Volume 9 Issue 7
`
`
`November/December 2006
`h'...:I
`
`�··�:a
`
`
`
`
`The Review of American Pharmaceutical Business & Technology
`
`
`Jessica Kelly, Editor
`Introduction -
`
`
`Editorial Advisory Board
`
`44 Use of Disposable Technology in Biologics
`
`
`Manufacture
`
`
`Annette Koch, Christe!ie Wittische-Larod,e,
`Raman Applications in Drug Manufacturing
`
`ElocHe De Roo and Alain Pralong
`Processes
`
`F.Hoffmann-La Roche Ltd
`Dimuthu Jayavvkkrama, Arwa El i-iagrasy ar�d
`
`
`
`
`Sh1h .. Ying Chang
`
`
`
`
`Pharmaceutical Research Institute, Bristol Myers
`
`Squibb Co.
`
`Opportunities for Rapid Microbial Methods
`
`
`50
`
`AnthrJny M. Cundell, Ph.D.
`
`Consulting Microbiologist
`
`ear-n rare opy: Why It Is Still the
`
`
`Number One in PAT
`Emil W. Ciur
`
`Leachable Study on Solid Dosage form
`
`58
`
`
`Xueguang Fang, Nkk Cherico, Dan1on
`Barbacci, Angeia M. Harmon, Matt Piserchio
`and Molly Perpall
`Merck & Co., Inc.
`Research Laboratories
`
`s in Drug Discovery
`r
`
`
`Considerations for Successfully Replacing a
`
`
`
`Chromatography Data System (CDS) in a
`
`Regulated Environment
`From Molecules to Pharmaceutical Products -
`
`
`
`
`Anthony Pecora
`
`
`The Drug Substance/Drug Product Interface
`
`Wyeth Consumer Healthcare
`
`Martyn Tir.ehurst �nd Robert Docherty
`
`
`Pharmaceutical Sciences, Pfizer Global R&D
`
`64
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`
`
`
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`Delivery Strategies to Support Development of
`70
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`Peptide Therapeutics
`
`Afeksander Swietlow, Ph.D. and
`Yves Mayeresse and R•ornain Veillon
`
`Paul Burke, Ph.D.
`GlaxoSmithKline
`
`Pharmaceutics, Amgen, Inc .
`
`• President -Nigel Russell
`
`
`'.President of Sales -Adam Young
`
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`;/, unt Executive -Monica McArthur
`
`Russell Publishing L.L.C.
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`9200 Keystone Crossing
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`Manager -Andrea Sherrow
`. lation
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`Indianapolis, IN 46240-2182
`0.Director -Allison
`USA
`Reppert
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`RECEIVED
`JAN ·o 2 2007
`HETERICK MEMORIAL UBR
`OHIO NORTHERN.\J.NIVER
`
`Published by
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`American Pharmaceutical Review
`(ISSN -1099-8012) is published
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`American Pharmaceutical Review
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`bility for any inaccuracies that may appear or loss suffered directly or indirect­
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`ly by any reader as a result of any advertisement, editorial, photographs or
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`other material published in American Pharmaceutical Review.
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`Printed in the USA
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`5
`
`
`
`
`
`American Pharmaceutical Review
`
`REGITC00138777
`
`Regeneron Exhibit 1076.001
`
`

`

`
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`
`
`
`lllffl
`
`11111
`
`DRUG DELIVERY
`
`•
`
`I I SI r ti s I
`t I t r -
`1111
`fill
`f t
`r1 s r r I
`r ts
`
`1111
`
`David E. Overcashier, Edwin K. Chan, and Chung C. Hsu
`
`
`
`
`Late Stage Pharmaceutical and Device Development
`
`Genentech, Inc.
`
`vial to a syringe for administration, prefilled syringes reduce contain­
`
`
`
`
`
`
`
`
`er overfill. For a 1 mL subcutaneous injection, the overfill can be
`re-filled syringes offer advantages in the delivery of injectable
`
`
`
`
`
`
`reduced from 30% (or more) of the delivered dose to 2% (or less).
`
`
`
`
`biopharmaceutical products, including increased user-conven­
`
`
`
`For high-concentration biopharmaceutical products with high bulk
`
`
`
`
`
`
`ience and decreased product wastage. Prefilled syringe manu­
`
`
`
`
`
`
`production costs, the reduced overfill can result in substantial cost
`·· .. facturing
`
`
`
`
`involves the manufacturing, preparation and sterilization of
`savings.
