D··ug i.lel1v8ry tedmol, ..:1v .
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`
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`
`May 2009 Vol 9 No s
`
`e c h n o l o g y
`
`www.drugdeliverytech.com
`IN THIS
`ISSUE
`
`·
`
`-
`
`[DDV1a a
`Sel~c
`Ba:r:rier
`
`PROPERTY OF THE
`NATIONAL
`LIBRARY OF
`MEDIC::,:l~N~E _ _;. ........ - . . . . . - i ....... . . . . . - . ~~,,"
`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 !1111
`-=r:PHARMA
`
`Protein/Peptide
`Manufacturing
`Cindy H. Dubin
`
`Winning
`Partnerships
`Matt Siefert, MBA
`
`66
`
`69
`
`Regeneron Exhibit 1012.001
`
`

`

`AzlcYgJJi!!!JJ§[
`
`The Total Product Development Company™
`
`Get the most out of your resources
`with a single outsourcing partner!
`Azopharma Product Development Group offers bundled
`services from key sections of the drug development
`process including the Preclinical, CMC and Clinical phases
`that extend your financial resources by maximizing
`communication and minimizing downtime! Contact
`Azopharma to develop a comprehensive solution for your
`product development needs.
`
`AZOPHARMA PRODUCT DEVELOPMENT CROUP OF COMPANIES,
`
`Az012!]"?.Jt:[!1.?'"
`
`Integrated product development including
`synthesis, analysis, formulation and CTM
`manufacturing for all dosage forms
`
`~ AVIVOcuN··
`~ ~
`Clinical Services
`Human clinical pharmacology and monitoring
`services for Phase 1-111 clinical trials.
`
`~ ~rJL~J,i,r:f
`
`Preclinical services in support of early
`product development.
`
`May 2009 Vol 9 No 5
`
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`Ralph Vitaro
`
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`Dan Marino, MSc
`dmarino@drugdeliverytech.com
`
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`
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`
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`
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`
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`
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`reproduced or transmitted in any form or by any means, elect10riic or mechanical. including by photocopy, recording,
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`
`Th is m ater ial was copied
`at the NLMand:mayb,e
`
`Regeneron Exhibit 1012.002
`
`

`

`· This material may be protected by Copyright law (Title 17 U.S. Code)
`
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`Drug Delivery of Sensitive Biopharmaceuticals With
`Prefilled Syringes
`By: Arno Fries, PhD
`"":
`.:..:.....·
`.·., .. ·. ·, ·· ... .
`
`.
`
`R ccombinant proteins, monoclonal
`
`antibodies, and other
`
`'
`..
`
`_
`
`.. _biopharmaceuticals offer medication
`
`for life-threatening diseases. I lowever, these
`
`products consist of sensitive molecules. Among
`
`the causes for chemical and physical instability
`
`are leachables in container closure systems.'·'
`
`Silicone Oil
`
`Tungsten Needle Shield
`
`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.' f'or these
`
`reasons, strategies to prevent aggregation
`
`pathways and monitor aggregate levels in
`
`biopharmaceutieal formulations arc important
`
`elements of product development.''
`
`of proteins). I3iopharmaccutic,1ls arc primarily
`
`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
`
`lcachablcs. 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
`
`\
`
`.\
`
`I
`I ,
`
`I
`
`\
`\
`
`\
`
`I
`
`BIOMOLECULES RAISE
`THE BAR
`
`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 several
`
`reasons.'·'" Biomolecules contain, due to their
`
`large size, a high number of functional groups
`
`that are prone to react with other compounds.
`
`This opens a wide range of pathways for
`
`;
`·; .,
`
`undesirable reactions with lcachablcs. In
`
`addition, the stability of biopharn1accutical
`
`products hinges on the three-dimensional
`
`orientation of the molecules (cg, native folding
`
`a,
`0
`0
`N
`>,
`
`"' ::E
`
`22
`
`PREFILLED SYRINGES
`
`I3oth for the ultimate end-users and
`
`biophannaccutical companies, prcfillcd
`
`syringes offer advantages over traditional
`
`Container closure compatibility is a
`
`regulatory rcquircmclll to protect the potency,
`
`efficacy, and safety of therapeutics. In glass(cid:173)
`
`based syringe systems, a range of materials gets
`
`in immediate contact with active ingredients:
`
`container systems."·" Medical staff and patients
`
`si licone oil, tungsten, closure, plunger. glass.
`
`prefer ready-to-use injection solutions in
`
`syringes because they arc convenient and
`
`and (for staked needle syringes) adhesive 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
`
`reneetcd by change control procedures in the
`
`to gain competitive advantages ;111d increase
`
`market shares. '"·" When molecules arc
`expensive to manufacture, prcfillcd syringes
`
`biopharmaceutical industry. When the rubber
`
`formulation of an established needle shield is
`
`modificll by the supplier. 93.3%, of the
`
`increase revenues and earnings as they reduce
`
`companies run complete stability studies."
`
`product overfill compared to vials. Due to these
`
`An evolving trend among
`
`benefits, the use of prcfillcd syringes grows at
`
`biopharmaccutical companies is to enter closer
`
`double-digit rates. The trend is predicted to
`
`p:irtrn:rships with syringe suppliers and to
`
`continue over the coming years.''·''' I lowevcr, for
`
`scrutinize all aspects of their processes. The
`
`stability reasons. a number ofbiothcrapeut ics is
`
`paradigm from biopharrnaccutical
`
`This mate-ria I \.vas copied
`at. the N:LM and mav :he
`
`Regeneron Exhibit 1012.003
`
`

