solutions in prcfillcd
`
`lcachables. Because these products often
`
`syringes arc not leveraged .
`
`contain the active molecule in low
`
`concentrations, trace amounts of contaminants
`
`might interact with the whole quantity.
`
`THE PROCESS IS THE
`PRODUCT
`
`PREFILLED SYRINGES
`
`Container closure compatibility is a
`
`regulatory rcquircmelll to protect the potency,
`
`Both for the ultimate end-users and
`
`efficacy, and safety of therapeutics. In glass(cid:173)
`
`based syringe systems, a range or materials gets
`
`I
`
`\
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`
`Strength, efficacy, and safety of active
`
`molecules are closely related to their chemical
`
`and physical properties. Most
`
`biopharmaceuticals are more sensitive toward
`
`product contact materials from container
`
`closure systems than small molecules. The
`
`di !Terence can be attributed to seve ral
`
`reasons.'·"' Biomolecules contain, due to their
`
`large size, a high number of functiona l groups
`
`that are prone to react with other compounds.
`
`This opens a wide range of pathways for
`
`;
`·; .,
`
`undesirable reactions with lcachables. In
`
`addition, the stability of biopharn1accutical
`
`products hinges on the three-dimensiona l
`
`orientation of the molecules (cg, native folding
`
`biopharmaceutical companies. prcfillcd
`
`syringes offer advantages over tradi tional
`
`in immediate contact wit h active ingredients:
`
`container systems."·" Medical staff and patients
`
`silicone oil, tungsten, closure, plunger. glass.
`
`prefer ready-to-use injection solutions in
`
`and (for staked need le syringes) adhesive and
`
`syringes because they arc convenient and
`
`needle (f,igurc I). The fact that closures arc
`
`prevent medication errors. The industry is
`
`considered product contact materials is
`
`utilizing these benefits with life cycle strategics
`
`reflected by change control procedures in the
`
`to gain competitive advantages and increase
`
`biophannaceutkal industry. When the rubber
`
`market shares. '"·" When molecules arc
`
`formulation of an established needle shicltl is
`
`expensive to manufacture, prcfillcd syringes
`
`modifiell by the supplier. 93.3%, of the
`
`increase revenues aml earnings as they reduce
`
`companies nm complete stability studies."
`
`prnduct overfill compared to vials. Due to these
`
`An evolving trend among
`
`benefits, the use or pre fil led syringes grows at
`
`biopharmaccutical companies is to enter closer
`
`double-digit rates. The trend is predicted to
`
`p:1rtrn:rships with syringe suppliers and to
`
`continue over the coming years.''·''' l lowcvcr, for
`
`scrutinize all aspects of their processes. The
`
`stability reaso ns. a number or biotherapeutics is
`
`paradigm from biopharmacc uti cal
`
`This m.atecri,a l wascopie<I
`attliE Nl:M and mavb.e
`
`Regeneron Exhibit 1012.003
`
`

`

`i\ 'i-hi\,·1 ' ,, -J r1 ' t"f\
`1ir, _D_) ·_·_ .. ) i_r_; l1·1 i1r'\\.r:.·r111_[1) \\r·
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`
`..
`
`. ·.""'
`
`manufacturing, "the process is the product," is bei ng
`
`How can alknli ion lcaclrnblcs in glass
`
`I. I units." These data reflect that EC 33 glass
`
`transferred to the production of prefi llcd syringes.
`
`syringes be reduced'/ The principal strategics are
`
`tubing contains lower quantities of sodiun1 oxide
`
`The rationale behind this shift in attention is that all
`
`use of glass material with lower sodium content,
`
`(4'Yo) than EC 51-52 glass.
`
`substances used during glass cutting, forming,
`
`treatment of the glass surface, and a combination
`
`Syringe barrels produced fro111 EC 51-52
`
`printing, needle staki ng, washing, siliconization,
`
`of both. Figure 2 compares analytical results wit h
`
`glass and treated with ammoni u111 sulfate (AST)
`
`assembly, packaging, and sterili zation arc potential
`
`I-ml long Luer cone syringes manufactured with
`
`contain on average 1.0 ppm sodium oxide in
`
`contact materials with sensitive bio111oleculcs.
`
`these methods.
`
`accordance to ISO 4802-2 testing. El' titration
`
`13iopharmacculical companies w.mt to catalog these
`
`Syringe barrels from Type l borosilicate glass
`
`(AST: 0.44 1111 I ICI, untreated barrels: 0.90 1111
`
`materials and understand how syringe suppliers
`
`with extension coefficient 51-52 (EC 51-52)
`
`1 lCI ) and pl l measurement (A ST: pH 6.0,
`
`control their processes.