`
`
`
`
`
`components, followed by filling and sealing the syringe. This report
`
`
`
`
`
`The advantages provided by the prefilled syringe delivery sys­
`.. reviews typical
`
`
`processing steps and provides examples of our prod­
`
`
`
`tem have resulted in wide and increasing use of the configuration. US
`
`
`
`
`f uct/process development studies. Various syringe manufacturing
`
`
`
`sales of prefillable syringes have been reported to reach 200 million
`
`
`
`
`
`
`!\•Options are available, including the choice between "bulk" syringes
`
`
`
`units annually, with growth rates of 20% per year. World-wide annu­
`
`
`
`
`
`to fill" and "ready immediately before filling) t (washed and sterilized
`
`
`
`
`al sales (particularly Europe) exceed 1 billion units, increasing by 8-
`
`
`
`
`
`: ; / syringes ( washed and sterilized by the syringe manufacturer, then
`10% per year [l, 2].
`
`
`
`
`
`;/ delivered in sealed tubs to the filling site). Other options include
`
`
`
`Prefilled syringes, like vial dosage forms, are compnsed of
`
`
`
`
`
`
`syringe barrel size, Luer and staked needle formats, needle gauge and
`
`
`
`
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`glass and elastomeric components; however, additional parametern
`
`
`
`
`length, the type and application method of silicone on the syringe bar­
`
`
`
`
`need to be evaluated. These include processing details such as the s1l­
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`
`
`
`rel interior, elastomeric tip closure and plunger-stopper compounds
`
`
`
`
`iconization of components, component actuation forces and the forces
`
`
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`
`
`.and product-contacting coatings, product filling-pump types, and
`
`
`required for solution delivery with the syringe. The effects of
`
`
`
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`
`
`
`syringe closure (stoppering) methods. We compared coated and
`
`
`
`
`plunger-stopper composition and barrel siliconization on drug stabil­
`
`
`
`
`
`com­for optimal delivery. Needle-shield .uncoated plunger-stoppers
`
`
`
`
`ity require investigation, as these materials will contact the d1:1g solu­
`
`
`
`
`Syringe end-user operation. t• pounds were evaluated for convenient
`r.:
`
`
`
`
`tion continuously during the storage of the drug product. This report
`
`
`
`y force for effect on deliveri needles of various sizes were evaluated
`
`
`
`summarizes typical prefilled syringe manufacturing processes,
`
`
`
`
`• ,across a range of solution viscosities. Protein stability in prefilled
`
`
`
`
`including component preparation, filling, and stoppering (sealing).
`� •.. t, 0syringes
`was evaluated.
`Our studies concluded
`that prefilled
`syringe
`
`
`
`
`
`We also describe examples of development studies, covering both
`i .. ,,.l components and processes
`need to be selected according
`to end-user
`
`
`
`
`syringe physical properties and protein stability.
`i • requirements.
`t/
`Prefilled Syringe Manufacturing
`
`�:-l 1ntroduction
`
`
`
`
`Prefilled syringe manufacturing can be separated into four gen­
`l Prefilled
`syringes
`have become important
`options
`in the pack­
`
`
`
`
`eral steps: (1) component manufacturing, (2) component preparation,
`!! aging and distribution
`ofbiopharmaceuticals.
`Such delivery
`systems
`
`
`
`
`
`including sterilization, (3) aseptic filling and stoppering, and ( 4)
`tprovide
`several advantages.
`Drug administration
`is simplified,
`which
`
`
`
`
`labeling, plunger rod attachment, and secondary packaging. We
`radds convenience
`for healthcare
`professionals
`and patients.
`In addi­
`
`describe each of these areas below.
`(i: tion, prefilled syringes
`reduce
`risk of misidentification,
`dosage error,
`}: and contamination.
`By eliminating
`transfer
`of drug solution
`from a
`i,
`t American
`•
`
`11
`
`
`
`Pharmaceutical Review
`
`REGITC00138778
`
`Regeneron Exhibit 1076.002
`
`

`

`DRUG DELIVERY
`
`stoppers, with fluoropolymer or other coatings on product-cont
`
`
`acting
`Preti/led Syringe Components
`
`
`
`
`
`
`surfaces to reduce extractables [6]. Such coatings have been report.:;;'_.{
`
`
`
`
`
`Prefilled syringe (PFS) components consist typically of a glass
`
`
`
`ed to be useful in reducing product degradation or adverse reactions , .. ·
`
`
`
`
`
`
`
`syringe barrel, having a Luer finish or staked (glued-in) needle, an
`
`in patients [7-9].
`
`
`
`
`elastomeric tip closure, an elastomeric plunger-stopper, and a plunger
`
`
`
`
`rod (see Figure 1). The labeled syringe may also be equipped with an
`
`
`
`
`
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`external anti-needle-stick safety device and/or packaged in a thermo­
`Preti/led Syringe Component Preparation
`
`
`
`
`
`
`
`As performed for vials and stoppers, prefilled syringe compo�
`formed tray.