`

`.. , .. - ... ·- · . ·---, -· • .~.••• •• -
`
`· - - - - -.... ~ • [ • •
`
`, .... .. , ... ·Ao"o h ·;, - , ,., ,,. ~ .
`
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`
`manufacturing, "the process is the product," is bei ng
`
`How ca n alkali ion leachablcs in glass
`
`1.1 units. '' These data reflect that EC 33 glass
`
`transferred to the production of prefillcd syringes.
`
`syringes be reduced'/ The principal strategics are
`
`tubing contains lower quant ities of sodiu111 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 from EC 51-52
`
`printing, needle staking, washing, siliconization,
`
`of both. Figure 2 compares analytical resul ts with
`
`glass and treated with ammonium sulfate (AST)
`
`assembly, packaging, and sterilization arc potential
`
`I-ml long Luer cone syringes 111anufacturcd with
`
`contain on average 1.0 ppm sodiu111 oxide in
`
`contact materials with sensi tive bio111olcculcs.
`
`these 111ethods.
`
`accordance to ISO 4~02-2 testi ng. EP titrati on
`
`8iopharmaceutical companies want to catalog these
`
`Syringe barrels fro111 Type l borosilicate glass
`
`(AST: 0.44 ml llCI, untreated barrels: 0.90 1111
`
`materials and understand how syringe suppliers
`
`with extension coefficient 51-52 (EC 51-52)
`
`1 ICI ) :ind pl I measurement (A ST: pH 6.0,
`
`control their processes.
`
`contain on average 2.3 ppm residual sodium oxide
`
`untreated barrels: pl I 6.6) rnn fi rm this result. Th..:
`
`The following outlines recent advances in the
`
`on the interior surface. Quantitative analysis is
`
`increase in pl I or surface-treated barre ls is 0.5
`
`field of pre filled syringes. Strategies to mitigate
`
`achieved by flame atom emission spectrometry
`
`units, which is 0.6 units lower than in untreated
`
`stability ri sks for sensitive biopharmaceuticals arc
`
`according to ISO 4802-2." When the barrels arc
`
`barrels. For ammonium sull'atc trcalincnt , dosing
`
`discussed . Special focus is placed on alka linity,
`
`manufactu red from Type I borosilicate glass or
`
`pumps arc used to spray an aqueous solution of the
`
`tungsten, and silicone oil as sources of
`
`extension coefficient 33 ( EC 33 ), analysis shows a
`
`agent onto the inner surface or syringe barrels.
`
`incompatibilities.
`
`significantly reduced sodium oxide level of 1.2
`
`During the anneal ing step or the syringe
`
`pH RANGE
`
`When sensitive pro<lucts arc applied in glass
`
`syringes, the pH value of the formulation needs to
`
`ppm. This result is in line wi th data according to
`
`manufacturi ng process, residual sodium oxide is
`
`·Er testin g by equivalence titration with (l.01 M
`
`converted under heat into the much better wa ter(cid:173)
`
`hydrochloric ac id (EC 33: 0.46 ml I ICI, EC 51-52:
`
`0.90 ml I ICI) and pl I 111casurcmcnt with pl I meter
`
`(EC 33: pl l 6.1, EC 51-52: pl! 6.6, aqua bi-dest.:
`
`pl I 5.5).'' Syringes from EC 33 glass increase the
`
`soluble sodium sulfa te as follows: Na,O +
`(Nll.,),SO, ....., Na,SO, + 2 Nil ,+ 11,0. Removal or
`sodium sulfate is achieved downstream durin g
`
`be considered.'" Elevated pf! might trigger
`
`oxidation and hydrolys is ofbiophamrnccuticals.
`
`For the production of syringe barrels, glass
`
`tubing from Type I borosil icate 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% B,0 / Al,O,, and up to 7%,
`
`Na,O. The role of sodi um is to lower the forming
`
`temperatures of glass to I ,000°C to I ,200°C, a
`
`prerequisite for industrial converting processes.
`
`\l'\ Glass is a we ll-charac terized material, and Type I
`
`~ borosilicate has cxccllcnl hy<lrolytic rcsistance.! 1
`g However, the material is being heated during the
`g; syringe manufacturing cycle, and at temperatures
`
`0
`~ above 800°C, sod iun1 cations arc n1igrating from
`
`.. :E:
`
`inside the glass barrel to the surface. Each single
`
`>,
`en
`~ syringe-forming step increases the quantity of
`<=
`-5 sod iwn oxide on the glass surface by l 51Xi to
`~
`t 30%." When an aq ueous formulation is filled and
`~ stored in a syringe, sodium cations arc being
`:, c leached from the glass surface into solution. This
`causes in unbuffered sol utions an increase in pH.
`
`>
`
`O'>
`
`24
`
`pH value of aqueous solutions by 0.6 units,
`
`significantly the amount or alkali io ns on the glass
`
`1V,1shing of the syringe barrels and reduces
`
`whereas EC 5 1-52 glass barrels increase the pll by
`
`,.
`
`.
`
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`
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`F (G U .. R. E 2
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`
`N
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`
`1.5
`
`1.0
`
`0.5
`
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`
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`
`1.0
`
`0.8
`
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`
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`
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`
`EC 51-52
`
`EC 33
`
`EC 51-52/AST
`
`EC 33/AST
`
`00
`.. -, ... '.
`
`EC 51-52
`
`EC 33
`
`EC 51-52/AST
`
`EC 33/AST
`
`Alkalinity & pH Shift in Glass Syringes
`
`l1l is m ateri.a l w .ascopied
`3tthe N.LM .3nd m.3y be
`
`Regeneron Exhibit 1012.004
`
`