`
`contain on average 2.3 ppm residual sodium oxide
`
`untreated barrels: pl I 6.6) confirm this result. The
`
`The following outlines recent advances in the
`
`on the interior surface. Quantitative analysis is
`
`increase in pl I of surface- treated barrels is 0.5
`
`field of pre filled syringes. Strategies to mitigate
`
`achicveu by fl ame atom emission spectrometry
`
`units, which is 0.6 units lower than in untreated
`
`stabi lity risks for sensitive biopharmaceuticals arc
`
`according to ISO 4802-2." When the barrels arc
`
`barrels. For ammonium sulfotc treatment, dosing
`
`discussed. Special focus is placed on alkalinity,
`
`ma nufactured from Type I borosilicate glass of
`
`pumps arc used to spray an aqueous solution of the
`
`tungsten, and si licone oil as sources of
`
`extension coefficient 33 ( EC 33 ). analysis shows a
`
`agent onto the inner surl:1ce or syri nge barrels.
`
`incompatibilities.
`
`signific;1nt ly reduced sodium oxide level of 1.2
`
`During the anneali ng step of the syringe
`
`pH RANGE
`
`When sensitive products arc applied in glass
`
`ppm. This result is in line with data according to
`
`manufacturi ng process, residual sodium oxide is
`
`·Er testing by equ ivalence titration with 0.0 I M
`
`converted under heat into the muc h better wa ter(cid:173)
`
`hydrochloric acid (EC 33: 0.46 ml I !Cl, EC 51-52:
`
`soluble sodium sul fate as follows: Nap+
`
`0.90 1111 I ICI) and pl I measurement with pl I meter
`
`(Nll..),SO,-> Na,SO, + 2 Nil , + 11,0. Removal or
`
`syringes, the pH value of the formulation needs to
`
`be considered.'" Elevated pH might trigger
`
`oxidation and hydrolysis of biopharmaccuticals.
`
`For the production of syringe barrels, glass
`
`tubing from Type l borosilicate glass according to
`
`USP, EP, and JP is used . Standard glass tubing has
`
`an extension coefficient of 51-52 and consists of
`
`70% to 80% SiO,, 15% 13,0/ Al,O,, and up to 7%,
`
`Na,O. The role of sodi um is to lower the forming
`
`temperatures of glass lo l ,000°C to l ,200°C, a
`
`prerequisite for industrial converting processes.
`
`"' Glass is a we ll-characterized material, and Type I
`
`inside the glass barrel to the surface. Each single
`
`~ borosilicate has cxccllcnl hydrolytic resistance.ii
`"'
`g However, the material is being heated during the
`g, syringe manufacturing cycle, and at tem peratures
`0
`.. ::E
`';:, above 800°C, sodium cations arc migrating from
`:,,,
`"'
`~ syringe-form ing step increases the quantity of
`-6 sod ium oxide on the glass surface by l 5'Yu to
`~
`t 30%." When an aqueous formu lation is filled and
`~ stored in a syringe, sodium ·cations arc being
`"' ::, o leached from the glass surface into solution. This
`24 causes in unbuffered solutions ,in increase in pH.
`
`C
`
`>
`
`(EC 33: pl!(, .!, EC 51-52: pl! 6.6, aq ua bi-dcst.:
`
`sodium su lfate is ac hieved tlownstream during
`
`pl I 5.5 )." Syringes from EC 33 glass increase the
`
`washing of the syri nge barrels and reduces
`
`pH val ue of aqueous solutio ns by 0.6 units,
`
`significantl y the amount of alkali ions on the glass
`
`whereas EC 51-52 glass barrels increase the pll by
`
`surface .
`
`,.
`
`,:&-.... ,, ~---'-"~·- _
`
`•
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`.,
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`.. . · ~.,.,,,,"".'~:~-:w~r~~ .s··-'· .
`........... ..._. ...... ._ ... 1.....,., .... .:..,0.~ ..... ~ . . . . . . ~ ................ ,,~ ...... ,, t);~,..,..~~:..i..,/~1~~;..:,t,JJ~..,,µ,1,...;_ ...
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`1.0
`
`0.5
`
`0.0
`
`1.2
`
`1.0
`
`0.8
`
`0 .6
`
`0.4
`
`0.2
`
`0.0
`
`EC 51-52
`
`EC 33
`
`EC 51 -52/AST
`
`EC 33/AST
`
`··:: . ·.··.