`
`
`
`
`nents require preparation before use, involving washing, siliconiza­
`
`
`
`tion and sterilization. Two general types of component processing are;:/;
`
`
`available, termed "bulk" (or "in-line") and "ready-to-fill" (or "tub").\
`
`
`
`
`"Bulk" syringe processing is similar to vial filling in that component'
`
`
`
`
`
`
`
`preparation and sterilization are carried out at the filling site shortly
`
`
`
`
`
`before filling. "Ready-to-fill" syringes, by contrast., are washed, sil(-/;
`
`
`
`
`conized, and sterilized in sealed tubs by the syringe manufacture;,/4;:
`
`
`
`then shipped to the filling site where the drug solution is filled.
`
`Plunger-stopper
`Syringe Barrel
`
`1111
`
`A W, •
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`� � -, ♦ C�!_ed_·•---,.-... -. �----}� ; f"
`:,1r4: :::·: :-.· .)F---.. • If&
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`
`6 12 18 24
`
`
`Storage Duration at 5°C (mo.)
`
`,
`
`CD
`u
`
`0
`
`LL ::-2 (9
`
`♦Coated
`
`!
`
`,
`
`,) /
`
`The syringe barrel is typically formed from Type I borosilicate
`
`
`
`
`
`
`
`
`
`tubing glass, meeting USP and EP requirements. Syringe barrels are
`
`
`
`
`
`available across a wide range of sizes, typically 0.5, 1.0, 1.5, 2.25,
`
`
`
`3.0, 5.0, and 10 mL. Syringe standard sizes and dimensions are given
`
`
`
`
`elsewhere [3]. Glass prefillable syringes are available from several
`
`
`
`
`manufacturers, with manufacturing sites in the US, France, Germany,
`
`
`
`
`
`
`Switzerland, Italy, Mexico, Japan, and elsewhere. Plastic prefillable
`
`
`
`
`
`syringes are also available, providing potential advantages such as
`
`
`
`
`
`
`decreased weight, protein adsorption, dimensional variability, and
`0
`
`
`
`
`increased durability. Plastic containers must, however, be evaluated
`
`
`
`
`for suitability including water vapor transmission, oxygen transmis­
`sion and extractables.
`Syringes are available with Luer and staked needle finishes.
`
`
`
`
`�: -�---------�-�· B If;
`
`
`Common needle configurations for subcutaneous dosing are 270
`
`
`
`
`(outside diameter 0.4 mm), 1/2" long, and 250 (diameter 0.5 mm),
`10 J, .. ----.
`
`
`
`
`5/8" long; other needle sizes are available, particularly in larger diam­
`
`
`
`eters (to 21G (diameter 0.8 mm)) and lengths required for intramus­
`♦
`a ---------------rlj
`
`
`
`
`
`cular and intravenous dosing. Needle tubing standard sizes, diame­
`6 4 ■·.Unc.oated
`
`
`
`
`ters, and compositions are specified elsewhere [4].
`Syringes are typically sealed at the front end before filling by
`
`
`
`
`
`
`
`
`an elastomeric rubber tip cap or needle shield. These items are man­
`
`
`
`ufactured by several manufacturers known for producing elastomer­
`
`
`
`
`
`
`ic closures for vials -in various compounds. As with elastomeric vial
`2
`O _0 ___ 6 __ 1_2 __ 1_8 __ 2_4-----i3J
`i
`
`
`
`
`closures, needle shields and tip caps can be made of either dry natu­
`I
`
`
`
`
`
`
`ral rubber or synthetic rubber. Dry natural rubber compounds have
`
`
`
`
`been linked with allergic reactions in some patients [5) and may have
`
`
`
`
`higher extractables compared with synthetic elastomers. Needle
`
`
`
`
`
`shields and tip caps may, however, present decreased surface area for
`.l
`
`
`
`potential interaction with product solution, compared with vial stop­
`for vari..'
`
`
`Bulk syringe component preparation may be eligible
`
`
`
`pers and prefi!led syringe plunger-stoppers.
`
`ous processing options. Silicone application to the barrel inner suv"
`
`
`
`
`
`
`
`Other options in elastomeric rubber tip closures are plastic
`opera�d,?
`
`
`
`face -performed in order to attain a lubricated, easily
`
`
`
`
`
`outer shells, which may provide rigidity, dimensional control, and a
`syringe - may be carried out by different methods, such as sprayiri�>
`
`
`
`
`
`
`tamper evident overlayer.
`emul·,
`
`or wiping. The lubricant may consist of oil, or an oil-in-water
`
`
`
`
`
`
`Prefilled syringe plunger-stoppers are subject to many of the
`in so-call,e,4/
`
`
`sion. Syringes subsequently may be heated, resulting
`
`
`
`
`
`same requirements as vial stoppers (e.g., low extractables, container
`and interij-:c.t/
`
`
`''baked silicone" in an effort to reduce silicone mobility
`
`
`
`
`
`
`
`closure integrity), so are typically made of similar materials (e.g.,
`
`tion with the drug product. Regardless of silicone
`
`
`
`
`
`halobutyl rubber). Plunger-stoppers are also available, as are vial
`
`
`
`
`
`Storage Duration at 5°C (mo.)