`

`ll
`i]
`
`I •
`
`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
`
`0nd treated with ammonium sulfate contain merely
`~-5 ppm residual sodium oxide on the interior
`
`1urfocc. This is 78% lower than in untreated
`iYringcs from EC 51-52 glass. The pH of aqueous
`
`1olutions in barrels from EC 33 tubing that arc
`1mmonium sulfate treated increases by 0.2 units, a
`jecreasc of 82% compared to standard syringes.
`
`organometallic complexes and with molecules
`
`can be further reduced by controlling the abrasion
`
`containing donor atoms to chelate complexes under
`
`of tungsten pi ns or through substitution of tungsten
`
`formation of O-W-0, 0-W-S, 0-W-N, S-W-N, and
`
`with other materials. Wear of forming pins can be
`
`S-W-S bonds. The metal and its compounds arc
`
`lowered by horizontal barrel-forming technology.
`
`also known as heterogeneous and homogeneous
`
`This manufacturing process is using lower
`
`catalysts that convert high quantities of substrates
`
`temperatures compared to vertical-forming
`
`through non-stoichiometric reactions.-" Other metal
`
`techniques. Other methods are directed at
`
`fhc combination of both methods (EC 33 glass and
`
`kachables occasionally found in drug products (cg,
`
`controlling the physical properties of the forming
`
`AST) effects the strongest reduct ion 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 efficient strategy to
`
`in manufacturing equipment) arc known for sim ilar
`
`9-10 transition metals can be employed. This
`
`control a!blinity and pl 1-rclated interactions
`
`interactions with active molecules.'
`
`approach allows tungsten-free syringe forming.
`
`between sensitive biopharmaceuticals and glass-
`
`Prcfillcd syringes formed with tungsten pins
`
`However. intake of material from substitute pins
`
`based prefilled syringes.
`
`contain trace amounts of tungsten 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 effects of tungsten
`
`plunger placement under vacuum intensify the
`
`on their products arc better understood than for
`
`contact between active molcculcs and tungsten
`
`most other transition metals. Forming pins from
`
`Transition metals arc known as a cause for
`
`because air bubbles in the cone of the syringe arc
`
`non-metallic materials and alternative techniques of
`
`instability of sensit ive products.' Tungsten can
`
`undergo interactions with protein tlicrapeutics,
`
`leading to oxidation, aggregation, and
`
`degradation.''··'"
`
`In manufacturing 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 wem-rcsistant, the metal is
`
`prone to oxidation under the conditions of syringe
`
`forming with temperatures up to J,250°C. On the
`
`surface of tungsten pins, tungsten (IV) oxide (WO,)
`
`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
`
`polytungstalcs. which arc stabilized al low pl!.''·"
`
`These large anions arc highly charged species. They
`
`can interact wi th bipolar protein molecules through
`
`electrostatic attraction and induce formation or
`
`pulled out."
`
`syringe 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 fom1ulations. spiking studies in
`
`quantitative physicochemical analysis have been
`
`early phase development with material extracted from
`
`developed. Extractable tungsten concentrations arc
`
`used tungsten (metal) pins me recommended.
`
`typically below 500 ppb and can be lower than I 00
`
`Subsequent stability studies in prcfilled syringes
`
`ppb, depending on manufacturing cycle and
`
`verify the preliminary tbta and specify accepted
`
`washing process. Staked needle syringes contain
`
`tungsten (metal) !cvcls. Advanced manufacturing
`
`the lowest amount of extractable tungsten as most
`
`methods for prefillcd syringes together with targeted
`
`U')
`
`0 z
`
`"' 0
`
`0
`N
`>,
`
`"' ::i:
`
`>,
`0)
`.9
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`C:
`.c
`u
`~
`<".'
`
`-~ .;
`
`a
`0)
`
`2
`0
`
`Cone Forming With Tungsten Pins
`L__~~~.!lllll~.!.rts~wf::ll;....._~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ _ _ J 25
`3tthe NU,il'andmavbe,
`
`Regeneron Exhibit 1012.005
`
`