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`
`EC 51-52
`
`EC 33
`
`EC 51-52/AST
`
`EC 33/AST
`
`Alkalinity & pH Shift in Glass Syringes
`
`Th ismateria l was copied
`at the NLM and m ay l>e
`
`Regeneron Exhibit 1012.004
`
`

`

`ll
`il
`I f
`
`.
`
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`
`.
`
`.
`
`LA~fDfYl\tJL:.ELOJ. [Q)[LfLu\Y.lEITlW
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`
`Quantitative analysis according to ISO 4802-2
`
`colloidal solutions and aggregates.".,, Tungsten
`
`of the bore is covered by the needle.
`
`shows that syringes manufactured from EC 33 glass
`
`compounds can also react with hydrocarbons to
`
`Incorporation of tungsten in syringe barrels
`
`and treated with ammonium sulfate contain merely
`
`organometallic complexes and with molecules
`
`can be further reduced by controlling the abrasion
`
`r.5 ppm residual sodium oxide on the interior
`
`containing donor atoms to chelate complexes under
`
`of tungsten pins or through substitution of tungsten
`
`1urfacc. This is 78'Yo lower than in untreated
`
`formation of O-W-0, 0-W-S, 0-W-N, S-W-N, and
`
`with other materials. Wear of forming pins can be
`
`iyringcs from EC 51-52 glass. The pH of aqueous
`
`S-W-S bonds. The metal and its compounds arc
`
`lowered by horizontal barrel-forming technology.
`
`1o lutions in barrels from EC 33 tubing that arc
`
`also known as heterogeneous and homogeneous
`
`This manufacturing process is using lower
`
`,mmonium sulfate treated increases by 0.2 units. a
`
`catalysts that convert high quantities of substrates
`
`temperatures compared to vertical-forming
`
`;lecreasc of 82% compared to standard syringes.
`
`through non-stoichiometric reactions:" Other metal
`
`techniques. Other methods are directed at
`
`fhe combination of both methods (EC 33 glass and
`
`leachables occasionally found in drug products (cg,
`
`controlling the physical properties of the forming
`
`AST) efTccts the strongest reduction of alkali
`
`Fe'·, Ni'·, and Mn"' from stainless steel tanks used
`
`pins. As a substit ute for tungsten. alloys from group
`
`lcachablcs. This provides an efTicicnt strategy to
`
`in manufacturing equipment) arc known for similar
`
`9-10 transition metals can be employed. This
`
`control alkal inity and pl I-related interactions
`
`interactions with active molecules.'
`
`approach allows tungsten-free syringe forming.
`
`between sensitive biopharmaccuticals and glass-
`
`Pre filled syringes formed with tungsten pins
`
`However, intake of material from substitute pins
`
`based prcfillcd syringes.
`
`contain trace amounts of tt111gsten compounds in
`
`into syringe barrels cannot be ruled out. Some
`
`TUNGSTEN LEACHABLES
`
`the cone section, which is part of the product
`
`biopharmaceutical companies prefer the use of
`
`contact surface. Syringe filling processes with
`
`tungsten pins because potential efTects of tungsten
`
`Transition metals arc known as a cause for
`
`instability of sensitive products.' Tungsten can
`
`undergo interactions with protein therapeutics,
`
`leading to oxidation, aggregation. am!
`
`<lcgradat ion.,, .. '"
`
`In manufodurin g processes of glass syringes,
`
`tungsten metal is commonly used due to its heat
`
`resistance . Pins from this material arc keeping the
`
`bore open while the cone is being mechanically
`
`shaped with forming wheels (Figure 3).
`
`Tungsten is well characterized and stands out
`
`among all metals with the highest melting point
`
`(J,422°C), the highest tensile strength at elevated
`
`temperatures, and the lowest vapor pressure." Even
`
`though tungsten is very wcm-resistant, the metal is
`
`prone to oxidation under the conditions of syringe
`
`forming with temperatures up to I ,250°C. On the
`
`surface of tungsten pins, tungsten (IV) oxide (WO,)
`
`4 can be formed at temperatures under 400°C and
`
`tungsten (YI) oxide (WO,) between 500°C and
`
`800°C. In aqueous solution, tungsten (YI) oxide
`
`produces a mixture of soluble mono. oligo, and
`
`polytnngstatcs, wh ich arc stabilized at low pl I."·"
`
`These large anions arc highly charged species. They
`
`can interact w ith bipolar protein molecules through
`
`electrostatic attraction and induce limnation of
`
`plunger placement under vacuum intensify the
`
`on their products arc better understood than for
`
`contact between active molecules and tungsten
`
`most other transi ti on metals. Forming pins from
`
`because air bubbles in the cone of the syringe arc
`
`non-metallic materials and alternative techniques of
`
`pulled out :"
`
`syri nge forming are at an experimental stage.