`
`type, quantity a,�i:F•
`
`
`
`American Pharmaceutical Review
`
`78
`
`REGITC00138779
`
`
`
`Regeneron Exhibit 1076.003
`
`

`

`DRUG DELIVERY
`
`iw iJw,u",v� method, the stability of the drug product in the syringe
`
`
`
`rs into filled syringes. plunger-stoppeing syringes and placing
`
`
`
`
`
`
`
`
`Ready-to-fill syringes are typically filled in the tray, with filling and
`
`rnust be evaluated [10].
`
`
`
`
`
`
`stoppering achieved using multiple filling needles (usually two to ten)
`Bulk syringe sterilization is typically performed by dry heat or
`
`
`
`
`
`
`
`
`The syringe front closure (needle shield or tip cap) is mount­
`
`
`
`moving relative to the syringes in a raster pattern.
`
`
`
`on the barrel before or after sterilization, depending on the materi­
`
`
`and processing conditions employed.
`
`Prefilled Syringe Filling
`
`
`Plunger-stoppers can be washed, siliconized to facilitate
`Syringe filling machines employ the same solution dispensing
`
`
`
`
`
`
`
`and steam-steril-or,occ:ss;1w111Ly in manufacturing and user operation,
`
`
`
`technologies as those used for vials. Rotary-piston pumps are the
`
`and rolling diaphragm
`
`
`most common, with peristaltie, time-pressure,
`
`
`
`
`Bulk syringe filling occurs in a continuous process with
`
`
`
`
`
`methods also available. Syringe filling may be conducted in a bot­
`
`
`
`
`
`and stopper­to filling conveying system syringes moved on a linear
`
`
`
`tom-up mode in order to reduce splashing and foaming.
`
`
`
`
`
`two to ten). (typically filling needles ing stations using multiple
`
`
`
`
`Syringe stoppering (the insertion of plunger-stoppers into the
`
`
`
`
`Ready-to-fill syringes, in contrast, undergo preparation by the
`
`
`
`
`filled syringes) is normally carried out by one of two methods, inser­
`
`
`
`
`
`siliconization, consisting of washing, syringe barrel manufacturer,
`
`
`
`
`tion tube or vacuum. Insertion tube stoppering consists of sliding the
`assembly
`
`
`with the tip closure, then sealing into tubs. Tubs consist of
`
`
`
`stopper into a metal tube, which compresses the stopper radially;
`
`
`
`
`
`syringes hanging vertically (tip downward) by the finger flange in a
`
`
`
`inserting the tube (with stopper) into baek of the glass syringe barrel;
`
`
`
`plastic tray with holes arranged in a rectangular anay, typically 64,
`
`
`
`
`pushing the stopper out of the tube and retracting the tube, leaving the
`
`
`
`
`100, or 160 syringes per tub (number depending on syringe size).
`
`
`
`stopper in the syringe bane!. Vacuum stoppering, by contrast,
`
`
`Sealed tubs are bagged and packed in corrugated cartons, then
`
`
`
`
`
`
`involves placing the filled syringe ( either singly or in groups of 100
`
`
`
`nrcicessf:a in an ethylene oxide (EtO) sterilizer in order to achieve
`
`
`or so) in a chamber under vacuum, then placing the plunger-stopper
`
`sterilization of the syringes.
`
`into the back of the barrel. Following this, the vacuum is released,
`
`
`
`Ready-to-use plunger-stoppers are also available. These may be
`
`
`
`and ambient pressure pushes the plunger-stopper into the low pres­
`
`
`
`
`washed, siliconized, scaled into bags and sterilized (gamma-irradia­
`
`
`
`
`
`sure region within the barrel. Depending on processing variables
`
`by the component manufacturer.
`
`
`
`
`
`
`(e.g. fill tolerances, syringe dimensions, solution properties, vacuum
`
`
`
`
`Sterilized, packaged, ready-to-fill syringes and plunger-stop­
`
`
`
`levels for vacuum stoppering), the vacuum stoppering method may
`
`
`
`
`pers are then shipped to the filling site. The filling operation includes
`
`
`
`
`
`
`provide smaller headspace (air bubble) sizes, compared with the
`
`
`
`
`
`transfer of syringe tubs into the aseptic filling area, followed by fill-
`
`insertion tube method.