`

`,i\.·. ·ii h\\\J A'. \.:,Jr-1:q 1n,· .. \ ffi,i"r/:( \(\\1frt1·r.~\Y
`iI'1!.Ur ,~ .!"l1 ·,1 L..Lb .!Jj/ '.!.i1..:.:.i~ ''i L:!--.. ..
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`... _,.,...._ .. ~.,---"7~·-··"-"• .. ,., . . ~- . ~ --t -.. , ... ~- .
`
`stability studies ensure that interactions of highly
`
`of the lubricant in the following way."·'" I !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 to the glass surface. The interactions
`
`drug products, interactions with sensitive
`
`between polydimethylsiloxanc and molecules from
`
`biophurmaceuticals 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 silicone oil into Si(R)O
`
`Prefillcd syringes are containers and drug
`
`coating as illustrated in Figure 4." The thickness of
`
`\
`,...si
`\
`
`'I' Si ,.,,,
`-si ,,
`
`-si
`I
`I
`
`-si
`/
`
`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
`
`silicone oil layers on the glass surface can be
`
`measured by renectometry. A comparative study
`
`Glass
`
`PDMS
`
`using cartridges as glass containers found for oily
`
`Model of Silicone Coating
`
`siliconization a layer thickness with a mean of
`
`232.67 nm and for baked siliconization of 76.83
`
`nn1.·1
`
`'
`
`1
`
`Parenteral biopharmaeeutical products vary
`
`4. End user: QC testing of the samples,
`
`widely in nature. The sensitivity of the active
`
`filled-syringe stability studies, and
`
`substance, the viscosity of the formulation, the
`
`ev,iluation
`
`drug delivery system, ,md its mode or operation
`
`(cg, prcfillcd syringes either manually or driven by
`
`5. Supplier: Scale-up, process validation,
`
`and industrial manufacturing of the
`
`uniformity of the layers. In established
`
`manufacturing processes on the lines of syringe
`
`suppliers, biopharmaccutical companies, and
`
`CMOs, syringes an: oily siliconized by spraying
`
`0.4- to 1.0-mg silicone oil (cg, Dow Corning 360,
`
`Medical Fluid) into the barrels.
`
`Advanced siliconization technology has been
`
`devel oped to lower the level of free (non-bound)
`
`silicone oil in prefilled syringes. The baked
`
`siliconization method uses emulsions of silicone oil
`
`"' (cg, Dow Corning 365, 35% Dimcthicone NF
`~ E111ulsion, diluted in HPW) sprayed into syringe
`en
`~ barrels followed by heat treatment in a tunnel.
`
`autoinjector device) determine the principal
`
`requirements. Silicone coatings ofprcf'illcd
`
`syringes can be customized to meet specific needs.
`
`Yari,llion of rroccss raramcters adapts the
`
`characteristics of the siliconizntion. Best results
`
`are obtained when syringe manufacturer (supplier)
`
`and biophannaceutical company (end user) partner
`
`and work along the following project steps:
`
`J. End user: Specification of accepted
`
`silicone oil levels and system
`
`functional ity
`
`Proprietary techniques and downstream washing
`
`2. Supplier: Development of baked
`
`syringes
`
`Fundamental understanding or the design
`
`space of baked siliconization 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 set