`
`Proprietary methods for the extraction of
`
`To evaluate product stability of
`
`tungsten from syringe barrels and the subsequent
`
`biopharmaceutical fonm1 lations, spiking studies in
`
`quantitative physicochcmical analys is have been
`
`early phase development with material extracted from
`
`developed. Extractable tungsten concentrations arc
`
`used tungsten (metal) pins arc recommended.
`
`typically below 500 ppb and can be lower than I 00
`
`Subsequent stability studies in prefilled syringes
`
`ppb, depending on manufacturing cycle and
`
`verify the preliminary data and specify accepted
`
`washing process. Staked needle syringes contain
`
`tungsten (metal) levels. Advanced manufacturing
`
`the lowest amount of extractable tungsten as mos\
`
`methods for prcfillcd syringes together with targeted
`
`"' 0 z
`0, g
`°' 0
`
`0
`N
`
`>, .. ::E
`
`>,
`0,
`..9
`0
`C:
`.c
`u
`~
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`
`a
`0,
`
`2
`0
`
`Cone Forming With Tungsten Pins
`L.-.~~~.!llal&liabl!a~~~~~~~~~~~~~~~~~~~__J25
`atthe NLManclmavba
`
`Regeneron Exhibit 1012.005
`
`

`

`,i,.· ·1ih'f\JA'. \.:::Jfl~q'f\,·\ ff"ln··, i'r;ff \f\\1frt1r~\Y
`ir1!.!.Jr \~ .!"ll ·,j ~Lb LLV ~~ !_ \'j LJ-......
`,.DJ f 'V J ·t .:: ;
`
`stability studies ensure that interactions of highly
`
`of the lubricant in the following way.".," l!eat-
`
`sensitive biomolecules with tungsten are prevented.
`
`induced polymerization reactions reduce fractions
`
`SILICONE LUBRICANTS
`
`Even though silicone oil is inert toward most
`
`of low molecular weight from the silicone oil.
`
`Removal of water enables the lubricant to spread
`out evenly over the glass surface and creates a thin,
`
`uniform film. Mono-layers of the lubricant arc
`affixed 10 the glass surface. The interactions
`
`drug products, interactions with sensitive
`
`between polydimcthylsiloxanc and molecules from
`
`biopharmaceuticals have been observed. Such
`
`the glass surface range from van der Waals forces
`
`incompatibilities include aggregation, deformation,
`
`to covalent Si-0 bonds. This means thermal
`
`and inactivation of native protein structures.'·"
`
`fixation processes convert si licone oil into Si(R)O
`
`coating as illustrated in Figure 4." The thickness of
`
`silicone oil layers on the glass surface can be
`
`measured by reflectometry. A comparative study
`
`\
`..,si
`,,..
`\
`Si ,.,,,
`-si
`I
`-si ,,
`I
`
`-si
`/
`
`Glass
`
`PDMS
`
`Prcfillcd syringes are containers and drug
`delivery systems at the same time. Functionality of
`
`these systems (viable activation and gliding forces
`
`of the plunger) is accomplished by siliconization.
`
`Silicone oils are viscous, inert materials with
`
`excellent characteristics as hydrophobic
`
`lubricants:"·"' They consist of a mixture of
`
`polydimethylsiloxane (PDMS) molecules with Si-
`
`0 chains, which vary in length and number of OH
`
`groups. This molecular structure determines how
`
`silicone oil layers arc adsorbed onto glass surfaces
`
`and the distribution, thickness, composition, and
`
`uniformity of the layers. ln established
`
`using cartridges as glass containers found for oily
`
`Model of Silicone Coating
`
`sil iconization a layer thickness with a mean of
`
`232.67 nm and for baked siliconization of76.83
`
`nn1:w
`
`Parenteral biopharmaccutical products vary
`
`4. End user: QC testing of the samples,
`
`widely in nature. The sens iti vity of the active
`
`filled-syringe stability studies, and
`
`substance, the viscosity of the for111ulation, the
`
`eval uation
`
`drug delivery system, and its mode of operation
`
`(cg, prcfillcd syringes either manually or driven by
`
`autoinjector device) determine the principal
`
`5. Supplier: Scale-up, process validation.
`
`and industrial manufacturing of the
`
`syringes
`
`manufacturing processes on the lines of syringe
`
`suppliers, biopharmaccutic,1! companies, and
`
`CMOs, syringes arc oily siliconizcd by spraying
`
`0.4- to 1.0-mg silicone oi l (cg, Dow Corning 360,
`
`Medical Fluid) into the barrels.