`
`Introducing
`PharmaFocus™ Tubing
`
`• Plat;num-rnred silicone e:astoa:?r designed for thE 11eecls of the pharmac➔utical marl,etplace
`
`The Rigid Testing
`
`
`
`
`• 3ic:o:n;:iadbility Sr,2cifirntiow:
`USP Class Vl
`
`f;J'" Jr.1.31
`
`;.-:,(;A. ,?.J Cf�ct 1·17 . .2600
`
`The Risi.Id Source
`0 More th·,m :'.O years of �i!icone r,1anu,acturing ExpGrience are applied to eve,y p,ojud we make
`
`•Helix Medicc1.I Certificatio;·,s:
`
`Mamrfa:::turec; ,u::cf:Jrrling to GMFs
`1:;.o ?3485 wrtHie::J
`
`
`Jlegf.;terecf FDA M,'!•Jfr::ai Device f�cf/ity
`
`The Bltdd Tubing
`• Cost-effoctive ,ilico,1e tu,;ing delivering co1,sistent C:l'illity 2t the right lev,,1 of assur2r1ee
`
`
`
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`•i'.<.vailable in 11 po[Jiilar size combinations
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`• Matrrial ce,ti11c.:.tion and lol tr.:.ceabilily included
`
`M E D C A L
`
`Call today for a tree cat,;::1!og or to place an
`
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`
`
`order i800) 266-4421 • www.heli�1.Kdical.corn
`
`79
`
`
`
`American Pharmaceutical Review
`
`Please circle #47
`
`
`REGITC00138780
`
`Regeneron Exhibit 1076.004
`
`

`

`DRUG DELIVERY
`
`sol
`
`40
`
`�
`
`� 30
`
`J: 20
`
`0
`0
`
`l
`
`0Natural
`
`;J Sy nth etic-2
`Batch 1
`
`En Syn:thetic-2 Batch 2
`
`6 12 18
`30
`Time @ 5°C (Mo.)
`Storage
`
`24
`
`Prefilled
`Syringe
`Labeling
`and Packaging
`Syringes
`are typically
`labeled
`and packaged
`using automate.1j/;:'."
`equipment.
`Syringe
`labels
`may include
`dosing lines or
`graduation
`marks,
`or such information
`may be pre-printed
`rel. Plastic
`plunger
`rods can be automatically
`inserted
`into the
`syringe, by threading
`or snapping
`into the back of the pmng(:r-ston.:z:i
`per. Syringes
`may be packaged
`in thennoformed
`trays with
`Tyvek lid.
`
`••
`
`Prefilled Syringe
`Testing
`In our lab, various
`tests were performed
`to evaluate the
`propr�/''.
`ties of prefilled
`syringes
`at the time of filling,
`as well as across
`the 0
`anticipated
`product
`shelf life. Tests were aimed at evaluating
`thf f
`physical
`properties
`of the syringe
`to be encountered
`by the user (e:f(!
`removing
`the needle
`shield,
`dispensing
`the drug solution)
`as well a�Y;
`the biochemical
`properties
`of the drug solution.
`Described
`belowife.
`�
`· ·
`some examples
`of such prefilled
`syringe
`testing.
`Evaluation .. Xi;}
`Plunger-stopper
`from suppfi�rs·
`Prefilled
`syringe
`plunger-stopp
`ers are available
`in various
`elastomeric
`rubber
`compounds,
`with options
`in film co.�t:,,; .. /
`ings, as described
`above. In one study,
`we compared
`physical
`prqp-r
`erties of a typical
`uncoated
`elastomeric
`plunger-stopper
`with thosedft
`e force (aJst. f
`a film-coated
`plunger-stopper.
`Plunger-s
`topper breakloos
`termed "initial
`glide force") and glide force (also termed "dynam1&\
`glide force") testing
`measured
`the forces
`required
`to initiate
`and sus" :
`tain,
`respectively,
`the movement
`of the plunger
`to expel the contentS:.
`testing sysf,
`of the syringe.
`Testing
`was carried
`out using a material
`nt&; �
`represe
`tern with a crosshead
`speed of approximately
`4 mm/sec,
`tive of manual syringe
`delivery
`to patient.
`stopp,�rti
`Test results
`showed that syringes
`with the two plunger-
`had similar delivery
`properties.
`The breakloose
`force (some 5-7 :NX.J
`lower than that deter;
`[ 1 N=0.225
`lb] for coated
`stoppers
`was slightly
`2A). The slight diff�r.:-;�
`mined for uncoated
`stoppers,
`6-8 N (Figure
`force could be due to the effect of the coating, iis (
`ence in breakloose
`between the two plunger-stoppers teste.d >
`well as to other differences
`Glide forces for the two col11c:h.
`( e.g.,
`rubber
`compound
`and geometry).
`2B). Note that glide fore:� ?
`ponents
`were equivalent,
`at 9-10 N (Figure
`and to hydrodynarili¢>,
`is attributable
`to both stopper-barrel
`friction
`flow back-pressure
`as the drug solution
`is delivered
`through
`the
`dle; the latter
`property
`is further
`discussed
`below.