`
`of samples determine which silicone coating is
`
`ideal for purpose.
`
`/\ case study has demonstrated how
`
`customization of baked silicone coatings facilitates
`
`stability of sensitive molecules in pre filled
`
`syringes (cg, vaccine candidate in
`
`biopharrnaccutical development). The study has
`
`siliconization process for the specified
`
`attributes
`
`3. Supplier: Manufacturing of customized
`
`deepened the insight into the relationship between
`
`baked silicone syringes in sample
`
`siliconization parameters .ind critical quality
`
`quantities
`
`fhismatefral wasc<>i>ie<l
`atth,, N·LM .and m.ayl>e
`
`attributes."' The amount of extractable silicone oil
`
`could be reduced below the detection limit (0.03
`
`mg) or ICl'-/\ES according to EN ISO 11 XX5.
`
`Regeneron Exhibit 1012.006
`
`en
`0
`0
`
`"'
`processes vary depending on syringe supplier.
`~
`~ Critical quality attributes of the silieonization
`'
`{ process arc controlled through the settings of
`C: 1J siliconization pump and nozzle, the volume now of
`>-f silicone spray and air, the concentration of the
`~ silicone oil emulsion and tunnel temperature,
`g spcc,l and length. This technology alters the nature
`
`~
`
`Cl
`
`26
`
`

`

`;
`
`, •,-;
`
`/ .•••
`
`' • · - - • - -- -- - - - - - ,• • ·- • • .. .,,. ___ _ _ _ .. O',•H••
`
`With low levels of lubricant quantity, the specified
`
`syringe functionality was i'ulfillcd (plunger gliding
`
`REFERENCES
`
`forces in the range of 5 lo 10 N).
`
`Close partnerships between
`
`biopharmaceutical companies and syringe
`
`suppliers an: instrumental in comrolling 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 ofprcfillcd syringes can be custom(cid:173)
`
`engineered according to these needs.
`
`SUMMARY
`
`In today's biophannacc utical market,
`
`products arc exposed to fierce competition. The
`
`role of drug deli very strategics to di !Tcrcntiatc
`
`products is growing. A number of
`
`biopharmaccuticals has already been
`
`commercialized in the prefillcd syringe platform.
`
`l lowcvcr. syringe systems arc sources of potential
`
`incompatibil ities with sensitive molecules. The
`
`prcfillcd syringe indust ry has therefore engineered
`
`manufact uring processes that mitiga te stability
`
`risks from alkali ions, tungsten, and silicone
`
`lubrica nts. Advanced methods for surface
`
`treatment to control pl I, tungsten-reduced li.mning
`
`techniques, and baked si lieoni,:ation processes to
`
`immobilize silicone oil have been developed .
`
`Syringe manufacturers have established expertise
`
`in mate rial science and process tcchn\llogy to
`
`understand biopharmaccutical requirements.
`
`Evolving needs of highly sensitive pipeline
`
`products can be met with customized drug delivery
`
`systems. Current technology allows
`
`biopharmaccutic,il compan ies to exploit the
`
`benel'its or prcfilled syr inges and realize the full
`rotcntial of thdr products. +
`
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