`
`Advanced siliconization technology has been
`
`developed to lower the level of free (non-bound)
`
`si licone oil in prefilled syringes. The baked
`
`si liconization method uses emulsions of sil icone oil
`
`(cg, Dow Corning 365, 35% Dimcthicone NF
`"'
`~ Ernulsion, diluted in HPW) sprayed into syringe
`°' g barrels followed by heat treatment in a tunnel.
`g; Proprietary techniques and downstream washing
`0
`'
`: processes vary depending on syringe supplier.
`"'
`::.: Critical quality attributes of the siliconization
`i process arc controlled through the settings of
`C: 1J siliconization pump and nozzle, the volume flow of
`... ' r silicone spray and air, the concentration of the
`
`>,
`
`•
`
`01
`
`'
`
`~ silicone oil emulsion and tunnel temperature,
`~ spcctL and length. This technology alters the nature
`
`26
`
`requirements. Silicone coati ngs ofprcfillcd
`
`syringes can be customized to meet specific needs.
`
`Variation of process parameters adapts the
`
`characteristics of the siliconizntion. Best results
`
`are obtained when syringe manufacturer (supplier)
`
`and biopharmaceutical company (end user) partner
`
`and work along the following project steps:
`
`l . End user: Specification of accepted
`
`silicone oil levels and system
`
`functionality
`
`2. Supplier: Development of baked
`
`siliconization process for the specified
`
`attributes
`
`Fundamental understanding of the design
`
`space of baked sil iconization allows the syringe
`
`manufacturer to derive relevant process parameters
`
`from the specified quality attributes of the
`
`syringes./\ range of syringe samples arc produced
`
`through custom-engineered processes. Quality
`
`inspection and initial stability studies with the sci
`
`of sa111plcs determine which silicone coating is
`
`ideal for purpose.
`
`/\ case study has demonstrated how
`
`customization of baked si licone coatings facilitates
`
`stability of sensitive molecules in pre filled
`
`syringes (cg, vaccine candidate in
`
`biophannaccutical development). The study has
`
`3. Supplier: Manufacturing of customized
`
`deepened the insight into the relationship betwcrn
`
`baked silicone syringes in sa111ple
`
`siliconization parmnclcrs :rnd critical quality
`
`quantities
`
`Tlli:smater ical wca:scopied
`at the NtM and m.ay be
`
`attributes.'" The amount of extractable silicone oil
`
`could be reduced below the detection limit (0.03
`
`mg) of ICl'-/\ES according to EN ISO I 1885.
`
`Regeneron Exhibit 1012.006
`
`

`

`With low levels of h1bricant quantity, the specified
`
`syringe functionality was fulfilled (plunger gliding
`
`REFERENCES
`
`forces in the range or 5 to IO N).
`
`Close partnerships between
`
`biopbarmaceutical companies and syringe
`
`suppliers arc instrumental in controlling the impact
`
`of product contact materials on sensitive
`
`biotherapeutics. Principal requirements regarding
`
`drug ddivery systems arc ideally defined and
`
`specified in an early phase of biopharmaccutical
`
`development. Manufacturing processes and quality
`
`attributes of prcfillcd syringes can be custom(cid:173)
`
`engineered according to these needs.
`
`SUMMARY
`
`In today's biopharmaccutical market ,
`
`products arc exposed to fierce compet ition. The
`
`role of drug delivery strategics to differentiate
`
`products is growing. A number of
`
`biopharmaceuticals has already been
`
`commercialized in the prcfillcd syringe platform.
`
`J lowevcr, syringe systems arc sources of potential
`
`incompatibilities with sensitive molecules. The
`
`prefillcd syringe industry has therefore engineered
`
`manufacturing processes that mitigate stability
`
`ri sks from alb li ions, tungsten, and silicone
`
`lubricants. Advanced methods for surface
`
`treatment to control pl I, tungsten-reduced forming
`
`techniques, and baked si liconiiation processes to
`
`immobilize sil icone oil have been developed.
`
`Syringe manufacturers have establishcJ expertise
`
`in material science and process technology to
`
`understand biopharmaccutical requirements.
`
`Evol ving needs of highly sensitive pipeline
`
`products can be met with customized drug delivery
`
`systems. Current technology allows
`
`biopharmaccuticnl companies to cxploit the
`
`bencrits or pre filled syringes and re:ilizc the fu ll
`rotential of thdr products. +
`
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