`
`80
`American
`Pharmaceutical
`Review
`
`REGITC00138781
`
`Regeneron Exhibit 1076.005
`
`

`

`1
`
`100
`10
`Viscosity ( cP)
`
`Evaluation
`Shield
`Needle
`the force required
`force measures
`(NS) removal
`Needle shield
`we eval­
`In this study,
`to pull the NS off the front end of the syringe.
`I, Synthetic-2")
`("Synthetic-
`compounds
`rubber
`uated two synthetic
`testing
`The material
`("Natural").
`compound
`rubber
`and one natural
`speed of some 8 mm/sec,
`was
`with crosshead
`above,
`described
`· system
`of manually
`to mimic the operation
`used. The rate was expected
`the NS from the syringe.
`removing
`compound
`Needle shield
`. Synthetic-
`whereas
`forces,
`removal
`I gave high and variable
`consistent
`showed optimal,
`Natural
`and compound
`.Synthetic-2
`3. Compound Synthetic-2
`might be pre-
`see Figure
`forces;
`f removal
`allergenic)
`(potentially
`extractables
`in order to avoid the higher
`. ferred
`(data not shown).
`Natural
`with compound
`••associated
`
`·· Needle
`Evaluation
`Diameter
`we carried
`out
`properties,
`physical
`In a third study of syringe
`gauge and
`of needle
`glide force, as a function
`•,.evaluation
`of syringe
`such delivery
`to learn whether
`We were interested
`viscosity.
`_solution
`a tube
`flow through
`drop for laminar
`for pressure
`predictions
`matched
`•. (the tube being the syringe
`may be useful
`Such information
`needle).
`for which
`gauge for drug products
`needle
`the optimal
`tin determining
`than that of water.
`is greater
`the viscosity
`!Method
`with a crosshead
`as above,
`glide forces
`syringe
`{! We measured
`for a range of configurations, including
`needles
`of
`•{ speed of 3 mm/sec,
`to nominal
`gauge 30G to 23G, corresponding
`sizes (needle
`};tvarious
`to 0.34 mm [4]) and three plunger-stopper
`of 0.15
`diameters
`l)nside
`spanned
`a
`tested
`Solutions
`and one uncoated).
`(two coated
`1; types
`.range of viscosities,
`solution),
`as
`to 80 cP (sucrose
`from 1 cP (water)
`For comparison,
`wall friction).
`well as empty syringes
`(to assess
`using the Hagen-Poiseuille
`(H-P)
`were estimated
`i:extrusion
`forces
`flow in a tube [11]:
`for laminar
`liequation
`
`•0,
`
`Pharmaceutical
`Review
`American
`
`REGITC00138782
`
`Regeneron Exhibit 1076.006
`
`

`

`)t}
`rs to pre;� ,J
`prefilled
`syringe
`and injection
`device
`drug product
`develope
`
`
`
`
`diet delivery parameters for various syringe and solution properti:es./ tJ.
`<sf
`
`Protein Stability Evaluation
`In addition to characteriz
`ing syringe
`physical parameters, we ll
`Where:
`in the pre filled syringe cont"•. ·· .f
`
`
`
`evaluated the stability of various proteins
`
`Q: Volumetric flow rate
`figuration.
`Evaluation
`methods
`included
`chromatograph
`ic analysis ot? J
`µ: Fluid viscosity
`
`
`
`
`
`protein solutions to detect physical (e.g. aggregation) and ehemic1tL' :1'
`
`L: Needle overall length
`· · · I
`
`
`(e.g. deamidation) changes.
`
`R: Radius (inner) of needle
`The degradation rates of Protein-I in prefilled
`
`
`syringes werf f
`
`
`
`P,, P,: Pressure (at inlet, outlet of needle)
`
`
`
`similar to those in glass vials, as determined by ion exchange chro-; ;;r ";;
`aphy' f
`
`matography (Figure 5A) and by size exclusion chromatogr
`
`
`The pressure drop, P,-P,, is related to the force applied to the plunger
`
`
`
`
`
`
`
`(Figure SB). A second molecule, Protein-2, in prefilled
`
`syringes wai• ;1/f
`
`
`on the needle (the rod. We set P,=0 assuming no back pressure
`profile to ,:, ·· 1
`
`
`demonstrated in multiple studies to have a similar stability
`
`
`
`
`
`assumption is not stiictly true for injection into tissue).
`that in glass vials (Figure
`6). Other assays
`conducted on these pro�l.
`/zl
`reins indicated
`equivalent
`stability
`for prefilled
`syringe
`and vial for�;
`mats. These studies
`demonstrate
`that despite
`the exposure
`of the druf c'.•
`of materials including glass, sili�.
`
`solution to a diverse combination
`. cl
`
`cone, and one or more elastomers -prefilled syringes
`
`can provide a• J
`high producf
`convenient,
`efficient
`delivery
`system while maintaining
`·
`quality.
`
`
`
`By rearranging, then substituting the appropriate values for parame­
`
`F= SQµLxA
`nR4
`Equation 3 enables one to estimate the extrnsion force F
`
`
`
`
`
`
`
`
`
`required to dispense solution from the syringe through the needle.
`
`Note that the extrusion force is very sensitive to the tube internal
`80 t) ·�
`ll.
`
`
`
`
`
`radius (fourth-power dependence); thus small changes in needle diam­
`
`
`eter can result in large changes in force. The force thus determined
`·a;
`
`
`
`
`neglects wall friction, so that needs to be evaluated separately for each
`syringe-stopper system.
`
`
`
`Viscosity of each test solution was determined using a eonc­
`70
`
`
`
`
`
`
`and-plate viscometer. Viscosity of0.7-mL samples was determined at
`0
`6 12 18
`
`
`a shear rate of 1000 sec·' and room temperature. Since the H-P equa­
`30
`24
`
`
`
`tion predicts that the extrusion force is highly dependent on the tube
`
`Storage Duration at 5°C (mo.)
`
`
`
`
`
`internal radius, we also measured, using an automated vision system,
`
`
`
`
`
`needle inside diameters (ID) to obtain the appropriate value for use in
`
`
`the calculation ("radius" (R) term).
`-�•
`
`
`
`Glide forces measured for forty-four combinations of solution,
`98
`
`
`
`
`
`plunger-stopper, and needle were detennined. Forces increased with
`97
`=-----=--=-
`==-
`
`
`
`
`increased viscosity and decreased needle diameter, as expected.
`,◊Vial =--:
`::e
`1•Pre-Hloo Syringe.·
`
`
`
`
`Differences between different plunger-stopper types were negligible
`0
`96
`
`
`
`
`(data not shown). Resutts were generally higher than the force pre­
`
`
`dicted by Equation 3.
`0
`
`
`Net glide forces were calculated in order to determine the forces
`
`
`
`
`
`required to extrude the solution through the needle. This was per­
`
`
`
`formed by subtracting, for each syringe-stopper configuration, the
`
`
`
`
`glide force detennined for empty syringes (assessing wall friction, l -
`
`3 N) from the measured glide force. The net glide forces thus deter­
`Conclusions
`high yield
`
`
`
`Prefilled syringes can provide safe, easy-to-use,
`
`
`mined are plotted in Figure 4, along with lines illustrating the extru­
`
`delivery systems for injectable bi.opharmaceuticals. A wide range:9f
`
`
`
`
`
`
`sion forces calculated by Equation 3. It can be seen that the equation
`and site, '
`
`
`
`
`
`syringe configurations, including syringe barrel material
`
`
`
`
`provides an excellent preaiction for actual net glide force, allowing
`
`(3)
`
`85
`
`A
`0\/1111
`•Pre-Filled Syringe
`
`e<:,
`
`>
`
`75
`
`•
`◊
`
`100 ~1
`-,
`,t,
`• •
`..
`•
`99
`
`-
`
`�--�
`
`I
`
`I
`
`95
`
`6 12
`18
`30
`24
`°C (mo.)
`
`Storage Duration at 5
`
`Results
`
`American Pharmaceutical Review
`
`82
`
`REGITC00138783
`
`
`DRUG DELIVERY
`
`(1)
`
`(2)
`
`
`
`A = Cross sectional area of syringe barrel lumen
`
`Where:
`
`
`F = Glide force
`
`
`
`
`ters, we obtain:
`
`,>}:;
`
`; ",, �
`
`//<,:
`
`Regeneron Exhibit 1076.007
`
`

`

`DRUG DELIVERY
`
`formats), and plunger-stopper (or Luer-tip i' needle gauge and length
`
`
`
`
`
`
`
`
`
`options are avail­manufacturing ii/; composition, are available. Various
`
`
`
`
`(and and sterilization methods ll){able, such as syringe siliconization
`
`
`
`
`
`!!r•"bulk" syringe manufacturing and ready-to-fill configurations), and
`
`
`
`
`
`t'filling and stoppering (sealing) techniques. Prefilled syringe end-use
`
`
`
`
`,,tproperties, such as the forces required to remove the needle shield and
`
`
`
`and the depend on components ll!Wh:teliver the solution from the syringe,
`
`
`
`
`mr;manufacturing process. The force required to deliver the solution
`
`
`
`lle model for by the Hagen-Poiseui( through the needle can be predicted
`
`
`
`
`fqr pro­can provide stable container ilffrflow. Prefilled syringes laminar
`
`
`
`
`syringe componentsthat prefilled li/ftein drugs. Overall, it is apparent
`,,,,,
`
`
`
`
`processes need to be selected according to end-user requirements.
`
`l 99 12.i ...
`� 98
`I97
`96
`
`I ao
`•
`,,,L,, __ 7
`
`95 0
`6 12 18
`30
`24
`
`
`Storage Duration at 5°C (mo.)
`
`OnDrugDelivery, 2005: p. 9-11.
`
`
`3.ISO, Prefi.lled Syringes Part 4: Glass Barrels for Injectables.
`
`
`
`
`
`for Standardization: International
`
`1996, International Organization
`
`Standard, no. 11040-4. 1-4.
`
`
`
`
`4.ISO. Stainless steel needle tubing for the manufacture of medical
`
`
`devices. 1991, International Organization for Standardization:
`
`
`International Standard, no. 9626. 1-16.
`
`
`
`
`5.Primeau, M-N., NF. Adkinson, and R. G. Hamilton, Natural rubber
`
`
`
`
`
`pharmaceutical vial closures release latex allergens that produce skin
`
`
`
`
`
`reactions. Journal of Allergy & Clinical Immunology, 2001. 107(6): p.
`958-62.
`
`
`
`
`
`6.DeGrazio, F, Packaging in Prejilled Syringe Systems: Selection
`The Trend for Growth
`
`and Evaluation. Pre/Wed Syringes:
`
`
`Strengthens, OnDrugDelivery, 2006: p. 20-22.
`
`
`
`7.Boven, K., et al., The increased incidence of pure red cell aplasia
`
`
`
`with an Eprex formulation in uncoated rubber stopper syringes.
`
`
`Kidney Int., 2005. 67(6): p. 2346-2353.
`
`
`
`
`8.Villalobos, A.P., S.R. Gunturi, and G.A. Heavner, Interaction of
`
`
`Polysorbate 80 with Erythropoietin: A Case Study in
`
`
`
`Protein-Sw:factant Interactions. Pharm: Res., 2005. 22(7): p. 1186-
`1194
`
`
`
`9.Sharma, B., et al., Technical Investigations into the Cause of the
`
`
`
`Increased Incidence of Antibody-Mediated Pure Red Cell Aplasia
`
`
`Associated with Eprex. Eur J Hosp Pharm, 2004. 5(5): p. 86-91.
`
`
`
`10.Jones, L.S., A. Kaufmann, and C.R. Middaugh, Silicone oil
`
`
`
`
`induced aggregation of proteins. Journal of Pharmaceutical Sciences,
`
`2005. 94(4): p. 918-27.
`
`
`
`11.Whitaker, S., Introduction to Fluid Mechanics. Prentice-Hall
`
`
`
`International Series in the Physical and Chemical Engineering
`
`
`
`
`ciences. 1968, Englewood Cliffs, NJ: Prentice-Hall. 457.
`
`David Overcashier is a Senior Engineer in the Late Stage
`
`
`
`Pharmaceutical and Device Development Department at •,*
`l'l0Acknowfedgements
`
`
`
`Genentech, where he was worked for 13 years. He has carried ii'.
`
`
`in this investiga­I\ We appreciate the support of our colleagues
`
`
`
`
`
`
`out prefilled syringe filling tests and product evaluation for pro-
`
`
`
`and by Racho Jordanov ii);Ji,on. Manufacturing assistance was provided
`
`
`
`tein product candidates. Previou.sly he worked on lyophilization
`' [
`
`
`
`
`
`Lo, by Jun Liu, Sabrina Wt1:0avid Figur. Technical support was provided
`
`
`
`
`
`process development, scale-up (mcludmg three marketed prod-1r,
`
`
`
`
`-;;;;Mary Nguyen, Al Stem, and Rita Wong. Project guidance and support
`
`
`
`
`ucts), and characterization. David received his BS degree from if
`
`
`Wwere provided by Patty Kiang and Tue Nguyen.
`
`
`the University of California, Davis, and his MS from the Ii
`
`
`University of Washington, Seattle both in Chemical '!
`1<: ' ,'
`if References
`'1
`
`
`{J. Polin, JB., The Ins and Outs of Prefilled Syringes. Pharmaceutical
`Engineering.
`
`
`Medical Packaging News, 2003. 11 (5): p. 40-43.
`
`
`
`
`Why New Prefilled Syringes: iW/!2. Schoenknect, T. and M Romacker,
`
`
`
`
`
`To correspond with the author, please contact the editor at:
`ii\[�
`',1;,pevelopments
`
`
`
`Are Important In Injectable Delivery Today Prejilled
`editoriall@russpub.com
`
`
`ii/$yringes: Innovations that Meet the Growing Demand,
`
`��
`
`$3
`
`
`
`
`
`American Pharmaceutical Review
`
`REGITC00138784
`
`
`
`Regeneron Exhibit 1076.008
`
`